Prevalence and Determinants of Parathyroid Dysfunction in Elderly Patients on Hemodialysis

Background: The goal of this study was to investigate underlying factors of parathyroid dysfunction in elderly patients undergoing maintenance hemodialysis. Methods: A total of 286 patients on maintenance hemodialysis were included. Hemoglobin, serum creatinine (Scr), blood urea nitrogen (BUN), serum calcium, serum phosphorus (P), intact parathyroid hormone (iPTH), and serum albumin (Alb) were measured and analyzed both before and after dialysis. Results: A higher incidence of low iPTH level (<150 pg/l) was observed in the elderly group than that in the non-elderly group (55.8 vs. 36.7%, p < 0.05). Elderly patients had a shorter dialysis duration, lighter dry weight, lower concentrations of BUN, Scr, P, iPTH, Alb and standard protein nitrogen present rate (nPNA) compared to that of non-elderly group patients (p < 0.05). Conclusions: Low iPTH level occurs more frequently in elderly hemodialysis patients. Furthermore, age, serum P, serum Alb and nPNA were independently associated with a low iPTH level.

Keywords: Hemodialysis; Chronic renal failure; Parathyroid hormone

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The increasing occurrence of chronic kidney disease (CKD) is a growing public health issue worldwide. CKD is often associated with various complications including cardiovascular disease, progressive loss of kidney function and premature death [[1]]. In the meantime, abnormal mineral metabolism and bone disease are common in CKD patients and are important causes of morbidity and decreased quality of life [[2]].

Renal osteodystrophy is the term that has been used traditionally to describe the abnormalities in bone morphology that develop in CKD [[5]]. In clinical practice, bone biopsy is used infrequently because it is an invasive and often expensive procedure and the samples obtained require specialized processing that is not widely available. The most common forms of renal osteodystrophy are attributable largely to variations in serum levels of intact parathyroid hormone (iPTH). As such, serum iPTH levels have been used as a surrogate indicator of bone turnover. Together with measurements of serum calcium (Ca), phosphorus (P), and alkaline phosphatase, the serum iPTH level has been used as an important marker for diagnosis, severity assessment, and treatment of renal osteodystrophy [[7]].

Despite the development of the preventive measures [[4]], the number of patients with CKD is increasing at a rate of 5-8% annually. Elderly patients, who constitute the majority of dialysis patients [[8]], suffer the largest increase in the incidence and prevalence of end-stage disease. Little has been reported on Ca-P metabolism abnormalities and parathyroid dysfunction in elderly patients on hemodialysis.

The aim of this study was to investigate the prevalence and determinants of Ca-P metabolism abnormalities and parathyroid dysfunction in elderly patients on hemodialysis.

A total of 286 stabile patients on maintenance hemodialysis (MHD) for at least 3 months were recruited from The 7th People's Hospital of Shanghai, Jingan District Central Hospital of Shanghai, and The 455th Hospital of PLA, during the period of January 2010 to December 2010. They were divided into two age groups: elderly (≥65 years) and non-elderly or control (<65 years). Conventional hemodialysis treatment in these patients was carried out 2-3 times a week, 4-5 h each time. In addition, hemodiafiltration online was performed 1-2 times per month in most of the patients. These patients had a blood flow of 230-250 ml/min and a dialysate Ca concentration of 1.5 mmol/l. According to the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (K/DOQI) Guidelines [[9]], hemopoietin, rocaltrol and Ca carbonate (there are no other phosphate binders or particular VDRAs in use) were applied to individual patients when appropriate, judging from the individual situation. Patients' parathyroid status was divided based on target recommendations of K/DOQI - hypoparathyroid (iPTH <150 pg/ml) and hyperparathyroid (iPTH >300 pg/ml).

Patients included in the study were free of active infections, overt heart failure, history of malignancy, and diseases that requires immunosuppressive treatment. The protocol was approved by the local hospital ethical committee. Clinical data of patients were extracted from the hospital records.

