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Measuring Vitamin, Mineral, and Trace Element Levels in Dialysis Patients Hesham Shaban, Muhammad Ubaid-Ullah, and Jeffrey S. Berns Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Interpretation of laboratory tests is quite often very different in patients who are on dialysis compared to the general population, as what is “normal” or used as a laboratory reference range for reporting of laboratory tests in the general population may not be readily applicable to individuals with advanced chronic and end-stage kidney disease. This article addresses interpretation and use of tests used to measure common vitamins and trace minerals in the blood.
patient had low levels (6). In another small study, serum folate levels were 37% lower among patients treated with high-flux dialyzers compared to those treated with low-flux dialyzers, although RBC folate levels were not different between these groups (8). Other investigators found no difference in serum folate levels between patients treated with conventional (15 hour/ week) HD (9). Vitamin B12
Folate Folate (folic acid) is important in the production of red blood cells (RBC). The most common consequence of folic acid deficiency is development of megaloblastic anemia. In a cost-effective analysis of testing in anemia, checking serum B12 or folate (1) in all anemic patients was determined not to be cost effective; a similar analysis has not been done in patients with anemia who are on dialysis. Folate can be measured in both serum and red blood cells (RBC). It is generally recommended that the serum folic acid levels be checked if the mean corpuscle volume (MCV) is >110 fl; however, doing so will miss approximately 5% of patients with folate deficiency. Therefore, if there is high clinical suspicion with a normal serum folic acid level, the RBC concentration should be checked (2,3). Among dialysis patients, some studies have reported that serum folate levels are generally normal (>10 nmol/l or >2 ng/ml) (4,5), while others have suggested that low or low-normal levels are common (6). One study found that 10% of HD patients had low serum levels (7). Patients on CAPD tend to have higher serum and RBC folate levels than HD patients (Table 1). Folic acid levels were low in 71.7% of hemodialysis (HD) patients, but only 3% of patients on chronic ambulatory peritoneal dialysis (CAPD) in one report. When RBC folate was tested, however, only 10% of HD patients and none of the CAPD Address correspondence to: Jeffrey S. Berns, MD, Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 6 (November–December) 2014 pp. 582–586 DOI: 10.1111/sdi.12260 © 2014 Wiley Periodicals, Inc.
Levels of vitamin B12 (cyanocobalamin) can also be directly measured in the serum. In the general population, the serum concentration has low sensitivity for tissue deficiency (10). Methylmalonic acid (MMA) is increased relatively early in the course of vitamin B12 deficiency (11) and is both highly sensitive and specific for tissue vitamin B12 deficiency (12). Published values for serum vitamin B12 and MMA levels in ESRD patients can be found in Table 1. Neither MMA nor vitamin B12 are effectively removed by HD (8,9,13). Vitamin B12 levels are generally within the normal range in patients on PD (14). L-Carnitine The main biological role of L-carnitine (levocarnitine) is to facilitate the transport of fatty acids across the inner mitochondrial membrane (15). Total, free, and acyl carnitine levels decrease with HD (16,17) (Table 2). During the first month of HD, these levels fall by approximately 30% and after 12 months, levels are typically decreased about 40% from baseline, with stable levels thereafter (15,17). Patients on nocturnal HD tend to have a greater fall in carnitine levels, particularly the acetyl form, compared to conventional hemodialysis (18). Patients on CAPD tend to maintain total carnitine levels in the normal range, but with reduced free carnitine levels (19). Trace Minerals Essential trace minerals, such as iron, zinc, copper, manganese, and fluoride make up less than 0.01% of total body weight and have a
