Role of Vitamin K2 in Chronic Kidney Disease

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:

• 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.

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