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

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

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Introduction

Chronic kidney disease progression is linked to a variety of negative outcomes, such as incident kidney failure despite replacement treatment, hastened cardiovascular disease, disability, and death. As a result, in the therapy of a patient with chronic renal disease, delaying kidney function decrease is critical. Identifying the source of kidney illness is a crucial initial step that may necessitate particular treatments. Optimization of blood pressure and blockage of the renin-angiotensin-aldosterone system, particularly if albuminuria is present, are effective treatments that apply to the great majority of patients with chronic kidney disease.

Recent research suggests that sodium/glucose cotransporter 2 inhibitors are particularly efficient therapy for diabetics and albuminuria patients. Glycemic management is critical for individuals with type 2 diabetes to avoid microvascular problems, and glucagon-like peptide 1 receptor agonists may help lower albuminuria levels. Correcting metabolic acidosis, keeping an optimal body weight, eating a low-sodium, low-animal-protein diet, and avoiding possible nephrotoxins such nonsteroidal anti-inflammatories, proton-pump inhibitors, and iodinated contrast are some of the other treatments.

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 an 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?

  1. All-cause mortality is reduced
  2. CKD progresses more slowly at the lower BP goal
  3. Incidence of KFRT is higher at the lower BP goal
  4. 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?

  1. CKD G3aA1 with UACR of 10 mg/g
  2. CKD G4A1 with critical bilateral renal artery stenosis
  3. CKD G3bA3 with UACR of 3,000 mg/g
  4. CKD G3bA3 with UACR of 1,200 mg/g and history of repeated falls

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).

For Question 1, (a) reduced all-cause mortality is the correct answer. A lower BP goal did not slow 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 of 3,000 mg/g would most likely benefit from a lower BP goal based on subgroup analysis from clinical trials.

Patients with A1 albuminuria, 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.

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?

  1. No change in therapy because her BP is controlled
  2. Change atenolol to Angiotensin receptor blocker (ARB)
  3. Change chlorthalidone to an ARB
  4. 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?

  1. Add an ARB to the current regimen
  2. Change lisinopril to a mineralocorticoid receptor antagonist (MRA)
  3. Increase the lisinopril dosage
  4. 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.  Multiple trials have demonstrated that ACEI or ARB therapy delays CKD progression among individuals with albuminuria (Table 2).

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 while β-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 goal.

In Question 4, (c) increasing the lisinopril dose is the best answer. Combination 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.

Glycemic Control

Case 4: A 48-year-old man with type 2 diabetes is seen for a routine follow-up visit. He has stable CKD (G3aA2 for 3years) in addition to retinopathy, hypertension, and hyperlipidemia. He is currently taking losartan at 50 mg daily, metoprolol at 75 mg twice daily, metformin at 500 mg twice daily, and atorvastatin at 20 mg daily.

His BP is 127/68 mm Hg with a heart rate of 64 bpm. The remainder of the physical examination is unremarkable. Laboratory evaluation demonstrates his eGFR is 52 mL/min/1.73 m2, UACR 35 mg/g, and hemoglobin A1c (HbA1c) 7.9%.

Question 5: Which one of the following interventions would be most likely to slow the progression of his CKD?

  1. Increase losartan to reduce BP to < 120/80 mm Hg
  2. Change metoprolol to a dihydropyridine calcium channel blocker
  3. Increase metformin to target HbA1c < 7%
  4. No changes, as the management of hypertension andglycemic control are at goal

The 2020 KDIGO guidelines on diabetes in CKD recommend that HbA1c goals be individualized based on CKD severity, comorbidities, and hypoglycemia risk, among other factors (Table 3).

Dosing adjustments or discontinuation of glucose-lowering agents are often necessary as CKD progresses. In particular, insulins, sulfonylureas, and meglitinides are more likely to cause hypoglycemia in a patient with reduced kidney function.

For Question 5, (c) targeting a HbA1c of 7% or less is the best option among those listed to help slow CKD progression. In patients with CKD G4-G5 or significant competing comorbidities where risk of hypoglycemia is higher and benefits of intense control less well established, the HbA1c target should be individualized. The patient’s BP is currently controlled to goal, and further reduction or substitution of a dihydropyridine calcium blocker for a β-blocker has not been shown to slow CKD progression

SGLT2 Inhibitors

Case 3: The patient returns for a follow-up visit. His CKD has steadily worsened over the past 12 months. Laboratory studies reveal:

Question 6: Which one of the following interventions would be the next best step?

  1. Start treatment with a SGLT2 inhibitor to reduce albuminuria
  2. Start treatment with a SGLT2 inhibitor to achieve an HbA1c <7%
  3. Do not start treatment with a SGLT2 inhibitor because of a risk for worsening hyperkalemia
  4. Do not start treatment with a SGLT2 inhibitor because of a risk for worsening hyponatremia

Case 5: A 70-year-old woman with moderate obesity (body mass index [BMI] of 32 kg/m2) and uncontrolled diabetes mellitus (HbA1c 8.2%) returns to discuss the management of her CKD G3aA2. Her history includes coronary artery disease and recurrent furunculosis requiring antibiotics several times per year.

