OBJECTIVE

Dialysis patients display an increased mortality which is associated with cardiovascular calcifications. Diabetes mellitus and ethnicity are known factors that affect the extent of cardiovascular calcifications. However, most studies have investigated mixed cohorts with diabetics and/or mixed ethnicity.

METHODS

Cardiovascular calcifications were assessed in non-diabetic Caucasian haemodialysis patients by the semiquantitative Adragao calcification score (X-ray pelvis and hands) and a novel composite calcification score encompassing the Adragao score as well as calcifications detected by X-ray of the fistula arm, echocardiography of heart valves and carotid ultrasound.

RESULTS

Using multivariate analysis, age, male gender, dialysis vintage, lower Kt/V, calcium-phosphate product, smoking and high-sensitivity CRP were independent risk factors for cardiovascular calcifications as assessed by the Adragao or the composite score. Pulse wave velocity was independently related to both calcification scores. Body mass index, cholesterol, triglycerides, iPTH and serum levels of fetuin-A and uncarboxylated matrix Gla protein were not associated with cardiovascular calcifications.

CONCLUSIONS

In our cohort of non-diabetic Caucasian haemodialysis patients, age, male gender, dialysis vintage, smoking, calcium-phosphate product, high-sensitivity CRP and lower Kt/V were independent risk factors for cardiovascular calcifications. Whether lowering the calcium-phosphate product and increasing dialysis efficiency can reduce cardiovascular calcifications in dialysis patients remains to be determined.

We report the prevalence of chronic kidney disease (CKD) and related complications in a national cohort of RTR (n=9542), and compare this with dialysis patients. The majority of RTR were classified as having CKD stage 2T (21.6%) or 3T (57.5%) with 15.7% classified as CKD stage 4T and 3.1% as stage 5T. Only 2.1% of RTR were in CKD stage 1T. The proportion of patients with stage 4T and 5T CKD who lost their graft in the following year was 8% and 49%, respectively. The prevalence of anemia (hemoglobin <11 g/dL) increased from 4.4% in stage 1T to 51.5% in stage 5T and compared with 30% in dialysis patients (p<0.0001). Hypertension, hyperphosphatemia, elevated Ca x PO(4), raised iPTH and hypoalbuminemia rose with increasing CKD stage. For many variables, the achievement of standards was lower in stage 5T RTR than in dialysis patients. There were center differences in median estimated glomerular filtration rate and percentage of patients with hemoglobin <11 g/dL (p<0.0001). In conclusion, many patients in stage 4T-5T have CKD-related complications that fall below targets established for nontransplant CKD patients. They are at increased risk of graft loss. More attention needs to be paid to managing these complications and preparing these patients for a return to dialysis and/or retransplantation.

Osteoprotegerin (OPG), receptor activator of the nuclear factor κB ligand (RANKL) and fibroblast growth factor-23 (FGF-23) play a central role in renal osteodystrophy. We evaluated OPG/RANKL and FGF-23 levels in 51 children with chronic kidney disease (CKD) [n = 26 stage 3 or 4 (CKD3-4) and n = 25 stage 5 (CKD5)] and 61 controls. Any possible association with intact parathyroid hormone (iPTH) and bone turnover markers was also investigated. The OPG levels were lower in the CKD3-4 group (p < 0.001) and higher in the CKD5 group (p < 0.01) than in the controls, while RANKL levels did not differ. The FGF-23 levels were higher in both patient groups (p < 0.0001), while the levels of phosphate and iPTH were higher only in the CKD5 group (p < 0.0001). There were independent positive correlations between OPG and RANKL (β = 0.297, p < 0.01) and FGF-23 (β = 0.352, p < 0.05) and a negative correlation with the bone resorption marker TRAP5b (β = -0.519, p < 0.001). OPG was positively correlated with iPTH (R = 0.391, p < 0.01). An independent positive correlation between FGF-23 and phosphate (β = 0.368, p < 0.05) or iPTH (β = 0.812, p < 0.0001) was noted. In conclusion, we found that higher OPG levels in patients with CKD stage 5 correlated with the levels of RANKL, FGF-23, iPTH, and TRAP5b. These findings may reflect a compensatory mechanism to the negative balance of bone turnover. High FGF-23 levels in early CKD stages may indicate the need for intervention to manage serum phosphate (Pi) levels.

BACKGROUND

There are no controlled trials on the efficacy of oral bicarbonate therapy in patients with mild to moderate chronic kidney disease (CKD). This prospective randomized controlled study was done to evaluate the effects of correction of metabolic acidosis on renal functions and bone metabolism in this group of patients.

METHODS

Forty patients were randomized to treatment with oral bicarbonate or placebo for a period of 3 months. Investigations at baseline included venous pH, bicarbonate, renal functions, serum iPTH, and bone radiology. The treatment group (Group B) received daily oral sodium bicarbonate therapy at a dose of 1.2 mEq/kg of body weight. Their venous blood pH and bicarbonate levels were estimated weekly to keep blood pH near 7.36 and bicarbonate at 22-26 mEq/L by adjusting the dose of sodium bicarbonate. At the end of 3 months, all the tests were repeated in both groups.