Data on baseline characteristics (age, gender), duration of dialysis, and standard indicators of dialysis care (systolic blood pressure, diastolic blood pressure), and laboratory test results were analyzed.

After fasting for at least 12 h, samples (8-10 ml) of venous blood were collected from each subject between 08:00 and 09:00 h the next morning. After colt formation, the samples were centrifuged (4,000 rpm) at 4°C for 10 min. The serum samples were stored at -80°C until use.

Concentrations of hemoglobin (Hb), serum creatinine (Scr), blood urea nitrogen (BUN), Ca, P, and albumin (Alb) were measured. High-sensitive C-reactive protein (hs-CRP) measurements were performed according to methods described in the literature [[8]]. iPTH (normal range 10-69 pg/ml) was determined using a chemiluminescence method. Serum BUN was also detected after dialysis. Ultrafiltration volume, body weight after dialysis and dialysis time were also recorded. Serum Alb-corrected Ca (Ac-Ca), urea removal index (Kt/V) and normalized protein equivalent of nitrogen appearance (nPNA) were calculated according to the following formula:

Ac-Ca = Serum total Ca + 0.02 × (40-Alb)

Kt/V = - ln(R - 0.008 × t) + (4-3.5 × R) × UF/BW

nPNA = 0.0229 × (Kt/V + 3.74 Kr/V) × (C1 + C2) + 0.17

where ln is natural logarithm, R is C2/C1, t is dialysis time (h), UF is ultrafiltration volume (liters), BW is body weight (kg) after dialysis, and C1 and C2 are serum BUN before and after dialysis respectively.

All data are presented as mean ± SD. Continuous variables were checked for normal distribution assumption using the Kolmogorov-Smirnov statistics and analyzed by Student's t test. Categorical data were analyzed by χ2 test. Differences were considered significant when p < 0.05.

Logistic regression analysis and two-way ANOVA (accounting for samples design by weight estimation methods) was used to analyze the correlation between serum iPTH and various independent parameters (gender, age, dialysis time, diabetes mellitus, mean blood pressure, hemachrome, urea nitrogen, creatinine, corrected Ca, P, Alb, Kt/V and nPNA) and dependent (serum iPTH <150 pg/ml) variables. All variables with p < 0.1 in the regression analysis were included in multivariable models. We have also conducted a normality test to ensure that all included parameters follow normal distribution. All analyses were performed using the software SPSS 13.0 for Windows (SPSS, Inc., Chicago, Ill., USA).

A total of 286 stabile patients on MHD were included in the study and divided into two age groups: an elderly group (n = 147; 81 male, 66 female; age 72.7 ± 5.3 years) and a non-elderly or control group (n = 139; 75 male, 64 female; age 50.6 ± 8.5 years). The clinical characteristics of patients in the elderly and control groups are presented in table 1. The main causes of chronic renal failure were significantly different between the two groups: in the elderly group the most common cause was essential hypertension (35.4%) followed by chronic glomerulonephritis (21.1%) and diabetes mellitus (19.7%), while in the control group the most common cause was chronic glomerulonephritis (43.2) followed by diabetes mellitus (23.7%) and essential hypertension (12.2%).

Graph: Table 1 Clinical characteristics of patients in the indicated groups

Patients in the elderly group had a shorter duration of dialysis (p < 0.01), lighter dry weight (p < 0.01), higher systolic blood pressure (p < 0.01) and lower diastolic blood pressure (p < 0.01) than patients in the control group. Additionally, a lower proportion of patients in the elderly group were on vitamin D and Ca carbonate (p < 0.01) than in the control group.

The elderly group had lower concentrations of serum BUN (p < 0.01), Scr (p < 0.01), serum Alb (p < 0.01) and nPNA (p < 0.02) but higher concentrations of hs-CRP compared with the control group. There was no significant difference in Hb (p > 0.05) and Kt/V (p > 0.05) between the two groups (table 2).

