Current prevalence of vitamin B6 deficiency in hemodialysis and peritoneal dialysis patients

ORIGINAL

RESEARCH

Current Prevalence of Vitamin B6 Deficiency in Hemodialysis and Peritoneal Dialysis Patients Cheryl L. Rock, PhD, RD, FADA, * Martha Bidigave DeRoeck, MS, RD, f Daniel W. Gorenzo, PhD,# Margaret G.]ahnke, RD,g‘Richard D. Swartx, MD,(l and Joseph 111.Messana, MDT

Objective: To describe the current prevalence of vitamin Bs deficiency based on erythrocyte glutamic pyruvic transaminase (EGPT) index in dialysis patients. Design: Cross-sectional descriptive study. Setting: Four ambulatory clinical sites, including two hemodialysis clinics, one outpatient clinic for peritoneal dialysis patients, and one site providing care to both hemodialysis and peritoneal dialysis patients (a universityaffiliated medical center). Patients: One hundred five adult dialysis patients (63 men and 42 women; ages 21 to 84 years) participated in this study. The ethnic makeup of the patient population in this study is as follows: 76 white, 24 black, and 5 patients of unknown ethnic@ Seventy-five percent were hemodialysis patients, and 25% were peritoneal dialysis patients. Intervention: Vitamin B6 status was measured with the EGPT index. Assessment of dietary intake during the preceding 3 months was conducted with a standardized food frequency questionnaire. Body composition was estimated with skinfold thickness measures. Main outcome measure: Fifteen (14%) patients were found to be vitamin B6 deficient on the basis of an abnormal EGPT index of ~1.25. Vitamin B6 supplementation, dietary vitamin Bs or protein intake, type of dialysis, medication usage, gender, age, and ethnic group were not associated with or predictive of vitamin B6 status. Diabetes comorbidity and abnormal EGPT index were significantly associated (P < .02), and logistic regression analysis revealed diabetes to be a significant independent predictor of vitamin B6 deficiency (odds ratio = 7.32, 95% confidence interval = 2.06-25.99). Conclusion: Diabetes comorbidity is associated with increased risk for vitamin B6 deficiency in dialysis patients. 8 1997 by the National Kidney Foundation, Inc.

D

IALYSIS PATIENTS have increased risk for deficiencies of water-soluble vitamins,‘,2 which has been attributed to inadequate intake, increased losses during the dialysis procedure, and

*Associate

Professsor, Department

University of Cal@& fGradunte Student,

ofFamily

San Diego, LaJolla, Program in Humm

Michigan, Am Arbor, Ml, #Research Investiptor, Departmer~t

ojFamily

Michigan, Ann Arbor, MI. $Graduate Student, Program itI Human Michigan, Awn Arbor, MI. IlProfessor, Department ofInternal Medicine, Programs, UGmsity ofMichigarr, Ann Arbor,

10

and Preventive CA. Nutrition, Practice, Nutritim, Co-Director Ml.

Medicine, University University University ofDia@

altered metabolism caused by renal dysfunction.3-5 Ross et al6 observed low plasma concentrations of pyridoxal-5-phosphate (PLP) in unsupplemented peritoneal dialysis patients, which they attributed

ljAssistant Professor, Departmenf oj,flnternal Medicine, Dialysis Programs, UGversity ofMichigm, Ann Arbor, oj of 4

Funded

in part by researchgrantfrom

ofthe National Kidney Foundation. Address reprint requests to Cheryl

the Council L. Rock,

Co-Director MI.

ott Rerwl PhD,

RD,

of

Nutrition FADA,

Department of Family and Preventive Medicine, Cancer Prevetrtiorr and Corrtrol, University of Cdfwnin San Diego, 9500 Cilmm Drive, La Jolla, CA 92093.0901. Q 1997 by the Natiorml Kidney Found&w, Im. 1051-2276/97/0701-0003~03.00

