Role of Vitamin K2 in Chronic Kidney Disease

Clinical Study Evaluating the Role of Vitamin K2 as Adjuvant Therapy to Angiotensin Converting Enzyme Inhibitor on Blood Pressure, Proteinuria and Bone Metabolism in Patients With Chronic Kidney Disease

This randomized placebo controlled double blind parallel clinical study will be conducted on 44 non-dialysis chronic kidney disease (CKD) patients (Stages 2-3b).Clinical Study Evaluating the Role of Vitamin K2 as Adjuvant Therapy to Angiotensin Converting Enzyme Inhibitor on Blood Pressure, Proteinuria and Bone Metabolism in Patients with Chronic Kidney Disease. Patients will be recruited from, Internal Medicine Department, Nephrology Unit, Alexandria Main University Hospital, Egypt. Patients with albumin-to-creatinine ratio ≥ 30 mg/g, with serum Potassium < 5 mEq/L and newly diagnosed patients with hypertension. The study duration will be 6 months. The patients will be randomized using stratified random block method into two groups.

Group 1: Control group Non-dialysis chronic kidney disease (CKD) patients (Stages 2-3b). Patients will be treated with ramipril 10 mg/day and a placebo match vitamin K2 capsules once per day.The dose of ramipril may be modified according to blood pressure control.

Group 2: Vitamin K2 (menaquinone-7) Non-dialysis chronic kidney disease (CKD) patients (Stages 2-3b).Patients will be treated with ramipril 10 mg/day and vitamin K2 capsules (menaquinone-7) 90 mcg/day. The dose of ramipril may be modified according to blood pressure control.

Participants will be followed-up by weekly telephone calls and monthly direct meetings to assess their adherence for 6 months.

Study Overview

• Status: Recruiting
• Conditions: Chronic Kidney Diseases
• Intervention / Treatment: Drug: Placebo; Drug: Vitamin K 2

Detailed Description

Chronic kidney disease (CKD) is defined by a reduction in the kidney function (shown by reduced estimated glomerular filtration rate (eGFR) or markers of kidney damage, or both, for at least three months).

It varies depending on the amount of blood pressure control, the degree of proteinuria, the previous rate of decline in GFR, and the underlying renal disease, including diabetes.

Phosphorus excretion decreases in many kidney disorders, and as a result, the amount of fibroblast growth factor 23 (FGF-23) rises.FGF-23 levels have appeared to predict risk of death in individuals with chronic renal disease as the estimated glomerular filtration rate declines, and a corresponding increase in FGF-23 can be noted.

FGF-23 is a hormone with a molecular weight of 30 kDa works on fibroblast growth factor receptors (FGFR1-4) in the kidney, heart, colon, and parathyroid gland. It is secreted by osteocytes and, to a lesser extent by osteoblasts into the bloodstream. A rise in FGF-23 could indicate kidney dysfunction, and concurrent bone disease. Patients with CKD are well known to have greater risk for developing bone fractures.

The term "chronic kidney disease-mineral bone disorder" (CKD-MBD) refers to the decline in bone quality and the subsequent development of disorders in bone and mineral metabolism caused by impaired kidney function. In addition to PTH, vitamin D, calcium and phosphorus, fibroblast growth factor-23 (FGF-23) play a role in CKD-MBD.

Treatment of the underlying disease, if possible, and treatment of secondary factors, such as increased blood pressure and proteinuria, are the two main ways to limit the rate of CKD progression. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are renin-angiotensin system (RAS) inhibitors that are more effective than other antihypertensive medications in reducing proteinuria and slowing the rate of progression of proteinuria during CKD, regardless of the etiology.

Ramipril inhibits ACE, which lowers FGF-23 expression in the kidney and attenuates proteinuria. Angiotensin inhibition frequently causes mild to moderate decrease in GFR and hyperkalemia following the treatment initiation or following dose escalation. If CKD is progressive, hyperkalemia may develop quickly after the start of treatment or at a later time.