Graph: Table 2 Biochemical parameters of Ca-P metabolism abnormalities and parathyroid dysfunction in the groups of subjects studied

To assess Ca-P metabolism abnormalities and parathyroid dysfunction, various biochemical parameters were measured. The data were analyzed by univariate comparison and the results are summarized in table 2. The elderly group had lower concentrations of serum P (p < 0.01) and iPTH (p < 0.01), and a larger proportion of patients also had a low iPTH level (<150 pg/ml) compared to the control group. However, there was no significant difference in Ac-Ca level (p > 0.05) between the two groups.

To further determine the associations between age and iPTH levels, we divided the study population into seven age groups. The trend that iPTH levels decrease as ages increase was obvious for both male and female subgroups (two-way ANOVA, p < 0.01 for age, p = 0.132 for gender; p < 0.001 for the interaction gender × age) (online suppl. Appendix 1, fig. 1; for all online suppl. material, see www.karger.com/doi/10.1159/000357969).

The results of multivariate analysis are presented in table 3. Serum P (OR 1.290, 95% CI 1.192-1.367; p = 0.003), Alb (OR 1.135, 95% CI 1.014-1.221; p = 0.024) and nPNA (OR 1.098, 95% CI 1.034-1.158; p = 0.032) were highly correlated with serum iPTH, indicating that they may be the independent risk factors of parathyroid dysfunction in elderly patients on MHD.

Graph: Table 3 Correlations between parathyroid dysfunction and variables in elderly patients on hemodialysis

To study serum iPTH and phosphate levels, we divided the entire patient population into four subcategories: low nPNA - non-elderly, low nPNA - elderly, high nPNA - non-elderly, and high-nPNA elderly. Analysis showed it was only in the elderly group that the percentage of patients with low P and/or low iPTH levels in low nPNA subgroups was significantly more than that in the high nPNA subgroups, p < 0.01 (online suppl. Appendix 1, table 1).

Even though there is no worldwide standard on the definition of old or elderly persons, the United Nations accept 60+ to be used as cutoff to refer to the older population. Most developed countries have used the chronological age of 65 years or above as a definition of elderly or older persons. And this age (65) was also used to define the elderly group in this study.

The occurrence of hemodialysis among elderly patients has increased in recent years. According to the report of United States Renal Data System (USRDS), the percentage of dialysis patients 65 years and older has risen from 5.0% in 1973 to 38.0% in 1990 and further to 60.3% in 2004. In China the percentage of patients with end-stage renal disease (defined as those who need renal replacement therapy) had increased at a rate of 11% annually over the last decade, followed by the increase in the total number of elderly hemodialysis patients. In our current study, the percentage of dialysis patients 65 years and older is 51.4% in the total sample of 283 patients.

CKD patients are often accompanied with the disorder of bone mineral metabolism, which is usually defined as chronic kidney disease-mineral and bone disorder (CKD-MBD) by Kidney Disease: Improving Global Outcomes (KDIGO) [[7]]. Clinically, CKD-MBD is characterized by Ca-P metabolism abnormalities, parathyroid dysfunction and vitamin D metabolism abnormalities. According to the level of iPTH, CKD-MBD can be divided into three subtypes: low conversion type of bone disease, high conversion type of bone disease, and hybridism type of bone disease.

Adynamic bone disease (ABD) is a low conversion type of bone disease where the level of iPTH is lower than normal. In the last 20 years, the incidence of secondary hyperparathyroidism and aluminum poisoning bone diseases has decreased while that of ABD has increased to 15-60% [[10]], even among 40-70% in patients undergoing peritoneal dialysis [[12]]. In our study, there was a higher incidence of patients with low iPTH (<150 pg/l) in the elderly group versus that of patients with low iPTH in the non-elderly group (55.8 vs. 36.7%).

