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NDT Advance Access originally published online on December 2, 2005
Nephrology Dialysis Transplantation 2006 21(4):968-974; doi:10.1093/ndt/gfi311
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© The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Clinical Nephrology

A high body mass index and female gender are associated with an increased risk of nodular hyperplasia of parathyroid glands in chronic uraemia

Carlo Basile1, Carlo Lomonte1, Luigi Vernaglione2, Francesco Casucci1, Domenico Chimienti1, Andrea Bruno1, Savino Cocola1, Erminia Antonicelli Verrelli1 and Francesco Cazzato1

1 Division of Nephrology, Miulli General Hospital, Acquaviva delle Fonti and 2 Division of Nephrology, Hospital of Manduria, Manduria, Italy

Correspondence and offprint requests to: Carlo Basile, MD, Via C. Battisti 192, 74100 Taranto. Email: basile.miulli{at}libero.it



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. A persistent hyperphosphataemia represents one of the most important factors in the development of secondary hyperparathyroidism (sHPTH). The present prospective study was designed in order to test the hypothesis that a higher body mass index (BMI) may predispose to a larger body burden of phosphate (P), influencing by that way the severity of sHPTH.

Methods. Histological studies were performed on 168 parathyroid glands of 42 consecutive adult Caucasian haemodialysis patients (20 males and 22 females) referred for first parathyroidectomy (PTx): each parathyroid gland was graded as 0, when only or mainly diffuse hyperplasia was found, or as 1, when only or mainly nodular hyperplasia was found. Thus, parathyroid histology was scored on a 5-point scale: 0 = diffuse hyperplasia in the four glands; 1 = nodular hyperplasia in one gland; 2 = nodular hyperplasia in two glands; 3 = nodular hyperplasia in three glands; 4 = nodular hyperplasia in the four glands. For sake of simplicity, the three less severe histological gradings, i.e. scores 0–2 were grouped together and indicated as score group 2.

Results. The distribution of the patients was the following: 28.6% were in the score group 2, 23.8% in the score group 3 and 47.6% in the score group 4 (20 patients, 14 of whom were females). The output of the one-way ANOVA with the histological scores as grouping variable and age, dialysis duration, BMI and pre-PTx serum iPTH, alkaline phosphatase (ALP), calcium (Ca) and P as predictors showed that only BMI was different among the three histological scores (P = 0.001). By stratifying the analysis by gender, the relationship between BMI and histological scores was confirmed only in females (P = 0.006).

The stratification of the entire cohort into two groups according to the cut-off value of BMI = 25 kg/m2 showed that: (i) score 4 was more prevalent in the high-BMI group and score 2 in the normal-BMI group (P = 0.01); (ii) female gender was more represented in the high-BMI group (12 out of 18 patients, P = 0.04); and (iii) the pre-PTx serum P levels were significantly higher in the high-BMI group (P = 0.008). The output of the linear multiple regression analysis with pre-PTx serum P as dependent variable and BMI, pre-PTx serum ALP and Ca as independent variables (selected according to the statistical significance in the bivariate correlations) showed that only serum Ca and BMI were statistically significant predictors of serum P levels.

Conclusions. A high BMI and female gender are associated with an increased risk of nodular hyperplasia of parathyroid glands in adult Caucasian haemodialysis patients. The two risk factors, above all if combined in the same patient, appear to predispose to a larger body burden of P, increasing by that way the severity of sHPTH.

Keywords: body mass index; female gender; haemodialysis; hyperparathyroidism; parathyroidectomy; phosphataemia



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
A large number of uraemic patients develop a refractory secondary hyperparathyroidism (sHPTH); in fact, the mean annual incidence of first parathyroidectomy (PTx) is about 30 per 1000 patient-years in those dialysis patients treated for more than ten years [1]. Actually, a very recent report showed that PTx rates in U.S. haemodialysis patients increased between 1998 and 2002 [2]. In a time when effective treatment strategies are increasingly available, PTx could be viewed as indicating a medical failure. The reasons of the failure of response of parathyroid glands to a wide therapeutic armamentarium must be looked for in several domains, such as intrinsic factors linked to the large volume of the glands themselves with nodular hyperplasia, a reduced density of vitamin D and calcium-sensing receptors, and a persistent hyperphosphataemia, which represents one of the most important factors of resistance to calcitriol treatment and, also, one of the most important factors in the development of sHPTH [3]. Our preliminary unpublished observations seemed to suggest that haemodialysis patients having a larger body mass index (BMI) had higher serum phosphate (P) levels than normal BMI patients. Thus, we hypothesized that a higher BMI may predispose to a larger P body burden, thus influencing the multicompartmental kinetics of P and, consequently, the severity of sHPTH. The present prospective study was designed in order to answer two main questions: (i) is BMI associated with the clinical expression of sHPTH in long-term haemodialysis patients? and (ii) if yes, may the relationship between BMI and the clinical expression of sHPTH be mediated by different P body burdens in patients with different BMI?