Patients with CKD typically have low vitamin K levels. Moreover, vitamin K2 appears to have supportive role in the treatment of primary hypertension. The RAAS was involved in this model of salt-induced arterial hypertension and the administration of vitamin K2 produced an inhibitory effect on the RAAS mediated pathways. Proteinuria and the stage of chronic kidney disease have previously been linked to low peripheral vitamin K status. It was documented that both the deficiency of vitamin K and 25 OH-vitamin D was associated with progressive decline in renal function and with the increased albumin/creatinine urinary excretion ratio. Additionally, some proteins involved in bone mineralization require vitamin K2 as a cofactor. Vitamin K2 supplementation could have a protective role on both bone and cardiovascular health in patients with CKD. Indeed, a synergistic interplay has been suggested between vitamins D and K in exerting bone protection properties, and in improving cardiovascular health.

The aim of this work is to evaluate the role of vitamin K2 as adjuvant therapy to angiotensin converting enzyme inhibitor on blood pressure, proteinuria and bone metabolism in patients with chronic kidney disease (CKD).

All the participants will be subjected to the following:

1. Demography, History and Physical Examination

   - Age, sex, sex distribution ratio (M/F) will be determined. Measurement of weight in nearest kilogram and height in nearest centimeter will be measured using Detecto Scale with subsequent calculation of body mass index according to the following formula: BMI= [Weight (kg) ÷ Height2(m)].

   Full medical history will be taken to avoid inclusion of any patient with confounding disease or medication in the study.

   - Measurement of blood pressure will be done using a mercury sphygmomanometer in accordance with recommendations of the American Heart Association and standardized office blood pressure measurements. The mean values of the duplicate measurements will be recorded. The blood pressure will be assessed at baseline and every 4 weeks. Measurements of routine parameters at baseline, through evaluation of:

   - Fasting blood glucose

   - Alanine aminotransferase (ALT)

   - Serum total bilirubin

   - In addition, prothrombin time or international normalization ratio (INR) will be also assessed.

   Assessment of Proteinuria at the time of enrollment, 3 and 6 months after intervention. Proteinuria will be assessed using urine dipstick test. Albumin-to-creatinine ratio will be calculated by dividing the urinary albumin concentration by the urinary creatinine concentration. Assessment of kidney functions at baseline, 4 weeks, 3 and 6 months after initiation of ACEI by assessment: Serum creatinine, Estimated glomerular filtration rate (eGFR) in mL/min/1.73m2 which will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, 2021, blood urea nitrogen and serum potassium Evaluation of Chronic Kidney Disease-Mineral and Bone Disorder Chronic Kidney Disease-Mineral and Bone Disorder (CKD MBD) will be assessed at baseline and at the end of intervention through evaluation of: - Serum level of Fibroblast growth factor-23 (FGF-23) - Serum Parathyroid hormone (PTH) level

   - Serum concentration of 25 (OH) vitamin D.

   • Serum calcium
   • Serum phosphorus

   Clinical outcome will be assessed at baseline and 6 months after Intervention through:

   - Evaluation of Health Related Quality of Life (HRQOL) using the validated Arabic version of -Kidney Disease and Quality of Life- Short Form (KDQOL-SF™) version 1.3 questionnaire which was formerly used in Egypt for patients with CKD.

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Dina Abdel Hamid, Masters; Phone Number: +2001020198970; Email: pg_87899@pharm.tanta.edu.eg

Study Locations

• Egypt
  • Capital Of Gharbia Governorate.
    • Tanta, Capital Of Gharbia Governorate., Egypt, 31527
      • Recruiting
      • faculty of pharmacy Tanta University
      • Contact: Tarek Mostafa, Doctorate Degree; Phone Number: +2001154594035; Email: tarek.mostafa@pharm.tanta.edu.eg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years old.
• Both sexes.
• Patients matched in the duration of CKD.
• Non-dialysis chronic kidney disease (CKD) patient with estimated glomerular filtration rate (GFR) 30-89 mL/min/1.73m2 (Stage 2-3b).
• Patients with albumin-to-creatinine ratio ≥ 30 mg/g.
• Patients with serum Potassium < 5 mEq/L.
• A newly diagnosed patients with hypertension.

