Evaluation of Microbial and Endocrinological Parameters in Dialysis Patients With Sepsis

Chronic kidney disease (CKD) is a major global public health challenge, affecting millions of individuals worldwide. A significant proportion of these patients progress to end-stage kidney disease (ESKD), necessitating renal replacement therapies such as hemodialysis (HD). Beyond the gradual decline in renal function, CKD is associated with a high burden of comorbidities, particularly cardiovascular disease (CVD) and infections .Patients with CKD undergoing hemodialysis are especially vulnerable to infections, which represent a major contributor to morbidity and mortality in this population. This increased susceptibility is largely attributable to secondary immunodeficiency associated with kidney disease (SIDKD), the repeated need for vascular access, and the presence of multiple coexisting conditions.

Vascular access through catheters, grafts, or fistulas is essential for dialysis treatment. According to the 2023 USRDS report, in 2021, over 85% of individuals who began hemodialysis initiated treatment using a central venous catheter (CVC). Patients undergoing hemodialysis with a central venous catheter (CVC) are at increased risk for catheter-related bloodstream infections (CRBSIs), which are associated with significant morbidity, including a higher incidence of cardiovascular events, increased mortality, and substantial healthcare costs.6-10 The incidence of catheter-related infections has been reported to range from 1.1 to 5.5 episodes per 1,000 CVC days.

A retrospective study reported a median time of 163 days to the first episode of CRBSI.13 Several studies have identified a range of risk factors associated with CRBSI in hemodialysis patients. These include diabetes mellitus, age under 75 years, prolonged use of tunneled or implanted catheters, immunosuppressive therapy, colonization with methicillin-resistant Staphylococcus aureus (MRSA), and a history of bacteremia or bacteriuria within three months prior to catheter insertion. Additional factors include dialysis vintage, the site of catheter placement, number of catheterizations and abnormal laboratory parameters such as low albumin, elevated C-reactive protein (CRP), and reduced hemoglobin levels.

Diagnosis of CRBSI is challenging, as not all bacteremia in dialysis patients originates from catheters.

Diagnosis requires at least 1 positive blood culture from a peripheral source (dialysis circuit or vein) and no other apparent source, with either positive semiquantitative (\>15 CFU/ catheter segment, hub or tip) or quantitative (\>102 CFU/catheter segment, eg, hub or tip) culture, whereby the same organism (species and antibiogram) is isolated from the catheter segment (eg, hub or tip) and a peripheral source (dialysis circuit or vein) blood sample. If available, the following would be supportive: Simultaneous quantitative cultures of blood samples with a ratio of ≥3:1 (catheter hub/tip vs peripheral \[dialysis circuit/vein\]); differential period of catheter culture versus peripheral BC positivity of 2 hours. According to the Centers for Disease Control and Prevention (CDC), a compatible clinical presentation, along with at least one positive peripheral blood culture and no other identifiable source of infection, combined with growth of the same organism from a tunneled catheter tip, either positive semiquantitative culture (\>15 CFU/catheter segment) or quantitative culture (\>10³ CFU/catheter segment), supports the diagnosis of a catheter-related infection.

However, peripheral venous access is often limited in dialysis patients due to the need to preserve veins for future vascular access creation. Due to the challenges associated with obtaining peripheral venous blood samples, a study conducted in Canada compared the results of peripheral blood cultures to cultures taken from tunneled catheters and from the dialysis machine during treatment. This study demonstrated that blood cultures drawn from the dialysis circuit during treatment had higher sensitivity and specificity for detecting catheter-related bloodstream infections compared to peripheral blood cultures. Despite these findings, current guidelines for evaluating catheter-related bloodstream infections have not changed, and there is still a recommendation to obtain catheter hub/tip vs peripheral \[dialysis circuit/vein\]).

Parathyroid hormone (PTH) may influence immune function, yet data on PTH fluctuations during infections in dialysis patients are limited. Studies suggest low PTH levels are associated with recurrent infections and increased mortality.

Fluctuations in parathyroid hormone (PTH) levels during infection may be driven by elevated levels of pro-inflammatory cytokines such as IL-6 and IL-1β, which upregulate the expression of calcium-sensing receptors (CaSR) on the parathyroid gland, thereby leading to suppressed PTH secretion.

In critically ill patients, including those with septic shock or extensive burns, hypocalcemia has been frequently observed. This phenomenon may be partially explained by the presence of high extracellular calcium concentrations in necrotic tissues, which can stimulate pro-inflammatory cytokine release and activate the CaSR, contributing to inflammation-induced hypocalcemia. Notably, CaSR has been proposed to function as a chemokine-like receptor, promoting inflammatory responses and cytokine recruitment.

In addition to its role in calcium-phosphate homeostasis, PTH is known to modulate immune function. Elevated PTH levels promote T-lymphocyte proliferation and IL-2 secretion, whereas suppressed PTH levels-particularly below 65 pg/mL-have been associated with reduced CD4/CD8 ratios and increased susceptibility to infections in dialysis patients.

Moreover, low PTH levels have been linked to malnutrition and the development of malnutrition-inflammation complex syndrome (MICS), a condition commonly observed in the dialysis population.

Despite the biological rationale outlined above, it remains unclear whether PTH levels fluctuate during infection and whether such changes carry prognostic significance. A clinical observation in the dialysis unit at the Galilee Medical Center led to the hypothesis that PTH levels decrease during episodes of sepsis.

This study aims to characterize whether a significant decline in PTH levels occurs during sepsis, while simultaneously evaluating additional metabolic parameters such as white blood cell count, hemoglobin, platelets, calcium, phosphate, albumin, and CRP. Furthermore, we plan to assess the rate of PTH recovery following clinical resolution of infection and explore its potential association with clinical outcomes, including recurrent infections, cardiovascular morbidity, and mortality.

Research Hypothesis:

1. In hemodialysis patients with catheter-related bloodstream infections, blood cultures drawn from the dialysis machine are expected to detect infection as effectively, or possibly more effectively, than peripheral venous blood cultures. 2. Changes in parathyroid hormone (PTH) levels may indicate an increased risk of mortality, potentially informing treatment adjustments and monitoring strategies in dialysis patients with acute infections.

Study Objectives:

1. To compare the diagnostic yield of blood cultures obtained from three different sources in hemodialysis patients:

* Central venous catheter (CVC), * Dialysis machine (during treatment), * Peripheral vein. 2. To measure PTH levels during sepsis and compare them to baseline pre-infection levels, with serial follow-up of PTH values post-recovery. 3. To assess clinical outcomes including infectious and cardiovascular complications, and mortality, in correlation with PTH levels in patients experiencing sepsis.

• Rate of Recurrent Infections Within 90 Days of Hospital Discharge [Срок оценки: 90 days post-discharge]
• Incidence of Cardiovascular Events Within 90 Days of Hospital Discharge [Срок оценки: 90 days post-discharge]
• All-Cause Mortality Within 180 Days of Hospital Discharge. [Срок оценки: 180 days post-discharge]