Question 7: In counseling her on the potential benefits and risks of therapy with an SGLT2 inhibitor, for which one of the following adverse effects is she at greatest risk?

  1. Genitourinary fungal infections
  2. Lower extremity amputation
  3. Severe hypoglycemia
  4. Acute kidney injury

In recent years, SGLT2 inhibitors have emerged as new, exciting therapies for delaying CKD progression, particularly among patients with type 2 diabetes and/or albuminuria. Current ADA and EASD guidelines recommend that SGLT2 inhibitors be considered in all patients with type 2 diabetes at risk of CKD progression, regardless of cardiovascular disease history.

Initial reports of the potential kidney protective effects of SGLT2 inhibitors came from cardiovascular outcome trials. In 2019, the results of the landmark CREDENCE trial were published. This trial, the first to examine the association of a SGLT2 inhibitor with a primary kidney outcome, reported that among patients with type 2 diabetes and CKD G2-G3bA3, randomization to canagliflozin was associated with a 30% lower risk (95% CI, 18%-41%) of developing a composite outcome compared with placebo.

For Question 6, SGLT2 inhibitors are associated with (a) a reduction in albuminuria and a 30% to 40% decreased risk of CKD progression. This class of medications is not commonly associated with hyponatremia or hyperkalemia and results in only a small reduction in HbA1c.

For Question 7, although all of the choices have been reported with the use of SGLT2 inhibitors, the most common is (a) genitourinary fungal infection.

GLP-1 Receptor Agonists

Case 6: A 60-year-old man with type 2 diabetes mellitus and CKD G4A3 (eGFR 27 mL/min/1.73 m2 ) has stable UACR (1,800 mg/g for 1 year). His BP is 126/70 mm Hg and HbA1c is 9.0%. His medications include lisinopril at 40 mg daily, diltiazem sustained release at 180 mg daily, and insulin glargine.

Question 8: Which one of the following interventions would be appropriate to manage risk factors associated with CKD progression?

  1. Addition of a GLP-1 receptor agonist to reduce HbA1c but at an increased risk for hypoglycemia
  2. Addition of metformin rather than a GLP-1 receptor agonist due to the favorable side-effect profile of metformin
  3. Addition of a GLP-1 receptor agonist to slow progres-sion to KFRT without change in albuminuria
  4. Addition of a GLP-1 receptor agonist to reduce BP to <120/80 mm Hg

The GLP-1 receptor agonists are another novel class of diabetes medications that improve kidney outcomes. In the AWARD-7 trial, dulaglutide 0.75 mg or 1.5 mg weekly resulted in slower eGFR decline over 52 weeks compared with daily insulin glargine among participants with type 2 diabetes, CKD G3-G4, and a UACR > 300 mg/g. Furthermore, UACR reduction occurred with dulaglutide in a dose-dependent manner.

For Question 8, studies best support (a) a reduction in UACR after addition of a GLP-1 receptor agonist. There is an increased risk of hypoglycemia when used concurrently with insulin, and a reduction in the rate of progression to KFRT has not been shown. While GLP-1 receptor agonists may result in a small reduction in BP, lowering to <120/ 80 mm Hg has not been shown to slow CKD progression. Initiating metformin would be inappropriate at this eGFR.

Chronic Metabolic Acidosis and  Dietary Protein Restriction

Case 7: A 63-year-old woman with CKD G4A2 and osteopenia returns for a follow-up visit, having been last seen 4 months ago. She underwent left nephrectomy 30 years ago after trauma. She reports no interval symptoms, and her weight has been stable. Her eGFR has slowly declined from 33 to 28 mL/min/1.73 m2 over the past 2 years, with her last 2 total carbon dioxide values in the range of 19 to 21 mmol/ L. On physical examination, her BP is 118/65 mm Hg, her lungs are clear, and she has trace pedal edema.

Question 9: Which one of the following is most accurate in treating metabolic acidosis associated with CKD?

  1. Modest dietary protein restriction should decrease urine ammoniagenesis
  2. Dietary supplementation with sodium bicarbonate should decrease bone mineral density
  3. Modest dietary protein restriction should increase skeletal muscle catabolism

Case 8: A 58-year-old man with IgA nephropathy has had progressive CKD over the past 18 months. His eGFR is 29 mL/min/1.73 m2 with total carbon dioxide ranging between 18 and 20 mmol/L.

Question 10: Which one of the following interventions has the greatest efficacy in improving metabolic acidosis?

  1. Increase daily fruit intake to 4 servings
  2. Add sodium bicarbonate as a 650-mg tablet daily
  3. Ensure 2 servings of pasta daily
  4. Replace one serving of red meat with one serving of fish daily

Metabolic acidosis is a common complication of CKD due to impairments in the kidney’s ability to excrete acid. Dietary composition also influences acid-base balance, with animal-derived proteins contributing primarily hydrogen ions, and fruits and vegetables contributing alkali. Thus, treatment of metabolic acidosis in patients with CKD typically relies on 3 strategies: reduction of dietary animal protein, increased consumption of fruits and vegetables, and administration of oral alkali salts. Metabolic acidosis is a risk factor for KFRT, decreased bone mineralization, and sarcopenia. Correction of metabolic acidosis may slow CKD progression.

