Acute Kidney InjuryPhase 4NCT06646328
Oxidative Stress and Circulating Nuclear DNA (cfDNA) in Acute Kidney Injury and Continuous Renal Replacement Therapies.
A Phase 4 study testing Central venous access, Pump-assisted circuit and Heparin sodium in people with Acute Kidney Injury, run by Fernando Sanchez at 1 site in Spain.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Kidney Injury
- What is being tested?
- Central venous access, Pump-assisted circuit and Heparin sodium
- Type of treatment
- Injection or infusion, Medical device, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteSpain
- Study dates
- 9 Jun 2018to 30 Apr 2021
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 11Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Oxidative Stress and Circulating Nuclear DNA (cfDNA) in Acute Kidney Injury and Continuous Renal Replacement Therapies. Effect of Two Anticoagulation Strategies of the Extracorporeal Purification System in Renal Function Recovery.
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.
Read the 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.
- Conditions
- Acute Kidney Injury
- Being tested
- Central venous access, Pump-assisted circuit, Heparin sodium, Regional citrate anticoagulation, Blood and ultrafiltrate samples
- Keywords
- Biocompatibility, Renal replacement therapies, Oxidative stress, Myeloperoxidase, Nucleosomes, Regional citrate anticoagulation, Heparin
- Medical subject headings
- Acute Kidney Injury
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Central venous accessProcedure or surgery
Venous access will be achieved with a 13 Fr double lumen catheter into the internal jugular or femoral vein.
Pump-assisted circuitDevice
Also called Continuous renal replacement therapy, CRRT
The pump-assisted circuit to be used will be Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany). EMIC2® Fresenius Medical Care high-flux synthetic membrane will be used
Heparin sodiumDrug
Also called Non-fractional heparin, Heparin
Non-fractional heparin will be used in one arm with an initial dose of 500-1000 IU/hour with adaptation of the infusion to the patient and the clotting time.
Regional citrate anticoagulationOther
Regional citrate anticoagulation will be used in the other arm with an initial dose of 3 mmol/L and with a calcium reinfusion solution at an initial dose of 2 mmol/L, with adaptation of both infusions to the patient ionic calcium levels.
Blood and ultrafiltrate samplesProcedure or surgery
Blood 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. The ultrafiltrate will be collected directly from the outlet of the hemofilter (ultrafiltrate concentration [Cuf]).
The samples will taken at the beginning of CRRT (T0) and at the following times: T0, Ci; after 60 min (T1) and after 24 hours (T2) of CRRT, Ci, Co and Cuf.
Venous access will be achieved with a 13 Fr double lumen catheter into the internal jugular or femoral vein.
| Study group | Role | What they receive |
|---|---|---|
| Heparin | Active comparator | 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. Receives: Procedure: Central venous access; Device: Pump-assisted circuit; Drug: Heparin sodium; Procedure: Blood and ultrafiltrate samples |
| Citrate | Experimental | 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. Receives: Procedure: Central venous access; Device: Pump-assisted circuit; Other: Regional citrate anticoagulation; Procedure: Blood and ultrafiltrate samples |
What is being measured
The primary outcome is the main question the study is designed to answer.
Recovery of renal function
Impact of circulating nuclear DNA (cfDNA) and oxidative stress on duration of renal replacement therapy (RRT) in ICU.
Measured: Through study completion, an average of 20 days.
Recovery of renal function
Impact of circulating nuclear DNA (cfDNA) and oxidative stress on change of Creatinine from baseline to ICU discharge.
Measured: Through study completion, an average of 20 days.
Recovery of renal function
Impact of circulating nuclear DNA (cfDNA) and oxidative stress on change of Creatinine from baseline to hospital discharge.
Measured: Through study completion, an average of 20 days.
Secondary outcomes (14)
Activation and elimination of free radicals
Changes in plasma concentration of glutathione (GSH) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
Measured: 24 hours
Activation and elimination of free radicals
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.
Measured: 24 hours
Activation and elimination of biomarkers of inflammation
Changes in plasma concentration of mieloperoxidase (MPO) from baseline (before the initiation of the therapy) to 24 hours after de initiation of the therapy.
