Sains Malaysiana 49(3)(2020): 613-624

http://dx.doi.org/10.17576/jsm-2020-4903-16

 

Vitamin K Status in Diabetic Patients with Chronic Kidney Disease Stage 3-5 and its Effects on Chronic Kidney Disease - Mineral Bone Disorder

(Status Vitamin K pada Pesakit Kencing Manis dengan Kegagalan Ginjal Kronik Tahap 3-5 dan Kesannya kepada Penyakit Ginjal Kronik - Gangguan Mineral Tulang)

 

S. JAYAKUMAR1, ELENA AZIZAN2, SHAMSUL AZHAR SHAH3, ARBAIYAH BAIN1 & ABDUL HALIM ABDUL GAFOR1*

 

1Nephrology Unit, Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Federal Territory, Malaysia

 

2Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Federal Territory, Malaysia

 

3Department of Community Health, UKM Medical Molecular Biology Institute, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000 Kuala Lumpur, Federal Territory, Malaysia

 

Received: 9 October 2019/Accepted: 13 November 2019

 

ABSTRACT

Diabetic kidney disease (DKD) is common in Malaysia. Vitamin K deficiency among DKD patients may be associated with higher incidence of chronic kidney disease-mineral bone disorder (CKD-MBD).  This study was conducted to determine the prevalence of vitamin K deficiency in diabetic patients with CKD stage 3-5. We also correlated vitamin K deficiency with baseline demographic, biochemical results and analysed the effects of vitamin K levels on CKD-MBD. This was a single centre cross-sectional study on diabetic patients with CKD stage 3-5. Demographic profiles were recorded, blood samples were measured for vitamin K level (phylloquinone, proteins induced by vitamin K absence II (PIVKA-II), prothrombin time) and bone markers (parathyroid hormone (PTH), alkaline phosphatase, corrected calcium and phosphate). This study was approved by UKM ethic and research committee (FF-2018-375). Forty-five patients with a median age of 70 (IQR:13) years were recruited.  Majority were females (53.3%) and Malays (64.4%).  Prevalence of patients with insufficient vitamin K was 28.9 % based on the low level of phylloquinone (<0.4 nmol/L), 93.3% based on high PIVKA-II level (>0.66 ng/mL) and 2.2% based on prolonged prothrombin time (>14.5 s). PIVKA-II was found to be positively correlated with serum creatinine and PTH levels. There were positive correlations between phylloquinone with serum triglyceride and total cholesterol. Prothrombin time was found to be negatively correlated with corrected calcium and total cholesterol. Malay race (p = 0.039) and high serum PTH (p = 0.016) were significantly associated with higher PIVKA-II concentrations. Multivariable analysis showed serum triglyceride (OR 0.112; CI 95 % (0.02-0.66); p = 0.017) and serum PTH (OR 1.997; CI 95 % (1.01-3.95); p = 0.047) were independent predictors for abnormal phylloquinone and PIVKA-II levels, respectively. In conclusion, the prevalence of Vitamin K deficiency was high in diabetic patients with CKD stage 3-5. Serum triglyceride and serum PTH were independent predictor of Vitamin K deficiency.

 

Keywords: Chronic kidney disease-mineral bone disease; diabetic kidney disease; phylloquinone; protein induced by vitamin K absence II (PIVKA II); prothrombin time

 