RESULTS

After oral bicarbonate therapy (OBT), there was a significant decline in the rise of blood urea level in Group B associated with a sense of well-being in 50% patients. The rise in parathormone (PTH) was six times the baseline value in Group A and only 1.5 times baseline value in Group B, although not statistically significant. There was no significant change in total calcium, phosphorus, alkaline phosphatase, creatinine, total protein, or albumin levels.

CONCLUSIONS

Correction of metabolic acidosis in patients with moderate CKD attenuates the rise in blood urea and PTH, which might prevent the deleterious long-term consequences of secondary hyperparathyroidism.

BACKGROUND

The aim of this study was to assess left ventricular (LV) systolic and diastolic function and myocardial performance (the Tei index) by tissue Doppler imaging (TDI) in patients with primary hyperparathyroidism (PHPT).

METHODS

We prospectively evaluated 21 patients with PHPT [nine women, 12 men; aged 50 +/- 11 years, serum calcium 2.9 +/- 0.17 mmol/l, intact PTH (iPTH) 51.5 +/- 52.1 pmol/l] and 27 healthy control subjects (13 women, 14 men; aged 49 +/- 10 years, serum calcium 2.35 +/- 0.12 mol/l, iPTH 2.9 +/- 0.9 pmol/l). LV systolic and diastolic function was assessed by conventional echocardiography and by TDI. Early diastolic (Em), late diastolic (Am) and peak systolic (Sm) mitral annular velocities, the ratio Em/Am and the Tei index were calculated from TDI measurements. Mitral inflow velocities, colour M-mode flow propagation velocity (Vp), relative wall thickness (RWT) and LV mass index (LVMI) were assessed by two-dimensional echocardiography.

RESULTS

Em and Em/Am were lower in patients with PHPT than in healthy controls (11.2 +/- 1.5 cm/s vs. 13.5 +/- 2.5 cm/s, P = 0.005; 0.94 +/- 0.27 vs. 1.36 +/- 0.44, P = 0.02, respectively). In patients with PHPT, the Tei index was significantly higher than that in controls (0.45 +/- 13.6 vs. 0.33 +/- 8.1, P = 0.02). Peak (E) velocity and the ratio of E to peak late (A) velocity (E/A) were lower in those with PHPT than in those without (59 +/- 15 cm/s vs. 72 +/- 19 cm/s, P = 0.02; 0.8 +/- 0.15 vs. 1.1 +/- 0.33, P = 0.001, respectively). Patients with PHPT had significantly higher RWT (0.50 +/- 0.02 cm vs. 0.41 +/- 0.02 cm, P = 0.0001), isovolumetric relaxation time (IVRT) (115 +/- 13 ms vs. 103 +/- 11 ms P = 0.04) and A velocity (79 +/- 16 cm/s vs. 68 +/- 13 cm/s P = 0.05) than controls. Vp was lower in PHPT patients than in healthy subjects (42 +/- 9.98 cm/s vs. 54 +/- 19.01 cm/s P = 0.04). There were no significant differences between the two groups regarding LV end-diastolic and end-systolic dimensions, LVMI, deceleration time of the mitral E wave, Am and Sm.

CONCLUSIONS

TDI analysis of mitral annular velocities, Em/Am and the Tei index is useful for assessing LV diastolic dysfunction in patients with PHPT. The parameters obtained from the lateral mitral annulus by TDI can be used for the identification of LV diastolic dysfunction in PHPT patients.

Some authors have praised the value of fine needle aspiration (FNA) with measurement of intraparathyroid intact parathyroid hormone (iPTH) for localization of the hypersecreting gland(s) in recurrent or persistent primary hyperparathyroidism (HPT). The aim of the present study was to determinate whether FNA for iPTH assay is an effective procedure to distinguish between normal and hypersecreting parathyroid glands. We performed a prospective study of 170 patients who underwent cervicotomy. They were divided into three groups: group A, 50 patients with thyroid diseases; group B, 100 patients with primary HPT; group C, 20 patients with secondary HPT. We performed intraoperative FNA for iPTH measurement from the thyroid, and from the normal and enlarged parathyroid glands, and we compared the different intraglandular iPTH assays. In group A, the intraparathyroid iPTH level was < 1000 pg/ml in 68% of the patients. In group B, in the pathological parathyroid gland iPTH was>> 1000 in 88%; conversely, in the normal adjacent parathyroid glands it was < 1000 in 79%. In group C, intraparathyroid iPTH of enlarged glands was>> 1000 in 80%. Intrathyroid iPTH was < 100 pg/ml in 96% for the three groups. We conclude that FNA for intraglandular iPTH measurement is an effective tool for distinguishing between normal and pathological parathyroid glands in the setting of primary HPT (p < 0.05), and between thyroid and parathyroid glands in groups A and B. But the procedure should be carried out in conjunction with the sestamibi scan and ultrasonography before surgical reintervention.

OBJECTIVE

Cinacalcet reduces serum calcium in kidney transplant recipients with hypercalcemic hyperparathyroidism. Its effect on bone, however, has not been investigated in this population.

METHODS

We prospectively examined bone turnover, histomorphometry and density as well as serum bone biomarkers in 10 transplant recipients before and after treatment with cinacalcet.