Exclusion Criteria:

• Patients with elevated level of potassium ≥ 5 mEq/L.
• Patients with diabetes.
• Patients with cancer.
• Patients with heart disease.
• Patients with hepato-biliary disease and other liver diseases.
• Patients with kidney stones and urinary tract infection.
• Patients with an overactive thyroid gland.
• Patients with bleeding disorder.
• History of drug allergy to ACEI or ARBs.
• Pregnant and breastfeeding women.
• Patients with blood pressure ≥180/110 or <100/60.
• Patients on alteplase, azothiopurine, everolimus, sirolimus, lithium, non-steroidal anti-inflammatory drugs (epifenac, tenoxicam, Celecoxib….), potassium retentive diuretics (amiloride, spironolactone), other ACEIs and ARBs will be excluded to avoid possible drug-drug interactions with ramipril.
• Patients on omega-3 fatty acids; vitamins (especially A, C, E, K), Chemotherapy and oral anticoagulant (warfarin), cholestyramine, orlistate will be excluded to avoid possible drug interactions that could affect vitamin K2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Group 1: Control group; Non-dialysis chronic kidney disease (CKD) patients (Stages 2-3b). Patients will be treated with ramipril 10 mg/day and a placebo match vitamin K2 capsules once per day. The dose of ramipril may be modified according to blood pressure control. Participants will be followed-up by weekly telephone calls and monthly direct meetings to assess their adherence for 6 months.	Drug: Placebo; Placebo match vitamin K2 capsules once per day.
Active Comparator: Vitamin K2 (menaquinone-7); Non-dialysis chronic kidney disease (CKD) patients (Stages 2-3b).Patients will be treated with ramipril 10 mg/day and vitamin K2 capsules (menaquinone-7) 90 mcg/day. The dose of ramipril may be modified according to blood pressure control. Participants will be followed-up by weekly telephone calls and monthly direct meetings to assess their adherence for 6 months.	Drug: Vitamin K 2; Patients will be treated with vitamin K2 (menaquinone-7) 90 mcg/day.; Other Names: menaquinone-7

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in proteinuria level be assessed using Albumin-to-creatinine ratio (ACR) ratio (mg/g)	Assessment of Proteinuria at the time of enrollment, 3 and 6 months after intervention. Albumin-to-creatinine ratio will be calculated by dividing the urinary albumin concentration by the urinary creatinine concentration (mg/g)	The study duration will be 6 months
The change in blood pressure (mmHg) will be done using a mercury sphygmomanometer	Measurement of blood pressure will be done using a mercury sphygmomanometer in accordance with recommendations of the American Heart Association and standardized office blood pressure measurements. The mean values of the duplicate measurements will be recorded. The blood pressure will be assessed at baseline and every 4 weeks.	The study duration will be 6 months
The change in Blood urea nitrogen (BUN) (mg/dl)	Assessment of BUN (mg/dl) at baseline, 4 weeks, 3 and 6 months after initiation of ACEI	The study duration will be 6 months
The change in serum potassium (meq/l).	Assessment of serum potassium (meq/l) at baseline, 4 weeks, 3 and 6 months after initiation of ACEI	The study duration will be 6 months
The change in serum creatinine (mg/dl)	Assessment of serum creatinine (mg/dl) at baseline, 4 weeks, 3 and 6 months after initiation of ACEI	The study duration will be 6 months
The change in serum urea (mg/dl)	Assessment of serum urea (mg/dl) at baseline, 4 weeks, 3 and 6 months after initiation of ACEI	The study duration will be 6 months
The change in kidney function test measured by creatinine clearance (eGFR) mL/min/1.73m2 which will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, 2021	Assessment of kidney functions at baseline, 4 weeks, 3 and 6 months after initiation of ACEI by assessment: Estimated glomerular filtration rate (eGFR) in mL/min/1.73m2 which will be calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, 2021.	The study duration will be 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in chronic kidney disease-mineral and bone disorder related parameters by assessment Serum level of Fibroblast growth factor-23 (FGF-23) (pg/ml)	Evaluation of Chronic Kidney Disease-Mineral and Bone Disorder Chronic Kidney Disease-Mineral and Bone Disorder (CKD MBD) will be assessed at baseline and at the end of intervention through evaluation of: - Serum level of Fibroblast growth factor-23 (FGF-23) (pg/ml)	The study duration will be 6 months.
The change in serum phosphorus level (mg/dl)	The change in serum phosphorus level (mg/dl) will be assessed at baseline and at the end of intervention through evaluation	The study duration will be 6 months.
The change in I-PTH (pg/ml)	The change in I-PTH (pg/ml) will be assessed at baseline and at the end of intervention through evaluation	The study duration will be 6 months.
The change in vitamin D level (ng/ml)	The change in vitamin D level (ng/ml) will be assessed at baseline and at the end of intervention through evaluation	The study duration will be 6 months.
The change in serum calcium level (mg/dl)	The change in serum calcium level (mg/dl) will be assessed at baseline and at the end of intervention through evaluation	The study duration will be 6 months.
Clinical outcome will be assessed by Kidney Disease and Quality of Life- Short Form (KDQOL-SF™) version 1.3 questionnaire	Clinical outcome will be assessed at baseline and 6 months after Intervention through: - Evaluation of Health Related Quality of Life (HRQOL) using the validated Arabic version of -Kidney Disease and Quality of Life- Short Form (KDQOL-SF™) version 1.3 questionnaire which was formerly used in Egypt for patients with CKD.	The study duration will be 6 months.

