What is the definition, staging criteria, and recommended monitoring schedule for cardiovascular‑kidney‑metabolic syndrome?

Cardiovascular-Kidney-Metabolic (CKM) Syndrome: Definition, Staging, and Monitoring

CKM syndrome is a newly defined clinical entity that recognizes the pathophysiological interconnection between metabolic risk factors, chronic kidney disease, and cardiovascular disease, requiring systematic staging and risk-stratified monitoring to prevent progression and adverse outcomes.

Definition

CKM syndrome describes the multidirectional relationships among excess/dysfunctional adipose tissue, metabolic disorders (insulin resistance, dyslipidemia, hypertension), chronic kidney disease, and cardiovascular disease 1, 2, 3. This framework evolved from the older "metabolic syndrome" concept to explicitly incorporate kidney disease and cardiovascular outcomes as integral components rather than separate complications 4.

The syndrome originates in excess and/or dysfunctional adipose tissue, which secretes proinflammatory and prooxidative products leading to damaged tissues in arteries, the heart, and kidneys, with reduction in insulin sensitivity 4. Approximately 25% of the US population has at least one CKM condition based on NHANES data from 1999-2020 4.

Staging System

CKM syndrome is classified into 5 stages (0-4) based on the presence of risk factors, metabolic abnormalities, kidney dysfunction, and cardiovascular disease 3, 4:

Stage 0: No Risk Factors

• No excess adiposity
• No metabolic risk factors
• Normal kidney function (eGFR ≥90 mL/min/1.73 m² and UACR <30 mg/g)
• No cardiovascular disease 3

Stage 1: Excess Adiposity or Metabolic Risk Factors

• Central obesity (waist circumference ≥102 cm in men, ≥88 cm in women) 5
• Elevated triglycerides ≥150 mg/dL 5
• Low HDL cholesterol (<40 mg/dL in men, <50 mg/dL in women) 5
• Blood pressure ≥130/85 mmHg 5
• Impaired fasting glucose ≥100 mg/dL 5
• Presence of 3 or more of these criteria defines metabolic syndrome 5

Stage 2: Metabolic Disorders or Moderate Kidney Disease

• Type 2 diabetes (HbA1c ≥6.5%) 5
• CKD Stage 2-3a (eGFR 45-89 mL/min/1.73 m² with evidence of kidney damage OR UACR 30-299 mg/g) 5
• No established cardiovascular disease 3

Stage 3: Early Cardiovascular Disease or Advanced Kidney Disease

• CKD Stage 3b-4 (eGFR 15-44 mL/min/1.73 m²) 5
• UACR ≥300 mg/g 5
• Subclinical cardiovascular disease (elevated coronary artery calcium, left ventricular hypertrophy, increased arterial stiffness) 5
• No clinical cardiovascular events 3

Stage 4: Established Cardiovascular Disease

• Clinical cardiovascular disease (myocardial infarction, stroke, heart failure, peripheral artery disease) 5, 3
• CKD Stage 5 (eGFR <15 mL/min/1.73 m² or dialysis) 5

Diagnostic Evaluation

Initial Assessment for All Patients

Measure both eGFR and urinary albumin-to-creatinine ratio (UACR) on a random spot urine sample, as both provide independent prognostic information 5, 6:

• eGFR calculation: Use CKD-EPI 2021 equation (race-free) 5, 6
• UACR measurement: Preferred over urine dipstick for accurate quantification 5, 6
• CKD diagnosis: Requires eGFR <60 mL/min/1.73 m² OR UACR ≥30 mg/g persisting for ≥3 months 5, 6

Metabolic Assessment

• Fasting glucose and HbA1c 5
• Lipid panel (total cholesterol, LDL, HDL, triglycerides) 5
• Waist circumference measurement 5
• Blood pressure (target <130/80 mmHg in CKD patients) 5