RESULTS

After 18-24 months of treatment with cinacalcet, bone formation decreased in 7, increased in 2, and remained zero in 1 patient (p = 0.11). Trabecular bone volume was maintained. Trabecular number decreased (p = 0.03), but trabecular thickness was unchanged (p = 0.17). Osteoid decreased (p = 0.02) and osteoblast surface increased (p = 0.02). Bone mineral density of the femur remained stable in 1 patient, decreased in 2 patients, but increased in 7 patients (p = 0.153). Serum calcium concentration (p = 0.005), iPTH (p = 0.01) and calcitonin concentration decreased (p = 0.03), while 25(OH) vitamin D(3) increased (p = 0.02). No fractures were reported. Graft function remained stable.

CONCLUSIONS

While cinacalcet might decrease bone formation rate, it did not change bone volume, and bone mineral density of the femur increased. Therefore, the use of cinacalcet in hypercalcemic hyperparathyroidism might be safe with regard to the bone disease present after kidney transplantation.

OBJECTIVE

The aim of the present study was to measure concentrations of vitamin D metabolites and intact parathyroid hormone (iPTH) serum concentrations and an urinary bone resorption marker in two groups of elderly subjects, who differed markedly in their sedentary status and seasonality.

METHODS

193 institutionalized elderly people of a long-stay geriatric ward (106 women: mean age 82; 87 men: mean age 78) were studied during wintertime. 312 ambulatory elderly people (109 women: mean age 74; 203 men: mean age 76) were studied during summertime. Concentrations of calcidiol (25(OH)D), calcitriol (1,25(OH)2D) and serum iPTH, as well as urinary N-telopeptides (NTX) were measured.

RESULTS

Vitamin D deficiency (defined as serum 25(OH)D < 12 ng/ml) was present in 86% of institutionalized at the expected nadir (wintertime), compared to 15% of the ambulatory elderly subjects at the expected maximum (summertime). Serum calcitriol concentrations were significantly lower in institutionalized subjects (p = .0001). However intact PTH concentrations did not differ significantly between institutionalized and ambulatory elderly. Institutionalized and female subjects showed higher urinary NTX excretion (female institutionalized: 131.9; female ambulatory: 66.8/male institutionalized: 76.3 male ambulatory: 45.8 nmol/mmol).

CONCLUSIONS

This cross-sectional study documented very low serum calcidiol and calcitriol concentrations and high urinary N-telopeptide excretion in institutionalized elderly people. There was no difference in serum iPTH concentrations between institutionalized and ambulatory elderly. This finding could not be explained by the differences in calcidiol and calcitriol concentration, nor urinary NTX excretion. These results suggest that other factors than vitamin D deficiency, such as lower mobility status and sedentary life style, might have an important role in the regulation of iPTH and mechanisms of bone loss in the elderly.

BACKGROUND

Restless legs syndrome (RLS) is a sensorimotor disorder characterized by an uncontrolled need to move extremities accompanied by unpleasant sensations, which frequently leads to sleep disturbances. In hemodialysis (HD) patients, the previously reported RLS prevalence varied enormously, between 6% and 60%. In our study, we investigated the RLS prevalence in HD patients for the first time in Greece.

METHODS

A continuous sample of HD patients was studied between January and September of 2010 in six dialysis units in Greece. RLS diagnosis was based on the essential clinical criteria of the International RLS Study Group (IRLSSG). The standardized incidence ratio (SIR) for RLS in HD patients was calculated in comparison to data from a recent survey of the general population in Greece.

RESULTS

In our study of 579 HD patients in Greece (236 women; mean age, 65±13years), the prevalence of RLS was elevated in comparison to the general population (26.6% vs 3.9%), with an SIR of 5.4 (95% confidence interval [CI], 4.6-6.3). In the fully adjusted model, the risk for RLS in HD patients was reduced in older age (odds ratio [OR], 0.98 [95% CI, 0.96-0.99]) and increased in women (OR, 1.60 [95% CI, 1.05-2.43]) in cases with elevated levels of β2 microglobulin (OR, 1.15 [95% CI, 1.01-1.32]) and intact parathormone (iPTH) (OR, 1.30 [95% CI, 1.08-1.56]).

CONCLUSIONS

A high RLS prevalence was recorded in a large HD population in Greece, clearly suggesting the need for enhanced awareness of RLS in nephrology. The RLS risk was increased in women and in younger HD patients as well as in those with elevated β2 microglobulin and iPTH levels.

BACKGROUND

Recently, nicotinamide has been suggested as an effective drug for hyperphosphatemia in hemodialysis patients. The authors assessed the efficacy and safety of nicotinamide in these patients with lower doses and longer duration than other studies.

METHODS

Forty eight patients with fasting serum phosphorus >5 mg/dl enrolled in this randomized clinical trial study and were randomly assigned to two equal-sized groups of nicotinamide or placebo. The study lasted 8 weeks. In the first four weeks, nicotinamide was administered at 500 mg/day, and in the second four weeks at 1,000 mg/day. Blood samples were tested at baseline, week 4, and week 8.

