Endotoxin, Neutrophil Function and Albumin in Renal Insufficiency

NCT01362569 | Completed DMC

• 1 other identifier: P23532
• Study Type: observational
• Target: 239
• Locations: 1 country
• Sites: 1

Brief Summary

Chronic kidney disease is widespread in the western world with bacterial infection and sepsis as common complication. It has been shown that innate immune defence, represented by dysfunction of neutrophil granulocytes, is impaired in chronic kidney disease. Another impact of chronic kidney disease on innate immunity is the chronic activation of neutrophils leading to high levels of inflammatory cytokines, thus contributing to protein oxidation. Oxidation of human serum albumin (HSA), the major plasma protein, occurs in chronic kidney disease and leads to further activation of neutrophils. Another important impact of HSA oxidation is the decrease of its binding capacity leading to impaired detoxification ability of albumin. This includes reduced clearance of endotoxin, a major component of the gram negative bacterial cell wall. Circulating endotoxin is recognized by complex formation with lipopolysaccharide binding protein (LBP) followed by binding to CD14 and toll-like receptor (TLR) 4. High systemic endotoxin levels occur in chronic kidney disease and may be the result of decreased clearance ability of HSA and increased gut permeability in combination with intestinal bacterial overgrowth. High systemic endotoxin is associated with worse outcome in several diseases and could be used as predictor for mortality in chronic kidney disease patients. Endotoxemia in renal insufficiency leads to impaired neutrophil function and to increased albumin oxidation. Oxidized albumin is not able to bind endotoxin adequately any more, which leads to a further increase in oxidative stress and neutrophil dysfunction, resulting in a vicious cycle. 195 patients with renal dysfunction will be enrolled and divided into 5 groups. Additionally, samples of 25 age and sex-matched healthy controls will be collected. This concept will change the understanding of several aspects of chronic kidney disease and will potentially help to stratify patients into different groups at risk according to their endotoxin status, and their immune and albumin dysfunction. The results of this study will have important implications into the development of novel therapeutic strategies

Conditions

Chronic Renal Insufficiency; Acute Renal Failure

Keywords

endotoxin; neutrophil function; albumin function

Outcome Measures

Primary Outcomes (1)

• Endotoxin levels (EU/ml and qualitative positive/negative)

  Percentage of patients with measurable endotoxin serum levels in each group.

  Day 0

Secondary Outcomes (2)

• albumin oxidation (%), albumin binding capacity (ratio), neutrophil function (%),

  Day 0

• microbiome composition

  Day 0

Study Arms (6)

predialytic renal insufficiency

Patents without renal replacement therapy

hemodialysis/hemofiltration patients

patients undergoing regular hemodialysis/hemofiltration

peritoneal dialysis patients

patients undergoing peritoneal dialysis

acute renal failure

patients with acute renal failure

post renal transplantation

patients after renal transplantation

healthy controls

control group

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

1. 50 predialytic patients (a) 25 patients with an eGFR between 30 and 45 (KDIGO 3B) and (b) 25 patients with an eGFR between 15 and 30 (KDIGO 4) 2. 50 patients undergoing hemodialysis or hemodiafiltration for ESRD (a) 25 patients under therapy with sevelamer and (b) 25 patients without sevelamer 3. (a) 25 patients undergoing peritoneal dialysis for ESRD without signs of infection and (b) 25 patients undergoing peritoneal dialysis for ESRD with peritonitis 4. 25 patients with acute renal failure 5. 45 patients after kidney transplantation (a) 15 patients with an eGFR \> 45, (b) 15 patients with an eGFR between 30 and 45 and (c) 15 patients with an eGFR \< 30 6. 25 age and sex-matched healthy controls

You may qualify if:

• Age between 18-80 years, informed consent Groups 1a, 1b, 2a, 2b, 3a, 3b Patients with chronic kidney disease as defined previously \[65\] either
• a) with an eGFR between 30 and 45 (KDIGO 3B)
• b) with an eGFR between 15 and 30 (KDIGO 4)
• a) undergoing hemodialysis for ESRD
• b) undergoing hemodiafiltration for ESRD
• a) undergoing peritoneal dialysis for ESRD without signs of infection
• b) undergoing peritoneal dialysis for ESRD with peritonitis ≥2 out of the 4 criteria (\>100 leucocytes/50%neutrophils, cloudy peritoneal dialysate, typical clinical presentation with fever and abdominal pain, positive culture from the peritoneal dialysate)
• Group 4 Patients with acute kidney injury (AKIN 3 \[66\] defined as an increase in serum creatinine to 300% (3-fold) from baseline or serum creatinine 4.0 mg/dl with an acute rise of at least 0.5mg/dl or urine output of \< 0.3ml/kg/h 24h or anuria 12h) Initiation of acute renal replacement therapy
• Group 5 Stable patients after kidney transplantation with either an eGFR \> 45, between 30 and 45 or \< 30
• Group 6: Healthy controls

You may not qualify if:

• Malignancy, pregnancy,chronic inflammatory bowel disease, celiac disease, active alcohol abuse, any severe organ dysfunction unrelated to renal dysfunction Groups 1a, 1b, 2a, 2b, 3 Organ transplantation Clinical evidence of active infection (except for group 3b) Treatment with antibiotics within the last 2 weeks (except for group 3b)
• Group 4 Preexisting ESRD
• Group 5 Clinical evidence of active infection Treatment with antibiotics within the last 2 weeks
• Group 6:
• Any evidence of acute or chronic disease

Sponsors & Collaborators

• Vanessa Stadlbauer-Koellner, MD: lead
• Austrian Science Fund (FWF): collaborator

Study Sites (1)

Department of Internal Medicine

Graz, 8036, Austria

Location

Biospecimen

Retention: SAMPLES WITHOUT DNA

Serum, Plasma, Urine

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Acute Kidney Injury

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Vanessa Stadlbauer, MD

  Medical Univeristy of Graz

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: PD. Dr. med

Study Record Dates

• First Submitted: May 23, 2011
• First Posted: May 30, 2011
• Study Start: July 1, 2011
• Primary Completion: January 1, 2014
• Study Completion: December 1, 2015
• Last Updated: October 11, 2017

Record last verified: 2017-10

Locations

AU (1)