The reason for the increase in ABD incidence remains unclear. Some studies suggested that a low iPTH level and the inhibition of osteoblasts may be major underlying factors [[13]]. An inverse correlation between age and iPTH level has been proposed in past studies [[14]]. Iatrogenic factors may also contribute to hypoparathyroidism: compared to non-elderly patients, elderly patients are more likely to be treated with Ca-based phosphate binders. A relatively higher Ca burden may suppress PTH production [[16]]. It was also reported that that low conversion type of bone disease in elderly patients was associated with a reduction of sex hormones [[17]], oxidative stress and Klotho dysregulation [[18]].

In the present study, we compared the baseline clinical characteristics between elderly group and control group patients who had been on MHD for at least 3 months. There were significant differences in duration of dialysis, dry weight, and systolic and diastolic blood pressures between the two groups. It was also shown using univariate analysis that patients in the elderly group had lower concentrations of serum BUN, Scr, Alb and nPNA, and higher concentrations of hs-CRP. Additionally, the percentage of patients in the elderly group using vitamin D and Ca carbonate were lower than in the control group (p < 0.01). This phenomenon is unlikely to be the result of overtreatment of secondary hyperparathyroidism since active vitamin D and Ca carbonate levels were less prevalent in the elderly group than in the non-elderly group.

What was surprising was that by using multivariate analysis, age, P, Alb and nPNA were independent risk factors of parathyroid dysfunction in the elderly patient group. We also observed that only in the elderly group was the percentage of patients with low serum P and/or low serum iPTH level in low nPNA groups significantly higher than that in the high nPNA subgroups (p < 0.01). There was no significant difference on the percentage of patients with low serum P and/or low serum iPTH level between the low nPNA and high nPNA subgroups of the non-elderly group (p > 0.05).

Due to the fact that elderly patients have decreased gastrointestinal peristalsis, a lower absorbance ability and lower resistance to infections, they typically have a lower dry weight, lower levels of nPNA, serum Alb and serum phosphate. These deficiencies made elderly patients more prone to malnutrition. It was thus believed that malnutrition may be the major reason for hypoparathyroidism in elderly hemodialysis patients. The other mechanisms on hypoparathyroidism in elderly hemodialysis patients need to be studied further because there were no data on sex hormones, oxidative stress and Klotho dysregulation in the present study.

It is known that the decrease of the function of bone formation and reabsorption reduces the capacity to buffer excess Ca loads in patients with a low conversion type of bone disease. This reduced capacity leads to an increase of ectopic calcification (e.g. arterial calcification) and mortality rate in dialysis patients [[18]]. Low bone turnover may predispose elderly patients to a stronger vascular aging under certain pro-calcifying agents such as an excessive load of Ca salts. Relative hypoparathyroidism is associated with ABD as well as with an increased risk of vascular calcification and bone fracture. Vascular calcification and bone fracture are known to dramatically increase mortality in dialysis patients. Therefore, we suggest that special attention should be paid to the management of elderly diabetic patients with hypoparathyroidism. A significantly better survival rate in MHD patients undergoing Ca-free phosphate binders against Ca-based phosphate binders was limited to elderly patients in the post hoc analysis of several randomized controlled trials [[19]].

One main limitation could be as follows: in our current cross-sectional study, the analysis only provided the association between any possible parameter and parathyroid dysfunction, but not a definition of these risk factors. Furthermore, data on cardiac function, blood vessel elasticity, renin and angiotensin levels, and sex hormone were rarely available in these patients, which constrained us from doing a more detailed analysis. Hence, we just gave a relative comprehensive description on the possible associative factors of low iPTH in the elderly hemodialysis patients.

In conclusion, the present study showed that age, serum P, serum Alb and nPNA were independent associative factors of low iPTH in elderly patients undergoing MHD. This result indicates that malnutrition may be the major reason for low iPTH in elderly patients on MHD.

The authors have no conflicts of interest to disclose.