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Frequently Asked Questions

Frequently Asked Questions

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    1. What is the prevalence of chronic kidney disease in patients with type 2 diabetes?

    • In 2019, 37.3 million (around 11.3%) Americans had diabetes, including approximately 1.9 million Americans with type 1 diabetes. Approximately 35.4 million (around 10.7%) Americans have type 2 diabetes (T2D).1

    • Of those with T2D, approximately 40% develop chronic kidney disease (CKD).2

    • Diabetes is a major cause of end-stage kidney disease in the United States.3

    • In 2017-2020, the overall awareness of CKD stages 3-4 among patients with CKD and diabetes is about 28%.4

     

    2. How often should patients with type 2 diabetes be screened to measure kidney function and damage?

    • Screening should start from diagnosis of type 2 diabetes and should be repeated at least once per year thereafter (ADA 2023; ADA/KDIGO Consensus; AACE 2022).5,6,7

    • Kidney function can be measured by calculating the estimated glomerular filtration rate (eGFR) from a blood sample.8 An eGFR <60 mL/min/1.73 m2 indicates reduced kidney function (ADA-KDIGO consensus report, 2022).6

    • Kidney damage is indicated by abnormally high levels of certain proteins in urine (proteinuria). One such protein is albumin.8 High levels of albumin in urine (albuminuria) determined using a technique such as the spot urine albumin-to-creatinine ratio [UACR]) indicates kidney damage (abnormal: UACR ≥30 mg/g) (ADA-KDIGO consensus report, 2022).6

    • Abnormal eGFR (<60 mL/min/1.73 m2) or UACR (≥30 mg/g) or both should be confirmed by repeat testing (with or without other markers of kidney damage) before a chronic kidney disease diagnosis is made (ADA, 2023; ADA-KDIGO consensus report, 2022).5,6

     

    3. What are the screening recommendations/tests for chronic kidney disease in patients with type 2 diabetes?

    • Spot urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) should be used to screen for chronic kidney disease (CKD) at least annually in patients with type 2 diabetes.6  

    • The American Society of Nephrology (ASN) and National Kidney Foundation (NKF) advocate using the 2021 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation, which calculates eGFR without regard to race, to estimate glomerular filtration rate (GFR) from creatinine, age, and sex.6

    • Calculation of UACR in single-voided spot urine samples is most convenient to measure albuminuria. UACR has marked variability; therefore, a confirmatory urine sample within 3-6 months is recommended.6

     

    4. What are the guideline recommendations (ADA, KDIGO, and AACE) for screening and diagnosing chronic kidney disease in patients with type 2 diabetes?

    • People with chronic kidney disease (CKD) may not have symptoms, so CKD is often diagnosed through routine screening (ADA-KDIGO consensus report, 2022).6

    • Two important diagnostic markers of CKD are a reduced estimated glomerular filtrate rate (eGFR) (<60 mL/min/1.73 m2; normal is ≥90 mL/min/1.73 m2) and abnormally high levels of the protein albumin in urine (called albuminuria; urine albumin-to-creatinine ratio [UACR] ≥30 mg/g; normal is <30 mg/g) (ADA-KDIGO consensus report, 2022).6

    • ADA (2023/11.1a), ADA-KDIGO consensus report, and AACE (2022/R 6.1) recommend that people with type 2 diabetes should be screened for CKD at least annually, and this should be done by measurement of both urinary albumin levels (such as via the spot UACR) and calculation of the eGFR from a blood sample.5,6,7

    • KDIGO has codified a CKD classification scheme based on eGFR and albuminuria that is endorsed by the ADA. The KDIGO heatmap recommends comprehensive CKD staging that uses both eGFR and albuminuria to determine risk of progression, monitoring frequency, and nephrologist referral, and to guide treatment (ADA/KDIGO consensus report, 2022).6

    • CKD is defined as persistently reduced eGFR (<60 mL/min/1.73 m2), persistently elevated urine albumin excretion (UACR ≥30 mg/g), or both, for ≥3 months.6,9

     

    5. What is the preferred test for albuminuria (proteinuria)?

    • The preferred test for albuminuria is urine albumin-to-creatinine ratio (UACR) in a spot urine sample.5-7

    • Early morning urine specimens are ideal, although samples collected at any time of day may be used. UACR has marked variability; therefore, a confirmatory urine sample within 3-6 months is recommended.6

