The relationship between intact parathyroid hormone levels and daily physical activity in hemodialysis patients

INTRODUCTION

Poor physical activity and decreased daily activities are commonly seen in hemodialysis (HD) patients and related with increased mortality (1). Various factors such as renal anemia, skeletal muscle dysfunction, mental and social changes, accelerated aging, long-term inactivity, unemployment, decreased quality of life, and depression may contribute to low physical activity in dialysis patients (2, 3). The kidney plays a leading role in maintaining calcium-phosphorus homeostasis and it is the target organ for various hormones, such as parathyroid hormone. Thus, along with the progression of chronic kidney disease (CKD), various abnormalities of mineral and bone metabolism develop, which causes morbidity and mortality (4). Apart from increased morbidity and mortality, osteitis fibrosa, osteomalacia, and adynamic bone disease were also related with vascular calcification (5, 6), along with muscle strength (7), bone pain (8), health-related quality of life (HRQoL) (4, 8) and depression (8) – conditions that may be related with physical activities. Indeed, in patients without renal failure, hyperparathyroidism was related with reduced daily activity (9).

Surprisingly, however, there is a lack of recognition on the part of the nephrology community regarding the relationship between bone mineral disorders and daily physical activity. Thus, this study was performed to specifically analyze the relationship between intact parathyroid hormone (intact-PTH) levels and daily activities of HD patients assessed by the Nottingham Extended Activities of Daily Living Scale (NEADLS).

MATERIALS AND METHODS

The subjects for our cross-sectional investigation were regular HD patients attending the HD unit in a state hospital. The study was in accordance with the declaration of Helsinki and written informed consent was obtained from all patients. The exclusion criteria were as follows: patients with peripheral arterial disease, patients with cerebrovascular disease, patients with acute coronary event (occurring in last six months), interferon treatment (in the last three months), patients with acute exacerbation of chronic obstructive lung disease, patients receiving antidepressants and nutritional support, and patients who did not want to participate.

Inclusion criteria were as follows: regular HD patients with at least three months of HD treatment and who were willing to participate.

The sociodemographic and clinical characteristics of the patients were recorded. Body mass index (BMI) was calculated as the ratio of dry weight in kilograms (end-dialysis weight) to height squared (in square meters).

Self-reported sociodemographic characteristics of the patients (Tab. I) including age, sex, living status (living alone or with partner), smoking status (smoker or non-smoker), educational level (illiterate, elementary school, secondary school, high school or university graduate), marital status (married, unmarried, divorced), economical status (monthly money income is satisfactory or unsatisfactory), sleep disturbance; (defined as the presence of frequent awakenings, difficulty in falling asleep or poor quality of sleep) previous renal transplantation (present or absent), HD access (fistula, graft or catheter), presence of diabetes mellitus (yes or no), presence of coronary artery disease (yes or no) and history of cerebrovascular disease were recorded. Coronary artery disease was defined as the presence of previous myocardial infarction, angina pectoris or a coronary revascularization procedure.

Patients were asked to rate their appetite status on a scale from 1 to 5 (very good, good, fair, poor and very poor appetite, respectively) (10).

The dialysis prescription included 4 h to 4.5 h of HD, with blood flow rates of 300 ml/min to 400 ml/min, using standard bicarbonate dialysis solution. All patients were clinically euvolemic. The routine laboratory parameters were measured before the beginning of HD session, including predialysis blood urea nitrogen and creatinine, serum hemoglobin, albumin, high sensitive C-reactive protein (hs-CRP), predialysis calcium and phosphorus, intact-PTH, total cholesterol, HDL-cholesterol and LDL-cholesterol, and triglycerides. Post-dialysis serum urea nitrogen concentrations used to calculate the urea reduction ratio were also measured.

Urea kinetic modeling was performed in order to assess the delivered dose of dialysis by the formula: spKt/V= -Ln (R-0.008xt) +(4-[3.5xR])xUF/W where spKt/V is a single-pool Kt/V, R is the ratio of post dialysis to pre-dialysis serum urea nitrogen, t is time on dialysis in hours, UF is the amount of ultrafiltration in liters and W is post-dialysis body weight in kilograms.

The normalized protein equivalent of total nitrogen appearance (nPNA), also known as normalized protein catabolic rate (nPCR), was calculated to estimate the daily protein intake by the following formula:

nPNA (g/kg/d): C/[36.3+ 5.48(spKt/V)+ 53.5/ (spKt/V)]+0.168

where C is the predialysis concentration of serum urea nitrogen in milligrams per deciliter.

After being given a brief explanation, measurements of depressive behavior using Beck Depression Inventory (BDI), HRQoL using short form 36 (SF-36), and measurement of daily activities using Nottingham Extended Activities of Daily Living Scale (NEADLS) were performed for each patient during regularly scheduled dialysis treatments. Assistance was available for patients who were illiterate.