RESULTS

In nicotinamide group, the mean phosphorus level decreased from 5.9 ± 0.58 mg/dl to 4.77 ± 1.43 mg/dl in week 4 (P = 0.002) and to 4.66 ± 1.06 mg/dl in week 8 (P = 0.000). The mean calcium-phosphorus product decreased significantly with the same pattern as phosphorus. High-density lipoprotein level increased from 42.46 ± 8.01 mg/dl to 55.71 ± 11.88 mg/dl in week 4 (P = 0.000) and to 65.25 ± 20.18 mg/dl in week 8 (P = 0.000). Levels of serum calcium, uric acid, SGOT, SGPT, and iPTH didn't change significantly. Compared to baseline, the platelet counts were decreased in both week 4 and week 8. No significant changes were observed in placebo group.

CONCLUSIONS

In our patients, nicotinamide effectively decreased phosphorus, increased high-density lipoprotein, and caused thrombocytopenia. Since nicotinamide lowered platelet counts and caused thrombocytopenia in lower doses than other studies in these patients, it is necessary to plan other studies for assessing the safety of the drug especially in different populations.

BACKGROUND

The significance of nodal metastases, very common in papillary thyroid cancer, and the role of lymph node dissection in the neoplasm management, are still controversial. The impact of lymph node involvement on local recurrence and long-term survival remains subject of active research. With the aim to better analyze the predictive value of lymph node involvement on recurrence and survival, we investigated the clinico-pathological patterns of local relapse following total thyroidectomy associated with lymph node dissection, for clinical nodal metastases papillary thyroid cancer, in order to identify the preferred surgical treatment.

METHODS

Clinical records, between January 2000 and December 2006, of 69 patients undergoing total thyroidectomy associated with selective lymph node dissection for clinical nodal metastases papillary thyroid cancer, were retrospectively evaluated. Radioiodine ablation, followed by Thyroid Stimulating Hormone suppression therapy was recommended in every case. In patients with loco regional lymph nodal recurrence, a repeated lymph node dissection was carried out. The data were compared with those following total thyroidectomy not associated with lymph node dissection in 210 papillary thyroid cancer patients without lymph node involvement, at preoperative ultrasonography and intra operative inspection.

RESULTS

Incidence of permanent hypoparathyroidism (iPTH < 10 pg/ml) and permanent monolateral vocal fold paralysis were respectively 1.4 % (1/69) and 1.4% (1/69), similar to those reported after total thyroidectomy "alone". The rate of loco regional recurrence, with positive cervical lymph nodes, following 8 year follow-up, was 34.7% (24/69), higher than that reported in patients without nodal metastases (4.2%). A repeated lymph node dissection was carried out without significant complications.

CONCLUSIONS

Nodal metastases are a predictor of local recurrence, and a higher rate of lymph node involvement is expected after therapeutic lymph node dissection associated with total thyroidectomy. The prognostic significance of nodal metastases on long-term survival remains unclear, and more prospective randomized trials are requested to better evaluate the benefits of different therapeutic approaches.

A case-control study was undertaken to understand the etiopathology of the bone deformities among young children in a fluoride-affected village of the Bihar State. Two villages were selected: one village with high fluoride in drinking water (7.9 +/- 4.15 ppm), and the other village with normal levels of fluoride (0.6 +/- 0.31 ppm) as the control village. The source of drinking water was bore wells in both the villages. Two hundred and forty subjects from 54 households (HHs) of the high-fluoride village (HFV) and 1443 subjects from 197 HHs of the control village were selected for the study. Dental mottling (DM) was observed in 50% and skeletal deformities of various forms were observed in 20% of the total population of HFV, whereas, in the control village, DM was 6% and skeletal deformities were absent. The prevalence of both, DM and skeletal deformities was high in the younger age group of 1.5 to 14 years. Genu valgum, genu varum, bowing of tibia, saber shin, and widening of the lower ends of long bones at the wrist were the typical skeletal deformities observed among affected children in the HFV. X-rays of the children with deformities revealed varying degrees of bending of bones and enlargement of epiphyseal ends of metaphyses with fraying of bone and ligamental calcification. A survey indicated significantly low calcium and high phosphorus intake among the population of the HFV as compared to that of the control village, possibly resulting from low intake of milk and high intake of potatoes, respectively. The mean urinary fluoride level was significantly higher in the children of the HPV, both with and without deformities, as compared to that of the control village. The mean serum 25 OHD3 (25 Hydroxy Vitamin D) and calcium levels were significantly lower and alkaline phosphatase activity was significantly higher among the children with deformities as compared to those without deformities from the HFV and the control village. Serum intact parathyroid hormone (IPTH) levels were high in children both with and without deformities in the HFV as compared to those in the control village. No significant differences were observed in the concentration of serum and urinary creatinine, and Cu, and Mg levels between the HFV and the control village. It can be concluded that some of the children from the HFV manifested severe bone deformities (rickets), which were confirmed by the existence of low serum calcium and vitamin D levels.

