Kidney News January 2012, 4#1 : Page 3
January 2012 | ASN Kidney News | 3 Calcium Paradox Continued from page 1 cine, Robley Rex VA Medical Center and University of Louisville School of Medicine in Louisville, KY. “A fall in 1,25 hydroxyvitamin D is the first measurable change in mineral metabo-lism noted during the course of CKD, long before the onset of hyperparathy-roidism, hyperphosphatemia, or hy-pocalcemia. The nearly universal prev-alence of bone mineral disorders in this population suggests strongly the need for vitamin D replacement.” In December of 2010, the Institute of Medicine (IOM) raised the Recom-mended Daily Allowance (RDA) of vi-tamin D for young adults from 200 IU (International Units) to 600 IU while the RDA for people over 70 was raised to 800 IU. Vitamin D3 is a vital cofactor in both bone mineralization and calcium absorption in the intestines. When synthesized in the kidneys, the vitamin is released into the circulation and acts as a hormone, regulating (among other things) the concentration of calcium and phosphate in the bloodstream, promoting the healthy mineralization, growth, and remodeling of bone tissue. It does this by binding to vitamin D-binding protein (VDR). The binding of vitamin D3 to the VDR acts as a transcription factor that modulates gene expression of transport proteins such as TRPV6 and calcindin, which are involved in calcium absorption in the intestine. Vitamin D also acts to inhibit vas-cular calcification by blocking the release of fat-derived inflammatory cytokines that contribute to both in-flammation and adhesion in the arter-ies and elsewhere. These cytokines play a role in atherosclerosis and osteoporo-sis. Several inflammatory cytokines are induced by oxidative stress, and are a factor in chronic inflammation. Also taking center stage for its role in mediating calcium regulation is Vi-tamin K. Research shows that without adequate vitamin K to meditate this process, calcium saturates the arte-rial walls and other soft tissues. It ap-pears that vitamin K deficiency helps to explain the “calcium paradox”—the apparent relationship between oste-oporosis and atheroscelosis. The discovery that blood vessel cells can transform into bone-forming cells confirmed this link. While low vita-min D is linked with arterial disease and osteoporosis, vitamin K’s role is to stimulate bone formation and modify specific Gla proteins that prevent calci-fication outside of bone tissue. How does Vitamin K help prevent calcification outside of bone? It acts as a co-factor required to convert the amino acid glutamate into one of about 15 human proteins with Gla domains, including matrix Gla protein (MGP). MGP is a vitamin K–dependent protein secreted in cartilage, lung, heart, kidney, and arteries. While the precise mechanism of action is not completely understood, it is generally accepted that MGP is a strong inhibi-tor of soft tissue calcification. In the April 2010 issue of the Clini-cal Journal of the American Society of Nephrology, Leon Schurgers noted that “Vitamin K–dependent MGP acts as a calcification inhibitor,” and that, “lev-els of the inactive, dephosphorylated, uncarboxylated MGP (dp-uc MGP) increased progressively in a CKD set-ting, and thus could be a marker for vascular calcification in CKD.” Noting that “the majority of dialysis patients exhibit pronounced vitamin K deficiency,” the authors of a February 2011 Journal of the American Society of Nephrology article said that more study needs to be done to see whether vitamin K supplementation improves outcomes in hemodialysis patients. The article, “Circulating nonphospho-rylated carboxylated gla protein pre-dicts survival in ESRD,” was jointly authored under G.Schlieper of the Department of Nephrology and Clini-cal Immunolgy, Rheinishe -Westfalishe Technische, in Aachen, Germany. Know your Vitamin K: Some Forms Protect Heart and Kidneys More than Others By Leon Schurgers Vitamin K has long been regarded solely as a coagulation co-factor, thus the name “the coagulation vita-min.” This concept is now outdated. Vitamin K-dependent proteins have a role outside coagulation. Vitamin K can be subdivided into vitamin K1 and the menaquinones (vitamin K2). Vitamin K is a fam-ily name for a series of compounds that have in common a 2-methyl-1,4-naphthoquinone ring structure but differ in their aliphatic side chain at the 3-position. Most studies on Vitamin K use either K1 or menaquinone-4 (MK-4). The reason for this is that both syn-thetic vitamins have been available on the market for many years. Aware-ness of the beneficial properties of long-chain menaquinones like MK-7 only arose in the last decade. Stud-ies by our group and others showed that long chain menaquinones ben-efit from great intestinal absorption, a long plasma half-life, and a high bioactivity compared with both K1 and MK-4. After absorption, all K vitamins are incorporated into chylomicrons and enter the bloodstream, and are then rapidly cleared by the liver. A vi-tamin K deficiency is therefore very uncommon in the normal population. A redistribution of K vitamins for extrahepatic tissues occurs in the liver. The hypothesis is that only at