Reducing Kidney Function Decline in Patients With CKD: Core Curriculum 2021

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Teresa K. Chen, Christopher J. Sperati, Sumeska Thavarajah, and Morgan E. Grams

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An estimated 8% to 16% of the world’s population has chronic kidney disease, defined by low glomerular filtration rate or albuminuria. Progression of chronic kidney disease is associated with adverse outcomes, including incident kidney failure with replacement therapy, accelerated cardiovascular disease, disability, and mortality. Therefore, slowing kidney function decline is paramount in the management of a patient with chronic kidney disease. Ascertaining the cause of kidney disease is an important first step and may compel specific therapies. Effective approaches that apply to the vast majority of patients with chronic kidney disease include the optimization of blood pressure and blockade of the renin-angiotensin-aldosterone system, particularly if albuminuria is present. Recent studies suggest that sodium/glucose cotransporter 2 inhibitors are highly effective treatments in patients with diabetes and/or albuminuria. For patients with type 2 diabetes, glycemic control is important in preventing the development of microvascular complications, and glucagon-like peptide 1receptor agonists may help reduce albuminuria levels. Other strategies include correcting metabolic acidosis, maintaining ideal body weight, following diets that are low in sodium and animal protein, and avoiding potential nephrotoxins such as nonsteroidal anti-inflammatories, proton-pump inhibitors, and iodinated contrast.

Introduction

Chronic kidney disease (CKD) affects more than 697 million individuals worldwide and is associated with increased morbidity and mortality. In 2017, 1.2 million deaths and 35.8 million disability-adjusted life-years were attributed to CKD. Among Medicare beneficiaries in the United States, annual spending for kidney failure with replacement therapy (KFRT) and earlier stages of CKD exceeded $120 billion. Different causes of kidney disease may require specific treatments such as immunosuppressive therapy. However, some strategies to delay the progression of CKD to KFRT are applicable to most patients. Early detection and treatment to slow kidney function decline are paramount to improving outcomes in patients with CKD. Hallmarks of CKD management include control of hypertension and hyperglycemia, inhibition of the renin-angiotensin-aldosterone system (RAAS), correction of metabolic acidosis, lifestyle modification, and avoidance of nephrotoxins. Two new classes of medications, sodium/glucose cotransporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists, also improve kidney outcomes among individuals with diabetes and/or albuminuria.

Additional Readings

➢ GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395:709-733.

➢ Saran R, Robinson B, Abbott KC, et al. US Renal Data System 2019 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2020;75(1)(suppl 1): S1-S64.

Blood Pressure Control

Case 1: A 60-year-old man with CKD glomerular filtration rate category 3b (G3b) and albuminuria category 2 (A2, corresponding to a urinary albumin-creatinine ratio [UACR] of 30-300 mg/g), hypertension, and stable angina returns for a follow-up visit. His estimated glomerular filtration rate (eGFR) has declined from 57 to 44 mL/min/ 1.73 m2 over the past 13 years. His blood pressure (BP) averages 135/72 mm Hg on a regimen of valsartan at 320 mg daily, amlodipine at 5 mg daily, and indapamide at 1.25 mg daily.

Question 1: Based on the results of SPRINT, which one of the following statements is most accurate regarding a systolic BP goal of <120 versus <140 mm Hg?

a) All-cause mortality is reduced

b) CKD progresses more slowly at the lower BP goal

c) Incidence of KFRT is higher at the lower BP goal

d) Incidence of kidney transplantation is lower at the lower BP goal

Question 2: Which one of the following patients would be most appropriate for a lower BP goal to help slow the progression of CKD?

a) CKD G3aA1 with UACR of 10 mg/g

b) CKD G4A1 with critical bilateral renal artery stenosis

c) CKD G3bA3 with UACR of 3,000 mg/g

d) CKD G3bA3 with UACR of 1,200 mg/g and history of repeated falls

For the answers to the questions, see the following text.