In order to evaluate the relationship of PGE2 to hypercalcemia in cancer patients, 101 patients were screened with a radioimmunoassay for plasma prostaglandin E2 (PGE2) (NL less than 100 pg/ml). Of the 101 patients, 31 were hypercalcemia. Mean PGE2 (+/- SEM) of the 31 patients was 199 +/- 36 pg/ml. Among the 70 normocalcemic patients, mean +/- SEM PGE2 was 85 +/- 12 pg/ml (range = less than 25--225 pg/ml) (P less than 0.001). Seventeen hypercalcemic patients were initially treated with saline and furosemide, then were prospectively screened for serum parathormone (iPTH) and PGE2. Fourteen of 17 patients were then treated empirically with indomethacin (25 mg b.i.d.) for 72 hours and the PGE2 assay was repeated. Prior to therapy with indomethacin (mean +/- SEM), Ca++ = 12.2 +/- 1.5 mg/dl (NL 8.4--10.6 mg/dl), PGE2 = 87.1 +/- 36.8 pg/ml, (range = less than 25--209 pg/ml), and iPTH = 406 +/- 266 pg/ml (NL less than 400 pg/ml) (range = less than 100--825 pg/ml). PGE2 was elevated before treatment in 6/14 patients (breast, colon, renal, lung, neck tumors, and myeloma). Following treatment with indomethacin, PGE2 and calcium fell to normal levels in three patients (breast, colon, renal carcinomas). These results suggest: (1) A bimodal distribution of PGEs exists in hypercalcemic cancer patients. (2). There was some evidence of lack of whole molecule iPTH suppression in these patients. (3) Multiple stimuli of calcium mobilization may play an important etiologic role in a few hyercalcemic cancer patients and may explain the failure of indomethacin to control serum Ca++ in some patients with elevated PGE2.

In an attempt to identify factors that may indicate which patients with sarcoidosis are likely to manifest a clinical abnormality in calcium homeostasis, we measured serum concentrations of calcium, angiotensin converting enzyme activity (ACE), 25-hydroxyvitamin D (25-OH-D), 1,25-dihydroxyvitamin D (1,25-(OH)2-D), and immunoreactive parathyroid hormone (iPTH) in 19 patients with biopsy proven sarcoidosis, seven of whom were either frankly hypercalcemic or hypercalciuric. These data were compared to the ability of cultured pulmonary alveolar macrophages (PAM) from the same patients to metabolize [3H]25-OH-D3 to [3H]1,25-(OH)2-D in vitro. All seven hypercalcemic/hypercalciuric patients with sarcoidosis had a serum ACE level greater than 40 IU/L (normal less than 35 IU/L). All five patients with hypercalcemia (Ca greater than or equal to 10.5 mg/dl) had a serum 1,25-(OH)2-D concentration above the normal range (greater than 60 pg/ml), and in all 19 patients the serum calcium was positively correlated to the serum 1,25-(OH)2-D concentration (r = 0.55, p less than 0.01). The capacity of PAM to synthesize [3H]1,25-(OH)2-D3 in vitro was. with one exception, greater in cells from patients with diffuse infiltrative pulmonary disease (roentgenographic stage II or III) and positively correlated to the serum calcium concentration (r = 0.72, p less than 0.001) and serum ACE (r = 0.43, p less than 0.05). Cultured PAM from the five hypercalcemic patients, all of whom demonstrated diffuse pulmonary disease on chest x-ray, showed a [3H]1,25-(OH)2-D3 synthetic capacity in vitro 2.5-fold greater than that for group as a whole and 6-fold greater than in cells from nonhypercalcemic patients with sarcoidosis.

Latent hypoparathyroidism (LHP), the inability to increase midmolecular parathyroid hormone levels appropriately during a hypocalcemic challenge, was reported previously in an asymptomatic woman with tetralogy of Fallot. This women's fourth child died with DiGeorge anomaly. Seven years later, we restudied the index patient with LHP and evaluated three generations of her family for parathyroid dysfunction, cardiac abnormalities, and del 22(q11). Deletions were found in six relatives, three with conotruncal cardiac defects and three with a structurally normal heart. We found significant transgenerational noncardiac phenotypic variability, including learning difficulties, dysmorphic facial appearance, and psychiatric illness. A spectrum of parathyroid gland dysfunction associated with the del 22(q11) was seen, ranging from hypocalcemic hypoparathyroidism to normocalcemia with abnormally low basal intact parathyroid hormone (iPTH) levels. In addition, LHP found in the index patient 7 years ago had evolved to frank hypocalcemic hypoparathyroidism. In this family, which is the largest family with 22q11 deletions studied to date, parathyroid gland dysfunction evolved over time. We suggest that the calcium parathyroid hormone axis of unrelated patients with del 22(q11) be followed closely for the development of hypocalcemic hypoparathyroidism.

Circulating levels of PTH and related parameters of calcium and phosphate metabolism were measured in healthy free-living elderly and young subjects residing in the Southwest to determine if parathyroid function changes with aging. Serum immunoreactive PTH (iPTH) was measured with two well characterized antisera; an amino (N)-terminal antiserum which cross-reacts with the biologically active domain (1-34) and recognizes intact hormone, and a midregion (44-68) antiserum which cross-reacts with intact hormone and biologically inactive midregion/C-terminal fragments. Serum iPTH in both RIAs was significantly increased in the elderly population. An age-related increase was also found for total urinary cAMP and serum alkaline phosphatase, whereas the tubular reabsorptive maximum for phosphate (TmP/GFR) decreased with age. No difference was found between men and women of the same age group for serum iPTH, urinary cAMP, or serum alkaline phosphatase. TmP/GFR declined with age in men, but not women. Correspondingly, serum phosphate was significantly lower in elderly men than in elderly women. Urinary calcium excretion was higher in elderly women than in men of the same age group. Neither serum total or ionized calcium decreased with age. In conclusion, the age-related increase in N-terminal PTH and alterations in associated parameters of phosphate and calcium metabolism are consistent with increased parathyroid function as men and women age. Factors other than PTH are responsible for the sex-related differences observed in TmP/GFR, calcium excretion, and serum phosphate. The cause of the increased circulating levels of apparently biologically active PTH is unclear, but extends beyond the age-related decrease in renal function.