Journal

ofRenal

Nutritim,

Vol

7. No

1 (January),

1997:

pp IO-16

VITAMIN

to inadequate dietary intake and impaired phosphorylation of precursors. Kopple et al’ found a high prevalence of vitamin Bh deficiency based on low baseline erythrocyte glutamic pyruvic transaminase (EGPT) activity and increased EGPT index in unsupplemented patients undergoing hemodialysis or peritoneal dialysis therapy, which could be normalized by providing 5 to 10 mg vitamin B6/d. Based on serial measures of erythoxaloacetate transminase rocyte glutamate (EGOT) activity in patients receiving various amounts of supplemental vitamin Bf,, Descombes et al8 concluded that administering 150 mg/wk would prevent vitamin Bb deficiency in these patients. Currently, vitamin supplements that include 10 mg vitamin Bh/d are generally recommended as a standard component of nutritional care and are prescribed for the majority of dialysis patients.“,“’ Two major considerations contribute to variability in previous investigations of vitamin Bh status of dialysis patients. First, the different approaches used in the biochemical assessment of the status of this vitamin are known to be influenced by disparate factors and thus are likely to yield different prevalence figures, Second, the various reports involve patient populations that differ considerably with respect to whether vitamin supplementation had been prescribed, which will unquestionably influence micronutrient status. Also, numerous dietary and nondietary factors such as protein intake and age have been shown to influence vitamin Be requirements and status in the general population, and these factors have not been previously examined in dialysis patients.” The purpose of this cross-sectional study was to describe the current prevalence of vitamin B6 deficiency, based on EGPT index, in a representative sample of hemodialysis and peritoneal dialysis patients. A second objective was to examine the relationships among vitamin Bb status, demographic variables, dietary intake, and other possible factors in this patient population.

Methods Subjects Patients with end-stage renal disease who were being treated regularly with hemodialysis or peritoneal dialysis were recruited during an 1&month period beginning in October, 1993, from four ambulatory clinical sites. Two of the sites were

Bh DEFICIENCY

11

hemodialysis units, one site was an outpatient clinic in which peritoneal dialysis patients were provided care, and one site provided care to both hemodialysis and peritoneal dialysis patients (a university-affiliated medical center). Criteria for inclusion in this study were the following: 18 years of age or older, clinical stability, and capability of providing informed consent. Clinical stability was defined as the lack of active malignancy or concurrent acute illness in a patient who had been receiving dialysis treatments for a minimum of 3 months. Exclusion criteria were the following: pregnancy or lactation at the time of the study, and major mental disabilities that would limit the patient’s ability to give competent and informed consent. Procedures for this study were approved by the Institutional Review Board of the University of Michigan and the Mission Health-St. Joseph Mercy Hospital Clinical Research Committee.

Procedures Eligible patients at each clinical site were offered a chance to participate in this study. After providing informed consent, each patient was asked to complete a food frequency questionnaire. Patients who were unable to read were queried with the questionnaire items verbally, and their responses were recorded. Demographic data (age, gender, and ethnicity) and medical information used in the analysis were obtained by review of medical records. Medical information also included cause of end-stage renal failure, past medical history, current medications, and use of prescribed or recommended nutritional supplements.

Body composition was estimated using caliper measurements(Lange, Cambridge, MD) of skinfold thickness and percent of body fat was calculated by the method of Durnin and Wormersley.” Height, current weight, and estimated dry weight were obtained from eachpatient’s medical record. Actual measuredweight can be problematic in patients with chronic renal &lure because of water retention and edema. A better reflection of lean body massand adiposetissue, and a figure that ismore comparableto the weight of individuals without renal disease,is the estimated dry weight. This is operationally defined asthe asymptomatic minimum body weight, after dialysis, when the patient is neither hypertensive nor

12

ROCK

hypotensive. ‘a Estimated body mass index (kg/ ma) was calculated using the patient’s height and the current estimated dry weight.