RESULTS

Initially, 134 patients were enrolled. One patient with an ischemic leg ulcer and had peripheral revascularization procedure and four patients with history of cerebrovascular disease were excluded. Although patients with coronary artery disease were included; three patients with acute coronary event (occurring in last six months) were excluded. One patient who had received interferon treatment in last three months was also excluded. Two patients with acute exacerbation of chronic obstructive lung disease and nine patients who did not want to participate were excluded. The study was conducted in the remaining 114 patients. The etiologies of the ESRD were as follows.

Glomerulonephritis in 12, diabetes mellitus in 31, hypertension in 29, vesicouretheral reflux and pyelonephritis in 8, nephrolithiasis in 3, polycystic kidney disease in 3, amyloidosis in 6, analgesic nephropathy in one, and ischemic nephropathy in 2. The etiology for ESRD was unknown in 19. The demographic characteristics of the patients were given in Table I. The clinical and laboratory data of 114 HD patients were shown in Table II. The data of quality of life, depression scores and daily activities in 114 HD patients are given in Table III. In the whole group, Pearson correlation analysis revealed that NEADLS was correlated with age (r = -0.514, p = <0.0001), appetite score (r = -0.272, p = 0.003), nPNA (r = 0.280, p = 0.003), bun (r = 0.236, p = 0.012), creatinine (r = 0.231, p = 0.0139), albumin (r = 0.235, p = 0.012), phosphorus (r = 0.193, p = 0.04), intact-PTH, (r = -0.198, p = 0.034) BDI score (r = -0.198, p = 0.035), physical functioning (r = 0.338, p = <0.0001), role-physical limitation (r = 0.345, p<0.0001), general health perception (r = 0.300, p = 0.001), vitality (r = 0.302, p.0.001), social functioning (0.335, p<0.0001), role emotional (r = 0.294, p = 0.001), mental health (r = 0.270 p = 0.004), PCS (r = 0.403, p<0.0001), and MCS (r = 0.267, p = 0.004).

The patients were divided into four quartiles according to intact-PTH values. The value of intact-PTH for <25^th (Group 1), <25^th-50^th (Group 2), 50^th-75^th (Group 3) and >75^th (Group 4) quartiles were <132.5 pg/ml, ≥132.5 <261.0, ≥261.0 <510.4 and ≥510.4 respectively. The NEADLS scores were 25.3 ± 10.8, 35.0 ± 9.4, 27.2 ± 13.9 and 26.4 ± 12.9 as going from Group 1 to Group 4 (p = 0.009) (Fig. 1). Post-hoc analysis of these four groups revealed that only Group 1 and Group 2 (p = 0.012), and Group 2 and Group 4 (p = 0.034) were different with respect to NEADLS scores. There is also a tendency between Group 2 and Group 3 (p = 0.062). However, there were no statistical differences with respect to NEADLS scores between Group 1 and Group 3, between Group 1 and Group 4, and between Group 3 and Group 4 (p>0.05) (data not shown).

The results of stepwise linear regression of independent factors (as mentioned in statistics section) showed that age nPNA albumin, hs-CRP, presence of vitamin D treatment and intact-PTH were independently related with the NEADLS score (Tab. IV).

DISCUSSION

The present study demonstrated that increased age, nutritional markers (nPNA and albumin), vitamin D treatment, and a PCS of SF-36 were associated with daily activities in HD patients. As a novel finding, intact-PTH levels were inversely associated with daily activities in the whole group. However, the post-hoc analysis demonstrated that the association between intact-PTH and daily activity was not linear and daily physical activity was lower only in patients with the lowest and highest quartiles of intact-PTH.

Limitations in physical functioning are a major problem for patients on HD patients. Studies have shown that 24% to 36% of HD patients were unable to perform routine living activities without assistance (17, 18). Impaired physical functioning was associated with both quality of life (19) and mortality (20, 21). There has been debate about whether the poor physical functioning observed in HD patients is due to uremia or whether it is secondary to other conditions that often accompany uremia, such as inactivity and decondition, advanced age, malnutrition, or co-morbid illness (22). However, surprisingly few attempts have been made to determine factors related with physical functioning and daily activities in HD patients (7). This may be due to difficulty of evaluating physical activity in chronic HD patients who suffer not only from physical disabilities but also from mental changes and various co-morbid conditions. Assessing physical activity in those patients by standard physical performance tests is thus usually impossible, and therefore questionnaires designed to assess daily activity are needed (23). In the current study, then, the factors related with daily activities (as measured by a NEADLS) was investigated. Specifically for the first time, the relationship between intact-PTH and daily activities was evaluated in HD patients. Although in the whole group the intact-PTH levels were inversely related with daily activities, sub-group analysis revealed that not only higher and lower intact-PTH levels were associated with reduced daily activitity. Although the exact mechanism regarding the intact-PTH and daily activity is not known some speculations could be made.