OBJECTIVE

A large kindred with familial benign hypercalcemia (FBH) is described because of the new observation of developmental increases in serum immunoreactive parathyroid hormone (iPTH) levels in affected individuals that lead to significantly elevated values in adults.

METHODS

After identification of the proposita, 46 kindred members spanning 5 generations, ages 1.5 to 91 years, were surveyed biochemically and/or studied by chart review. Two hypercalcemic adults underwent biopsy of the iliac crest following tetracycline labeling for histomorphometric study.

RESULTS

Of the 46 individuals studied, 19 were found to be affected. Serum iPTH levels, determined in three separate immunoassays, became supranormal by about age 30 years in the group of 15 hypercalcemic subjects examined biochemically and appeared to increase further thereafter. Serum alkaline phosphatase activity and creatinine levels were normal in these individuals, but inorganic phosphate levels were lower than in unaffected kindred members. Three of five affected adults older than age 40 years who were studied radiographically had changes suggestive of osteomalacia. Biopsy of the iliac crest of one of the subjects, a 51-year-old woman, confirmed the presence of defective skeletal mineralization.

CONCLUSIONS

In this kindred, FBH in adults can be especially difficult to distinguish from primary hyperparathyroidism because serum iPTH levels may be elevated. Furthermore, the disorder may not be totally benign. Osteomalacia, perhaps due to mild hypophosphatemia, can develop during adulthood. Review of data from other kindreds for evidence of developmental elevations in serum iPTH levels with careful search for skeletal disease in late adult life will help to clarify if we have observed an unusual variant of FBH.

The vitamin D status was investigated in 94 geriatric patients in a Danish long-stay ward. The influence of mobility and thus possibility of outdoor activity was studied as well as the influence of regular vitamin D intake. Serum levels of 25-hydroxyvitamin D (25-OHD) were significantly reduced in all groups compared with age-matched controls. In 50% of the patients hypocalcaemia and elevated levels of alkaline phosphatase and immunoreactive parathyroid hormone (iPTH) were found in combination with severely reduced serum 25-OHD values (less than 5 ng/ml) indicating the presence of osteomalacia. Supplementation with 400 IU vitamin D daily in the winter months resulted in significantly higher 25-OHD levels and normocalcaemia while slightly elevated levels of alkaline phosphatase and iPTH persisted. The serum concentrations of 25-OHD were highest in the subjects who were not confined to bed. In these patients the biochemical parameters reflecting osteomalacia were normal. Low serum 1,25-dihydroxyvitamin D levels were found in the patients with low 25-OHD while 24,25-dihydroxyvitamin D levels were within the normal range in all groups and correlated with 25-OHD. Daily vitamin D supplementation appears to be indicated for geriatric patients, especially when bedridden, even in countries where the nutritional vitamin D intake is high.

BACKGROUND

Higher doses of calcitriol are effective in lowering markedly elevated 1,84 PTH levels of patients with renal secondary hyperparathyroidism. It has not been established, however, whether prophylactic administration of low doses of calcitriol prevents an increase of 1,84 PTH without causing side-effects, i.e. hypercalcaemia, hypercalciuria, or hyperphosphataemia.

METHODS

We carried out a placebo-controlled, double-blind prospective multicentre trial over 12 months in 45 patients with mild to moderate renal failure. Criteria for inclusion were S-creatinine 1.4 mg/dl and 1,84 PTH>> 6 pmol/l (normal 6). Calcitriol 0.125 microgram/day per os was compared with placebo. The patients received calcium carbonate per os if serum P exceeded 1.7 mmol/l.

RESULTS

Baseline 1,84 iPTH concentrations were not significantly different, i.e. 14.0 pmol/l (6.7-63.3) on placebo vs 16.2 (6.85-82.0) on calcitriol. Intention to treat analysis revealed a significant difference of final 1,84 iPTH, i.e. 27.8 (4.2-68.5) on placebo vs 18.2 (4.45-75.5) on calcitriol. On post-hoc analysis the difference was even more pronounced at S-creatinine concentrations above 3 mg/dl. S-calcium, S-phosphate, and urinary excretion of calcium did not change significantly on either placebo or on calcitriol. There were no episodes of hypercalcaemia or hyperphosphataemia. There was no significant difference of final S-creatinine or change in S-creatinine between placebo and calcitriol. One patient on calcitriol and two on placebo progressed to terminal renal failure. Bone alkaline phosphatase as a non-invasive index of bone metabolism was not decreased to subnormal levels.

CONCLUSIONS

The results document that a therapeutic window exists in patients with moderate renal failure and elevated of 1,84 iPTH, where low-dose calcitriol (0.125 microgram/day) prevents the increase in 1,84 iPTH without causing side-effects. This observation suggests that the parathyroid is more sensitive to calcitriol than intestine and bone.