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recommended daily intake (RDI) of less than 100 mg (20). The RDI for ultra-trace minerals such as selenium, arsenic, boron, chromium, iodine, silicon, nickel, and vanadium is typically less than 1 mg/day. Lead, aluminum, and mercury have no biological roles and are potential toxins. Patients on maintenance dialysis are exposed to large volumes of dialysate water and have variable clearance of trace minerals depending on dialytic modality, dialysis dose and frequency, dialyzer properties, compartmentalization, and concentration of competing and binding molecules (21–23). Optimal or normal blood and serum levels and the clinical significance of altered levels of most trace ele-
ments remain largely unclear (24–27). In general, HD patients have higher levels of cadmium, chromium, lead, and vanadium and lower levels of selenium, zinc, and manganese than the general population. Blood testing for trace metals should be triggered if there is high index of clinical suspicion of trace metal deficiency or toxicity (Tables 3 and 4). Zinc, Selenium, and Copper Zinc and selenium deficiency can be seen in ESRD patients, and are probably more common than actually diagnosed. Zinc deficiency is associated
TABLE 1. Vitamin levels Vitamin
RDA Units/day
Normal values (general population)
Serum levels in reported in patients on dialysis
Folate
400 lg (50)
B12
2.4 lg (58)
Serum: >10 nmol/L (4) >2 ng/ml (3) 13.1–74.3 nmol/l (59) RBC: 375–2500 nmol/l (4) 347–1167 nmol/l (59) >600 nmol/l (60) B12: 335–345 pmol/l (59) MMA: 60–210 pmol/l (59) >370 pmol/l = elevated (59)
Serum: 20.84 7.62 nmol/l (4) 14.1 nmol/l (range 6.6–75.6) (8) 5.8 3.6 ng/ml on PD (6) 2.0 1.1 ng/ml on HD (6) RBC: 1195.1 454 nmol/l (4) 1758 nmol/l (range 707–7399) (10) B12: HD 309 (range 186–504) pmol/l (61) Pre-HD 402 (range 276–1481) pmol/l (13) Post-HD 739 (range 47–1481) pmol/l (13) PD: 453 26 pmol/l (14) MMA: 987 (range 611–3402) pmol/l (61) Pre-HD 930 (range 527–2400) pmol/L (13) Post-HD 750 (range 540–1417) pmol/l (13)
TABLE 2. Carnitine levels RDA
Normal values (general population)
Total carnitine
Not established
53.3 8.4 lmol/l (16) 55.9 1.7 lmol/l (20) 49.2 9.3 lmol/l (17)
Free carnitine
Not established
47.1 7.7 lmol/l (16) 48.1 1.6 lmol/l (20) 43.3 8.6 lmol/l (17)
Acyl carnitine
Not established
6.2 2.4 lmol/l (16) 7.7 0.3 lmol/l (20) 6.7 2.1 lmol/l (17)
Serum levels in reported in patients on dialysis Pre-HD: 68.5 20.8 lmol/l (16) 68.1 11 lmol/l (16) Post-HD: 25.8 12.6 lmol/l (20) 36.1 2.0 lmol/l (21) >12 months of HD: pre-HD 42.6 5.4 lmol/l (17) Pre-HD 41.8 15.3 lmol/l (16) 36.5 5 lmol/l (21) Post-HD 11.4 6.1 lmol/l (16) 24.9 0.9 lmol/l (20) >12 months of HD pre-HD 22.0 5.4 lmol/l (17) Pre-HD: 22.7 10.4 lmol/l (16) 19.8 8.9 lmol/l (17) Post-HD 14.2 9.6 lmol/l (16) 11.5 0.5 lmol/l (20) >12 months of HD pre-HD 9.2 3.4 lmol/l (17)
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with delayed wound healing, reduced immunity, erythropoietin (EPO) resistance, dysgeusia, erectile dysfunction and reduced libido, and oxidative stress (28–30). Deficiency is more prevalent in diabetics (27). Zinc levels should be corrected for the serum albumin concentration (see Table 3) (27,31). Zinc replacement has been reported to improve anemia and reduce EPO requirements (32,33). In one study, serum Zn
Shaban et al.
