Does vitamin D receptor and calcium receptor activation therapy play a role in the histopathologic alterations of parathyroid glands in refractory uremic hyperparathyroidism?

BACKGROUND AND OBJECTIVES: Vitamin D receptor activation by vitamin D sterols and calcium-sensing receptor stimulation by cinacalcet are the most powerful treatments of secondary hyperparathyroidism. This study was aimed to assess a possible association between histopathologic changes of parathyroid tissue and treatment modality. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Studies were performed on 82 parathyroids of 22 adult white hemodialysis patients undergoing first parathyroidectomy. The type of hyperplasia and the distribution of chief and oxyphil cells, expressed as oxyphil/chief cell ratio, were assessed. Three groups could be studied according to treatment modality: group A consisted of 6 patients who were treated with cinacalcet, intravenous calcitriol, and phosphate binders; group B consisted of 6 patients who were treated with intravenous calcitriol and phosphate binders, and group C consisted of 10 patients who were treated with phosphate binders alone. RESULTS: Sixty-eight (82.9%) out of 82 glands removed showed nodular hyperplasia. It was more frequent in groups A and B than in group C. A stepwise forward logistic regression model showed that the probability of nodular hyperplasia was higher in patients who were on calcitriol and/or cinacalcet therapy, in female gender and in patients with a higher body mass index. Oxyphil/chief cell ratio also was significantly different among the three groups. Cinacalcet treatment was the only predictor of this ratio. CONCLUSIONS: An association was found between calcitriol and/or cinacalcet therapy and a high prevalence of nodular hyperplasia, and between cinacalcet therapy and high oxyphil/chief cell ratio. The meaning of the observed associations remains uncertain.

Post-parathyroidectomy serum phosphate kinetics is peculiar to female hemodialysis patients with a high body mass index.

BACKGROUND: Persistent hyperphosphatemia is one of the most important factors in the development of secondary hyperparathyroidism (sHPTH). Recently, we demonstrated that a higher body mass index (BMI) and female gender could predispose to a larger phosphate (P) body burden, thereby influencing the severity of sHPTH. METHODS: This prospective study aimed to verify if these two risk factors, i.e. BMI and female gender, also influenced calcium (Ca) and P kinetics in the immediate post-parathyroidectomy (PTx) period in 42 consecutive adult Caucasian anuric hemodialysis (HD) patients referred for first PTx. Serum Ca and P were measured pre-PTx and on the 5 consecutive post-PTx days; serum immunoreactive parathyroid hormone (iPTH) and alkaline phosphatase (ALP) levels were measured pre-PTx and 3 days post-PTx. RESULTS: Ablation of parathyroid tissue determined a significant reduction in serum iPTH, ALP, Ca and P (p = 0.001). The stratification of the cohort into four groups according to the cut-off value of BMI = 25 kg/m(2) and according to gender showed the following: males and females with BMI >25 kg/m(2) (analyzed both separately and as a subgroup including males and females) had significantly higher pre-PTx serum P levels, when compared with the respective sub-groups with BMI <25 kg/m(2) (p < 0.01); a significantly higher mean area under the concentration curve (AUC) of serum P was observed in the high BMI group (males and females), when compared with the low/normal BMI group (p = 0.03); the serum P kinetics in the 5 post-PTx days did not differ between the two groups of male patients (low/normal BMI males vs. high BMI males), whereas a significantly higher mean serum P AUC was observed in the high BMI female patients, when compared with the low/normal BMI female patients (p = 0.003); finally, the serum P kinetics in the 5 post-PTx days did not differ between the two groups of low/normal male and female patients, whereas a significantly higher mean serum P AUC was observed in the high BMI female patients, when compared with the high BMI male patients (p = 0.006). A linear multiple regression analysis with the serum P AUC of each patient as a dependent variable and BMI, gender, age and dialysis duration as independent variables showed that BMI (p = 0.0001) and female gender (p = 0.001) were independent predictors of the serum P AUC. CONCLUSIONS: High BMI and female gender are associated with peculiar serum P kinetics in the immediate post-PTx period, suggesting the existence of a larger P body burden in high BMI female HD patients. The existence of a larger P pool exclusively based on serum P kinetics prompts the need for further studies to better understand such intriguing aspects of bone pathophysiology in response to parathyroid gland removal in chronically uremic patients.

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

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/m(2) 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.

Female hemodialysis patients have an increased risk of nodular hyperplasia of parathyroid glands.