ABSTRAK

Penyakit ginjal yang disebabkan oleh kencing manis (DKD) sangat kerap berlaku di Malaysia. Kekurangan vitamin K dalam kalangan pesakit DKD mungkin berhubung kait dengan kejadian penyakit ginjal kronik-gangguan mineral tulang (CKD-MBD) yang tinggi. Kajian ini dijalankan untuk menentukan kelaziman kekurangan vitamin K pada pesakit DKD tahap 3-5. Kami juga mengkaji hubung kait kekurangan vitamin K dengan demografi dan biokimia asas dan menganalisis kesan paras vitamin K pada CKD-MBD. Ini adalah satu kajian rentas pada pesakit DKD tahap 3-5. Profil demografi direkodkan, sampel darah diambil untuk tahap vitamin K (filokuinon, proteins teraruh dengan ketiadaan vitamin K II (PIVKA-II), tempoh protrombin) dan penanda penyakit CKD-MBD (hormon paratiroid (PTH), fosfatase beralkasi, kalsium dan fosfat). Kajian ini telah diluluskan oleh Jawatankuasa Etika dan Penyelidikan UKM (FF-2018-375). Empat puluh lima pesakit dengan umur median 70 (IQR: 13) tahun telah direkrut. Majoriti adalah perempuan (53.3 %) dan Melayu (64.4 %). Peratusan pesakit dengan kekurangan vitamin K adalah 28.9 % berdasarkan tahap rendah filokuinon (<0.4 nmol/L), 93.3 % berdasarkan tahap PIVKA-II yang tinggi (> 0.66 ng/mL) dan 2.2 % berdasarkan masa protrombin yang berpanjangan (> 14.5 saat). PIVKA-II didapati mempunyai kaitan positif dengan nilai serum kreatinin dan PTH. Terdapat hubung kait positif antara filokuinon dengan serum trigliserida  dan  kolesterol. Tempoh protrombin didapati berhubung kait secara negatif dengan kalsium dan tahap kolesterol. Bangsa Melayu (p = 0.039) dan serum tinggi PTH (p = 0.016) adalah berkaitan dengan kepekatan PIVKA-II. Analisis pelbagai pemboleh ubah menunjukkan trigliserida serum (OR 0.112; CI 95% (0.02-0.66); p = 0.017) dan tahap PTH (OR 1.997; CI 95% (1.01-3.95); p = 0.047) adalah peramal untuk keabnormalan filokuinon dan tahap PIVKA-II. Kesimpulannya, kekurangan vitamin K kerap berlaku pada pesakit diabetes dengan CKD tahap 3-5. Serum trigliserida dan serum PTH adalah peramal bebas kekurangan Vitamin K.

 
Kata kunci: Filokuinon; penyakit buah pinggang diabetes; penyakit ginjal kronik - penyakit mineral tulang; protein teraruh dengan ketiadaan vitamin K II (PIVKA II); tempoh protrombin

 

REFERENCES

Abdulameer, S.A., Sahib, M.N. & Sulaiman, S.A.S. 2018. The prevalence of osteopenia and osteoporosis among Malaysian Type 2 diabetic patients using quantitative ultrasound densitometer. Open Rheumatology Journal 12: 50-64.

Abougalambou, S.S.I., Abougalambou, A.S. & Barghash, S.S. 2016. A study evaluating the prevalence of nephropathy among Type 2 diabetes patients attending a teaching hospital in Malaysia. Journal of Clinical Nephrology and Renal Care 2(1): 1-5.

Apalset, E.M., Gjesdal, C.G., Eide, G.E. & Tell, G.S. 2011. Intake of vitamin K1 and K2 and risk of hip fractures: The Hordaland health study. Bone 49(5): 990-995.

Azharuddin, M.K., O'Reilly, D.S., Gray, A. & Talwar, D. 2007. HPLC method for plasma vitamin K1: Effect of plasma triglyceride and acute-phase response on circulating concentrations. Clinical Chemistry 53(9): 1706-1173.

Belle, M., Brebant, R., Guinet, R. & Leclercq, M. 1995. Production of a new monoclonal antibody specific to human des-gamma- carboxyprothrombin in the presence of calcium ions. application to the development of a sensitive ELISA-Test. J. Immunoassay. 16(2): 213-229.

Berkner, K.L. & Runge, K.W. 2004. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. Journal of Thrombosis and Haemostasis 2(12): 2118-2132.

Beto, J.A., Fand, R.D.N., Pharmd, W.E.R. & Bansal, V.K. 2014. Medical nutrition therapy in adults with chronic kidney disease: Integrating evidence and consensus into practice for the generalist registered dietitian nutritionist. Journal of the Academy of Nutrition and Dietetics 114(7): 1077-1087.

Booth, S.L. & Al Rajabi, A. 2008. Determinants of vitamin K status in humans. Vitamins and Hormones 78: 1-22.

Bujang, M.A., Adnan, T.H., Hashim, N.H., Mohan, K., Kim Liong, A., Ahmad, G., Bak Leong, G., Bavanandan, S. & Haniff, J. 2017. Forecasting the incidence and prevalence of patients with end-stage renal disease in Malaysia up to the Year 2040. International Journal of Nephrology 2017: 2735296.

Chen, H., Li, X., Yue, R., Ren, X., Zhang, X. & Ni, A. 2016. The effects of diabetes mellitus and diabetic nephropathy on bone and mineral metabolism in T2DM patients. Diabetes Research and Clinical Practice 100(2): 272-276.

Cockayne, S., Adamson, J., Lanham-new, S., Shearer, M.J., Gilbody, S. & Torgerson, D.J. 2006. Vitamin K and the prevention of fractures: Systematic review and meta-analysis of randomized controlled trials. Archives of Internal Medicine 166(12): 1256-1261.