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Study protocol
The study protocol prescribed to enrol all adult haemodialysis patients referred to our division in order to undergo a first PTx from the beginning of 2004 to the end of April 2005. The protocol prescribed strict inclusion and exclusion criteria. The inclusion criterion was: first PTx (either total or subtotal) in which all the four parathyroid glands could be found and ablated in each patient. The exclusion criteria were: persistence of vitamin D treatment in the two weeks immediately preceding PTx; the detection and ablation of only three glands or less; a serum level of intact immunoreactive parathyroid hormone (iPTH) >150 pg/ml on the third post-PTx day, which might suggest the existence of an ectopic supernumerary gland.

Patients were put on a 36 h fasting (12 h pre- and 24 h post-PTx). They were administered calcium gluconate intravenously, and calcium carbonate and calcitriol per os according to a standardized protocol of post-PTx calcium refilling. Patients were dialyzed on the day before PTx and on the first, third and fifth post-PTx day.

Study procedures
Serum levels of albumin, iPTH, alkaline phosphatase (ALP), calcium (Ca) and P were determined at the PTx time point; serum Ca and P were then measured 4 h post-PTx and three times a day on the 5 consecutive post-PTx days, and the three daily measurements of serum Ca and P levels were averaged for each patient. Serum iPTH and ALP levels were measured on the third post-PTx day. Serum urea nitrogen was measured at the beginning and at the end of the dialysis run on the third post-PTx day. A standard bicarbonate haemodialysis treatment lasting 4 h was administered: calcium concentration in the dialysate was 1.75 mmol/l; a low-flux non-cellulosic membrane with a surface area ranging from 1.5 to 2.0 m2 was utilized; dialysate and blood flows were, respectively, 500 and 300 ml/min. Serum concentrations of albumin, Ca, P, ALP and urea nitrogen were measured by routine automated methods. Serum concentrations of iPTH were measured by chemiluminescence immunoassay (Nichols, San Juan Capistrano, California, USA; normal range: 10–65 pg/ml). Kt/Vurea was measured during the dialysis run of the third post-PTx day according to the algorithm suggested by Casino et al. [4]. The measured serum Ca levels were adjusted with the albumin levels when they were lower than 4.0 g/dl as follows: Ca = measured Ca levels + [(4.0 – albumin levels) x 0.8] mg/dl [5]. Actually, only one patient having serum albumin levels <4.0 g/dl needed such a correction.

Histological studies of the parathyroid glands were performed by the same pathologist on 7 serial sections of the glands. The pathologist was blinded as far as the gender and other clinical and biochemical data of the patients were concerned. Diffuse hyperplasia was defined as increased numbers of parenchymal cells with normal lobular structures, and nodular hyperplasia as at least one well-circumscribed, encapsulated and virtually fat cell-free accumulation of parenchymal cells. Nodular hyperplasia was considered a marker of histological severity and a score was attributed accordingly: each parathyroid gland was classified as 0, when only or mainly diffuse hyperplasia was found, or as 1, when only or mainly nodular hyperplasia was found. Thus, parathyroid histology was scored on a 5-point scale: 0 = diffuse hyperplasia in the four glands; 1 = nodular hyperplasia in one gland; 2 = nodular hyperplasia in two glands; 3 = nodular hyperplasia in three glands; 4 = nodular hyperplasia in the four glands. For sake of simplicity, the 3 less severe histological gradings, i.e. scores 0–2, were grouped together and indicated as score group 2. Furthermore, a semi-quantitative analysis of the glands was performed, according to cell types [6,7]. As we and others [6,7] have shown that oxyphil cells predominate significantly in nodular hyperplasia, the focus in the present study was put exclusively on the oxyphil cells, as far as the several parathyroid cell types are concerned.

BMI was defined as the ratio: body weight (kg)/height2 (m). The ranges of a normal BMI are 18–24 kg/m2 for females and 19–25 kg/m2 for males.