BACKGROUND: An association between female gender and more aggressive patterns of secondary hyper-parathyroidism (sHPTH) has been suggested: an increased incidence of refractory sHPTH seems evident in females; therefore, necessitating parathyroidectomy (PTx). METHODS: This study aimed to verify the existence of such an association and secondly to evaluate the impact of female gen-der on parathyroid gland histology. Therefore, a retrospective study was conducted on 67 patients who underwent first PTx (either total or subtotal) in our hospital from 1999-2003. Out of these patients, we selected 55 (28 males, 27 females, mean age 50.8 +/- 14.7 SD yrs, dialysis duration 109.2 +/- 62.4 months) in whom all four parathyroid glands were identified and removed. Serum levels of immunoreactive intact parathyroid hormone (iPTH), alkaline phosphatase, calcium and phosphate were determined at the PTx time point. The same pathologist performed the histological studies of the parathyroid glands on seven serial sections of the glands. Gland hyperplasia was classified as (1) exclusively diffuse (EDH) when only diffuse hyperplasia was found in the four glands; (2) exclusively nodular (ENH) when only nodular hyper-plasia was found in the four glands; (3) diffuse/nodular (D/NH), in which the four glands showed varying degrees of evolution towards both nodular and diffuse hyperplasia. RESULTS: EDH was found in 13 patients with a prevalence of males (11/13; 84.6%); ENH was found in 23 patients with a prevalence of females (15/23; 65.2%); D/NH was found in 19 patients with a similar prevalence between females and males (10 females and 9 males). The difference in the male/female prevalence among the three groups was statistically significant (chi2 test, p=0.015). Serum calcium was significantly higher in the ENH group (one-way analysis of variance, p=0.009). No difference was found among the three groups as far as age, dialysis duration, serum levels of iPTH, alkaline phosphatase and phosphate were concerned. CONCLUSIONS: Female gender is associated with more aggressive histological sHPTH patterns; this association seems to suggest that female gender predisposes to monoclonal proliferation of parathyroid glands in chronic uremia.

Are low plasma levels of 25-(OH)vitamin D a major risk factor for hyperparathyroidism independent of calcitriol in renal transplant patients?

BACKGROUND: Recently, some studies have emphasized the role of plasma 25-(OH)vitamin D (25OHD) levels in mineral metabolism dysregulation in chronic kidney diseases (CKDs). However, to date little attention has been paid to 25OHD metabolism abnormalities after renal transplantation (Tx). This cross-sectional study aimed to focus on its role in mineral metabolism dysregulation in functioning Tx. METHODS: Twenty-eight out of 75 Caucasian Tx patients were selected following strict inclusion and exclusion criteria. Two blood samples were effected at the end of the winter for the measurements of plasma 25OHD and calcitriol levels. Serum creatinine (Cr), alkaline phosphatase (SAP), immunoreactive intact parathyroid hormone (PTH), electrolytes and 24-hr proteinuria were also determined. The Kolmogorov-Smirnov test was used to evaluate the data distribution: serum Cr, Cr clearance, dialysis duration and PTH levels were non-normally distributed and were log-transformed. Values of p<=0.01 were assumed as statistically significant. RESULTS: Median serum Cr and PTH levels were, respectively, 1.0 mg/dL and 90.0 pg/mL (range 27-420; normal range 10-65); most of our Tx patients (78.5%) had serum PTH levels above the upper limit of normal values. Mean plasma 25OHD concentration was 19.6 +/- 8.9 SD ng/mL (range: 6-36). None had levels <5 ng/mL (severe deficiency); 10 patients (35.7%) had mild deficiency (5-15 ng/mL); 14 patients (50%) had vitamin D insufficiency (16-30 ng/mL); and only four patients (14.3%) had target levels (>30 ng/mL). Mean plasma calcitriol levels were 69.7 +/- 19.0 pg/mL (range 47-105; normal range 35-85). They were not significantly correlated to plasma 25OHD levels. Proteinuria (292.6 +/- 147.0 mg/24 hr) inversely correlated to plasma 25OHD levels (r=-0.480; p<0.01). The bivariate correlation analysis between logPTH and the other parameters showed a significant correlation for SAP (r=0.494; p=0.008), plasma 25OHD levels (r=-0.442; p=0.01), proteinuria (r=0.452; p=0.01), log serum Cr (r=0.551; p=0.002) and log Cr clearance (r=-0.534; p=0.003). The other parameters did not correlate significantly with logPTH, notably plasma calcitriol and serum phosphate levels. Only the parameters significantly correlated to logPTH in the bivariate correlation analysis were included in the back stepwise multiple linear regression analysis as independent variables (model: p<0.0001; R2=0.54): among them, only plasma 25OHD levels (Beta=-0.486; p=0.001) and log serum Cr levels (Beta=0.589; p=0.0002) were the dependent variable logPTH predictors. CONCLUSIONS: This cross-sectional study demonstrated that plasma calcitriol levels in a highly selected group of Tx patients were normal and not significantly correlated to either plasma 25OHD or serum PTH levels. Most patients (85.7%) had plasma 25OHD levels below the target value of 30 ng/mL; the latter were inversely correlated with serum PTH levels. Therefore, our study strengthens the suggestion that low plasma 25OHD levels are a major risk factor for secondary hyperparathyroidism (sHPTH) in Tx patients and stresses the importance of monitoring these patients.