Collins, A., Cashman, K.D. & Kiely, M. 2006. Phylloquinone (vitamin K1) intakes and serum undercarboxylated osteocalcin levels in Irish postmenopausal women. British Journal of Nutrition 95(5): 982-988.

Cozzolino, M., Ciceri, P., Galassi, A., Mangano, M., Carugo, S., Capelli, I. & Cianciolo, G. 2019. The key role of phosphate on vascular calcification. Toxins (Basel). 11(4): E213.

Cranenburg, E.C., Schurgers, L.J., Uiterwijk, H.H., Beulens, J.W., Dalmeijer, G.W., Westerhuis, R., Magdeleyns, E.J., Herfs, M., Vermeer, C. & Laverman, G.D. 2012. Vitamin K intake and status are low in hemodialysis patients. Kidney International 82(5): 605-610.

Elliott, M.J., Booth, S.L., Hopman, W.M. & Holden, R.M. 2014. Assessment of potential biomarkers of subclinical vitamin K deficiency in patients with end-stage kidney disease. Canadian Journal of Kidney Health and Disease 1: 13. doi: 10.1186/2054-3581-1-13.

Evenepoel, P., Claes, K., Meijers, B., Laurent, M., Bammens, B., Naesens, M., Sprangers, B., Pottel, H., Cavalier, E. & Kuypers, D. 2019. Poor vitamin K status is associated with low bone mineral density and increased fracture risk in end-stage renal disease. Journal of Bone and Mineral Research 34(2): 262-269.

Forbes, J.M. & Cooper, M.E. 2013. Mechanisms of diabetic complications. Physiological Reviews 93(1): 137-188.

Fusaro, M., Noale, M., Viola, V., Galli, F., Tripepi, G., Vajente, N., Plebani, M., Zaninotto, M., Guglielmi, G., Miotto, D., Dalle Carbonare, L., D'Angelo, A., Naso, A., Grimaldi, C., Miozzo, D., Giannini, S. & Gallieni, M. 2012. Vitamin K, vertebral fractures, vascular calcifications, and mortality: Vitamin K Italian (VIKI) dialysis study. Journal of Bone and Mineral Research 27(11): 2271-2278.

Gallieni, M. & Fusaro, M. 2014. Vitamin K and cardiovascular calcification in CKD: Is patient supplementation on the horizon? Kidney International 86(2): 232-234.

Ghaderian, S.B., Hayati, F., Shayanpour, S. & Beladi Mousavi, S.S. 2015. Diabetes and end-stage renal disease: A review article on new concepts. J. Renal. Inj. Prev. 4(2): 28-33.

Goh, B.L., Ong, L.M. & Lim, Y.N. 2014. 21st Report of the Malaysian Dialysis & Transplant Registry 2013. Kuala Lumpur: The National Renal Registry Malaysia:  https://doi.org/10.1143/JJAP.35.L657.

Holden, R.M., Morton, A.R., Garland, J.S., Pavlov, A., Day, A.G. & Booth, S.L. 2010. Vitamins K and D status in stages 3-5 chronic kidney disease. Clinical Journal of the American Society of Nephrology 5(4): 590-597.

Ikeda, Y., Iki, M., Morita, A., Kajita, E., Kagamimori, S., Kagawa, Y. & Yoneshima, H. 2006. Nutritional epidemiology intake of fermented soybeans, natto, is associated with reduced bone loss in postmenopausal women: Japanese population-based osteoporosis (JPOS) study. Journal of Nutrition 136(5): 1323-1328.

Kaesler, N., Magdeleyns, E., Herfs, M., Schettgen, T., Brandenburg, V., Fliser, D., Vermeer, C., Floege, J., Schlieper, G. & Krüger, T. 2014. Impaired Vitamin K recycling in uremia is rescued by Vitamin K supplementation. Kidney Int. 86(2): 286-293.

Khir, A.S., Pheng, A.C.S., Endocrinologist, C., Panel, E., Abdullah, A.B.J., Radiologist, C. & Surgeon, C.O. 2012. Clinical practice guidelines on management of osteoporosis. Osteoporosis 2012: 1-53.

Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. 2009. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney International Suppl. 113: S1-130.

Kim, J.A., Kim, J.E., Song, S.H. & Kim, H.K. 2015. Influence of blood lipids on global coagulation test results. Ann. Lab. Med. 35(1): 15-21.

Klawansky, S., Komaroff, E., Cavanaugh Jr., P.F., Mitchell, D.Y., Gordon, M.J., Connelly, J.E. & Ross, S.D. 2003. Relationship between age, renal function and bone mineral density in the US population. Osteoporosis International 14(7): 570-576.