Measuring Vitamin, Mineral, and Trace Element Levels in Dialysis Patients Hesham Shaban, Muhammad Ubaid-Ullah, and Jeffrey S. Berns Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
Interpretation of laboratory tests is quite often very different in patients who are on dialysis compared to the general population, as what is “normal” or used as a laboratory reference range for reporting of laboratory tests in the general population may not be readily applicable to individuals with advanced chronic and end-stage kidney disease. This article addresses interpretation and use of tests used to measure common vitamins and trace minerals in the blood.
patient had low levels (6). In another small study, serum folate levels were 37% lower among patients treated with high-flux dialyzers compared to those treated with low-flux dialyzers, although RBC folate levels were not different between these groups (8). Other investigators found no difference in serum folate levels between patients treated with conventional (15 hour/ week) HD (9). Vitamin B12
Folate Folate (folic acid) is important in the production of red blood cells (RBC). The most common consequence of folic acid deficiency is development of megaloblastic anemia. In a cost-effective analysis of testing in anemia, checking serum B12 or folate (1) in all anemic patients was determined not to be cost effective; a similar analysis has not been done in patients with anemia who are on dialysis. Folate can be measured in both serum and red blood cells (RBC). It is generally recommended that the serum folic acid levels be checked if the mean corpuscle volume (MCV) is >110 fl; however, doing so will miss approximately 5% of patients with folate deficiency. Therefore, if there is high clinical suspicion with a normal serum folic acid level, the RBC concentration should be checked (2,3). Among dialysis patients, some studies have reported that serum folate levels are generally normal (>10 nmol/l or >2 ng/ml) (4,5), while others have suggested that low or low-normal levels are common (6). One study found that 10% of HD patients had low serum levels (7). Patients on CAPD tend to have higher serum and RBC folate levels than HD patients (Table 1). Folic acid levels were low in 71.7% of hemodialysis (HD) patients, but only 3% of patients on chronic ambulatory peritoneal dialysis (CAPD) in one report. When RBC folate was tested, however, only 10% of HD patients and none of the CAPD Address correspondence to: Jeffrey S. Berns, MD, Perelman School of Medicine at the University of Pennsylvania, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 6 (November–December) 2014 pp. 582–586 DOI: 10.1111/sdi.12260 © 2014 Wiley Periodicals, Inc.
Levels of vitamin B12 (cyanocobalamin) can also be directly measured in the serum. In the general population, the serum concentration has low sensitivity for tissue deficiency (10). Methylmalonic acid (MMA) is increased relatively early in the course of vitamin B12 deficiency (11) and is both highly sensitive and specific for tissue vitamin B12 deficiency (12). Published values for serum vitamin B12 and MMA levels in ESRD patients can be found in Table 1. Neither MMA nor vitamin B12 are effectively removed by HD (8,9,13). Vitamin B12 levels are generally within the normal range in patients on PD (14). L-Carnitine The main biological role of L-carnitine (levocarnitine) is to facilitate the transport of fatty acids across the inner mitochondrial membrane (15). Total, free, and acyl carnitine levels decrease with HD (16,17) (Table 2). During the first month of HD, these levels fall by approximately 30% and after 12 months, levels are typically decreased about 40% from baseline, with stable levels thereafter (15,17). Patients on nocturnal HD tend to have a greater fall in carnitine levels, particularly the acetyl form, compared to conventional hemodialysis (18). Patients on CAPD tend to maintain total carnitine levels in the normal range, but with reduced free carnitine levels (19). Trace Minerals Essential trace minerals, such as iron, zinc, copper, manganese, and fluoride make up less than 0.01% of total body weight and have a