Cardiovascular Risk Assessment

• 12-lead ECG for all patients with hypertension 5
• Echocardiography when ECG is abnormal or cardiac symptoms present 5
• Consider coronary artery calcium scoring for risk stratification 5
• Carotid ultrasound for plaque detection in high-risk patients 5

CKD Complication Screening (eGFR <60 mL/min/1.73 m²)

• Complete metabolic panel (sodium, potassium, chloride, bicarbonate) 6
• Hemoglobin for anemia screening 5, 6
• Serum calcium, phosphate, intact PTH (when eGFR <45 mL/min/1.73 m²) 5, 6
• 25-hydroxyvitamin D 5, 6

Monitoring Schedule

Monitoring frequency is determined by the combined risk from eGFR and albuminuria categories 5, 6:

Low Risk (Green Zone)

• eGFR ≥60 mL/min/1.73 m² AND UACR <30 mg/g
• Monitor annually: eGFR, UACR, blood pressure, metabolic parameters 5, 6

Moderate Risk (Yellow Zone)

• eGFR 45-59 mL/min/1.73 m² with UACR <30 mg/g OR eGFR ≥60 with UACR 30-299 mg/g
• Monitor 2 times per year: eGFR, UACR, electrolytes, blood pressure 5, 6

High Risk (Orange Zone)

• eGFR 30-44 mL/min/1.73 m² OR UACR 30-299 mg/g with eGFR 45-59
• Monitor 3 times per year: eGFR, UACR, electrolytes, hemoglobin, metabolic bone parameters 5, 6

Very High Risk (Red Zone)

• eGFR <30 mL/min/1.73 m² OR UACR ≥300 mg/g
• Monitor 4 times per year (every 1-3 months): eGFR, UACR, electrolytes, hemoglobin, calcium, phosphate, PTH 5, 6
• Mandatory nephrology referral 5, 6

Additional Monitoring Considerations

• Potassium monitoring: Check within 2-4 weeks after initiating ACE inhibitors, ARBs, or mineralocorticoid receptor antagonists, then every 4 months 6
• HbA1c: Every 3-6 months in diabetic patients 5
• Lipid panel: Annually or more frequently if not at goal 5

Nephrology Referral Criteria

Refer to nephrology immediately when any of the following are present 5, 6:

• eGFR <30 mL/min/1.73 m² 5, 6
• UACR ≥300 mg/g with progressive increase despite optimal management 5, 6
• Rapid eGFR decline (>5 mL/min/1.73 m² per year or >10 mL/min/1.73 m² over 5 years) 6
• Continuously increasing albuminuria despite treatment 5, 6
• Uncertainty about etiology or atypical features suggesting non-diabetic kidney disease 6
• Difficulty managing CKD complications (anemia, metabolic bone disease, resistant hypertension) 6
• Hematuria, pyuria, or casts suggesting glomerulonephritis 6

Risk Stratification Tools

Use the PREVENT equations for cardiovascular risk prediction in CKM syndrome patients, as these incorporate eGFR and albuminuria in addition to traditional cardiovascular risk factors 3. This represents a major advancement over older risk calculators that did not account for kidney disease 3.

For CKD progression risk, apply the CKD Prognosis Consortium equations that combine eGFR and albuminuria categories 1, 3.

Common Pitfalls to Avoid

• Never rely on serum creatinine alone—always calculate eGFR using validated equations 6
• Never skip albuminuria testing—eGFR and UACR provide independent prognostic information for cardiovascular events, CKD progression, and mortality 5, 6
• Do not discontinue ACE inhibitors or ARBs for mild creatinine increases (<30%) in the absence of volume depletion 5, 6
• Do not combine ACE inhibitors with ARBs—this increases adverse events without additional benefit 6
• Do not assume normal-sized kidneys on ultrasound exclude CKD—diabetic kidney disease and infiltrative disorders maintain kidney size despite progressive dysfunction 6
• Do not wait to screen for CKD in type 2 diabetes—screening must begin at diagnosis, as 6.5% already have significant albuminuria and 28% have hypertension at presentation 6