Collaborators and Investigators

• Sponsor: Tanta University
• Investigators: Principal Investigator: Tarek Mostafa, PhD, Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Tanta, Egypt, 31527

Publications and helpful links

General Publications

• Liu TH, Tao WC, Liang QE, Tu WQ, Xiao Y, Chen LG. Gut Microbiota-Related Evidence Provides New Insights Into the Association Between Activating Transcription Factor 4 and Development of Salt-Induced Hypertension in Mice. Front Cell Dev Biol. 2020 Nov 13;8:585995. doi: 10.3389/fcell.2020.585995. eCollection 2020.
• Holden RM, Morton AR, Garland JS, Pavlov A, Day AG, Booth SL. Vitamins K and D status in stages 3-5 chronic kidney disease. Clin J Am Soc Nephrol. 2010 Apr;5(4):590-7. doi: 10.2215/CJN.06420909. Epub 2010 Feb 18.
• Fusaro M, Gallieni M, Porta C, Nickolas TL, Khairallah P. Vitamin K effects in human health: new insights beyond bone and cardiovascular health. J Nephrol. 2020 Apr;33(2):239-249. doi: 10.1007/s40620-019-00685-0. Epub 2019 Dec 19. Erratum In: J Nephrol. 2020 Jan 3;:
• Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. How much should we worry? Arch Intern Med. 1998 Jan 12;158(1):26-32. doi: 10.1001/archinte.158.1.26.
• Dai B, David V, Martin A, Huang J, Li H, Jiao Y, Gu W, Quarles LD. A comparative transcriptome analysis identifying FGF23 regulated genes in the kidney of a mouse CKD model. PLoS One. 2012;7(9):e44161. doi: 10.1371/journal.pone.0044161. Epub 2012 Sep 6.
• Shane E, Mancini D, Aaronson K, Silverberg SJ, Seibel MJ, Addesso V, McMahon DJ. Bone mass, vitamin D deficiency, and hyperparathyroidism in congestive heart failure. Am J Med. 1997 Sep;103(3):197-207. doi: 10.1016/s0002-9343(97)00142-3.
• Rodriguez-Garcia M, Gomez-Alonso C, Naves-Diaz M, Diaz-Lopez JB, Diaz-Corte C, Cannata-Andia JB; Asturias Study Group. Vascular calcifications, vertebral fractures and mortality in haemodialysis patients. Nephrol Dial Transplant. 2009 Jan;24(1):239-46. doi: 10.1093/ndt/gfn466. Epub 2008 Aug 25.
• Ix JH, Katz R, Kestenbaum BR, de Boer IH, Chonchol M, Mukamal KJ, Rifkin D, Siscovick DS, Sarnak MJ, Shlipak MG. Fibroblast growth factor-23 and death, heart failure, and cardiovascular events in community-living individuals: CHS (Cardiovascular Health Study). J Am Coll Cardiol. 2012 Jul 17;60(3):200-7. doi: 10.1016/j.jacc.2012.03.040. Epub 2012 Jun 13.

Study record dates

Study Major Dates

• Study Start (Actual): July 15, 2023
• Primary Completion (Estimated): July 15, 2024
• Study Completion (Estimated): July 15, 2025

Study Registration Dates

• First Submitted: June 26, 2023
• First Submitted That Met QC Criteria: July 4, 2023
• First Posted (Actual): July 12, 2023

Study Record Updates

• Last Update Posted (Actual): January 17, 2024
• Last Update Submitted That Met QC Criteria: January 14, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Proteinuria, Bone Metabolism, Vitamin K2
• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Renal Insufficiency; Chronic Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Renal Insufficiency, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Micronutrients; Vitamins; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Vitamin K 2; Menaquinone 7
• Other Study ID Numbers: Vitamin K2 in CKD

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No