Can Chronic Kidney Disease (CKD) cause false elevation of Protein Induced by Vitamin K Absence or Antagonist-II (PIVKA-II) levels?

Can CKD Cause False Elevation of PIVKA-II?

Yes, CKD can cause elevated PIVKA-II levels independent of hepatocellular carcinoma, primarily due to vitamin K deficiency and altered vitamin K metabolism that occurs in kidney disease, making PIVKA-II a less specific biomarker for HCC in this population.

Mechanisms of PIVKA-II Elevation in CKD

Vitamin K Deficiency in CKD Patients

• Vitamin K deficiency is highly prevalent in CKD patients, with studies showing abnormal PIVKA-II concentrations in 46.4% of peritoneal dialysis patients, indicating subclinical vitamin K deficiency 1
• CKD patients have significantly altered vitamin K metabolism, with reduced tissue concentrations of phylloquinone (K1) in liver, spleen, and heart tissue 2
• The kidneys play a critical role in vitamin K metabolism, and CKD impacts this process early in the disease course, leading to functional vitamin K deficiency 2

Altered Vitamin K Metabolism and Transport

• CKD profoundly disrupts lipoprotein-mediated vitamin K transport, with dialysis patients incorporating very little menaquinone-7 (MK-7) into HDL and LDL particles compared to healthy individuals 3
• HDL particles from CKD patients demonstrate reduced carboxylation activity (low vitamin K activity) compared to controls, indicating impaired vitamin K function 3
• There is decreased expression of vitamin K recycling (Vkor) and utilization (Ggcx) enzymes in CKD, further compromising vitamin K-dependent protein carboxylation 2

Clinical Correlation with Kidney Function

• PIVKA-II levels correlate positively with creatinine concentrations (r = 0.406, p < 0.032) in peritoneal dialysis patients, suggesting a direct relationship between kidney dysfunction and PIVKA-II elevation 1
• PIVKA-II is weakly associated with aortic calcification in CKD patients, reflecting the broader impact of vitamin K deficiency on vascular health 4

Clinical Implications for HCC Screening

Reduced Specificity in CKD

• PIVKA-II elevation occurs not only in HCC but also in non-HCC individuals with vitamin K deficiency, making it a less specific marker in CKD populations 5
• The baseline elevation of PIVKA-II in CKD patients due to vitamin K deficiency can confound HCC diagnosis and screening efforts 5

Recommended Approach

• Joint detection of PIVKA-II with other biomarkers (such as AFP) significantly improves diagnostic accuracy for HCC in CKD patients, compensating for the reduced specificity 5
• Consider assessing vitamin K status through dietary history, medication review (particularly warfarin, proton pump inhibitors, and statins), and clinical context before attributing elevated PIVKA-II solely to HCC 3
• The highest PIVKA-II levels in dialysis patients were noted when statins were combined with proton pump inhibitors, suggesting medication-induced vitamin K deficiency as an additional confounding factor 3

Common Pitfalls to Avoid

• Do not interpret isolated PIVKA-II elevation as diagnostic of HCC in CKD patients without considering vitamin K status and using complementary biomarkers 5
• Recognize that vitamin K supplementation may have reduced efficacy in CKD patients, particularly for menaquinone-7, due to impaired lipoprotein-mediated transport 3
• Be aware that vitamin K deficiency assessment should become standard procedure in CKD patients, as it affects both cardiovascular and potentially diagnostic outcomes 1