Why are patients with chronic kidney disease (CKD) prone to upper gastrointestinal bleeding (UGIB) and anemia?

Why CKD Patients Are Prone to Upper GI Bleeding and Anemia

Patients with chronic kidney disease face a dual hemostatic crisis: they simultaneously experience increased bleeding risk from uremic platelet dysfunction and multiple sources of blood loss, while developing anemia from decreased erythropoietin production, iron deficiency, and chronic blood losses. 1

Mechanisms of Increased Upper GI Bleeding Risk

Uremic Platelet Dysfunction

CKD creates a pro-hemorrhagic state through multiple platelet abnormalities 1:

• Defective platelet adhesion occurs from proteolysis of GPIb receptors and impaired von Willebrand factor interactions, preventing platelets from adhering to damaged blood vessel walls 1
• Reduced platelet aggregation results from competitive inhibition at the GPIIb/IIIa receptor by circulating fibrinogen fragments present in uremia 1
• Altered platelet synthesis includes decreased production of platelet activating factor and abnormal calcium mobilization 1
• Anemia itself worsens platelet function through indirect mechanisms that further compromise hemostasis 1

Quantified Bleeding Risk

The risk of upper GI bleeding increases progressively as renal function declines 2:

• Stage 3 CKD: 3.7 episodes per 100 patient-years 2
• Stage 4 CKD: 5.0 episodes per 100 patient-years 2
• Stage 5 CKD: 13.9 episodes per 100 patient-years 2
• Each 5 mL/min per 1.73 m² decrease in eGFR increases bleeding risk with a hazard ratio of 1.08 2

Medication-Related Bleeding

Common medications in CKD patients substantially increase bleeding risk 1, 3:

• 61% of CKD patients with anemia are prescribed aspirin 3
• 73% receive NSAIDs 3
• 53% are on both aspirin and NSAIDs simultaneously 3
• 14% take warfarin and 12% take clopidogrel 3
• Beta-lactam and third-generation cephalosporin antibiotics can impair platelet function 1

Occult GI Blood Loss in Dialysis Patients

Hemodialysis patients experience substantial ongoing blood losses 1:

• Occult gut bleeding: 6.27 mL/day (2.2 L/year) compared to 0.83 mL/day in healthy controls, favored by uremic enteropathy, platelet dysfunction, and anticoagulation 1
• Dialysis circuit losses: 165 mL/year from residual blood in tubing 1
• Catheter-related losses: 2.7 L/year for double-lumen catheters from purging protocols 1
• Routine blood sampling: 350-450 mL/year 1
• Total annual blood loss: 2.85 L/year with native fistula, or 5.5 L/year with catheter 1

Mechanisms of Anemia in CKD

Multifactorial Causes

The British Society of Gastroenterology emphasizes that anemia in CKD is multifactorial, with iron deficiency being a major element alongside other mechanisms 1:

• Decreased erythropoietin (EPO) production is the primary mechanism, as failing kidneys cannot produce adequate EPO 1
• Iron deficiency from reduced intake, decreased absorption, and chronic blood losses 1
• Functional iron deficiency where iron stores exist but cannot be mobilized due to inflammation 1
• Hemolysis and plasma cell dyscrasias may contribute 1

Prevalence and Severity

Anemia prevalence increases with declining renal function 1:

• CKD is especially likely to cause anemia when GFR <30 mL/min/1.73 m² 1
• 22.2% of CKD patients have WHO-defined anemia 3
• 8.6% have hemoglobin ≤11 g/dL 3
• Mean hemoglobin is 13.2 g/dL in CKD versus 13.7 g/dL without CKD 3

Iron Deficiency Patterns

Iron deficiency in CKD has distinct characteristics 1:

• Absolute iron deficiency is defined as transferrin saturation ≤20% with ferritin ≤100 μg/L (predialysis/peritoneal dialysis) or ≤200 μg/L (hemodialysis) 1
• 82.7% of patients with microcytic anemia and 58.8% with normocytic anemia (Hb ≤11 g/dL) have low ferritin (<100 μg/L), indicating iron stores are depleted in the majority of normocytic anemia cases 3
• Normocytic anemia predominates: 80.5% with Hb ≤11 g/dL, 72.7% with Hb ≤10 g/dL 3

Clinical Implications and Mortality Risk

Increased Mortality from UGIB

CKD and ESRD patients admitted with primary UGIB have dramatically elevated mortality risk 4:

• CKD patients: OR 1.47 (95% CI 1.21-1.78) for all-cause in-hospital mortality 4
• ESRD patients: OR 3.02 (95% CI 2.23-4.1) for all-cause in-hospital mortality 4
• History of previous UGIB and low serum albumin independently predict higher bleeding risk 2

Comorbidity Burden

CKD patients with anemia have higher rates of cardiovascular disease 3:

• Hypertension: 67.2% versus 54% in non-CKD 3
• Diabetes: 30.7% versus 15.4% in non-CKD 3

Key Clinical Pitfalls

The majority of CKD patients with confirmed iron deficiency anemia warrant GI investigation to exclude treatable pathology, as long as they are fit for procedures 1. However, decisions should be made in conjunction with nephrology 1.

Oral iron supplementation often fails in CKD: 56.3% of CKD patients with anemia had been prescribed oral iron, yet it did not correct their anemia 3. Oral iron is poorly absorbed in CKD and causes significant GI side effects 1.

Medication review is critical before considering erythropoietin or parenteral iron 3, as the high prevalence of antiplatelet and anticoagulant use (53% on both aspirin and NSAIDs) contributes substantially to bleeding risk 3.