Oral Vitamin D: Potential Influence on Hemoglobin Levels in ESRD Patients with Anemia
Anemia among people with chronic kidney disease (CKD) is common. Approximately 50 percent of people with CKD show signs of anemia, which increases progressively with declining kidney function. Approximately 90 percent of people on renal replacement therapy are anemic. Furthermore, patients with anemia have an increased risk of all-cause mortality. The current standard treatment for anemia in dialysis patients is to target low hemoglobin (Hgb) with the administration of erythropoiesis stimulating agents (ESAs), which include epoetin alpha, darbopoietin and methoxy polyethylene glycol-epoetin beta. In addition, within the last five years research has indicated that a normalization of serum vitamin D, aided by pharmacological doses of oral vitamin D supplement, may also improve Hgb levels. Although not yet conclusive, vitamin D normalization may offer a viable supplemental or alternative therapy for patients who experience hyporesponsiveness or negative side effects with ESAs.
Causes of anemia and iron deficiency
The causes of anemia in CKD are multifactorial. The most-common cause is a decrease of erythropoietin production with a worsening glomerular filtration rate (GFR). This may be exacerbated by other contributing factors, such as iron deficiency, folate and vitamin B12 deficiencies, reduced red blood cell life span, and suppression of erythropoiesis within the uremic state. Careful evaluation of the etiology of anemia for each individual is an important step in determining treatment of anemia.
Many people on renal replacement are iron deficient; however, the mechanism for iron loss has been poorly defined. One common suspect is poor iron cycling, which is most likely influenced by both chronic inflammation and poor dietary intestinal absorption. Laboratory methods of determining iron deficiency include testing serum or plasma transferrin, ferritin and Hgb levels. However, in the face of inflammation, these laboratory markers are commonly elevated and do not reflect true body stores of iron.
Research trials have attempted to examine the mechanisms affecting iron and blood cell utilization in the context of inflammation. In particular, the iron exporter ferroportin is upregulated by the amount of available iron and is degraded by the iron-regulating protein hepcidin. Previous studies evaluating hepcidin indicate its potential role in the maintenance of increased Hgb levels. Studies have shown that Hgb levels are inversely related to changes in hepcidin.
Vitamin D and iron regulation
Several studies have examined vitamin D as a possible mediator of hepcidin. Normalized blood values of vitamin D (> 30 ng/mL) have been associated with lower levels of hepcidin and improved anemia indicators. However, resolving hypovitaminosis D can lead to variations in hepcidin reduction. These varied results may be due to an inverse, dose-dependent relationship as well as to use of the oral form of inactive vitamin D as opposed the activated form of vitamin D (1,25-(OH)D, such as calcitriol). Therefore, the goal of current research is to clarify both the appropriate form of vitamin D and dose recommendations to lower hepcidin and normalized serum vitamin D levels.
One study of healthy volunteers found that a one-time high dose of 100,000 IU vitamin D2 yielded a 35 percent decrease in circulating hepcidin levels. Another 2016 study found a 73 percent decrease in hepcidin with a 250,000 IU dose of D3. Although neither study found statistical differences in Hgb levels, results indicate the role vitamin D could play in iron cycling. A follow-up study found an oral dose of 500,000 IU resulted in significantly higher increases in Hgb over time than a 250,000 IU dose in ventilated ICU patients. These results were found independent of inflammatory markers. Similarly, a 2011 cohort trial conducted in a hemodialysis clinic on patients with anemia found a decreased need for epoietin alpha in all study patients when an oral dose of D2 was administered over four to six weeks. Although these results were not statistically significant, the authors conclude that additional clinical trials are warranted and may result in changes to anemia management protocols in dialysis units.
Vitamin D is currently a key treatment in managing hyperparathyroidism and renal osteodystrophy in CKD. However, optimum levels of vitamin D are controversial and evidence linking serum vitamin D levels to bone density has been varied. It is perhaps due to this lack of evidence that serum vitamin D is not a standard test on renal lab panels in many dialysis clinics. Vitamin D supplementation for anemia management is not currently supported by sufficient clinical data. However, existing data do indicate that when vitamin D levels are normalized with high-dose oral vitamin D supplementation, iron cycling and (possibly) Hgb may improve. Vitamin D normalization may offer a safe and cost-effective therapy option for anemic patients who are hyporesponsive to ESAs. Additional trials may help to more clearly define optimal doses of vitamin D for hepcidin—and, ultimately, anemia—management.