Measured: 24 hours
Activation and elimination of biomarkers of inflammation
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.
Measured: 24 hours
Activation and elimination of biomarkers of cell damage
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.
Measured: 24 hours
Mass transfer and clearance of free radicals
Changes in plasma concentration of glutathione (GSH) from before to after the passage of blood through the filter
Measured: 24 hours
Mass transfer and clearance of free radicals
Changes in plasma concentration of glutathione disulfide (GSSG) from before to after the passage of blood through the filter
Measured: 24 hours
Mass transfer and clearance of biomarkers of inflammation
Changes in plasma concentration of mieloperoxidase (MPO) from before to after the passage of blood through the filter
Measured: 24 hours
Mass transfer and clearance of biomarkers of inflammation
Changes in plasma concentration of c-reactive protein (CRP) from before to after the passage of blood through the filter
Measured: 24 hours
Mass transfer and clearance of biomarkers of cell damage
Changes in plasma concentration of circulating nuclear DNA (cfDNA) from before to after the passage of blood through the filter
Measured: 24 hours
Length of stay
Length of stay in ICU
Measured: From ICU admission until the date of ICU discharge or date of death from any cause, whichever came first, assessed up to 90 days
Length of stay
Length of stay in hospital
Measured: 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
Mortality
ICU mortality
Measured: Through study completion, an average of 20 days.
Mortality
Hospital mortality
Measured: Day 90 after ICU admission
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Oct 2024
- Study start9 Jun 2018
- Primary completion30 Apr 2021
- Study completion30 Apr 2021
Why it stopped: Enrollment slower than anticipated and interrupted by COVID-19 pandemic
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (59)Papers the sponsor has linked to this study.
- Other trials for Acute Kidney InjuryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Fernando Sanchez
- Sponsor type
- University, hospital or other
- Collaborators
- Hospital Universitario de la Plana, Hospital General Universitario de Castellón
- Responsible party
- Sponsor-investigator, Fernando Sanchez, Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana
- Investigators
- Fernando Sanchez, MD, Study chair, La Plana Health Department. Valencian Health CounselingFernando Sanchez, MD, Study director, La Plana Health Department. Valencian Health CounselingFernando Sanchez, MD, Principal investigator, La Plana Health Department. Valencian Health Counseling
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06646328
- Sponsor's protocol ID
- FER-CIT-2016-01
- Other IDs
- 2016-004361-12, 2016
- Status last verified
- Oct 2024
- First submitted
- 31 Jul 2018
- Last updated
- 18 Oct 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Hetzel GR, Schmitz M, Wissing H, Ries W, Schott G, Heering PJ, Isgro F, Kribben A, Himmele R, Grabensee B, Rump LC. Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial. Nephrol Dial Transplant. 2011 Jan;26(1):232-9. doi: 10.1093/ndt/gfq575. Epub 2010 Sep 27.
PubMed 20876598Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004 Aug;8(4):R204-12. doi: 10.1186/cc2872. Epub 2004 May 24.
PubMed 15312219Mehta RL, Chertow GM. Acute renal failure definitions and classification: time for change? J Am Soc Nephrol. 2003 Aug;14(8):2178-87. doi: 10.1097/01.asn.0000079042.13465.1a. No abstract available.
PubMed 12874474Herrera-Gutierrez ME, Seller-Perez G, Maynar-Moliner J, Sanchez-Izquierdo-Riera JA; Grupo de trabajo "Estado actual del fracaso renal agudo y de las tecnicas de reemplazo renal en UCI. Estudio FRAMI". [Epidemiology of acute kidney failure in Spanish ICU. Multicenter prospective study FRAMI]. Med Intensiva. 2006 Aug-Sep;30(6):260-7. doi: 10.1016/s0210-5691(06)74522-3. Spanish.
PubMed 16949000Liaño F, Candela A, Tenorio MT, Rodríguez-Palomares JR. La IRA en la UCI: Concepto, clasificaciones funcionales, epidemiología, biomarcadores, diagnóstico diferencial y pronóstico. En: Poch E, Liaño F, Gaínza F, eds. Manejo de la disfunción aguda del riñón del paciente crítico en la práctica clínica (primera ed.). Madrid: Ergon; 2011. pp. 1-21.