Kohlmeier, M., Saupe, J., Shearer, M.J., Schaefer, K. & Asmus, G. 1997. Bone health of adult hemodialysis patients is related to vitamin K status. Kidney International 51(4): 1218-1221.

Krueger, T., Westenfeld, R., Ketteler, M., Schurgers, L.J. & Floege, J. 2009. Vitamin K deficiency in CKD patients: A modifiable risk factor for vascular calcification? Kidney International 76(1): 18-22.

Lamon-Fava, S., Sadowski, J.A., Davidson, K.W., O’Brien, M.E., McNamara, J.R. & Schaefer, E.J. 1998. Plasma lipoproteins as carriers of phylloquinone (Vitamin K1) in humans. The American Journal of Clinical Nutrition 67(6): 1226-1231.

Larsson, S.C., Traylor, M. & Markus, H.S. 2018. Circulating vitamin K1 levels in relation to ischemic stroke and its subtypes: A mendelian randomization study. Nutrients 10(11): E1575.

Levey, A.S., Stevens, L.A., Schmid, C.H., Zhang, Y.L., Castro, A.F., Feldman, H.I., Kusek, J.W., Eggers, P., Van Lente, F., Greene, T. & Coresh, J. 2009. A new equation to estimate glomerular filtration rate. Annals. of Internal Medicine 150(9): 604-612.

Marinova, M., Lütjohann, D., Westhofen, P., Watzka, M., Breuer, O. & Oldenburg, J.A. 2011. Validated HPLC method for the determination of vitamin K in human serum - First application in a pharmacological study. The Open Clinical Chemistry Journal 4: 17-27.

McCabe, K.M., Adams, M.A. & Holden, R.M. 2013. Vitamin K status in chronic kidney disease. Nutrients 5(11): 4390-4398.

Newman, P., Bonello, F., Wierzbicki, A.S., Lumb, P., Savidge, G.F. & Shearer, M.J. 2002. The uptake of lipoprotein-borne phylloquinone (Vitamin K1) by osteoblasts and osteoblast-like cells: Role of heparan sulfate proteoglycans and apolipoprotein E. Journal of Bone and Mineral Research 17(3): 426-433.

Pilkey, R.M., Morton, A.R., Boffa, M.B., Noordhof, C., Day, A.G., Su, Y., Miller, L.M., Koschinsky, M.L. & Booth, S.L. 2007. Subclinical Vitamin K deficiency in hemodialysis patients. American Journal of Kidney Diseases 49(3): 432-439.

Pillai, A., Eranki, V., Shenoy, R. & Hadidi, M. 2011. Age related incidence and early outcomes of hip fractures: A prospective cohort study of 1177 patients. Journal of Orthopaedic Surgery and Research 6: 5. https://doi.org/10.1186/1749-799X-6-5.

Quick, A.J. 1975. The role of vitamins in hemostasis. Thromb. Diath. Haemorrh. 33(2): 191-198.

Sokoll, L.J. & Sadowski, J.A. 1996. Comparison of biochemical indexes for assessing status in a healthy adult population. American Journal of Clinical Nutrition 63(4): 566-573.

Tsugawa, N., Shiraki, M., Suhara, Y., Kamao, M., Tanaka, K. & Okano, T. 2006. Vitamin K status of healthy Japanese women: Age-related vitamin K requirement for gamma-carboxylation of osteocalcin. American Journal of Clinical Nutrition 83(2): 380-386.

Vissers, L.E., Dalmeijer, G.W., Boer, J.M., Monique Verschuren, W.M., van der Schouw, Y.T. & Beulens, J.W. 2013. Intake of dietary phylloquinone and menaquinones and risk of stroke. Journal of the American Heart Association 2(6): e000455.

van Ballegooijen, A.J., Cepelis, A., Visser, M., Brouwer, I.A., van Schoor, N.M. & Beulens, J.W. 2017. Joint association of low Vitamin D and Vitamin K status with blood pressure and hypertension. Hypertension 69(6): 1165-1172.

Yan, L., Zhou, B., Greenberg, D., Wang, L., Nigdikar, S., Prynne, C. & Prentice, A. 2004. Vitamin K status of older individuals in Northern China is superior to that of older individuals in the UK. British Journal of Nutrition 92(6): 939-945.

Zhang, Y., Zhou, W.E., Yan, J.Q., Liu, M., Zhou, Y., Shen, X., Ma, Y.L., Feng, X.S., Yang, J. & Li, G.H. 2018. A review of the extraction and determination methods of thirteen essential vitamins to the human body: An update from 2010. Molecules 23(6): E1484.

 

*Corresponding author; email: halimgafor@gmail.com

 

 

 

 

 

previous