For  Question 9, chronic metabolic acidosis is associated with progression of CKD, stimulates increased renal ammoniagenesis, increases bone resorption, and is associated with the development of sarcopenia. Therefore, the best answer is (a) as reducing protein intake will decrease dietary acid production.

For Question 10, the best answer is (a) since 4 servings of fruits and vegetables provide more alkali than low-dose sodium bicarbonate. Carbohydrates and animal meats contribute to net acid production, although replacing servings of red meat with fish may have other health benefits

Avoidance of Nephrotoxins

Case 9: A 62-year-old woman with recently diagnosed ovarian cancer has presented to the emergency department with a urinary tract infection and atrial fibrillation. Her medical history is notable for CKD G4A1 in the setting of hypertension and chronic hepatitis B. Her home medications include lisinopril, tenofovir disoproxil fumarate, and multivitamin.  Computed tomography imaging of her abdomen/ pelvis demonstrates a large ovarian mass with peritoneal carcinomatosis.

Question 11: Which one of the following medications is safest to use in the setting of CKD G4?

  1. Gentamicin
  2. Amiodarone
  3. Tenofovir disoproxil fumarate
  4. Cisplatin

Case 10: A 74-year-old man with CKD G4A2 in the setting of diabetes mellitus and IgA nephropathy is hospitalized for a nonhealing lower extremity ulceration. His eGFR is currently 23 mL/min/1.73 m2 , as compared with 26 mL/min/1.73 m2 1 month before. You are consulted before the planned lower extremity angiography for recommendations to reduce the risk for contrast-associated acute kidney injury.

Question 12: Which one of the following interventions is most appropriate before administration of intraarterial intravenous iodinated contrast in hospitalized patients with diabetes and CKD?

  1.  Oral N-acetylcysteine
  2. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor
  3. Vitamin C
  4. Normal saline hydration

Nephrotoxins can contribute to CKD progression by causing acute kidney injury, chronic interstitial nephritis, tubular dysfunction, or glomerular changes. Avoidance of nephrotoxins is not always possible, especially in the hospital or acute care setting; thus, an individualized approach that carefully weighs the risks versus benefits for each patient is necessary.

Many chemotherapeutic (eg, platinum-based agents, gemcitabine, immunotherapies) and antimicrobial (eg, aminoglycosides, colistin, amphotericin B, tenofovir disoproxil fumarate) agents require special attention in CKD given their potential for harm to the kidney and/or need for dose adjustments. Despite known toxicities, alternative drug options may not be appropriate due to susceptibility patterns or decreased efficacy. In such cases, counseling patients on the potential worsening of CKD, close monitoring of kidney function, and dose adjustments as needed is a reasonable approach.

For Question 11, the best answer is (b) because amiodarone does not require discontinuation or dose adjustment in CKD G4.

For Question 12, although all the listed agents have been reported to reduce the risk of contrast-associated kidney injury, the best answer is (d) because periprocedural hydration with normal saline is the most widely accepted prophylaxis.

Weight Loss and Bariatric Surgery

Case 11: A 54-year-old man has CKD G4A1 in the setting of diabetes mellitus and hypertension. His weight has been stable for the past year after losing 15 pounds. His medications include lisinopril at 40 mg daily and a GLP-1 receptor agonist. His BP is 125/70 mm Hg and BMI is 32 kg/m2 . His laboratory tests demonstrate an eGFR of 27 mL/min/1.73 m2, a UACR of 25 mg/g, HbA1c 7.2%, and serum uric acid of 8.1 mg/dL. The kidney failure risk equation predicts a 4.6% risk of kidney failure at 2 years.

Question 13: Which one of the following interventions would be most appropriate to reduce his risk of progression to kidney failure?

  1. Referral for bariatric surgery
  2. Starting allopurinol treatment
  3. Starting treatment with a second antihypertensive agent to lower his BP to <120/80 mm Hg
  4. No additional therapy

In observational studies, higher BMI has been associated with substantially greater risk of developing hypertension and diabetes and a more modest risk for CKD. Mechanisms for the latter association may be through the development of hypertension/diabetes, or there may independent effects through inflammation and hemodynamic alterations in the glomerulus.

Weight loss through lifestyle modification or bariatric surgery may improve kidney outcomes. In Question 13, of the options shown, response (d), or no additional therapy, would be the most appropriate intervention. Bariatric surgery at this BMI or a BP goal of <125/ 70 mm Hg have not been shown to slow the progression to KFRT. And, as discussed in the previous section, randomized controlled trials have not shown a benefit of uric acid–lowering therapy in preserving kidney function.

References

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2.           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.

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5.           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.

6.           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.

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

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

9.           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.

10.         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.

11.         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.

12.         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.