Clinical trial NCT02361736: Evaluate the Nephrotoxicity by 6% Hydroxyethyl Starch 130/0.4 in Old Patients During Orthopaedic Surgery
Official title: Evaluate the Nephrotoxicity by 6% Hydroxyethyl Starch 130/0.4 in Old Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Total Fluid Volume Increased
Lead sponsor: Tianjin Medical University General Hospital
Sponsor class: OTHER
Collaborators: name: Tianjin Union Medical Center
name: Tianjin First Central Hospital
First posted: 2015-02-12
Enrollment: 120
Sex: ALL
Minimum age (years): 65
Maximum age (years): 90
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL

Brief summary: Hydroxyethyl starch (HES) is commonly used as plasma expander during surgery but may be nephrotoxic as seen in studies in patients with sepsis. The investigators hypothesized that the possible nephrotoxicity of 6% HES 130/0.4 could be revealed by measurements of urinary and plasma neutrophil gelatinase-associated lipocalin and interleukin-18 (IL-18) in old patients with normal renal function during orthopaedic surgery.

Detailed description: Hydroxyethyl starch (HES) is widely used as volume expander to maintain circulation in patients during surgery, trauma, and in critical disease, where a rapid and sustained volume expansion is the goal. However, acute kidney injury (AKI) is sometimes a complication in these patients and HES might be a contributing factor. Acute kidney injury is often diagnosed using a sudden rise in plasma creatinine (p-crea) or an abrupt decrease in urine output. P-crea depends on sex, nutrition, medication,muscle mass, and age and it increases 24 to 48 h after renal injury, so the diagnosis of AKI is delayed when using p-crea alone as an indicator for renal damage. New technology allows for earlier diagnosis of AKI using measurements of biomarkers in urine. Neutrophil gelatinase-associated lipocalin (NGAL) is a small protein, which is filtered via the glomeruli and reabsorbed in the proximal tubules, and thus low concentrations of NGAL can be measured in the blood and urine. Approximately 6 h after a renal injury, NGAL increases rapidly due to an up-regulated expression and secretion in the epithelial cells of the thick ascending limb of Henle's loop, the distal tubules, and the collecting ducts. Thus, NGAL can be used as a marker of renal damage. However, infections and malignancies can give falsely increased levels.

Interleukin-18 (IL-18) is mainly created from proximal kidney tubules which is a proinflammatory factor that can be detected in earlier urine of AKI animal models. There is significant rise in IL-18 levels in urine of AKI confirmed cases(no chronic kidney disease, no urinary tract infections, no prerenal factors), specificity and susceptibility is 90%. As a result, IL-18 can be selected as a biomarker.

Intravenously administrated HES is excreted in urine but is also partly accumulated in the tissues. Studies in animals and humans showed that HES molecules were accumulated in the proximal tubule cells with subsequent vacuolization and swelling-a condition known as osmotic nephrosis. However, recent studies, primarily conducted in patients with sepsis, found impaired renal function even when using tetrastarch. In contrast, perioperative studies found no evidence of AKI after infusion of HES. The investigators hypothesized that 6% HES 130/0.4 had a nephrotoxic effect, which could be revealed by measurements of urinary and plasma NGAL and IL-18; that 6% HES 130/0.4 influenced kidney function differently than crystalloids(lactated Ringer's solution) due to the different pharmacokinetic properties of colloids compared with that of crystalloids.

Eligibility criteria: Inclusion Criteria:

* Old patients scheduled to undergo orthopaedic surgery under a intravertebral anesthesia. (American Society of Anesthesiologists physical status I-Ⅲ)

Exclusion Criteria:

* Allergy and contraindication to HES
* Infections and malignancies
* Sepsis
* History of heart failure or New York Heart Association(NYHA)\>Ⅲ
* Renal failure or Cr\>108μmol/L，BUN\>8.3mmol/L
* Undergoing dialytic treatments
* Intracranial hemorrhages
* Taking non-steroidal antiinflammatory agent for a long time
* Inability to understand the Study Information Sheet and provide a written consent to take part in the study

Primary outcomes:
measure: Concentration of NGAL in Urine on 5 Time Point
timeFrame: -1d, 0d, 1d, 3d, 5d after surgery
measure: Concentration of IL-18 in Urine on 5 Time Point
timeFrame: -1d, 0d, 1d, 3d, 5d after surgery
measure: Concentration of IL-18 in Plasma on 5 Time Point
timeFrame: -1d, 0d, 1d, 3d, 5d after surgery
measure: Concentration of NGAL in Plasma on 5 Time Point.
timeFrame: -1d, 0d, 1d, 3d, 5d after surgery
Secondary outcomes:
measure: Concentration of β2 Microglobulin in Urine
timeFrame: -1d, 0d, 1d, 3d, 5d after surgery
measure: Estimated Glomerular Filtration Rate(eGFR) on 5 Time Point
timeFrame: -1d, 0d, 1d, 3d, 5d after surgery
measure: Ratio of the Urine Trace Albumin and Creatinine(ACR) on 5 Time Point
timeFrame: -1d, 0d, 1d, 3d, 5d after surgery
Other outcomes:
Locations:
city: Tianjin
country: China
facility: Tianjin Medical University General Hospital
state: Tianjin
Study officials:
affiliation: Tianjin Medical University General Hospital
name: Yu Yonghao, M.D.,Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zhang Y, Yu Y, Jia J, Yu W, Xu R, Geng L, Wei Y. Administration of HES in elderly patients undergoing hip arthroplasty under spinal anesthesia is not associated with an increase in renal injury. BMC Anesthesiol. 2017 Feb 21;17(1):29. doi: 10.1186/s12871-017-0320-8.