Clinical Significance of Creatine Kinase in Hypertension
Elevated creatine kinase (CK) is independently associated with treatment-resistant hypertension and predicts failure of antihypertensive therapy, making it a clinically significant marker for identifying patients at high risk for difficult-to-control blood pressure.
Important Clarification: CK vs. Creatinine
The question asks about "creatinine kinase" but this appears to be a conflation of two distinct markers:
- Creatine kinase (CK): An enzyme that regenerates ATP
- Serum creatinine: A marker of kidney function
Both have clinical significance in hypertension, but they represent entirely different pathophysiological processes.
Creatine Kinase (CK) and Hypertension
Primary Clinical Significance
CK is the main predictor of antihypertensive treatment failure, with patients in the highest CK tertile (>145 IU/L) having a 3.7-fold increased odds of treatment failure compared to those in the lowest tertile (<88 IU/L), independent of age, sex, BMI, glucose, ethnicity, or education 1.
- Treatment failed in 72.9% of participants with the highest CK tertile versus only 46.7% in the lowest tertile 1.
- Hypertension prevalence increases progressively across CK tertiles: 26.8% in the lowest tertile to 41.2% in the highest tertile 1.
Mechanistic Understanding
CK rapidly regenerates ATP from ADP at sites of ATP-utilizing enzymes including Ca²⁺-ATPase, myosin ATPase, and Na⁺/K⁺-ATPase 2. This enhanced ATP availability increases:
CK inhibition substantially reduces contractility of human resistance arteries ex vivo, supporting a causal role 2.
Plasma Creatine and Incident Hypertension
Higher plasma creatine concentrations (the substrate for CK) are independently associated with incident hypertension, particularly in men 3:
- Each doubling of plasma creatine increases hypertension risk by 21% overall 3
- In men specifically, the hazard ratio is 1.26 (95% CI 1.11-1.44) 3
- This association is independent of sodium or protein intake 3
Serum Creatinine and Hypertension
Renal Function Assessment
All hypertensive patients require assessment of kidney function through serum creatinine with eGFR calculation and urine albumin-to-creatinine ratio (UACR) 4, 5.
- Use the race-free CKD-EPI equation for eGFR calculation, not MDRD or Cockcroft-Gault 5
- CKD is defined as eGFR <60 mL/min/1.73 m² or albuminuria ≥30 mg/g present for ≥3 months 4, 5
- The combination of reduced eGFR and proteinuria indicates greater cardiovascular and renal risk than either abnormality alone 5
Cardiovascular Risk Stratification
Even high-normal serum creatinine within the reference range independently predicts cardiovascular events in hypertensive patients 6:
- Event rate increases progressively across creatinine quartiles: 1.5 to 3.5 events per 100 patient-years 6
- Each 20 μmol/L (0.23 mg/dL) increase in creatinine confers a 30% excess cardiovascular risk (HR 1.30,95% CI 1.07-1.59) 6
- This persists after adjustment for 24-hour blood pressure, left ventricular hypertrophy, and other confounders 6
Stroke risk specifically is increased at creatinine levels above 116 μmol/L (90th percentile), with a relative risk of 1.6 even after full adjustment 7. This association is present in both normotensive and hypertensive subjects 7.
Chronic Kidney Disease and Resistant Hypertension
CKD is strongly associated with apparent treatment-resistant hypertension (aTRH) 4:
- 40% of patients with CKD stage 3-4 have aTRH 4
- aTRH prevalence increases with declining eGFR: 22.3% with eGFR >60,39.4% with eGFR 30-60, and 54.2% with eGFR <30 mL/min/1.73 m² 4
- Every 5 mL/min/1.73 m² decrease in eGFR increases odds of aTRH by 14% 4
- Doubling of proteinuria increases aTRH odds by 28% 4
Monitoring Creatinine During Antihypertensive Therapy
Expected Changes with ACE Inhibitors/ARBs
Small increases in serum creatinine (up to 30% from baseline) with ACE inhibitors or ARBs should not prompt medication discontinuation in the absence of volume depletion 4, 8:
- These increases reflect hemodynamic changes, not acute kidney injury 4
- Recheck serum creatinine and potassium within 7-14 days after initiating therapy 5
- In the ACCORD BP trial, participants with up to 30% creatinine increase had no increased mortality or progressive kidney disease 4
When to Discontinue Therapy
Discontinue ACE inhibitors/ARBs if 8:
- Serum creatinine exceeds 3 mg/dL 8
- Creatinine doubles from pretreatment value 8
- Acute kidney injury develops (50% sustained increase over short period) 4
Monitoring Schedule
- Annual measurement of serum creatinine, eGFR, and UACR for all hypertensive patients 5
- If moderate-to-severe CKD (eGFR <60 or UACR ≥30 mg/g), repeat at least annually 5
- Monitor serum potassium periodically in patients with eGFR <60 receiving ACE inhibitors, ARBs, or mineralocorticoid receptor antagonists 4
Nephrology Referral Criteria
Refer to nephrology when 5:
- eGFR <30 mL/min/1.73 m²
- Uncertainty about etiology of kidney disease
- Rapidly progressive kidney disease
- Active urinary sediment suggesting glomerulonephritis
- Difficult management issues arise
Clinical Pitfalls to Avoid
Confounding Factors for Creatinine Interpretation
eGFR formulas are unreliable in patients with extremes of muscle mass 9:
- Low muscle mass (elderly, cachexia) overestimates kidney function
- High muscle mass (athletes, bodybuilders) underestimates kidney function
- Consider cystatin C measurement as an alternative marker unaffected by muscle mass 9
Creatine supplementation falsely elevates serum creatinine without indicating kidney damage 9:
- Supplementation increases creatinine by 0.2-0.3 mg/dL through non-pathologic conversion 9
- This can lead to misdiagnosis of acute kidney injury or CKD 9
- If diagnostic uncertainty exists, discontinue supplementation and recheck in 1-2 weeks 9
Distinguishing Hemodynamic Changes from True Kidney Injury
Do not confuse hemodynamic creatinine increases with acute kidney injury 4:
- Up to 30% increase with RAS blockers is expected and acceptable 4
- Markers of tubular injury (NGAL, KIM-1) remain normal with hemodynamic changes 4
- True AKI requires 50% sustained increase over short period 4
Summary Algorithm for Clinical Practice
- Measure baseline CK in all hypertensive patients to identify those at high risk for treatment failure 1
- Assess kidney function with serum creatinine, eGFR (CKD-EPI), and UACR in all hypertensive patients 5
- Recognize that high-normal creatinine predicts cardiovascular events even within reference range 6
- Expect and tolerate up to 30% creatinine increase when initiating ACE inhibitors/ARBs 4
- Monitor annually and more frequently if CKD present 5
- Refer to nephrology if eGFR <30 or other concerning features 5