Statistical analyses
The distribution of the data was studied by means of the Kolmogorov–Smirnov test. Those non-normally distributed underwent a log-transformation. The comparisons of the continuous variables between groups were made by means of the Student's t-test for paired and unpaired data, while the {chi}2 test was utilized for the distributions between groups of the categorical variables. The sensitivity, the specificity and the accuracy of the serum pre-PTx log iPTH values in predicting the parathyroid histological score were assessed by means of the ROC curve analysis, using the histological scores as true positivities and the interquartile ranges of serum iPTH levels as predictors. The Pearson's correlation coefficient was utilized when appropriate, and both the one-way ANOVA with the Tukey's post-hoc test and the multiple linear regression models, stratified by potential confounders, were built in order to study the predictors of categorical and continuous outcomes, respectively. All the predictors considered in the models were chosen a priori and retained in the models if biologically plausible or when they showed a statistically significant correlation coefficient at the bivariate analysis. The sample size for each of the three histological score groups was estimated to be at least 10: this figure is able to achieve a power of 80% in detecting a statistically significant difference of 2.0 kg/m2 in BMI with a mean SD among groups of 2.0. All statistical inferences were performed with the use of the SPSS software package, version 10 (SPSS inc., Chicago, IL). Data are expressed as means±SD or percentage of total, and values of P<0.05 were assumed as statistically significant.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
Forty-six adult anuric Caucasian haemodialysis patients were referred to our division in order to undergo a first PTx by six dialysis units of our region from the beginning of 2004 to the end of April 2005. The indications to the surgical correction of sHPTH in these patients were the presence of one or more of the following clinical and/or laboratory data: pruritus not responsive to any treatment, Achilles’ tendon rupture, persistent hyperphosphataemia, refractoriness to vitamin D therapy (either intravenously or per os), persistent serum iPTH levels >800 pg/ml, severe radiological signs of osteitis fibrosa and a parathyroid gland size >1 cm. These indications to the surgical correction of sHPTH met the NKF-K/DOQI guidelines for parathyroidectomy [8]. Forty-two patients (20 males and 22 females) were considered eligible because four parathyroid glands could be ablated in each patient; then, 168 glands could be examined histologically. Two patients were excluded from the study because only three glands could be detected and removed; two, because a serum level of iPTH >150 pg/ml was detected on the third post-PTx day (in the latter patients further examinations revealed the existence of an ectopic supernumerary gland). Table 1 shows the demographic, clinical and biochemical characteristics of the entire cohort of 42 patients. Worth noting, no one was affected by diabetic nephropathy. Ablation of parathyroid tissue determined a significant reduction of serum iPTH, ALP, Ca and P (P<0.001) (Table 1). The histological examination of parathyroid glands showed that 28.6% of the patients were in the score group 2, 23.8% in the score group 3 and 47.6% in the score group 4 (Table 1).


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  		Table 1. Demographic, clinical, histological and biochemical characteristics of the 42 patients

 
The ROC curve analysis showed that the pre-PTx log iPTH values were neither sensitive nor specific or accurate in predicting the parathyroid histological scores (area 0.471, sensitivity 46.7%, specificity 45.5%, accuracy 46.3%, not shown in any table or figure). Thus, we chose the histological grading as the index of sHPTH in our inferences.

Table 2 shows the output of the one-way ANOVA with the histological scores as grouping variable and age, log dialysis duration, BMI and pre-PTx serum log iPTH, log ALP, Ca and P, and oxyphil cells as predictors. In the main analysis, only BMI was different among the three histological scores (P = 0.001). Moreover, the Tukey's post-hoc test showed that BMI of score group 4 was significantly different from that of score group 3 (P<0.05) and score group 2 (P<0.01). No differences in BMI were found between score groups 3 and 2. The adjustment of the main analysis for previous use of intestinal P chelation, vitamin D use or underlying nephropathy did not induce any change (not shown in any table or figure). By stratifying the analysis by gender, the relationship between BMI and histological scores was confirmed only in females (P = 0.006) and not in males (P = 0.52) (Table 3).