BACKGROUND

The prevalence of metabolic bone disease in patients with nephrotic syndrome (NS) at normal level of renal function remains uncertain.

METHODS

To address this issue, we studied 30 patients (20 men and 10 women, mean age 27.3 +/- 11.7 years) with NS who had normal renal function (mean creatinine clearance 103 +/- 4 ml/min). We evaluated their serum calcium, phosphorus, alkaline phosphatase, immunoreactive parathyroid hormone (iPTH), vitamin D metabolites, urinary calcium, and skeletal survey. The extent of bone mineralization was analyzed by histomorphometric analysis of iliac crest bone biopsy specimens in all patients. The findings on bone histology were correlated with biochemical parameters.

RESULTS

The mean duration of NS was 35.5 +/- 26.9 months, with a protein excretion of 7.3 +/- 3.2 g/24 hr and a serum albumin of 2.2 +/- 0.8 g/dl. Total serum calcium was 7.8 +/- 0.8 mg/dl, whereas ionized calcium was 5.7 +/- 0.7 mg/dl, phosphorus 3.2 +/- 1.2 mg/dl, and alkaline phosphatase 149 +/- 48.6 U/liter. Serum iPTH levels were normal in all except two patients. The mean serum 25-hydroxyvitamin D [25(OH)D] level was 3.9 +/- 1.2 ng/ml (normal 15 to 30 ng/ml), whereas 1,25-dihydroxyvitamin D was 24 +/- 4.7 pg/ml (normal 16 to 65). There was an inverse correlation between serum levels of 25(OH)D and the magnitude of proteinuria (r = -0.42, P < 0.05). The mean 24-hour urinary calcium excretion was 82 +/- 21 mg/day. The skeletal survey was normal in all patients. Bone histology was normal in 33.3% of the patients, whereas 56.7% had isolated osteomalacia (OSM), and 10% had an increased bone resorption in association with defective mineralization. The severity of OSM measured by mineralization lag time correlated linearly with the duration (r = 0.94, P < 0.0001) and the amount (r = 0.97, P < 0.0001) of proteinuria. All patients with NS for more than three years had histological changes. Patients with OSM had lower 25(OH)D and serum albumin as compared with those with normal histology (P < 0.005). Bone mineralization had no significant correlation with serum iPTH, divalent ions, or vitamin D levels.

CONCLUSIONS

OSM is a frequent finding in adult patients with NS, even at a normal level of renal function. Its severity correlates with the amount and duration of proteinuria.

Uremic pruritus is one of the common complications in long-term dialysis patients. Recently, researchers reported that immunohypothesis with high serum level of cytokines could be the cause of uremic pruritus. Polymethylmethacrylate (PMMA) artificial kidney (AK) has been reported to adsorb more serum cytokines than other high-flux AKs. In July 2006, 30 patients with severe uremic pruritus from 300 chronic hemodialysis (HD) patients in a single center entered this prospective study. Their dialyzers were changed to PMMA AK for 4 weeks. The severity of pruritus was evaluated every week using the results of a questionnaire (pruritus score). Laboratory assays including predialysis serum blood urea nitrogen (BUN), creatinine, beta2-microglobulin (beta2M), calcium, phosphate, intact parathyroid hormone (iPTH), total CO(2), ferritin, hematocrit, high-sensitivity C-reactive protein (hsCRP), IL-1beta, IL-2, IL-6, IL-18, tumor necrosis factor-alpha (TNF-alpha), Kt/V, and beta2M clearance were measured before and at the end of 4 weeks of PMMA AK use. PMMA AK was effective in reducing the pruritus score from 23.46 +/- 11.94 to 7.38 +/- 6.42 (P < 0.001). The effect of uremic pruritus relief appeared after 1 week of PMMA AK use. There were no significant differences in the laboratory assay results including predialysis serum BUN, Cr, beta2M, calcium, phosphate, calcium-phosphate product, iPTH, total CO(2), ferritin, hematocrit, hsCRP, IL-1beta, IL-2, IL-6, IL-18, TNF-alpha, Kt/V, and beta2M clearance. The mechanism for the beneficial effect of PMMA AK on uremic pruritus remains to be determined. PMMA AK may be a useful adjuvant therapy in chronic HD patients with severe uremic pruritus.

Sevelamer (Renagel), an orally administered metal-free cationic hydrogel polymer/resin that binds dietary phosphate in the gastrointestinal (GI) tract, is approved for use in the US, Europe and several other countries for the treatment of hyperphosphataemia in adult patients with end-stage renal disease (ESRD) on haemodialysis or peritoneal dialysis.Clinical evidence shows that sevelamer was at least as effective as calcium acetate and calcium carbonate at controlling serum phosphorus, calcium-phosphorus product (Ca x P) and intact parathyroid hormone (iPTH) levels, but generally reduced serum calcium levels to a greater extent and was associated with a lower risk of hypercalcaemic episodes than calcium-based phosphate binders. Sevelamer appeared to slow the progression of cardiovascular calcification in patients with ESRD and also had a beneficial effect on serum low-density lipoprotein-cholesterol (LDL-C) levels. In patients receiving chronic haemodialysis, there was no between-group difference in all-cause mortality between sevelamer and calcium-based phosphate binder therapy in the primary efficacy analysis in the large (n >2100), 3-year DCOR trial; in the smaller (n = 109) nonblind RIND trial in patients new to dialysis, data suggest there is an overall survival benefit with sevelamer versus calcium-based phosphate binder treatment. The relative survival benefits and cost effectiveness of these phosphate binder therapies remains to be fully determined. Sevelamer treatment was generally as well tolerated as calcium acetate or calcium carbonate treatment. Overall, sevelamer is a valuable option for the management of hyperphosphataemia in patients with ESRD on haemodialysis.