Dietary Assessment Dietary assessment was conducted with the Fred Hutchinson Cancer Research Center (Seattle, WA) Food Frequency Questionnaire and is based on the software for analysis, which Minnesota Nutrition Data System (University of Minnesota, Minneapolis, MN) nutrient database. The purpose of using a food frequency questionnaire was to characterize the patients across a range of dietary intake, which would permit examination of the relative importance of diet in predicting the primary outcome variable, EGPT index. Patients were asked to report their intake during the past 3 months, and these frequencies are adjusted based on reported preparation methods (eg, frying, adding butter or salad dressing) and serving size in the analysis.

Biochemical Measures Blood samples were collected in heparinized tubes and protected from light throughout processing and handling. In the majority of cases, blood samples were obtained at least 3 hours postprandially. Separation of plasma was accomplished with centrifugation at 2,300 g for 10 minutes. None of the samples appeared grossly lipemic after collection and separation. Erythrocytes were washed twice with normal saline and stored in aliquots at -70°C in cryogenic tubes until analysis. Biochemical measurement of vitamin Be status consisted of analysis of in vitro EGPT activity before and after PLP was added according to the method of Tonhazy et all3 The EGPT index was used to define vitamin B6 status as adequate (EGPT index of < 1.25) or deficient (2 1.25). To verify methodology and laboratory technique, this enzyme assay was also performed using erythrocytes obtained from 23 healthy subjects, using the same methods of collection and manner of blood processing described above.

ET AL

analysis. The primary outcome variable was vitamin B6 status as defined by results from the EGPT index assay, examined as a dichotomous variable as is the accepted use of this measure in vitamin Bb assessment.‘4%15 The relationships between patient characteristics of interest, dietary variables, and vitamin B6 status based on EGPT index were first examined with the appropriate univariate technique (chisquare or t test). Using the chi-square test, vitamin B6 status based on EGPT index (normal or deficient) versus gender, major ethnic group (eg, white, black), supplement use, type of dialysis (eg, hemodialysis, peritoneal dialysis), medication categories, and diabetes comorbidity was analyzed. Using the t test, the distributions of continuous variables such as estimated body mass index, age, plasma lipids, energy-adjusted protein intake, and other dietary variables in the two vitamin Bb status groups were compared. Correlations among the continuous variables (eg, estimated body mass index, age, energy, and protein intake) were examined using Pearson product-moment correlations. Previously reviewed by other investigators,16-18 total energy intake is highly correlated with many dietary factors, and therefore dietary variables were adjusted for energy in the tests of association. Other studies”~*” indicate that the most stable estimates of association and the greatest power to detect associations are provided by either the nutrient density method or the residual method. Thus, energy-adjusted associations described in the analysis of dietary variables in the present study are based on the nutrient density method of energy adjustment.i’ Based on the results of the univariate tests, a logistic regression model was developed for vitamin B6 status based on EGPT index. The model was established using forward and backward stepwise selection using the likelihood-ratio test to determine variables to be added or removed from the model. All analyses were performed using programs available in SPSS PC+ (version 6.1, 1994; SPSS, Chicago, IL). For descriptive purposes, results are expressed as the means + SEM.

Statistical Methods Initially, descriptive statistics were calculated on all variables. Those variables not normally distributed (eg, dietary variables) were log transformed to achieve normal distribution before

Results Study Subjects A total of 105 patients were recruited for this study: 76 white patients, 24 black patients, and 5

VITAMIN

EGPT Index

Table 1. Age and Anthropometric Characteristics of Dialysis Patients With or Without Vitamin B6 Deficiency Based on EGPT Index Adequate Vitamin Bs Status* (n = 90) Age (yr) Estimated body index (kg/m2) Body fat 1%)

Vitamin Bg Deficient* (n = 15)

57.3

k 1.8

59.1

2 3.8

24.6 20.3

5 .6 2 .9

22.3 2 1.1 17.5 F 1.6

mass

Note: Results are expressed as the mean 2 SEM. *Vitamin Bs status was defined as adequate (EGPT index of ~1.25) and deficient (EGPT index of ~1.25).