Parathyroid hormone excess has been pointed to as exerting toxic effects on various organs and body systems. It has been documented that excessive PTH affects the bioenergetics of skeletal muscle, impairing energy production, transfer, and utilization (24). In addition, the hormone may enhance muscle proteolysis and increase the release of alanine and glutamine in vitro (25). It was shown that muscle strength is likely to be an important predictor of physical performance (7). Since leg strength was not measured, this study provides no direct evidence about the relationship between muscle strength and physical performance. However, indirect evidence is available from the data regarding the correlation between serum creatinine and NEADLS. Since muscle mass is an important determinant of serum creatinine muscle strength, it may be important for performance of these activities. Indeed, in one study it was shown that in diabetic patients, higher serum PTH was associated with incident falls and for every 1 SD (36 pg/ml) increment in baseline serum PTH, there was approximately a 30% increased likelihood of reporting a fall in the subsequent year after adjusting potential confounders (26). Additionally, primary hyperparathyroidism is characterized by muscle weakness which improves with parathyroidectomy (27). In animal models, an infusion of PTH at high levels increased protein catabolism and decreased the number of type 2 muscle fibers, intracellular energy-rich phosphate compounds, and mitochondrial oxygen uptake (28, 29). Thus the combined effects of PTH on bone and muscle may partly explain the relationship between intact-PTH and reduced daily activity.

Another mechanism may be the bone pain related with both higher and lower intact-PTH levels (8). Although bone pain intensity was not measured in the current study, studies are needed to determine whether bone pain is associated with intact-PTH levels.

Vascular calcification (VC) and atherosclerosis induced by PTH levels may be one of the other potential explanations. Interestingly, both higher (5) and lower (6, 30). Intact-PTH levels were associated with VC. Additionally, levels of intact-PTH have been associated with prosclerotic effects on vascular smooth muscle cells (31). It was recently shown that there is also a strong relationship between VC and atherosclerosis that frequently develops in end-stage renal disease (32). Thus the permissive role of intact-PTH for arterial calcification and atherosclerosis induced at coronary artery vessels may diminish oxygen supply to the heart and diminish physical activity. On the other hand, the same pathologic processes at peripheral arterial level (even at a subclinical state) may compromise blood supply to bones and muscles and may reduce daily activity.

Increased age was negatively associated with daily activities, a finding that is in accord with the previous studies (7, 33, 34). Another important finding of the current study was the association between nPNA and daily activity. In one study it was demonstrated that dietary protein and energy intakes were associated with changes in measures of physical function in HD patients. The authors concluded that the association between intake and physical function could be mediated by the energy requirements of physical activity. For example, greater energy expenditure through physical activity is associated with better physical functioning and with greater energy intake to preserve energy balance (1).

Of note, there was no association between hs-CRP levels and daily physical activity. However, previous studies also did not find any association (1, 23, 35). There was also no relationship between dialysis adequacy and physical activity, as in other studies (7, 23).

The subjects of the current study have diverse etiologies. Therefore, the baseline levels of physical activities may differ among these patients, and these various etiologies may influence the daily activities score. However, this kind of diversity is valid for all studies with ESRD patients who have very different etiologies. Besides, there is no previous study which specifically investigates daily physical activity according to different disease etiologies. Another important question was the effect of parathyroidectomy on daily physical activity. In the current study, the mean intact PTH level was 361.9 ± 349.9 pg/ml. However, the distribution of intact PTH was not normal and 12 patients had intact PTH levels greater than 800 pg/ml. In addition to treatment with active vitamin D, we use paricalcitol (four patients), cinacalcet (three patients). If the patients are resistant to these treatments, we search for parathyroid adenoma by scintigraphy. During the study period, we detected that two patients had parathyroid adenoma and suggested surgery. One patient accepted and underwent the operation and other refused it. Since the number is not enough to make pre-op and post-op comparisons regarding daily physical activity, it may be quite interesting to study the change in daily physical activity before and after the parathyroidectomy operation. Hence this preliminary study may open a new area of research regarding this issue.

The current study has limitations that deserve mention. One of the major limitations of the study was lack of vitamin D levels, although the status of active vitamin D treatment has been included in the regression analysis. However, recent evidence suggests that intact-PTH levels, independent of vitamin D levels, may be important for maintaining muscle integrity and physical function (36). Another limitation was the lack of data regarding bone biopsy and bone mineral density. However although an overlap exists, PTH levels crudely estimate the type of bone lesion: higher intact-PTH levels were mostly related with osteitis fibrosa and lower intact-PTH levels were mostly related with adynamic bone disease.

The determination of daily activity was based on questionnaires and not on objective tests such as gait speed, time required to climb of stairs, and time required standing repeatedly from a chair without assistance. However, these tests are quite difficult to perform for HD patients (23). Given the fact that the NEADLS is easy to perform, it could be used for screening purposes for patients with advanced physical debility. Accordingly, the NEADLS may be further evaluated with more complicated tests. A temporal relationship between intact-PTH and daily activities cannot be suggested based on the current study due to its cross-sectional design. Lastly, since the study is cross-sectional and non-interventional, cause and effect relationships cannot be suggested.

In conclusion, both higher and lower intact-PTH levels were associated with reduced daily activity in HD patients. Larger cohort studies and intervention trials will be required to better understand the relationship between intact-PTH and daily activity in HD patients.

This study complies with the Helsinki Declaration of 1975 and written informed consent was obtained from all participants.