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  		Table 2. One-way ANOVA output with histological scores as grouping variable and age, log dialysis duration, BMI, pre-PTx serum log iPTH, log ALP, Ca, P and oxyphil cells as predictors

 

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  		Table 3. BMI-focused output of the one-way ANOVA stratified by gender with histological scores as grouping variable and age, log dialysis duration, BMI, pre-PTx serum log iPTH, log ALP, Ca, P and oxyphil cells as predictors

 
The stratification of the entire cohort into two groups according to the cut-off value of BMI = 25 kg/m2 showed that (Table 4): (i) the prevalence of the histological features was significantly different among the groups, score 4 being more prevalent in the high-BMI group and score 2 in the normal-BMI group (P = 0.01); (ii) the distribution of the genders was significantly different in the groups, female gender being more represented in the high-BMI group (12 out of 18 patients, P = 0.04); (iii) the duration of dialysis was significantly lower in the high-BMI group (P = 0.008); (iv) the pre-PTx serum P levels were significantly higher in the high-BMI group (P = 0.008); and (v) the frequency of previous vitamin D treatment was significantly different between the groups, the high-BMI group having been treated more frequently with such therapies (P = 0.04).


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  		Table 4. Demographic, clinical and biochemical characteristics of the 42 patients according to the cut-off BMI value of BMI = 25 kg/m2

 
The stratification of the female patients into two groups according to the cut-off value of BMI = 25 kg/m2 showed the following (Table 5): (i) the prevalence of the histological features was significantly different among the groups, score 4 being more prevalent in the high-BMI group, whereas a quite similar distribution of the three histological patterns was present in the normal-BMI group (P = 0.01); (ii) the duration of dialysis was significantly lower in the high-BMI group (P = 0.001); and (iii) the pre-PTx serum P levels were significantly higher in the high-BMI group (P = 0.04).


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  		Table 5. Demographic, clinical and biochemical characteristics of the female patients according to the cut-off BMI value of BMI = 25 kg/m2

 
Table 6 illustrates the output of the linear multiple regression analysis with pre-PTx serum P as dependent variable and BMI, pre-PTx log ALP and serum Ca as independent variables (selected according to the statistical significance in the bivariate correlations). In the main analysis, serum Ca and BMI were statistically significant predictors of serum P levels. This result was confirmed by stratifying the analysis by the histological scores, the underlying nephropathy and the previous use of P intestinal chelation or vitamin D (not shown in any table or figure). However, this finding, while persisting in females (BMI: P = 0.01 and serum Ca: P = 0.04), was not confirmed in males when the inference was stratified by gender (not shown in any table or figure).


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  		Table 6. Linear multiple regression analysis with pre-PTx serum P levels as dependent variable and BMI, log serum ALP and Ca levels as independent variables (chosen according to the statistical significance in the bivariate correlations)

 


   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
The present study was designed in order to answer two main questions: (i) is BMI associated with the clinical expression of sHPTH in long-term haemodialysis patients? and (ii) if yes, may the relationship between BMI and the clinical expression of sHPTH be mediated by different P body burdens in patients with different BMI? To answer the first question, we identified histological grading as the best outcome index: actually, iPTH, besides being a surrogate marker, showed to be also an inaccurate and unreliable index of clinical outcome in our hands. Then, we looked for any significant difference among the three histological scores: only BMI was identified in the main analysis; then, when stratifying by categorical variables, the relationship between BMI and the histological scores was confirmed only in females. Thus, the answer to the first question is: BMI is associated with the clinical expression of sHPTH; in other words, the higher the BMI the worse is the histological pattern of sHPT, but only in females.

The stratification of both the entire cohort and of the female cohort according to the cut-off value of BMI = 25 kg/m2 showed that the pre-PTx serum P levels were significantly higher in the high-BMI group; in addition, the output of the linear multiple regression analysis with pre-PTx serum P levels as dependent variable and BMI, pre-PTx serum ALP and Ca levels as independent variables showed that BMI was a statistically significant predictor of serum P levels. Furthermore, when the inference was stratified by gender, the relationship between serum P levels and BMI was confirmed only in females. Thus, the answer to the second question is: BMI is associated with P body burden; in other words, the higher the BMI the larger is P body burden, but only in females. Therefore, the sequence of pathophysiological events, at least in females, may be the following: a high BMI may predispose to a large P body burden which may lead to more aggressive histological patterns of sHPTH. Thus, it would seem that just as in primary hyperparathyroidism, female gender is important in the development of sHPTH. While estrogen has been reported to directly increase PTH gene expression and PTH secretion [9], it has also been suggested that the effect of the estrogen could be indirect (e.g. via calcium metabolism) [10].