patients of other (eg, Asian-American, Native American) or unknown ethnicities. The patients were aged 57.6 ? 1.6 years (range, 21 to 84 years). Sixty-three of the patients were men and 42 were women. The major causesof renal failure were primary kidney disease(ie, glomerulonephritis) in 33 (31%) patients, hypertension in 26 (25%) patients, diabetesin 23 (22%) patients, and other or unknown causesin 23 (22%) patients. Diabetes mellitus wasnamedasthe causeof the renal failure or asa comorbid condition in a total of 24 (23%) patients. Seventy-nine (75%)patients were receiving hemodialysis therapy, and the remainder (26, or 25%) were receiving peritoneal dialysistherapy. Data from completed food frequency questionnaires were available for 102 of the 105 patients because three of the questionnaires were misplaced. Seventy-six (72%) patients were prescribed multiple vitamin supplementscontaining vitamin Bb that provided 10 mg vitamin B6/d, for example, Nephrocaps (Fleming and Co, Fenton, MO) and Nephrovites (Rand D Laboratories, Marina de1Ray, CA).

Table 2. Dietary Intake, Excluding Supplements, Deficiency Based on EGPT Index Adequate Status*

Vitamin B6 (n = 87)

Energy (kcal/d) Protein (g/d) Carbohydrate (g/d) Fat (g/d)

1440 ? 68 53.9 k 2.7 165.1 + 8.8 64.0 ? 3.3

Vitamin Bs (mg/d) Vitamin B12 @g/d) Folate (ugld)

1.1 t .l 4.2 2 .2 168 5 9

Note: Results are expressed as the mean 2 SEM. ‘Vitamin B6 statuswas defined as adequate (EGPT tData from JD Kopple40 and Devine and DiChiro.9

13

B6 DEFICIENCY

Fifteen of total 105 patients were found to be vitamin B6 deficient on the basisof an abnormal EGPT index of 21.25. The difference between vitamin Bh deficiency in patients receiving hemodialysis and patients receiving peritoneal dialysis therapy wasnot significant (3 of 26 [12%] patients 1112 of 79 [15%] patients, respectively). Gender, age, and ethnicity were not significantly different in those patients deficient in vitamin B, versus patientswith adequatevitamin B6 status.Prescription medications used by the group identified as vitamin Bh deficient did not differ from those used by patients with adequate vitamin Bh status.Nine of the 15 patients who were vitamin Bh deficient had been prescribed vitamin supplementscontaining vitamin B,,, and a significant relationship between the use of vitamin supplementscontaining vitamin Bb and abnormal EGPT index was not observed (relative risk = .52; 95% CI = .151.62; P = .25). However, a significant association was observed between diabetescomorbidity and vitamin B, deficiency (chi square;P < .02). Age and anthropometric characteristicsdid not differ between the patients with vitamin B6 deficiency versus those without vitamin Bh deficiency (Table 1). Dietary intake (excluding supplements) of selectednutrients of the two groups of patients is shown in Table 2, in addition to recommended amounts of supplementation (prescribed for 72% of the patients, as described above). Significant differences in the dietary intake of total energy, macronutrients, and micronutrients of interest were not observed in these univariate comparisons. Variables used in the logistic regressionmodel for identifying the independent predictors for

of Selected

Vitamin

Nutrients of Patients With or Without Vitamin B6

B6 Deficient’ 1683 58.3 199.5 74.0

+ + 2 k

(n = 15)

Recommended Daily Supplement for Dialysis Patientst

152 5.8 21.1 7.5

-

1.1 2 .l 4.9 2 .7 209 k 24 index

of (1.25)

and deficient

10.0 3.0 1000 (EGPT

index

of 21.25).