Behrend T, Miller SB. Acute renal failure in the cardiac care unit: etiologies, outcomes, and prognostic factors. Kidney Int. 1999 Jul;56(1):238-43. doi: 10.1046/j.1523-1755.1999.00522.x.
PubMed 10411698Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005 Aug 17;294(7):813-8. doi: 10.1001/jama.294.7.813.
PubMed 16106006Bellomo R, Ronco C, Mehta R. Nomenclature for continuous renal replacement therapies. Am J Kidney Dis. 1996;28(suppl 3):S2-S7.
Liao Z, Zhang W, Hardy PA, Poh CK, Huang Z, Kraus MA, Clark WR, Gao D. Kinetic comparison of different acute dialysis therapies. Artif Organs. 2003 Sep;27(9):802-7. doi: 10.1046/j.1525-1594.2003.07282.x.
PubMed 12940902Alvestrand A, Ledebo I, Hagerman I, Wingren K, Mattsson E, Qureshi AR, Gutierrez A. Left ventricular hypertrophy in incident dialysis patients randomized to treatment with hemofiltration or hemodialysis: results from the ProFil study. Blood Purif. 2011;32(1):21-9. doi: 10.1159/000323140. Epub 2011 Jan 21.
PubMed 21252503Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998 Apr;31(4):607-17. doi: 10.1053/ajkd.1998.v31.pm9531176.
PubMed 9531176Degoulet P, Legrain M, Reach I, Aime F, Devries C, Rojas P, Jacobs C. Mortality risk factors in patients treated by chronic hemodialysis. Report of the Diaphane collaborative study. Nephron. 1982;31(2):103-10. doi: 10.1159/000182627.
PubMed 7121651Lonnemann G. Chronic inflammation in hemodialysis: the role of contaminated dialysate. Blood Purif. 2000;18(3):214-23. doi: 10.1159/000014420.
PubMed 10859424Panichi V, Rosati A, Bigazzi R, Paoletti S, Mantuano E, Beati S, Marchetti V, Bernabini G, Grazi G, Rizza GM, Migliori M, Giusti R, Lippi A, Casani A, Barsotti G, Tetta C; RISCAVID Study Group. Anaemia and resistance to erythropoiesis-stimulating agents as prognostic factors in haemodialysis patients: results from the RISCAVID study. Nephrol Dial Transplant. 2011 Aug;26(8):2641-8. doi: 10.1093/ndt/gfq802. Epub 2011 Feb 16.
PubMed 21325348Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, Le Gall JR, Druml W. Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med. 2002 Sep;30(9):2051-8. doi: 10.1097/00003246-200209000-00016.
PubMed 12352040
Study at a glance
From the registry record, last updated by the sponsor on 18 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Oxidative Stress and Circulating Nuclear DNA (cfDNA) in Acute Kidney Injury and Continuous Renal Replacement Therapies. Effect of Two Anticoagulation Strategies of the Extracorporeal Purification System in Renal Function Recovery.