Elevated serum phosphorus is associated with higher death risk in hemodialysis patients. Previous studies have suggested that both higher serum parathyroid hormone (PTH) level and higher dietary protein intake may contribute to higher serum phosphorus levels. However, it is not well known how these two factors simultaneously contribute to the combined risk of hyperphosphatemia in real patient-care scenarios. We hypothesized that the likelihood of hyperphosphatemia increases across higher serum PTH and higher normalized protein catabolic rate (nPCR) levels, a surrogate of protein intake. Over an 8-year period (July 2001-June 2009), we identified 69,355 maintenance hemodialysis patients with PTH, nPCR, and phosphorus data in a large dialysis provider. Logistic regression models were examined to assess the association between likelihood of hyperphosphatemia (serum phosphorus >5.5 mg/dl) and serum PTH and nPCR increments. Patients were 61±15 years old and included 46% women, 33% blacks, and 57% diabetics. Both higher serum PTH level and higher protein intake were associated with higher risk of hyperphosphatemia in dialysis patients. Compared with patients with PTH level 150-<300 pg/ml and nPCR level 1.0-<1.2 g/kg/day, patients with iPTH)600 pg/ml and nPCR>1.2 g/kg/day had a threefold higher risk of hyperphosphatemia (OR: 3.17, 95% CI: 2.69-3.75). Hyperphosphatemia is associated with both higher dietary protein intake and higher serum PTH level in maintenance hemodialysis patients. Worsening or resistant hyperphosphatemia may be an under-appreciated consequence of secondary hyperparathyroidism independent of dietary phosphorus load. Management of hyperphosphatemia should include diligent correction of hyper-parathyroidism while maintaining adequate intake of high protein foods with low phosphorus content.

Because intravenous (iv) calcitriol has greater bioavailability than oral calcitriol, it may be more efficacious in suppressing parathyroid hormone (PTH) secretion. In this study, the pharmacokinetics and efficacy of pulse oral and i.v. calcitriol were compared. Patients were randomized to receive 2 micrograms of i.v. or oral calcitriol after each dialysis. Two pharmacokinetic studies (PK1, PK2) were performed 10 days apart, during which the patients received calcitriol after each dialysis. Calcitriol bioavailability was determined from the area under the curve (AUCtime interval (hours) in pg/mL per h). After the PK phase, PTH was lowered to < 200 pg/mL by titrating calcitriol to a maximum of 12 micrograms/wk over 4 wk. Calcitriol was then maintained for another 18 wk unless serum calcium exceeded 11.5 mg/dL or Ca x P product exceeded 70; when these limits were reached, calcitriol was held and then restarted at a lower dose. After i.v. administration, peak serum calcitriol exceeded that achieved orally but by 1 h, calcitriol levels were similar. The AUC0-0.5 (105 +/- 12, i.v.; 9 +/- 4, oral) and AUC0.5-1 (68 +/- 6, i.v.; 30 +/- 7, oral) were higher with i.v. (P < 0.05), but cumulative AUC0-48 did not differ. Individual t1/2 values ranged from 10 to 129 h for PK1 and from 10 to 50 h for PK2. The t1/2 for oral calcitriol was 38 +/- 14 h for PK1 and 30 +/- 4 h for PK2 (not significant (NS)). The t1/2 for i.v. calcitriol was 26 +/- 5 h for PK1 and 19 +/- 3 h for PK2 (NS, PK1 versus PK2 and oral versus i.v.). When the PK1 oral and i.v. data were combined, the mean t1/2 was 32 +/- 7 h whereas the t1/2 for PK2 (oral and i.v.) was 22 +/- 3 h (P < 0.05). Baseline PTH levels were 510 +/- 90 pg/mL and 499 +/- 79 pg/mL, oral and i.v., respectively. Serum PTH level at 22 wk was not different between oral and i.v. groups, 153 +/- 38 pg/mL and 214 +/- 124 pg/mL in i.v. (NS). The percentage of PTH suppression was 66 +/- 7.4% in the oral group and 69 +/- 12% in the i.v. group (NS). A major degree of serum iPTH suppression occurred during the initial 4 wk of treatment, concomitant with a rise in serum calcium levels. Adverse effects were similar between groups, as were the average dosages of calcitriol and phosphate binders. In conclusion, the efficacy of intravenous and pulse oral calcitriol were similar in hemodialysis patients with secondary hyperparathyroidism. The early rise in serum calcium levels observed with treatment may have contributed significantly to the suppression of serum iPTH levels. The difference in bio-availability between the different routes does not have a clinically apparent effect. The t1/2 varied widely among individuals, whereas exposure to calcitriol may decrease the t1/2.