The results of the present study confirm previous data, i.e. an association between female gender and more aggressive histological sHPTH patterns [11], and demonstrate a novel finding: a higher BMI is associated with an increased risk of nodular hyperplasia of parathyroid glands in adult female Caucasian haemodialysis patients. It is well-known that the histological pattern expresses an increasing severity ranging from diffuse to nodular hyperplasia; in fact, histopathological studies have shown that parathyroid hyperplasia in sHPTH can switch from the initial diffuse hyperplasia to early nodularity, and then to nodular hyperplasia and ultimately to a single nodule [12]. In general, it is supposed that there is a continuum in the development of parathyroid hyperplasia, related to the duration of uraemia/dialysis; parathyroid cell proliferation is initially polyclonal, but later on it may be complicated by multiclonal or monoclonal proliferation [12], with a reduction in vitamin D and calcium-sensing receptor expression [13]. However, the present study clearly shows that the group of female patients with abnormally high BMI had exclusively nodular hyperplasia of the four glands in 91.7% of cases, despite significantly shorter time on dialysis as compared with the low/normal BMI (47.4 vs 100.3 months), with only 30% of patients in the score group 4. Thus, one might speculate that the dynamics of the development of parathyroid hyperplasia is different from what is generally supposed, and nodularity is not necessarily the end-pattern; some subjects develop diffuse and other subjects (the majority) nodular hyperplasia.

Furthermore, we demonstrated that a higher BMI is associated with a larger body burden of P in female haemodialysis patients, influencing by that way the severity of sHPTH. Why high-BMI female haemodialysis patients may have a larger P body burden is a matter of speculation; it might occur through either an increased dietary P intake or an increased fractional intestinal absorption or through a more complex and difficult intradialysis regulation among the several P pools [14], which might lead to a reduced removal of P by the haemodialysis treatment in the high-BMI patients. Obviously, two or all of the three conditions may coexist. We could not verify the existence of any of these conditions potentially explaining the larger P body burden in the high-BMI patients; we could just show that Kt/Vurea was not different between the high and normal BMI groups, but it is well-known that intradialysis P kinetics is quite different from that of small molecules [14]. A further intriguing source of speculation comes from a very recent paper, which compared subjects with normal kidney function, but differed because subjects affected by metabolic syndrome (i.e. with a BMI higher than normal) were characterized by lower serum P levels than normal subjects; the authors suggested that hypophosphataemia was probably due, among other factors, to an increased P transfer from the extracellular to the intracellular compartment [15].

Many studies have already reported an association between hyperphosphataemia and the magnitude of sHPTH, the failure to respond to treatment for sHPTH, or other surrogates of sHPTH, such as renal osteodystrophy [3,16–18]. Furthermore, an association between female gender and more aggressive sHPTH patterns has already been demonstrated [1,2,9,16–20]. Notably, when referring to the available literature data about the two risk factors combined, i.e. female gender and hyperphosphataemia, Indridason et al. [16], when studying 52 haemodialysis patients in a 4-week prospective study, found that only the changes in serum P, initial serum levels of iPTH levels and gender remained the predictors of short-term changes in iPTH in a multivariate regression analysis. Similar data were obtained by Gupta et al. [17] in 1270 prevalent haemodialysis patients in a stepwise multiple regression model; the determinants of maximum iPTH in the order of their importance were black race, serum P, absence of diabetes, young age, serum Ca and female gender. Finally, incubation studies of parathyroid tissue from haemodialysis patients showed that both the pre-PTx serum P level and female gender were associated with a decreased response to calcitriol when trying to identify, in a multiple regression analysis, independent variables that could have affected the percent cells in S phase (dependent variable) of the cell cycle [18]. Thus, the authors could conclude that a high P burden, as well as female gender, favour parathyroid cell proliferation and both may reduce the inhibition of parathyroid function by calcitriol [18].

The clinical relevance of our findings is considerable: aggressive strategies of prevention and treatment of sHPTH are recommended for all dialysis patients; and more aggressive strategies of prevention and treatment of sHPTH should be mandatory in high-BMI female patients. These include: a more rigorous dietary counselling coupled with a more strict patient compliance, a larger use of non-calcium-containing phosphate binders, more targeted strategies of vitamin D treatment (are vitamin D analogues to be preferred?) as far as duration and dose are concerned, a probably more precocious and extensive utilization of calcimimetics, and lastly, a more effective dialysis treatment. Daily dialysis currently appears to be the only technique capable of safely depleting excess P stores and maintaining patients in optimal P balance, although whether this will be practical for the majority of patients remains doubtful [14].

In conclusion, a high BMI and female gender are associated with an increased risk of nodular hyperplasia of parathyroid glands in adult Caucasian haemodialysis patients. The two risk factors, above all if combined in the same patient, appear to predispose to a larger body burden of P, increasing by that way the severity of sHPTH.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 26. 5.05
Accepted in revised form: 11.11.05


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