- ClinicalTrials.gov ID
- NCT06646328
- Acronym / sponsor ID
- FER-CIT-2016-01
- Conditions
- Acute Kidney Injury
- Keywords
- Biocompatibility, Renal replacement therapies, Oxidative stress, Myeloperoxidase, Nucleosomes, Regional citrate anticoagulation, Heparin
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Enrollment slower than anticipated and interrupted by COVID-19 pandemic
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Fernando SanchezUniversity, hospital or other
- Collaborators
- Hospital Universitario de la Plana, Hospital General Universitario de Castellón
- Study start
- 9 Jun 2018 (actual)
- Primary completion
- 30 Apr 2021 (actual)
- Study completion
- 30 Apr 2021 (actual)
- First posted
- 17 Oct 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Heparin | Active comparator | Procedure: Central venous access, Device: Pump-assisted circuit, Drug: Heparin sodium, Procedure: Blood and ultrafiltrate samplesCentral 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 | Experimental | Procedure: Central venous access, Device: Pump-assisted circuit, Other: Regional citrate anticoagulation, Procedure: Blood and ultrafiltrate samplesCentral 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Central venous accessVenous access will be achieved with a 13 Fr double lumen catheter into the internal jugular or femoral vein. | Procedure or surgery | Citrate, Heparin |
| Pump-assisted circuitAlso: Continuous renal replacement therapy, CRRTThe pump-assisted circuit to be used will be Fresenius multiFiltrate (Fresenius Medical Care GmbH, Bad Homburg v.d.H., Germany). EMIC2® Fresenius Medical Care high-flux synthetic membrane will be used | Device | Citrate, Heparin |
| Heparin sodiumAlso: Non-fractional heparin, HeparinNon-fractional heparin will be used in one arm with an initial dose of 500-1000 IU/hour with adaptation of the infusion to the patient and the clotting time. | Drug | Heparin |
| Regional citrate anticoagulationRegional citrate anticoagulation will be used in the other arm with an initial dose of 3 mmol/L and with a calcium reinfusion solution at an initial dose of 2 mmol/L, with adaptation of both infusions to the patient ionic calcium levels. | Other | Citrate |
| Blood and ultrafiltrate samplesBlood 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. The ultrafiltrate will be collected directly from the outlet of the hemofilter (ultrafiltrate concentration [Cuf]). The samples will taken at the beginning of CRRT (T0) and at the following times: T0, Ci; after 60 min (T1) and after 24 hours (T2) of CRRT, Ci, Co and Cuf. Venous access will be achieved with a 13 Fr double lumen catheter into the internal jugular or femoral vein. | Procedure or surgery | Citrate, Heparin |
Primary outcome
Recovery of renal function
Time frame: Through study completion, an average of 20 days.
Impact of circulating nuclear DNA (cfDNA) and oxidative stress on duration of renal replacement therapy (RRT) in ICU.
Recovery of renal function
Time frame: Through study completion, an average of 20 days.
Impact of circulating nuclear DNA (cfDNA) and oxidative stress on change of Creatinine from baseline to ICU discharge.
Recovery of renal function
Time frame: 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.
14 secondary outcomes
Activation and elimination of free radicals
Time frame: 24 hours
Activation and elimination of free radicals
Time frame: 24 hours
Activation and elimination of biomarkers of inflammation
Time frame: 24 hours
Activation and elimination of biomarkers of inflammation
Time frame: 24 hours
Activation and elimination of biomarkers of cell damage
Time frame: 24 hours
Mass transfer and clearance of free radicals
Time frame: 24 hours
Mass transfer and clearance of free radicals
Time frame: 24 hours
Mass transfer and clearance of biomarkers of inflammation
Time frame: 24 hours
Mass transfer and clearance of biomarkers of inflammation
Time frame: 24 hours
Mass transfer and clearance of biomarkers of cell damage
Time frame: 24 hours
Length of stay
Time frame: From ICU admission until the date of ICU discharge or date of death from any cause, whichever came first, assessed up to 90 days
Length of stay
Time frame: 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
Mortality
Time frame: Through study completion, an average of 20 days.
Mortality
Time frame: Day 90 after ICU admission
Results and safety
The study was stopped early (reason given: Enrollment slower than anticipated and interrupted by COVID-19 pandemic). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Oct 2024.
- Background: PubMed 20876598Hetzel GR, Schmitz M, Wissing H, Ries W, Schott G, Heering PJ, Isgro F, Kribben A, Himmele R, Grabensee B, Rump LC. Regional citrate versus systemic heparin for anticoagulation in critically ill patients on continuous venovenous haemofiltration: a prospective randomized multicentre trial. Nephrol Dial Transplant. 2011 Jan;26(1):232-9. doi: 10.1093/ndt/gfq575. Epub 2010 Sep 27.
- Background: PubMed 15312219Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P; Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004 Aug;8(4):R204-12. doi: 10.1186/cc2872. Epub 2004 May 24.
- Background: PubMed 12874474Mehta RL, Chertow GM. Acute renal failure definitions and classification: time for change? J Am Soc Nephrol. 2003 Aug;14(8):2178-87. doi: 10.1097/01.asn.0000079042.13465.1a. No abstract available.
