Curcumin on NFE2L2 Gene Expression, Antioxidant Capacity and Renal Function According to rs35652124 in Diabetic Nephropathy

NCT03262363 | Unknown Phase 2 DMC

• 1 other identifier: UIMER002
• Study Type: interventional
• Target: 176
• Locations: 1 country
• Sites: 1

Brief Summary

The increase in the prevalence of diabetes mellitus (DM) is one of the greatest public health challenges worldwide. Epidemiological studies have shown that DM is the leading cause of chronic kidney disease (CKD) in patients initiating renal replacement therapy. In our country, diabetes accounts for about 60% of all incidents of dialysis. On the other hand, CKD is currently considered a noxious disease because patients not only have the likelihood of progression to end-stage renal disease (ESRD), but because these renal alterations are associated with an increased risk of cardiovascular complications and premature death for the same cause. Most studies have focused on traditional risk factors (poor diet, physical inactivity and obesity) for the development and progression of renal damage, and less information exists on non-traditional factors such as oxidative stress and mainly, the low antioxidant response that characterizes both DM and nephropathy. In addition, there is a great variation in the susceptibility to and progression of kidney disease between different populations that is not explained by the presence of traditional factors and that could be triggered by genetic variations and its interaction with other components related to the environment and lifestyle. Fortunately, there is sufficient scientific evidence that early detection and modification of negative lifestyle factors can not only delay or halt the progression of the renal function decline to ESRD but can also significantly reduce the incidence of cardiovascular disease leading to premature death in most of these patients. Therefore, it is suggested that this risk may be determined by the interaction of lifestyle factors with the presence of susceptibility alleles, which may vary from one population to another. It is now known that hyperglycemia causes a state of oxidative stress and inflammation that can be counteracted by diet supplementation with some natural antioxidants such as curcumin. It has been shown that this molecule has multiple pharmacological properties: antioxidant, anti-inflammatory, cardioprotective, renoprotective, among others. In clinical trials a positive effect of curcumin has been seen in the treatment of diabetes and its complications. This has generated a relative optimism in the search for new curcumin treatment targets where oxidative stress is of great relevance, as is the case with CKD. However, there are still doubts about its efficacy as an adjuvant in the prevention of CKD. Additionally, the role played by interindividual variability in genes involved in the mechanism of action of curcumin is still incipient, more studies in this knowledge area are necessary.

Conditions

Chronic Kidney Diseases; Diabetes Mellitus, Type 2; Polymorphism

Keywords

nutrigenomics; Diet-gene interaction,; Curcumin,; Antioxidants,; Human NFE2L2 protein,; Polymorphism,; Diabetes,; Chronic kidney disease

Outcome Measures

Primary Outcomes (6)

• Change from Baseline expression Gen NFE2L2 at 3 months

  mRNA and active protein NRF2

  Baseline at 3 months

• Change from Baseline expression Gen NFE2L2 at 6 months

  mRNA and active protein NRF2

  Baseline at 6 months

• Change from Antioxidant capacity at 3 months

  Superoxide dismutase, hemoxygenase 1, Glutathion peroxidase using the ELISA technique

  Baseline at 3 months

• Change from Antioxidant capacity at 6 months

  Superoxide dismutase, hemoxygenase 1, Glutathion peroxidase using the ELISA technique

  Baseline at 6 months

• Change from Renal Function at 3 months

  Glomerular Filtration Rate (Serum creatinine) and Albuminuria (Albumin/Creatinine Ratio)

  Baseline at 3 months

• Change from Renal Function at 6 months

  Glomerular Filtration Rate (Serum creatinine) and Albuminuria (Albumin/Creatinine Ratio)

  Baseline at 6 months

Study Arms (2)

Curcumin/NFE2L2 A>G

EXPERIMENTAL

Patients in Experimental group 1 and 2 will receive 800 mg/day of curcumin (for which a bioavailability of about 90% has been demonstrated and greater than other curcuminoids, administered in two doses of 400 mg each (the presentation will be in capsules containing 400 mg of THC).

