Spironolactone on Acute Kidney Injury in Critically Ill Patients

NCT03206658 | Unknown Phase 3 DMC

• 1 other identifier: 1251
• Study Type: interventional
• Target: 90
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study was designed to evaluate the effect of spironolactone administration in the incidence and severity of AKI in patients critically ill with invasive mechanical ventilation (IMV) in the critical care unit. Patients in critical care unit (CCU) are the most at risk of developing AKI. In most cases a mechanism of ischemia/reperfusion has a central role in the development of AKI. Aldosterone has traditionally been recognized as a mediator that maintains water and sodium homeostasis. Nevertheless, there are enough evidence in humans and experimental models that aldosterone might mediate detrimental effects on renal function and structure in pathophysiological conditions. Indeed, several experimental studies from our laboratory have shown that mineralocorticoid receptor blockade protects the kidney against ischemia/reperfusion injury. The aim of this study is to know: o If mineralocorticoid receptor blockade may reduce the incidence and severity of AKI in critically patients with IMV in CCU. You may be able to enter in this study if:

• You are at least 18 years old.
• You are male or female
• You are with IMV.
• You are in CCU.
• Your serum K is less than 4.5 mEq/L
• Your BP is \>90/70 mmHg You cannot enter this study if:
• You have CKD
• You have AKI This study will recruit 90 patients from Instituto Nacional de Ciencias Médicas Salvador Zubiran in México City. The study will begin in April 2017. The patients will be randomized to one of 2 groups of treatment (Spironolactone 25 mg or placebo). All treatments looks identical (1 capsule), will be administered through the nasogastric tube. Neither the patients nor their doctors will be able to know or decide which group you are in. You will receive the medication during the first five days of stay in the critical care unit. As part of this trial, the doctors will ask your permission to get a sample urine during this days. They will use the samples to do tests in the laboratory (different to routine tests) that may help them to compare renal function and biomarkers of renal injury. Your participation will end 10 days after your entry into the critical care unit. The most common side effect of spironolactone is hyperkalemia.

Conditions

Acute Kidney Injury

Keywords

acute kidney injury; prevention; severity; biomarker

Outcome Measures

Primary Outcomes (1)

• level of urinary biomarkers of AKI

  determine the concentrations of NGAL, KIM-1, oxidative stress and Hsp72 in urine

  at the day 0, 1, 2, 3 , 4, 5, 7 and 10 from the inclusion in the study

Study Arms (2)

placebo oral capsules

PLACEBO COMPARATOR

Placebo capsules equal to those in the study drug, will be administered every 24 hours for the first 5 days after entry into the critical care unit

Drug: Placebo oral capsule

spironolactone

EXPERIMENTAL

capsules of spironolactone 25 mg equal to placebo, will be given every 24 hours for the first 5 days after entry to the critical care unit

Drug: Spironolactone 25 mg

Interventions

Spironolactone 25 mg DRUG

A dose of 25 mg of spironolactone will be administered orally or through the nasogastric /nasoenteral tube to the patients every 24 hours, at 8-9 am.

Also known as: aldactone 25 mg

spironolactone

Placebo oral capsule DRUG

The contents of a placebo capsule will be administered orally or through the nasogastric / nasoenteral tube to the patients every 24 hours, at 8-9 am.

Also known as: control group

placebo oral capsules

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients older than 18 years of age
• Patients critically ill requiring invasive mechanical ventilation with some organic failure in addition to respiratory failure.
• Organic scale failure will be categorized according to the (Sequential Organ Failure Assesment) scale and will be considered present when there is a score ≥2 in some organ / system, except renal.
• Patients with normal renal function or chronic kidney disease KDOQI 1-3
• Patients without acute renal injury according to the (acute kidney injury network) AKIN criteria.
• Normal serum K levels (less than or equal to 5 mEq / L).
• Women with (a) negative pregnancy test, (b) surgical sterilization, or (c) completed menopause.
• Systolic blood pressure\> 90 mmHg and mean arterial pressure\> 70 mmHg.
• Diuresis in the first 6 hrs from admission to intensive therapy\> 0.5 ml / kg / hr.
• The patient will give written and signed informed consent prior to any specific study procedure. However, if a patient can not do so before, his or her legal representative the Institute may give written informed consent.