- Background: PubMed 16949000Herrera-Gutierrez ME, Seller-Perez G, Maynar-Moliner J, Sanchez-Izquierdo-Riera JA; Grupo de trabajo "Estado actual del fracaso renal agudo y de las tecnicas de reemplazo renal en UCI. Estudio FRAMI". [Epidemiology of acute kidney failure in Spanish ICU. Multicenter prospective study FRAMI]. Med Intensiva. 2006 Aug-Sep;30(6):260-7. doi: 10.1016/s0210-5691(06)74522-3. Spanish.
- BackgroundLiaño F, Candela A, Tenorio MT, Rodríguez-Palomares JR. La IRA en la UCI: Concepto, clasificaciones funcionales, epidemiología, biomarcadores, diagnóstico diferencial y pronóstico. En: Poch E, Liaño F, Gaínza F, eds. Manejo de la disfunción aguda del riñón del paciente crítico en la práctica clínica (primera ed.). Madrid: Ergon; 2011. pp. 1-21.
- Background: PubMed 10411698Behrend T, Miller SB. Acute renal failure in the cardiac care unit: etiologies, outcomes, and prognostic factors. Kidney Int. 1999 Jul;56(1):238-43. doi: 10.1046/j.1523-1755.1999.00522.x.
- Background: PubMed 16106006Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, Schetz M, Tan I, Bouman C, Macedo E, Gibney N, Tolwani A, Ronco C; Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005 Aug 17;294(7):813-8. doi: 10.1001/jama.294.7.813.
- BackgroundBellomo R, Ronco C, Mehta R. Nomenclature for continuous renal replacement therapies. Am J Kidney Dis. 1996;28(suppl 3):S2-S7.
- Background: PubMed 12940902Liao Z, Zhang W, Hardy PA, Poh CK, Huang Z, Kraus MA, Clark WR, Gao D. Kinetic comparison of different acute dialysis therapies. Artif Organs. 2003 Sep;27(9):802-7. doi: 10.1046/j.1525-1594.2003.07282.x.
- Background: PubMed 21252503Alvestrand A, Ledebo I, Hagerman I, Wingren K, Mattsson E, Qureshi AR, Gutierrez A. Left ventricular hypertrophy in incident dialysis patients randomized to treatment with hemofiltration or hemodialysis: results from the ProFil study. Blood Purif. 2011;32(1):21-9. doi: 10.1159/000323140. Epub 2011 Jan 21.
- Background: PubMed 9531176Block GA, Hulbert-Shearon TE, Levin NW, Port FK. Association of serum phosphorus and calcium x phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis. 1998 Apr;31(4):607-17. doi: 10.1053/ajkd.1998.v31.pm9531176.
- Background: PubMed 7121651Degoulet P, Legrain M, Reach I, Aime F, Devries C, Rojas P, Jacobs C. Mortality risk factors in patients treated by chronic hemodialysis. Report of the Diaphane collaborative study. Nephron. 1982;31(2):103-10. doi: 10.1159/000182627.
- SPAIN. 2015. BOE-A-2015-14082. Royal Decree 1090/2015, of December 4, regulating clinical trials with medicines, Committees of Ethics of Research with medicines and the Spanish Registry of Clinical Studies.Link provided by the sponsor.
- EUROPEAN UNION. OJ L 158 27.5.2014. Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use and repealing Directive 2001/20 / EC.Link provided by the sponsor.
- SPAIN. 2007. BOE-A-2007-12945. Law 14/2007, of July 3, on Biomedical Research which regulates biomedical research. Official Gazette of the State, July 4, 2007, 159, pp. 28826 to 28848.Link provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Fernando Sanchez, MD study chair
La Plana Health Department. Valencian Health Counseling
Fernando Sanchez, MD study director
La Plana Health Department. Valencian Health Counseling
Fernando Sanchez, MD principal investigator
La Plana Health Department. Valencian Health Counseling
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Central venous access, Pump-assisted circuit and Heparin sodium in people with Acute Kidney Injury, run by Fernando Sanchez at 1 site in Spain.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 18 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Enrollment slower than anticipated and interrupted by COVID-19 pandemic). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Recovery of renal function (time frame: Through study completion, an average of 20 days.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06646328, which also lists 59 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Oct 2024.