The AHA/ACC recommend a goal BP <130/80 mm Hg for all patients with CKD, whereas the KDIGO guidelines recommend a target of ≤140/90 mm Hg when the UACR is <30 mg/d and ≤130/80 mm Hg when the UACR is ≥30 mg/d (Table 1). The KDIGO recommendations are based, in part, on 2 landmark randomized controlled trials. The AASK trial randomized participants without diabetes to a mean arterial pressure (MAP) goal of ≤92 versus 102- 107 mm Hg. Although there was no difference in the rate of eGFR decline or a composite clinical outcome (eGFR decline, KFRT, or death) overall, participants with a baseline urinary protein-creatinine ratio of >0.22 g/g were 27% less likely to develop a doubling of serum creatinine, KFRT, or death when randomized to intensive versus standard BP control in the extended cohort phase. The MDRD Study randomized participants to a MAP goal of 92 versus 107 mm Hg. Again, there were no differences overall, but participants with proteinuria of ≥3 g/d had lesser GFR decline in the intensive BP control group. These and other trials of BP control are summarized in Table 2.

More recently, SPRINT randomized adults without diabetes but at increased risk for cardiovascular events to asystolic BP < 120 mm Hg versus < 140 mm Hg. IntensiveBP control was associated with a lower risk of myocardial infarction, acute coronary syndrome, stroke, heart failure, and cardiovascular death (hazard ratio [HR], 0.75 [95%CI, 0.64-0.89]) and all-cause mortality (HR, 0.73 [95%CI, 0.60-0.90]). The results were consistent among participants with baseline CKD (n = 2,646). Intensive BPcontrol did not prevent adverse kidney outcomes (≥50%eGFR decline or KFRT). Among participants without baseline CKD (n = 6,677), intensive BP control resulted in ina 3.5-fold higher risk of ≥30% reduction in eGFRto < 60 mL/min/1.73 m2, a finding that may reflect the dynamic changes rather than true kidney injury.

For Question 1, (a) reduced all-cause mortality is the correct answer. A lower BP goal did not slow the progression of CKD, and SPRINT was not powered to assess KFRT and kidney transplantation events. For Question 2, (c) the patient with CKD G3bA3 and a UACR of 3,000 mg/would most likely benefit from a lower BP goal based on subgroup analysis from clinical trials. Patients with A1albuminuria, critical bilateral renal artery stenosis, or repeated falls are less likely to benefit from a lower BP goal or may be at higher risk of treatment-related complications.

Additional Readings

➢ Appel LJ, Wright JT, Greene T, et al. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med 2010;363(10):918-929. +ESSENTIAL READING

➢ Cheung AK, Rahman M, Reboussin DM, et al. Effects of intensive BP control in CKD. J Am Soc Nephrol. 2017;28(9):2812-2823.

➢ Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3(1):1-150. +ESSENTIAL READING

➢ Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med. 1994;330(13):877-884. +ESSENTIAL READING

➢ Ruggenenti P, Perna A, Loriga G, et al. Blood-Pressure Control for Renoprotection in Patients With Non-diabetic Chronic Renal Disease (REIN-2): a multicenter, randomized controlled trial. Lancet.2005;365(9463):939-946.

➢ SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103-2116. +ESSENTIAL READING

➢ Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/ AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6): e13-e115.

➢ Wright JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288(19):2421-2431.

RAAS Inhibition

Case 2: A 46-year-old woman with type 2 diabetes returns for her second appointment. Her history is notable for retinopathy and CKD G3aA3 attributed to diabetic kidney disease. She denies having orthostatic symptoms or chest discomfort. Her automated office BP is 118/75 mm Hg on atenolol and chlorthalidone. Laboratory testing reveals stable eGFR (at 55 mL/min/1.73 m2) with a UACR of 1,200 mg/g.