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MEASURING VITAMIN, MINERAL, AND TRACE ELEMENT LEVELS
recommended daily intake (RDI) of less than 100 mg (20). The RDI for ultra-trace minerals such as selenium, arsenic, boron, chromium, iodine, silicon, nickel, and vanadium is typically less than 1 mg/day. Lead, aluminum, and mercury have no biological roles and are potential toxins. Patients on maintenance dialysis are exposed to large volumes of dialysate water and have variable clearance of trace minerals depending on dialytic modality, dialysis dose and frequency, dialyzer properties, compartmentalization, and concentration of competing and binding molecules (21–23). Optimal or normal blood and serum levels and the clinical significance of altered levels of most trace ele-
ments remain largely unclear (24–27). In general, HD patients have higher levels of cadmium, chromium, lead, and vanadium and lower levels of selenium, zinc, and manganese than the general population. Blood testing for trace metals should be triggered if there is high index of clinical suspicion of trace metal deficiency or toxicity (Tables 3 and 4). Zinc, Selenium, and Copper Zinc and selenium deficiency can be seen in ESRD patients, and are probably more common than actually diagnosed. Zinc deficiency is associated
TABLE 1. Vitamin levels Vitamin
RDA Units/day
Normal values (general population)
Serum levels in reported in patients on dialysis
Folate
400 lg (50)
B12
2.4 lg (58)
Serum: >10 nmol/L (4) >2 ng/ml (3) 13.1–74.3 nmol/l (59) RBC: 375–2500 nmol/l (4) 347–1167 nmol/l (59) >600 nmol/l (60) B12: 335–345 pmol/l (59) MMA: 60–210 pmol/l (59) >370 pmol/l = elevated (59)
Serum: 20.84 7.62 nmol/l (4) 14.1 nmol/l (range 6.6–75.6) (8) 5.8 3.6 ng/ml on PD (6) 2.0 1.1 ng/ml on HD (6) RBC: 1195.1 454 nmol/l (4) 1758 nmol/l (range 707–7399) (10) B12: HD 309 (range 186–504) pmol/l (61) Pre-HD 402 (range 276–1481) pmol/l (13) Post-HD 739 (range 47–1481) pmol/l (13) PD: 453 26 pmol/l (14) MMA: 987 (range 611–3402) pmol/l (61) Pre-HD 930 (range 527–2400) pmol/L (13) Post-HD 750 (range 540–1417) pmol/l (13)
TABLE 2. Carnitine levels RDA
Normal values (general population)
Total carnitine
Not established
53.3 8.4 lmol/l (16) 55.9 1.7 lmol/l (20) 49.2 9.3 lmol/l (17)
Free carnitine
Not established
47.1 7.7 lmol/l (16) 48.1 1.6 lmol/l (20) 43.3 8.6 lmol/l (17)
Acyl carnitine
Not established
6.2 2.4 lmol/l (16) 7.7 0.3 lmol/l (20) 6.7 2.1 lmol/l (17)
Serum levels in reported in patients on dialysis Pre-HD: 68.5 20.8 lmol/l (16) 68.1 11 lmol/l (16) Post-HD: 25.8 12.6 lmol/l (20) 36.1 2.0 lmol/l (21) >12 months of HD: pre-HD 42.6 5.4 lmol/l (17) Pre-HD 41.8 15.3 lmol/l (16) 36.5 5 lmol/l (21) Post-HD 11.4 6.1 lmol/l (16) 24.9 0.9 lmol/l (20) >12 months of HD pre-HD 22.0 5.4 lmol/l (17) Pre-HD: 22.7 10.4 lmol/l (16) 19.8 8.9 lmol/l (17) Post-HD 14.2 9.6 lmol/l (16) 11.5 0.5 lmol/l (20) >12 months of HD pre-HD 9.2 3.4 lmol/l (17)
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with delayed wound healing, reduced immunity, erythropoietin (EPO) resistance, dysgeusia, erectile dysfunction and reduced libido, and oxidative stress (28–30). Deficiency is more prevalent in diabetics (27). Zinc levels should be corrected for the serum albumin concentration (see Table 3) (27,31). Zinc replacement has been reported to improve anemia and reduce EPO requirements (32,33). In one study, serum Zn
