What is the pathophysiology of ulcers in patients undergoing dialysis?

Pathophysiology of Ulcers in Dialysis Patients

Dialysis patients develop ulcers through a complex interplay of uremic toxin accumulation, platelet dysfunction, chronic inflammation, and mucosal injury—creating both increased susceptibility to ulcer formation and impaired healing mechanisms.

Core Pathophysiological Mechanisms

Uremic Toxin-Mediated Mucosal Damage

The accumulation of uremic toxins directly damages the gastroduodenal mucosa through multiple pathways 1, 2. Uremic toxins including indoxyl sulfate, acrolein, indole-3-acetic acid, urea, and p-cresol cause direct cellular damage to the gastrointestinal epithelium 3. These toxins create a state of intoxication affecting multiple organ systems, with the gastrointestinal tract being particularly vulnerable 1.

• The uremic milieu itself contributes to systemic inflammation and endothelial dysfunction that compromises mucosal blood flow and healing capacity 2
• Elevated blood urea nitrogen (BUN) levels, particularly when exceeding 300 mg/mL, correlate with severe gastrointestinal manifestations including mucosal erosions 4
• Uremic toxins alter the gastric mucosal barrier by disrupting tight junctions and reducing protective mucus production 1

Platelet Dysfunction and Coagulopathy

Uremic coagulopathy creates a paradoxical bleeding diathesis that significantly increases ulcer bleeding risk despite concurrent prothrombotic mechanisms 3. This represents a fundamental platelet dysfunction disorder rather than a quantitative abnormality 3.

The specific mechanisms include:

• Altered platelet synthesis with abnormal α-granule composition, impaired calcium mobilization, and dysregulated arachidonic acid metabolism collectively impair platelet function 3
• Defective platelet-vessel wall interactions occur through proteolysis of platelet glycoprotein (GP) Ib receptors and impaired von Willebrand factor binding 3
• Circulating fibrinogen fragments act as competitive inhibitors at the GPIIb/IIIa receptor complex, directly blocking normal aggregation pathways 3
• Coexistent anemia (hematocrit <25%) worsens bleeding through rheological effects by reducing platelet margination toward vessel walls 3

Chronic Inflammatory State

Dialysis patients maintain persistently elevated inflammatory markers that contribute to ulcer pathogenesis 2. Multiple dialysis-related factors including bioincompatible membranes, impure dialysate, back-filtration, clotted access grafts, and persistent infections drive chronic inflammation 2.

• Elevated C-reactive protein (CRP) predicts cardiovascular mortality and reflects ongoing systemic inflammation that impairs mucosal healing 2
• Vascular calcification and oxidative stress, both consequences of chronic inflammation, further compromise gastroduodenal blood flow 2
• The inflammatory milieu suppresses albumin synthesis, potentially impairing mucosal repair mechanisms 2

Dialysis-Specific Factors

Hemodialysis procedures themselves contribute to ulcer risk through hemodynamic instability and mandatory anticoagulation 3. The dialysis process induces significant reductions in cerebral and splanchnic blood flow, creating ischemic conditions in the gastroduodenal mucosa 3.

• Anticoagulation with heparin during hemodialysis transiently exacerbates bleeding from existing ulcers 1, 3
• Regular vascular access procedures create opportunities for bacterial seeding and systemic infection, perpetuating inflammation 2
• Failed kidney grafts in transplant patients returning to dialysis contribute additional inflammatory burden 2

Epidemiological Context

Hemodialysis patients have a 5-10 fold increased risk of peptic ulcer disease compared to the general population 5, 6, 7. The annual incidence of ulcer bleeding is approximately 10-12 times higher in chronic kidney disease patients than in those without kidney disease 7.

• Over 95% of peptic ulcer events in chronic kidney disease patients require hospital management, reflecting disease severity 7
• Maintenance hemodialysis patients are twice as likely to develop gastric ulcers compared to duodenal ulcers, a reversal of the typical pattern 7
• Gastrointestinal symptoms occur in 77% of dialysis patients, with higher prevalence in those dialyzed longer than 6 months 8

Contributing Risk Factors

Medication-Related Mechanisms

Common medications used in chronic kidney disease treatment directly affect ulcer risk 3, 5, 6. NSAIDs, antiplatelet agents (particularly clopidogrel), and corticosteroids significantly increase peptic ulcer risk in dialysis patients 5, 6.

• Interestingly, aspirin use in chronic kidney disease patients does not appear to increase peptic ulcer risk (adjusted OR 0.88), unlike NSAIDs and clopidogrel 7
• Beta-lactam and third-generation cephalosporin antibiotics can directly affect the coagulation pathway 3

Comorbidity Effects

Diabetes mellitus, coronary artery disease, cirrhosis, and history of uncomplicated peptic ulcer disease are independent risk factors for ulcer bleeding in hemodialysis patients 5, 6. These comorbidities likely act synergistically with uremia to impair mucosal defense mechanisms.

Clinical Pitfalls

• Do not assume all gastrointestinal bleeding in dialysis patients is ulcer-related—hiatus hernia is significantly more common in dialysis patients (27% vs 14% in controls) and may contribute to bleeding 8
• Helicobacter pylori prevalence is actually lower in dialysis patients (45% vs 73% in controls), suggesting uremia-related mechanisms predominate over infectious causes 8
• Single measurements of inflammatory markers may be misleading as they fluctuate significantly over time in dialysis patients 2
• The bleeding time should be measured preoperatively, as values >10-15 minutes indicate high hemorrhage risk 1