Question 3: Which one of the following would be the most appropriate antihypertensive therapy to help slow CKD progression?

a) No change in therapy because her BP is controlled to goal

b) Change atenolol to an angiotensin receptor blocker (ARB)

c) Change chlorthalidone to an ARB d) Add an ARB to the current 2-drug regimen

Case 3: A 56-year-old woman with CKD G3aA3 due to biopsy-proven diabetic kidney disease has an average out-of-office BP of 144/83 mm Hg on a regimen of lisinopril at 20 mg daily, chlorthalidone at 50 mg daily, and amlodipine at 10 mg daily. Her UACR is 800 mg/g.

Question 4: Which one of the following interventions would be most appropriate to reduce the risk of CKD progression?

a) Add an ARB to the current regimen

b) Change lisinopril to a mineralocorticoid receptor antagonist (MRA)

c) Increase the lisinopril dosage

d) Change chlorthalidone to indapamide For the answers to the questions, see the following text.

The cornerstone of albuminuria management is RAAS inhibition. The KDIGO guidelines recommend that all adults with CKD, hypertension and a UACR of >300 mg/ g be treated with an angiotensin-converting enzyme inhibitor (ACEI) or ARB. Among those with diabetes and UACR > 30 mg/g, ACEI or ARB use should be considered. RAAS inhibition in patients with CKD and hypertension is also supported by all major hypertension guidelines (Table 1). Multiple trials have demonstrated that ACEI or ARB therapy delays CKD progression among individuals with albuminuria (Table 3). The REIN trial, which randomized patients with CKD to ramipril versus placebo, showed that mean GFR decline was signifificantly slower in the ramipril group among participants with proteinuria ≥ 3 g/d. In the RENAAL study, patients with type 2 diabetes and CKD randomized to losartan treatment had a 16% lower risk of developing a doubling of serum creatinine, KFRT, or death compared with the placebo group. Similarly, IDNT reported that irbesartan treatment was associated with a lower risk of a doubling of serum creatinine, serum creatinine ≥ 6.0 mg/dL, KFRT, or death compared with amlodipine or placebo treatments among patients with hypertension and CKD attributed to type 2 diabetes. Finally, in AASK, the use of ramipril was independently associated with 22% and 38% lower risks of the clinical composite outcome (GFR decline ≥50% or ≥25 mL/min/1.73 m2 from baseline, KFRT, or death) compared with metoprolol and amlodipine, respectively.

The current literature does not support the use of dual blockade with an ACEI and ARB in diabetic kidney disease. VA NEPHRON-D, which randomized veterans with type 2 diabetes and CKD G2-G3bA3 to losartan plus lisinopril or losartan alone, was terminated early due to safety concerns, with the combination therapy group having a markedly higher risk of hyperkalemia (HR, 2.8 [95% CI, 1.8-4.3]) and acute kidney injury (HR, 1.7 [95% CI, 1.3- 2.2]) compared with the monotherapy group. Additionally, there was no significant difference in risk of kidney function decline between the 2 treatment groups, though the follow-up period was short (Table 3).

Decreased sodium intake may enhance the renoprotective effects of RAAS inhibitors. A meta-analysis of 11 studies (23 cohorts with 516 participants) reported that dietary sodium restriction (average decrease of 92 mmol/ d) was associated with a 32% lower urine albumin excretion. The reduction in urine albumin excretion was greater in the cohorts with concomitant RAAS blockade therapy than in those without (pooled mean differences of −41.9% and −17.2%, respectively; P = 0.01 for interaction), suggesting a synergistic effect of low sodium intake with RAAS inhibition. In a post hoc analysis of 500 participants in the REIN and REIN II trials receiving ramipril therapy, a diet with > 14 g/d of salt was associated with 3.3-fold and 2.4-fold greater risks of KFRT compared with diets of <7 g/d and 7 to 14 g/d of salt, respectively. Importantly, the proteinuria-reducing effects of ramipril were greatest in the low-sodium diet group. In another post hoc analysis of the RENAAL study and IDNT (n = 1,177), ARB therapy was associated with a 43% lower risk of a renal event, defined as a doubling of serum creatinine or KFRT, compared with non-RAAS inhibitor therapy among participants in the lowest tertile of the 24-hour urinary sodium-creatinine ratio with no significant difference in risk between the 2 treatment groups for higher tertiles of sodium intake (P < 0.001 for interaction; Fig 1). Given these findings, patients on RAAS inhibitors for the treatment of albuminuria should be encouraged to follow a low-sodium diet.

