Oxidative Stress and Circulating Nuclear DNA (cfDNA) in Acute Kidney Injury and Continuous Renal Replacement Therapies.
- Conditions
- Acute Kidney Injury
- Interventions
- Procedure: Central venous accessDevice: Pump-assisted circuitOther: Regional citrate anticoagulationProcedure: Blood and ultrafiltrate samples
- Registration Number
- NCT06646328
- Lead Sponsor
- Fernando Sanchez
- Brief Summary
Acute kidney injury (AKI) is the inability of the kidneys to perform their functions of purifying and cleaning the blood. It is a frequent complication in hospitalized patients, especially in those admitted to the ICUs. In these situations is common to use machines to artificially and temporarily replace renal function so waste products that can be toxic are removed from the body.
The purpose of this study is to assess the effectiveness and safety of two anticoagulation strategies of the extracorporeal purification system in critically ill patients with acute kidney injury treated with continuous renal replacement therapy (CRRT) evaluating the effect of both strategies in oxidative stress and extracellular nucleosomes and its influence on the recovery of renal function.
- Detailed Description
Acute kidney injury (AKI) is defined as a sudden deterioration of renal function that causes loss of electrolyte control, acid base status and fluid balance, with subsequent accumulation of nitrogenous waste products that should be eliminated by the kidney. It is a frequent complication in hospitalized patients, especially those admitted to Intensive Care Units (ICUs). Its etiology is usually multifactorial, usually in the context of multiorgan dysfunction syndrome (MODS). The epidemiology and risk factors associated with its development, as well as the type of treatment that these patients are currently undergoing, continues to be the subject of debate, given the impact it has on morbidity and mortality.
To temporary substitute renal function in critically ill patients continuous renal replacement therapies (CRRT) are frequently used. The classification and nomenclature of techniques depends on the duration, continuity and operational characteristics of the treatment system. Thus, we distinguish between continuous techniques and intermittent techniques. Peritoneal dialysis (PD) is rarely used in developed countries for the treatment of AKI in ICU. Intermittent hemodialysis (IHD) is the most frequently used technique, although its use in ICU has considerable limitations on fluid balance, uremia control and elimination of medium molecular weight molecules.
Due to the enormous difficulty of obtaining studies with the necessary statistical power to provide the degree of evidence needed to clarify questions regarding the indications, modalities and other technical aspects of the CRRT, it is commonly used the experience that both the clinical practice in chronic patients as the results of scientific research that intermittent techniques (IHD fundamentally) confers to the clinician.
In patients with IHD, certain conditions are associated with a worse prognosis and an increased risk of mortality. These can include cardiovascular diseases, diabetes mellitus (DM), atherosclerosis, infectious processes, malnutrition, inflammation, oxidative stress, iron deficiency, anemia, calcification, uremia and volume overload. AKI requiring a renal replacement technique (RRT) represents an independent risk factor for mortality in critically ill patients. Oxidative stress and inflammation play important roles in the initiation and extension phases of AKI, as well as in causing injury to distant organs after AKI.
In CRRT to prevent coagulation of the extracorporeal system requires the use of some method of anticoagulation. The most frequent anticoagulation strategies include systemic heparin and regional citrate administration. However, some undesirable effects of CRRT may affect the patient's outcome, including the risks of systemic bleeding and membrane biocompatibility induced by anticoagulants.
Heparin, the most widely used anticoagulant in these techniques, is considered the standard of treatment, however it is contraindicated in patients with a high hemorrhagic risk or in heparin-induced thrombocytopenia.
Regional citrate anticoagulation (RCA), in which only the extracorporeal circuit is anticoagulated by the chelating action of calcium by citrate, is a safe and effective alternative in these cases. RCA has also been described as superior to heparin in terms of biocompatibility, since heparin, in comparison with citrate, can activate the complement and induce neutrophil degranulation in the filter and activate the release of myeloperoxidase (MPO) from the endothelium. The use of citrate, in addition to providing greater biocompatibility and a similar or longer filter duration, could also be associated with less inflammation and possibly with a better survival compared to heparin use, and probably also with a better renal recovery.
Apoptosis is probably implicated as a pathophysiological mechanism in organ injury in the setting of sepsis and systemic inflammatory response syndrome.
The sum effect of the numerous risk factors present in critical patients with AKI treated with CRRT is cumulative, additive, interrelated, complex and often unexpected or completely unknown. Survival in patients with AKI requiring replacement therapy is lower than in other patient populations. At present the accuracy of prediction of mortality and morbidity depending on available biomarkers or clinical condition is not optimal to properly describe and stratify patients properly. The combination of several markers of simultaneous biochemical processes can help to better stratify patients, identify the best therapeutic targets, evaluate the response to different therapies and establish functional prognoses. The usefulness of a parameter that evaluates tissue damage with markers of specific biochemical processes could be considered.
The present randomized, controlled, parallel-group, single centre study aims to evaluate the biocompatibility of two strategies of anticoagulation of the extracorporeal system (RCA and heparin) by using markers of inflammation, oxidative stress and cellular damage and its repercussion in the recovery of renal function. In this setting it would be possible to establish functional prognoses in terms of renal function recovery and to better identify which strategy is most beneficial for each group of patients.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 20
- Adult intensive care patients (age > 18) admitted to the ICU with AKI requiring treatment with continuous renal replacement technique.