Combination Product: Curcumin/NFE2L2 A>G

Placebo/NFE2L2 A>G

PLACEBO COMPARATOR

Patients in control group 1 and 2, the placebo intervention will consist of administering sucralose capsules (a substance lacking pharmacological action, with no active principle and a lower intake of glucose compared to sucrose). Patients will receive 300 mg/day of sucralose distributed in two doses of 150 mg each.

Combination Product: Placebo/NFE2L2 A>G

Interventions

Curcumin/NFE2L2 A>G COMBINATION_PRODUCT

The administration will be orally and the patient will be instructed to take two capsules per day for one week, one in the morning 15 minutes before breakfast and another at night 15 minutes before dinner, accompanied by a cup of 240 mL of pure water. It will be indicated to continue with their usual medical treatment.

Also known as: Curcumin group

Curcumin/NFE2L2 A>G

Placebo/NFE2L2 A>G COMBINATION_PRODUCT

The administration will be orally and the patient will be instructed to take two capsules for 24 weeks, one in the morning 15 minutes before breakfast and another in the evening 15 minutes before dinner, accompanied by a 240 mL cup of pure water. They will be advised to continue their usual medical treatment.

Also known as: Placebo group

Placebo/NFE2L2 A>G

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• With T2DM according to the American Diabetes Association
• With any time of T2DM evolution
• With CKD stage 1-3a according to the K/DIGO guidelines

You may not qualify if:

• Incomplete evaluations
• That they have not been attached to the assigned intervention with an established frequency of \<80%
• Decide to withdraw from the study

Sponsors & Collaborators

• Unidad de Investigacion Medica en Enfermedades Renales: lead

Study Sites (1)

Umae Hospital de Especialidades

Guadalajara, Jalisco, 44340, Mexico

Location

Related Publications (15)

• United States Renal Data Sytem. 2016 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Bethesda, MD, 2016.

  BACKGROUND

• Gutiérrez JP, Rivera Dommarco J, Shamah Levy T, et al. Encuesta Nacional de Salud y Nutrición 2012. Resultados Nacionales. Cuernavaca, México: Salud Publica Mex; 2012.

  BACKGROUND

• Hernández Ávila M, Gutiérrez JP, editores. Diabetes mellitus: la urgencia de reforzar la respuesta en políticas públicas para su prevención y control. Cuernavaca, México: Salud Publica Mex; 2012.

  BACKGROUND

• Asociación Latinoamericana de Diabetes (ALAD). Guías ALAD sobre el diagnóstico, control y tratamiento de la diabetes mellitus Tipo 2 con medicina basada en evidencia. 1a ed. Latinoamérica: ALAD; 2013.

  BACKGROUND

• Hernández Ávila M, Rivera Dommarco J, Shamah Levy T. Encuesta Nacional de Salud y Nutrición 2016. Resultados Nacionales. Cuernavaca, México: Instituto Nacional de Salud Pública (MX), 2016.

  BACKGROUND

• Cueto Manzano AM, Cortés Sanabria L, Martínez Ramírez HR, et al. Enfermedad Renal Crónica Temprana: Prevención, diagnóstico y tratamiento. México: Médica Panamericana; 2013. pp. 250.

  BACKGROUND

• Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. Eur J Clin Invest. 2004 Dec;34(12):785-96. doi: 10.1111/j.1365-2362.2004.01429.x.

  PMID: 15606719 BACKGROUND

• Navarro JF, Milena FJ, Mora C, Leon C, Garcia J. Renal pro-inflammatory cytokine gene expression in diabetic nephropathy: effect of angiotensin-converting enzyme inhibition and pentoxifylline administration. Am J Nephrol. 2006;26(6):562-70. doi: 10.1159/000098004. Epub 2006 Dec 13.

  PMID: 17167242 BACKGROUND

• Uruno A, Furusawa Y, Yagishita Y, Fukutomi T, Muramatsu H, Negishi T, Sugawara A, Kensler TW, Yamamoto M. The Keap1-Nrf2 system prevents onset of diabetes mellitus. Mol Cell Biol. 2013 Aug;33(15):2996-3010. doi: 10.1128/MCB.00225-13. Epub 2013 May 28.