End-stage renal disease in leprosy.

BACKGROUND: Leprosy or Hansen's disease (HAD) undoubtedly remains an emergency in certain countries. It is an ancient deforming disease caused by Mycobacterium leprae. The countries with the highest endemic leprosy rate in 2000 were Brazil, India and Madagascar. In Italy, the old epidemic has been defeated and there are approximately 400 patients under constant monitoring with three to four new cases per year involving Italian residents. The kidney is one of the target organs during the splanchnic localization of leprosy. The histopathological renal lesion spectrum includes glomerulonephritis (GN), renal amyloidosis (RA) and interstitial nephritis (IN). Both proteinuria and chronic renal failure are the main clinical expressions of renal damage in leprosy. To the best of our knowledge, very little is reported concerning end-stage renal disease (ESRD) in leprosy patients both in the most important national and international renal registries and in the available literature. This study aimed to report the long-term experience of our department in this field. METHODS: To achieve this, we analyzed retrospectively the HAD Center (Gioia del Colle) database at ourhospital. RESULTS: Eight leprosy patients were dialyzed from 1980 to June 2003 (six males and two females), with a mean age of 61.0+/-8.9 SD yrs (range: 51-76) and a mean HAD duration of 36.1+/-5.1 yrs. The first clinical nephropathymanifestations were non-nephrotic proteinuria associated with chronic renal failure in four patients, and nephrotic proteinuria in four patients. Kidney biopsies performed in three patients showed two had RA, and one had IN. Two patients were treated initially by peritoneal dialysis; they were then switched to hemodialysis (HD) after 3 and 10 months because of recurrent peritonitis. HD treatment lasted 40.6+/-31.4 months (range: 9-101). Six patients died, one due to hyperkalemia, one because of a technical dialysis accident, and the remainder due to causes unrelated to the dialysis treatment. Two patients are still alive, treated with HD for 17 and 44 months. CONCLUSIONS: Uremia represents a late complication of leprosy and has a multifactorial genesis, although RA is among the most frequent causes, conventional bicarbonate HD appears to offer good results in the treatment of uremia in leprosy patients.

Calcitriol pulse therapy and histology of parathyroid glands in hemodialysis patients.

BACKGROUND: Calcitriol pulse therapy (CPT) is considered the most appropriate treatment of secondary hyperparathyroidism (sHPTH). This treatment inhibits parathyroid hormone (PTH) synthesis and secretion, suppresses parathyroid cell proliferation and controls parathyroid gland growth. However, not much is known about the effect of such therapy on parathyroid morphology. METHODS: To investigate this, we studied all first parathyroidectomies (PTx, either total or subtotal) effected in 30 hemodialysis (HD) patients referred to our surgery department by five regional dialysis units in 2000-2001. Six patients were excluded from the study because of either the persistence or the precocious relapse (in the 1st 6 months post-operation) of sHPTH. Twenty-four HD patients were considered eligible as four parathyroid glands were ablated in each patient; 96 glands were then examined histologically. The cohort consisted of 16 males and 8 females with a mean age of 54 +/- 13 SD yrs (range 20-73) and a dialysis duration of 142 +/- 71 months (range 14-289). Data concerning calcitriol treatment (doses, administration route and treatment duration) were collected for each patient. The patients were subdivided into two groups according to the treatment effected in the months preceding PTx: group A (n=13), treated by either intravenous (i.v.) (n=12) or per os (n=1) CPT, and group B (n=11), not treated at all with calcitriol or vitamin D sterols. Parathyroid gland morphology and the parenchymal cell distribution of the parathyroid glands were evaluated by a semiquantitative assessment. Serum intact PTH (iPTH), alkaline phosphatase (AP), calcium (Ca) and phosphate (P) levels were studied pre- and post-PTx. RESULTS: Chief cells (CC) were found in all glands, either alone or associated with oxyphil cells (OC). OC were present in 13 of 24 patients (54%); however, it must be underlined that they were present 12 times in group A parathyroid glands (92%), and only once in group B (9%) (p<0.01). Nodular hyperplasia was found in 71% (17/24) of patients: 92% (12/13) in group A, and 45% (5/11) in group B (p<0.05). There were no significant differences in age, gender, dialysis duration, serum levels of iPTH, AP, Ca and P levels between the two groups. CONCLUSIONS: There was a strong association between OC presence in parathyroid glands and CPT. Furthermore, nodular hyperplasia appeared to be associated significantly with CPT. There is still speculation regarding the meaning of these CPT effects on parathyroid gland histology and consequently on sHPTH pathophysiology.