You may not qualify if:

• Patients with chronic kidney disease stages 4-5 of KDOQI / renal replacement therapy.
• Patients with acute kidney injury according to the AKIN criteria at the time of admission to the intensive care unit
• Patients with refractory septic shock, defined as a state of hypotension requiring administration of ≥0.25 mcg / kg / min of noradrenaline.
• Patients with known adrenal insufficiency.
• Patients with indication for the administration of angiotensin-converting enzyme (ACE) blockers or angiotensin 2 receptor antagonists.
• Known allergy to spironolactone.
• Contraindication for orally medication or placement of any probe (SNG or SNE)
• It is considered that the patient is unlikely to survive the study period (30 days) or has a disease of rapid or terminal progression.
• The patient is participating in any other clinical trial involving the administration of a research drug at the time of the presentation during the course of the study or has been treated with a research drug within 30 days prior to enrollment.
• The patient has been enrolled in this study previously.
• The patient is pregnant or breastfeeding.

Sponsors & Collaborators

• Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran: lead
• National Council of Science and Technology, Mexico: collaborator
• Universidad Nacional Autonoma de Mexico: collaborator

Related Publications (16)

• Kuiper JW, Groeneveld AB, Slutsky AS, Plotz FB. Mechanical ventilation and acute renal failure. Crit Care Med. 2005 Jun;33(6):1408-15. doi: 10.1097/01.ccm.0000165808.30416.ef.

  PMID: 15942363 BACKGROUND

• Martensson J, Martling CR, Bell M. Novel biomarkers of acute kidney injury and failure: clinical applicability. Br J Anaesth. 2012 Dec;109(6):843-50. doi: 10.1093/bja/aes357. Epub 2012 Oct 9.

  PMID: 23048068 BACKGROUND

• Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV. Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int. 2002 Jul;62(1):237-44. doi: 10.1046/j.1523-1755.2002.00433.x.

  PMID: 12081583 BACKGROUND

• Liangos O, Perianayagam MC, Vaidya VS, Han WK, Wald R, Tighiouart H, MacKinnon RW, Li L, Balakrishnan VS, Pereira BJ, Bonventre JV, Jaber BL. Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol. 2007 Mar;18(3):904-12. doi: 10.1681/ASN.2006030221. Epub 2007 Jan 31.

  PMID: 17267747 BACKGROUND

• Briet M, Schiffrin EL. Aldosterone: effects on the kidney and cardiovascular system. Nat Rev Nephrol. 2010 May;6(5):261-73. doi: 10.1038/nrneph.2010.30. Epub 2010 Mar 16.

  PMID: 20234356 BACKGROUND

• Del Vecchio L, Procaccio M, Vigano S, Cusi D. Mechanisms of disease: The role of aldosterone in kidney damage and clinical benefits of its blockade. Nat Clin Pract Nephrol. 2007 Jan;3(1):42-9. doi: 10.1038/ncpneph0362.

  PMID: 17183261 BACKGROUND

• Greene EL, Kren S, Hostetter TH. Role of aldosterone in the remnant kidney model in the rat. J Clin Invest. 1996 Aug 15;98(4):1063-8. doi: 10.1172/JCI118867.

  PMID: 8770880 BACKGROUND

• Rocha R, Stier CT Jr, Kifor I, Ochoa-Maya MR, Rennke HG, Williams GH, Adler GK. Aldosterone: a mediator of myocardial necrosis and renal arteriopathy. Endocrinology. 2000 Oct;141(10):3871-8. doi: 10.1210/endo.141.10.7711.