14

ROCK

vitamin B6 deficiency based on EGPT index were age, type of dialysis therapy (hemodialysis 21 peritoneal dialysis), diabetes comorbidity, and energy-adjusted dietary intakes of vitamin Bb and protein. Diabetes comorbidity was the only variable that emerged as a significant independent predictor in these patients (odds ratio = 7.32; 95% confidence interval = 2.06-25.99; beta coefficient for diabetes = 1.99; P < 0.002).

Discussion Results from this study, which involved a relatively large and heterogeneous population of hemodialysis and peritoneal dialysis patients, indicate that diabetes comorbidity is strongly and independently associated with risk for vitamin Bb deficiency in this patient population. The likelihood of being identified as vitamin B6 deficient based on abnormal EGPT index was increased by more than sevenfold in the presence of diabetes comorbidity, irrespective of dietary vitamin B6 intake, use of vitamin supplements that provide additional vitamin Be, dietary protein intake, age, and other possible factors. An association between increased risk for vitamin B6 deficiency and diabetes comorbidity in these patients is supported by evidence from both laboratory and human studies.2’ Using the streptozotocin diabetic rat as a model, insulin inadequacy has been shown to result in a significant reduction in plasma concentrations of PLP and also to moderate activity of the coenzyme, aspartate aminotransferase, in liver mitochondria.22 In chronic conditions, these metabolic alterations may result in vitamin Bb deficiency by promoting accelerated metabolism and loss of the active form of the vitamin.21,22 Furthermore, streptozotonin diabetic rats have been observed to excrete abnormal quantities of kynurenine metabolites after a tryptophan load, a functional indicator of poor vitamin B6 status.23 In humans, acute ingestion of glucose in healthy subjects has also been shown to result in decreased plasma PLP and total vitamin B6 concentrations.24 In comparison with healthy individuals, patients with diabetes were reported to be more likely to have reduced serum pyridoxal concentrations in a study by Davis et al.25 The altered carbohydrate and protein metabolism associated with diabetes may increase the use and catabolism of PLP, the primary coenzyme form of vitamin Bg.

ET AL

In several previous investigations,‘~‘~J~~-*~a~ chronic renal failure has been associated with increased risk for vitamin B6 deficiency. Chronic renal failure causes metabolic alterations such as decreased pyridoxal phosphorylation, and dialysis therapy is associated with losses in the dialysate. Based on this evidence, supplementation with vitamin Bb, in addition to several other watersoluble vitamins, has become standard practice in the nutritional care of dialysis patients,” though there is some variability in the dosage reported to be necessary to maintain adequate vitamin Bb status.7s,27 Findings from the present study suggest that patients in whom diabetes coexists with chronic renal failure and who are receiving regular dialysis therapy may be at particular risk for vitamin B6 deficiency. Perhaps this is caused by the adverse effects that both of these disease processes (and dialysis therapy) have on vitamin Bs metabolism and balance. Results from the present study suggest that the amount of vitamin Be included in current vitamin formulations for patients provided dialysis therapy (10 mg/d) may not be su5cient to meet the needs of the dialysis patient with diabetes. In previous studies involving healthy subjects, the requirement for vitamin B6 has been shown to be directly related to protein intake.28 The level of dietary protein is among the considerations in the establishment of recommended dietary levels of vitamin B6.29 However, consumption of .8 versus 1.2 g protein/kg body wt did not change the response of various vitamin Bh status indicators during the dietary depletion study by RibayaMercado et a1,30 which suggests that the influence of dietary protein on vitamin B6 status may not be evident unless examined over a wide range of protein intakes. Increased vitamin Bb requirements of older adults versus younger adults have been suggested by several studies in which vitamin B6 indices have been examined.31-34 In the present study, increasing age was not observed to be significantly associated with likelihood of vitamin Bb deficiency despite the wide age range of the patients examined in this study. Cardiovascular disease (CVD) is the major cause of morbidity in patients with chronic renal failure who are managed with regular dialysis therapy,35-37 and poor vitamin B6 status may contribute to risk for CVD because of an association with homocysteine.38 Plasma homocysteine was not measured in the present study, but it is a