     

    6. How are the stages of chronic kidney disease defined/determined?

    • According to a consensus report from both KDIGO and ADA, chronic kidney disease (CKD) should be classified based on both estimated glomerular filtrate rate (eGFR) and albuminuria.6
       

    • The eGFR categories are as follows:

      • Grade 1 eGFR or “normal or High”: ≥90 mL/min/1.73 m2

      • Grade 2 eGFR or “mildly decreased”: 60-89 mL/min/1.73 m2

      • Grade 3a eGFR or “mildly to moderately decreased”: 45-59 mL/min/1.73 m2

      • Grade 3b eGFR or “moderately to severely decreased”: 30-44 mL/min/1.73 m2

      • Grade 4 eGFR or “severely decreased”: 15-29 mL/min/1.73 m2

      • Grade 5 eGFR or “kidney failure”: <15 mL/min/1.73 m2

     

    • The albuminuria categories are as follows:

      • Normal to mildly increased (A1): <30 mg/g

      • Moderately increased (A2): 30-299 mg/g

      • Severely Increased (A3): ≥300 mg/g  

     

    7. What is the prognosis of chronic kidney disease outcomes by eGFR and UACR categories?

    • In cohort studies, risks of progressive chronic kidney disease (CKD), cardiovascular events, and mortality all increase with categories of increasing albuminuria or decreasing estimated glomerular filtrate rate (eGFR).6

    • In the KDIGO heatmap, which is also endorsed by the ADA, the risk of CKD progression increases when a patient has a urine albumin-to-creatinine ratio (UACR) in the A2 (30-299 mg/g) and A3 (≥300 mg/g) categories, regardless of eGFR.6

    • In a summary of categorical meta-analyses for general population cohorts with UACR, the adjusted relative risks for all-cause mortality, cardiovascular mortality, kidney failure, acute kidney injury, and CKD progression increased for all eGFR categories (G1-G5) when albuminuria was in the A2 and A3 categories.8

     

    8. How does eGFR predict risk of renal and cardiovascular events?

    • According to the KDIGO heatmap, decreasing estimated glomerular filtrate rate (eGFR) by itself can predict the risk of chronic kidney disease (CKD) progression. As eGFR by itself decreases from the G2 category (60-89 mL/min/1.73 m2) to lower eGFR categories (G3a, G3b, G4, G5), the risk of CKD progression increases.6

    • Data from a meta-analysis of 21 general population cohort studies (with an overall 1,234,182 participants) showed that eGFR is an independent predictor of cardiovascular (CV) mortality from urine albumin-to-creatinine ratio (UACR) and that an eGFR <60 mL/min/1.73 m2 is significantly associated with increased CV mortality.10

    • In a retrospective cohort study of 2.2 million patients with diabetes, 157,196 patients with diabetes and CKD were compared with those without CKD. It was found that as eGFR categories advanced from stage 1-2 (60 to ≥90 mL/min/1.73 m2) to stage 3 (30-59 mL/min/1.73 m2) or 4-5 (29 to <15 mL/min/1.73 m2), there was an increase in the risk of end-stage renal disease, myocardial infarction, chronic heart failure, and stroke.8,11

    • In a summary of categorical meta-analyses for general population cohorts with UACR, the adjusted relative risks for all-cause mortality, CV mortality, kidney failure, acute kidney injury, and CKD progression all increased when eGFR was <60 mL/min/1.73 m2.8

     

    9. How does UACR predict risk of renal and cardiovascular events?

    • According to the KDIGO heatmap, decreasing urine albumin-to-creatinine ratio (UACR) by itself can predict the risk of chronic kidney disease (CKD) progression. As UACR by itself increases from the A1 category (<30 mg/g) to A2 (30-299 mg/g) or A3 (≥300 mg/g) categories, the risk of CKD progression increases. The A3 category, without regard to estimated glomerular filtrate rate (eGFR) categories, puts a patient at either high or very high risk of CKD progression.6

    • Data from a meta-analysis of 21 general population cohort studies (with an overall 1,234,182 participants) showed that UACR is an independent predictor of cardiovascular (CV) mortality from eGFR and that UACR ≥10 mg/g is significantly associated with increased CV mortality.10