  PMID: 23716596 BACKGROUND

• Gómez García EF, Martínez Ramírez HR, Cortés Sanabria L, et al. Cambios y mejoras en la calidad de la dieta en pacientes con enfermedad renal crónica temprana. En: Conferencia dentro del marco del XLVII Congreso Nacional de Nefrología; 2013 Sep 4-12; Guadalajara, Jalisco. México.

  BACKGROUND

• Balagopal P, George D, Patton N, Yarandi H, Roberts WL, Bayne E, Gidding S. Lifestyle-only intervention attenuates the inflammatory state associated with obesity: a randomized controlled study in adolescents. J Pediatr. 2005 Mar;146(3):342-8. doi: 10.1016/j.jpeds.2004.11.033.

  PMID: 15756217 BACKGROUND

• Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013 Jun;83(6):1029-41. doi: 10.1038/ki.2012.439. Epub 2013 Jan 16.

  PMID: 23325084 BACKGROUND

• Yoh K, Hirayama A, Ishizaki K, Yamada A, Takeuchi M, Yamagishi S, Morito N, Nakano T, Ojima M, Shimohata H, Itoh K, Takahashi S, Yamamoto M. Hyperglycemia induces oxidative and nitrosative stress and increases renal functional impairment in Nrf2-deficient mice. Genes Cells. 2008 Nov;13(11):1159-70. doi: 10.1111/j.1365-2443.2008.01234.x.

  PMID: 19090810 BACKGROUND

• Choi BH, Kang KS, Kwak MK. Effect of redox modulating NRF2 activators on chronic kidney disease. Molecules. 2014 Aug 20;19(8):12727-59. doi: 10.3390/molecules190812727.

  PMID: 25140450 BACKGROUND

• Atul A and Lakhwinder S. Pathogenesis of diabetic nephropathy and potential therapeutic effect of curcumin: A Review. Int J Pharm Bio Sci 2013;4:79-87.

  BACKGROUND

MeSH Terms

Conditions

Renal Insufficiency, Chronic; Diabetes Mellitus, Type 2; Diabetes Mellitus

Interventions

Curcumin

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; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Diarylheptanoids; Heptanes; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Catechols; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic

Central Study Contacts

LAURA CORTES-SANABRIA, PhD

CONTACT

(55)3339522038; cortes_sanabria@yahoo.com.mx

ERIKA FABIOLA GOMEZ-GARCIA, MsC

CONTACT

(55)3339522038; erikaf.gomezg@yahoo.com.mx

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Patient Blinding: Patients with EDN will be blinded to the intervention they will receive Evaluator Blinding: The principal investigator will be blinded to the intervention that patients will receive (curcumin or placebo), but will know the genotype distribution in both Experimental and Placebo groups. The external investigator will be blinded to the knowledge of the patients genotype, but will know the intervention group to which each patient was assigned according to a registry (but will not know the identity of the patients). The Doctorate Program Student will be blinded to the distribution of patients genotype and the type of intervention patients will receive. Statistical Blinding: An associated researcher will be blinded to the distribution of patients genotype and the type of intervention patients will receive, but not to the knowledge of the database.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The study starts from the classification of patients according to the genotype for the rs35652124 polymorphism (-653G\>A) of the NFE2L2 gene. Two Experimental groups and two Control groups will be formed according to the following: Experimental group 1: Diabetic patients with early CKD homozygous for the -653G (G/G) allele of the NFE2L2 gene that will receive curcumin. Experimental group 2: Diabetic patients with early CKD carrying the allele -653A (G/A or A/A) of the NFE2L2 gene that will receive curcumin. Control group 1: Diabetic patients with early CKD homozygous for the -653G (G/G) allele of the NFE2L2 gene receiving placebo. Control group 2: Diabetic patients with early CKD carrying the allele -653A (G/A or A/A) of the NFE2L2 gene who will receive placebo.

Study Record Dates

• First Submitted: August 18, 2017
• First Posted: August 25, 2017
• Study Start: August 1, 2018
• Primary Completion: February 28, 2019
• Study Completion: April 30, 2019
• Last Updated: May 30, 2018

Record last verified: 2017-09

Locations

ME (1)