- Patients able to accept being included in the study by signing the Informed Consent (IC). If the patient can not give consent, family consent is requested and, by default, the opinion of the person of trust or designated decision, if present. If there is no family present, trusted person or legal representative designated, the possibility of deferred consent is not contemplated. In this case the patient will not be included in the study.
- Age under 18 years old.
- Pregnancy and/or lactation.
- Terminal diseases or life expectancy lower than 48 hours.
- Increased risk of bleeding (defined as platelet count less than 40x109 / L, partial thromboplastin time (TTPA) over 60 seconds, prothrombin time (PT)international normalized ratio (INR) greater than 2.0 or recent major bleeding).
- Need of systemic anticoagulation therapy.
- Contraindication for heparin.
- Heparin-induced Thrombocytopenia (HIT).
- Dialysis in the 24 hours prior to inclusion.
- Hypercalcemia (> 3 mmol / L).
- Severe Hepatitis: glutamic oxaloacetic transaminase (GOT) or glutamic pyruvic transaminase (GPT) > 1000 IU / L.
- Cirrhosis.
- Inclusion in another research protocol.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Heparin Central venous access Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein. The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the heparin arm the anticoagulation technique to be used will be non-fractional heparin. Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration \[Ci\]) and postfilter (outlet filter plasma concentration \[Co\]) sites of the extracorporeal circulation circuit at different times. Heparin Pump-assisted circuit Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein. The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the heparin arm the anticoagulation technique to be used will be non-fractional heparin. Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration \[Ci\]) and postfilter (outlet filter plasma concentration \[Co\]) sites of the extracorporeal circulation circuit at different times. Heparin Heparin sodium Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein. The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the heparin arm the anticoagulation technique to be used will be non-fractional heparin. Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration \[Ci\]) and postfilter (outlet filter plasma concentration \[Co\]) sites of the extracorporeal circulation circuit at different times. Heparin Blood and ultrafiltrate samples Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein. The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the heparin arm the anticoagulation technique to be used will be non-fractional heparin. Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration \[Ci\]) and postfilter (outlet filter plasma concentration \[Co\]) sites of the extracorporeal circulation circuit at different times. Citrate Central venous access Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein. The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the citrate arm regional citrate anticoagulation of the extracorporeal purification system will be used to avoid coagulation of the circuit. Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration \[Ci\]) and postfilter (outlet filter plasma concentration \[Co\]) sites of the extracorporeal circulation circuit at different times. Citrate Pump-assisted circuit Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein. The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the citrate arm regional citrate anticoagulation of the extracorporeal purification system will be used to avoid coagulation of the circuit. Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration \[Ci\]) and postfilter (outlet filter plasma concentration \[Co\]) sites of the extracorporeal circulation circuit at different times. Citrate Regional citrate anticoagulation Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein. The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the citrate arm regional citrate anticoagulation of the extracorporeal purification system will be used to avoid coagulation of the circuit. Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration \[Ci\]) and postfilter (outlet filter plasma concentration \[Co\]) sites of the extracorporeal circulation circuit at different times. Citrate Blood and ultrafiltrate samples Central venous access will be achieved with a 13 Fr double lumen catheter placed into the internal jugular or femoral vein. The patient will be connected to the Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany) pump-assisted circuit with a high-flux synthetic membrane. In the citrate arm regional citrate anticoagulation of the extracorporeal purification system will be used to avoid coagulation of the circuit. Blood and ultrafiltrate samples will be taken from the prefilter (inlet filter plasma concentration \[Ci\]) and postfilter (outlet filter plasma concentration \[Co\]) sites of the extracorporeal circulation circuit at different times.
- Primary Outcome Measures
Name Time Method Recovery of renal function Through study completion, an average of 20 days. Impact of circulating nuclear DNA (cfDNA) and oxidative stress on change of Creatinine from baseline to hospital discharge.
- Secondary Outcome Measures
Name Time Method Length of stay From hospital admission until the date of documented hospital discharge or date of death from any cause, whichever came first, assessed up to 90 days Length of stay in hospital
Mortality Day 90 after ICU admission Hospital mortality
Mass transfer and clearance of biomarkers of cell damage 24 hours Changes in plasma concentration of circulating nuclear DNA (cfDNA) from before to after the passage of blood through the filter
Activation and elimination of free radicals 24 hours Changes in plasma concentration of glutathione disulfide (GSSG) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
Activation and elimination of biomarkers of inflammation 24 hours Changes in plasma concentration of c-reactive protein (CRP) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
Activation and elimination of biomarkers of cell damage 24 hours Changes in plasma concentration of circulating nuclear DNA (cfDNA) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
Mass transfer and clearance of free radicals 24 hours Changes in plasma concentration of glutathione disulfide (GSSG) from before to after the passage of blood through the filter
Mass transfer and clearance of biomarkers of inflammation 24 hours Changes in plasma concentration of c-reactive protein (CRP) from before to after the passage of blood through the filter
Trial Locations
- Locations (1)
Fernando Sánchez
🇪🇸Castellón De La Plana, Castellon, Spain