    • Data from a meta-analysis of 24 cohorts (19 general population cohorts, 3 high-risk cohorts of patients with diabetes, and 3 CKD cohorts), with 637,315 participants, showed that UACR independently improved prediction and outperformed eGFR for CV outcomes like CV mortality and heart failure.12

    • In a summary of categorical meta-analyses for general population cohorts with UACR, the adjusted relative risks for all-cause mortality, CV mortality, kidney failure, acute kidney injury, and CKD progression increased for all eGFR categories (G1-G5) when albuminuria was in the A2 (30-299 mg/g) and A3 (≥300 mg/g) categories.8

     

    10. In patients with type 2 diabetes, what are the guideline recommendations for treatment of chronic kidney disease?

    • The ADA Standards of Medical Care in Diabetes—2023 recommendations are5:
       

      • In nonpregnant people with diabetes and hypertension, either an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin II receptor blocker (ARB) is recommended for those with moderately increased albuminuria (urinary albumin-to-creatinine [UACR] 30-299 mg/g) (B) and is strongly recommended for those with severely increased albuminuria (UACR ≥300 mg/g) and/or estimated glomerular filtrate rate (eGFR) <60 mL/min/1.73 m2 (A).   

      • For people with type 2 diabetes (T2D) and diabetic kidney disease, use of a sodium-glucose cotransporter 2 inhibitor (SGLT-2i) is recommended to reduce chronic kidney disease (CKD) progression and cardiovascular (CV) events in patients with an eGFR ≥20 mL/min/1.73 m2 and UACR ≥200 mg/g (A).

      • For people with T2D and diabetic kidney disease, use of SGLT-2i is recommended to reduce CKD progression and CV events in patients with an eGFR ≥20 mL/min/1.73 m2 and UACR ranging from normal to 200 mg/g (B).  

      • In people with T2D and diabetic kidney disease, consider use of SGLT-2i (if eGFR ≥20 mL/min/1.73 m2), a glucagon-like peptide 1 receptor agonist (GLP-1 RA), or a nonsteroidal receptor antagonist (if eGFR ≥25 mL/min/1.73 m2) additionally for CV risk reduction (A).  

      • In people with CKD and albuminuria who are at increased risk for CV events or CKD progression, a nonsteroidal mineralocorticoid receptor antagonist (MRA) shown to be effective in clinical trials is recommended to reduce CKD progression and CV events (A).  

     

     

    • The KDIGO Clinical Practice Guideline for Diabetes Management in CKD—2022 recommendations are9:
       

      • Patients with diabetes and CKD should be treated with a comprehensive strategy to reduce risks of kidney disease progression and cardiovascular disease (CVD).

      • Treatment with an ACEi and ARB should be initiated in patients with diabetes, hypertension, and albuminuria, and these medications should be titrated to be the highest approved dose that is tolerated (1B).  

      • Treat patients with T2D, CKD, and an eGFR ≥20 mL/min/1.73 m2 with an SGLT-2i (1A).

      • Suggesting treatment with a nonsteroidal MRA with proven kidney or CV benefit for patients with T2D, eGFR ≥25 mL/min/1.73 m2, normal serum potassium concentration, and albuminuria (≥30 mg/g) despite maximum tolerated dose of renin-angiotensin system inhibitor (RASi) (2A).

      • Treat patients with T2D, CKD, and an eGFR ≥30 mL/min/1.73 m2 with metformin (1B).

      • In patients with T2D and CKD who have not achieved individualized glycemic targets despite use of metformin and SGLT-2i treatment, or who are unable to use those medications, a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA) is recommended (1B).

     

     

    • The ADA-KDIGO Consensus Report recommendations are6:
       

      • All patients with type 1 diabetes (T1D) or T2D and CKD should be treated with a comprehensive plan, outlined and agreed by health care professionals and the patient together, to optimize nutrition, exercise, smoking cessation, and weight, upon which are layered evidence-based pharmacologic therapies aimed at preserving organ function and other therapies to attain intermediate targets for glycemia, blood pressure, and lipids.

      • An ACEi or ARB is recommended for patients with T1D or T2D who have hypertension and albuminuria, titrated to the maximum antihypertensive or highest tolerated dose.

      • A statin is recommended for all patients with T1D or T2D with CKD, moderate intensity for primary prevention of atherosclerotic cardiovascular disease (ASCVD) or high intensity for patients with known ASCVD and some patients with multiple ASCVD risk factors.