For patients intolerant of ACEI/ARB therapy, an MRA can be considered. A recent meta-analysis of 31 randomized controlled trials evaluated the efficacy and safety forms (spironolactone, eplerenone, canrenone, or finerenone) compared with active control or placebo in reducing albuminuria. In the 18 trials (n = 2,036) that examined UACR as an outcome, proportional change in ACR from baseline to end of treatment was 22% lower inMRA treatment compared with active control and placebo. The effect persisted when comparing MRAs to placebo(n = 1,436 in 11 trials) in patients on ACEI/ARB therapy. When comparing MRAs to renin-angiotensin blockers, there was no significant difference in change in albuminuria (n = 201 in 2 trials), but the risk of incident hyperkalemia was 70% higher (n = 855 in 5 trials). Although the reduction in albuminuria is not a universally accepted surrogate endpoint for KFRT, the FIDELIO-DKDtrial of patients with type 2 diabetes and CKD (>98% on concomitant ACEI or ARB therapy) reported that finerenone conferred an 18% lower risk of compositekidney outcome (sustained decline in eGFR by ≥40% or to <15 mL/min/1.73 m2, KFRT, or death from kidney causes) compared with placebo. Thus, MRAs reduce albuminuria and may also slow CKD progression. Thesebenefifits, however, must be balanced against the potential risk of hyperkalemia.

In Question 3, (b) changing atenolol to an ARB is the correct answer. ACEIs and ARBs have been shown to slow the progression of CKD in patients with diabetes whileβ-blockers have not. In the management of hypertension,β-blockers are an add-on therapy after the use of first-line agents such as ACEIor ARBs and thiazide diuretics. Adding an ARB to the current regimen is less desirable, as this may result in hypotension in a patient with BP already controlled to the goal.

In Question 4, (c) increasing the lisinopril dose is the best answer. A combination of ACEI and ARB therapy is associated with an increased risk of adverse outcomes. Although an MRA may reduce albuminuria when combined with an ACEI or ARB, no randomized controlled trials have been performed to support changing an ACEI to an MRA with the intent of slowing progression to KFRT. Exchanging chlorthalidone for indapamide is not anticipated to slow this progression.

Additional Readings

➢ Alexandrou ME, Papagianni A, Tapas A, et al. Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease: a systematic review and meta-analysis of randomized controlled trials. J Hypertens. 2019;37(12):2307-2324. +ESSENTIAL READING

➢ Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229.

➢ Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861- 869. +ESSENTIAL READING

➢ D’Elia L, Rossi G, Schiano di Cola M, et al. Meta-analysis of the effect of dietary sodium restriction with or without concomitant renin-angiotensin-aldosterone system-inhibiting treatment on albuminuria. Clin J Am Soc Nephrol. 2015;10(9):1542-1552.

➢ Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903. +ESSENTIAL READING

➢ GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomized placebo-controlled trial of the effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuria, non-diabetic nephropathy. Lancet. 1997;349(9069):1857-1863.

➢ Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl. 2013;3(1):1-150. +ESSENTIAL READING ➢ Lambers Heerspink HJ, Holtkamp FA, Parving HH, et al. Moderation of dietary sodium potentiates the renal and cardiovascular protective effects of angiotensin receptor blockers. Kidney Int. 2012;82(3):330-337.

➢ Lewis EJ, Hunsicker LG, Clark WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851-860.

➢ Vegter S, Perna A, Postma MJ, et al. Sodium intake, ACE inhibition, and progression to ESRD. J Am Soc Nephrol.2012;23(1):165-173. +ESSENTIAL READING

➢ Wright JT, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288(19):2421-2431. +ESSENTIAL READING