hepatic vitamin K sufficiency is vi-tamin K (notably the long-chain me-naquinones) incorporated into LDL and available for extrahepatic tis-sues. Thus, the first signs of vitamin K insufficiency are seen in bone and vasculature. Indeed, the occurence of PIVKA-II (protein induced by vita-min K-absence II; ucFII) is very rare whereas uncarboxylated osteocalcin and uncarboxylated matrix Gla-pro-teins are very common in the general population. In cross-sectional analysis among ~5000 elderly apparently healthy individuals in the Netherlands, we have demonstrated that dietary vita-min K2 intake was inversely associ-ated with vascular calcification and mortality. After adjustment for poten-tial confounders, the cardiovascular mortality in the highest tertile for vita-min K2 intake was 50 percent lower than in the lowest tertile for vitamin K2 intake. Such association was not found for phylloquinone. These results were confirmed in a recent analysis of over 16,000 postmeno-pausal women. It was found that the forms of vitamin K2 with the highest cardioprotective activity were the long-chain menaquinones MK-7, MK-8, and MK-9. These are the forms found in cheese and curd cheese. In this study, the effect of vitamin K2 was a reduction of cardiovascular disease of 9 percent for every 10 µ g of dietary K2. Longitudinal studies in healthy volunteers and patients suffering from vitamin K deficiency will ad-dress whether vitamin K supple-mentation can inhibit vascular calci-fication and outcome. A recent pilot study demonstrated that the dose-dependent supplementation of MK-7 in hemodialysis patients resulted in a significant reduction of the circulat-ing inactive form of matrix Gla-pro-tein. Whether the supplementation of vitamin K2 could inhibit vascular calcification and subsequent cardio-vascular mortality is the subject of current research. Leon Schurgers, MD, is with the de-partment of biochemistry, Cardiovas-cular Research Institute Maastricht, Maastricht, the Netherlands. Hepatitis CKD Risk Continued from page 1 EuroSIDA international cohort of more than 16,500 HIV-infected patients, in-vestigators found that when compared to HIV-infected people who were negative for HCV antibodies, individuals who were positive for HCV antibodies had a 98 per-cent increased incidence of CKD. HCV antibodies indicate exposure to the virus at some point and may persist even if the virus is cleared from the body naturally or by treatment. Viremia, or cir-culating HCV RNA, indicates an active infection. Patients eligible for the study had at least three serum creatinine determina-tions after January 1, 2004. Their HCV antibody status was known. The base-line estimated glomerular filtration rate (eGFR) was the first one recorded, and CKD was defined either as an eGFR less than or equal to 60 mL/min/1.73 m 2 for individuals with baselines above this point, or as a 25 percent decline in eGFR for in-dividuals whose baseline was at or below 60 mL/min/1.73 m 2 . Among 8001 patients, 1964 (24.5 per-cent) were positive for HCV antibodies. Of these, 972 (49.5 percent) were HCV RNA-positive. At baseline, the median age was 41 years, the median CD4 T cell count was 439 cells/mm 3 (range 294–627), and the median eGFR was 97.6 mL/min/1.73 m 2 (range 83.8–113.0). Progression to CKD occurred in 410 patients (5.1 percent)—an incidence of 13.6 per 1000 person-years of follow up. For those who progressed to CKD these variables were accounted for: cumulative use of nephrotoxic drugs and antiretroviral drugs, CD4 counts and na-dirs, age, gender, and diabetes. Patients with HCV antibodies who had HCV viremia or had unknown HCV RNA status in their blood were at signifi-cantly higher risk for CKD. The higher the viral load, the higher the incidence of CKD (p< 0.04 for all viral loads greater than 615 IU/mL). Individuals with antibodies but who had undetectable viral loads (<615 IU/mL) were at no greater risk for CKD compared to patients without HCV antibodies. The incidence of CKD was not associated with the HCV viral genotype. Rockstroh said it is not known why patients with HCV are at higher risk for the development of CKD. “One point could be that patients who have chronic hepatitis C obviously will have different stages of liver disease, and in very end stage liver disease you can often have what we call hepatorenal syndrome, so there are perfusion issues with the kid-ney, and then you can get kidney failure,” he speculated. Another contributing factor could be altered drug metabolism by the liver, leading to levels of antiretroviral drugs that may cause renal tubular damage. A remaining question is whether suc-cessful treatment and clearance of HCV can reverse kidney disease. The EuroSIDA database probably has too few successfully treated patients to answer the question since many come from Eastern Europe, where treatment is often not available. At this point, Rockstroh recommends careful selection of any renal toxic antiret-roviral drugs. Beyond that, “we just have to monitor renal function and renal disease parameters more closely in [HIV] patients with hepatitis C in the future,” he said.
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