      • Metformin is recommended for patients with T2D, CKD, and eGFR ≥30 mL/ min/1.73 m2; the dose should be reduced to 1,000 mg daily in patients with eGFR 30-44 mL/ min/1.73 m2 and in some patients with eGFR 45-59 mL/min/1.73 m2 who are at high risk of lactic acidosis.

      • An SGLT-2i with proven kidney or CV benefit is recommended for patients with T2D, CKD, and eGFR ≥20 mL/min/1.73 m2. Once initiated, the SGLT-2i can be continued at lower levels of eGFR.

      • A GLP-1 RA with proven CV benefit is recommended for patients with T2D and CKD who do not meet their individualized glycemic target with metformin and/or an SGLT-2i or who are unable to use these drugs.

      • A nonsteroidal MRA with proven kidney and CV benefit is recommended for patients with T2D, eGFR ≥25 mL/min/1.73 m2, normal serum potassium concentration, and albuminuria (UACR ≥30 mg/g) despite maximum tolerated dose of RASi.

     

     

    • The AACE Clinical Practice Guideline 2022 recommendations are7:
       

      • Renin-angiotensin-aldosterone system blockade with an ARB or ACEi is recommended for persons with albuminuria (T1D or T2D) to reduce the risk of diabetic kidney disease or CKD in diabetes mellitus (DM) progression (Grade A; BEL 1).

      • An SGLT-2i with proven benefit is recommended as foundational therapy for persons with T2D and CKD with eGFR ≥20 mL/min/1.73 m2 to reduce progression of CKD and risk of CVD.

      • A GLP-1 RA with proven benefit is recommended for persons with T2D and diabetic kidney disease or CKD in DM with eGFR ≥15 mL/min/1.73 m2 for glycemic control and to reduce the risk of ASCVD and progression of albuminuria (Grade A; BEL 1).

      • A nonsteroidal MRA (finerenone) with proven kidney and CVD benefit is recommended for persons with T2D, eGFR ≥25 mL/min/1.73 m2, normal serum potassium concentration, and albuminuria (UACR ≥30 mg/g) despite a maximum tolerated dose of a RASi (Grade A; BEL 1).

     

    11. How are high albuminuria (microalbuminuria) and very high albuminuria (macroalbuminuria) categorized?

    • High albuminuria (microalbuminuria) is categorized as moderately increased albuminuria or urine albumin-to-creatinine ratio (UACR) of 30-300 mg/g (A2). According to KDIGO, the term “microalbuminuria” should be avoided, and the term “moderately increased albuminuria” should be used instead.13

    • Very high albuminuria (macroalbuminuria) is categorized as severely increased albuminuria or UACR of ≥300 mg/g (A3). According to KDIGO, the term “macroalbuminuria” should be avoided and the term “severely increased albuminuria” should be used instead.13

     

    Reference List

    1. American Diabetes Association. Statistics about diabetes. 2022. https://diabetes.org/diabetes-basics/statistics/. Accessed January 6, 2023.
    2. Bailey RA, et al. BMC Res Notes. 2014;7:415.
    3. Duru OK, et al. Curr Diab Rep. 2018;18(3):14.
    4. Centers for Disease Control and Prevention. Chronic Kidney Disease Surveillance System—United States. https://nccd.cdc.gov/ckd/detail.aspx?Qnum=Q98&Strat=Year%2c+Diabetes#refreshPosition. Accessed January 6, 2023.
    5. American Diabetes Association. Section 11. Diabetes Care. 2023;46(Suppl 1):S191-S202.
    6. de Boer IH, et al. Diabetes Care. 2022;45(12):3075-3090.
    7. Blonde L, et al. Endocr Pract. 2022;28(10):923-1049.
    8. Kidney Disease Improving Global Outcomes. Kidney Int Suppl. 2013;3:1-150.
    9. Kidney Disease Improving Global Outcomes. Kidney Int. 2022;102(5S):S1-S127.
    10. Matsushita K, et al. Lancet. 2010;375(9731):2073-2081.
    11. Wetmore JB, et al. BMC Endocr Disord. 2019;19(1):89.
    12. Matsushita K, et al. Lancet Diabetes Endocrinol. 2015;3(7):514-525.
    13. Levey AS, et al. Kidney Int. 2020;97(6):1117-1129.
    14. Yang J, et al. J Mol Endocrinol. 2009;43(2):53-64

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