  PMID: 11014244 BACKGROUND

• Nisula S, Kaukonen KM, Vaara ST, Korhonen AM, Poukkanen M, Karlsson S, Haapio M, Inkinen O, Parviainen I, Suojaranta-Ylinen R, Laurila JJ, Tenhunen J, Reinikainen M, Ala-Kokko T, Ruokonen E, Kuitunen A, Pettila V; FINNAKI Study Group. Incidence, risk factors and 90-day mortality of patients with acute kidney injury in Finnish intensive care units: the FINNAKI study. Intensive Care Med. 2013 Mar;39(3):420-8. doi: 10.1007/s00134-012-2796-5. Epub 2013 Jan 5.

  PMID: 23291734 RESULT

• Uchino 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.

  PMID: 16106006 RESULT

• de Mendonca A, Vincent JL, Suter PM, Moreno R, Dearden NM, Antonelli M, Takala J, Sprung C, Cantraine F. Acute renal failure in the ICU: risk factors and outcome evaluated by the SOFA score. Intensive Care Med. 2000 Jul;26(7):915-21. doi: 10.1007/s001340051281.

  PMID: 10990106 RESULT

• Gallagher M, Cass A, Bellomo R, Finfer S, Gattas D, Lee J, Lo S, McGuinness S, Myburgh J, Parke R, Rajbhandari D; POST-RENAL Study Investigators and the ANZICS Clinical Trials Group. Long-term survival and dialysis dependency following acute kidney injury in intensive care: extended follow-up of a randomized controlled trial. PLoS Med. 2014 Feb 11;11(2):e1001601. doi: 10.1371/journal.pmed.1001601. eCollection 2014 Feb.

  PMID: 24523666 RESULT

• Barrera-Chimal J, Perez-Villalva R, Cortes-Gonzalez C, Ojeda-Cervantes M, Gamba G, Morales-Buenrostro LE, Bobadilla NA. Hsp72 is an early and sensitive biomarker to detect acute kidney injury. EMBO Mol Med. 2011 Jan;3(1):5-20. doi: 10.1002/emmm.201000105. Epub 2010 Dec 14.

  PMID: 21204265 RESULT

• Morales-Buenrostro LE, Salas-Nolasco OI, Barrera-Chimal J, Casas-Aparicio G, Irizar-Santana S, Perez-Villalva R, Bobadilla NA. Hsp72 is a novel biomarker to predict acute kidney injury in critically ill patients. PLoS One. 2014 Oct 14;9(10):e109407. doi: 10.1371/journal.pone.0109407. eCollection 2014.

  PMID: 25313566 RESULT

• Pretorius M, Murray KT, Yu C, Byrne JG, Billings FT 4th, Petracek MR, Greelish JP, Hoff SJ, Ball SK, Mishra V, Body SC, Brown NJ. Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery. Crit Care Med. 2012 Oct;40(10):2805-12. doi: 10.1097/CCM.0b013e31825b8be2.

  PMID: 22824930 RESULT

• Trachtman H, Weiser AC, Valderrama E, Morgado M, Palmer LS. Prevention of renal fibrosis by spironolactone in mice with complete unilateral ureteral obstruction. J Urol. 2004 Oct;172(4 Pt 2):1590-4. doi: 10.1097/01.ju.0000140445.82949.54.

  PMID: 15371767 RESULT

MeSH Terms

Conditions

Acute Kidney Injury

Interventions

Spironolactone; Control Groups

Condition Hierarchy (Ancestors)

Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Lactones; Organic Chemicals; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods

Study Officials

• Norma Bobadilla-Sandoval, PhD

  INCMNSZ / IBB UNAM

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Norma Bobadilla-Sandoval, PhD

CONTACT

+5215532327451; nab@biomedicas.unam.mx

Mauricio Arvizu, MD

CONTACT

+5215527030681; arvizumh@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: PhD

Study Record Dates

• First Submitted: June 29, 2017
• First Posted: July 2, 2017
• Study Start: August 1, 2017
• Primary Completion: December 31, 2019
• Study Completion: December 31, 2019
• Last Updated: July 6, 2017

Record last verified: 2017-07

Data Sharing

• IPD Sharing: Will not share