Vl72lMIN

possibility that vitamin Bh inadequacy contributes to the risk for CVD because it is a necessary cofactor for normal metabolism of homocysteine. Increased plasmahomocysteine concentration is currently recognized as an important risk factor for CVD, although the specific molecular mechanism that explains the relationship has not been established.38.39Hyperhomocysteinemia is believed to be prevalent among patients with chronic renal failure.39 Vitamin B6 functions asa cofactor in key stepsof sulfur amino acid metabolism, so depletion of this micronutrient could contribute to the risk for this abnormality in this patient population.38 Currently, no single biochemical approach is accepted as the definitive or ideal indicator for assessment of vitamin B6 status.Among the static measures,quantification of plasmaPLP concentration is the most commonly used approach, but these levels can be influenced by several dietary and nondietary factors, such as serum albumin concentrations and activity pattems.14,‘SThe use of erythrocyte

transaminase

indices

(eg, EGPT),

such as that used in the present study, is an approach considered to be a more long-term or functional measure because of the life span of erythrocytes. l4 This approach conceptually involves the examination of a long-term indicator, and erythrocyte transaminaseindices do not respond promptly when dietary depletion is imposed but instead exhibit a lag time before an abnormality is evident, as shown in the study by Ribaya-Mercado et al.30An abnormal value observed with this approach suggestsa sustainedor long-term (rather than short-term) problem in achieving and maintaining the level of dietary intake that meets the patient’s

metabolic

15

B6 DEFICIENCY

needs.

One recognized limitation of the present study is that the useof a food frequency questionnaire is an imprecisemethod of dietary assessment. This is particularly true for evaluating a patient population in which food preparation methods that are recommended, such as boiling or soaking vegetablesfor long periods of time, may influence the micronutrient content of food.’ The potential biastoward the null or an overestimate of intake may have obscured relationshipsbetween dietary factors, such as the level of dietary vitamin B, intake, and the EGPT index. Also, only selected variablesthat may influence statuswere measured and analyzed because of the limitations in the depth and scope of the investigation. Additional

patient characteristicsthat were not examined in this study because of these limitations, such as duration of dialysis therapy, may be important predictors of vitamin B6 status. Also, results may not be applicable to all groups of dialysispatients, despite efforts to recruit a representative sample. However, the ethnic distribution of the patients in the present study was similar to that of the overall national distribution of patients receiving dialysistherapy for end-stagerenal failure, which was described as 66% white, 28% black, 2% Asian/Pacific Islanders, and 1% Native Americans.35 In conclusion, findings from the present study suggestthat hemodialysis and peritoneal dialysis patients with diabetes comorbidity have substantially increased risk of vitamin Bh deficiency, basedon abnormal EGPT index. However, factors such asage and dietary protein intake do not appearto be significant independent predictors of statusin this patient population. Altered carbohydrate and protein metabolism associated with diabetesmay increasevitamin B6 requirements of these patients, a hypothesis that is supported by evidence from laboratory animal studies and responseto acute carbohydrate feeding in healthy subjects. The association between diabetes and vitamin B6 status of dialysis patients observed in the present study deservesfurther examination to define the specific causalmechanism, which has been suggestedto be increasedmetabolism of the vitamin and a possiblerelationship with hyperhomocysteinemia in this high-risk group.

Acknowledgment The authors thank Dr Ahmed Rehan, Dr Martin Jones, Dr Daniel Lipschutz, Judith Weston, Diane Fisher, Terri Tomak, Lisa McDowell, and Sheri Amatucci for their assistance in patient recruitment: and Cathryn Carter, Matthew Kelly, Maria Galvez, Aidan Dysart, Dana Randall, Emily Malmon, Heather Kahn, and Jennifer Lovalvo for their contributions and technical assistance.

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