Vitamin D receptor genotype influences parathyroid hormone and calcitriol levels in predialysis patients.

BACKGROUND: BsmI vitamin D receptor (VDR) gene polymorphism has been associated with the severity of hyperparathyroidism in patients on hemodialysis. The aim of this study was to analyze the influence of this polymorphism on parathyroid function and serum calcitriol levels in patients with different degrees of chronic renal failure (CRF) before dialysis. METHODS: A total of 248 CRF patients, divided into three groups according to creatinine clearance (CCr; mild CRF group> 60 to 35 to 10 to 2.5 mmol/liter and serum phosphorus levels of> 1.6 mmol/liter or who needed phosphorus binding agents were excluded. The statistical analysis was done with the general factorial analysis of variance entering first PTH and then calcitriol as the dependent variable; the genotype (BB, Bb and bb), sex and CCr group were defined as factors; and covariables included serum calcium, serum phosphorus, 1/creatinine versus time slope, PTH when calcitriol was the dependent variable, and calcitriol when PTH was the dependent variable. RESULTS: When serum PTH levels were entered as the dependent variable, serum calcium, CCr group, and the interaction of genotype with the CCr group were found to be significant factors (P = 0.025, P <0.001 and P = 0.039, respectively). When serum calcitriol levels were entered as the dependent variable, genotype, the interaction of genotype with CCr, the CCr group, and the 1/creatine versus time slope were found to be significant (P = 0.027, P = 0.028, P <0.001 and P = 0.044, respectively). The marginal means of PTH, adjusted with the general factorial analysis of variance across the three groups were: (a) mild CRF group, BB 5.3 pmol/liter (CI 0 to 13.8), Bb 5.5 pmol/liter (CI 2 to 9), bb 5.4 pmol/liter (CI 0.6 to 10.2); (b) moderate CRF group, BB 6.2 pmol/liter (CI 1.5 to 10.9), Bb 7.8 pmol/liter (CI 5.3 to 10.3), bb 7.5 pmol/liter (CI 4.8 to 10.1); (c) severe CRF group, BB 9.3 pmol/liter (CI 4.2 to 14.3), Bb 17.1 pmol/liter (CI 13.9 to 20.2), bb 21.9 pmol/liter (CI 18.7 to 25.2). The marginal means of calcitriol adjusted with the general factorial analysis of variance across the three groups were: (a) mild CRF group, BB 47 pg/ml (CI 37 to 57), Bb 40.9 pg/ml (CI 37 to 44.8), bb 32.6 pg/ml (CI 26.8 to 38. 4); (b) moderate CRF group, BB 24.1 pg/ml (CI 18.3 to 29.8), Bb 26.6 pg/ml (CI 23.5 to 29.7), bb 25.3 pg/ml (CI 22 to 28.6); (c) severe CRF group, BB 27.4 pg/ml (CI 21.3 to 33.5), Bb 19.4 pg/ml (CI 15.5 to 23.2), bb 20.4 pg/ml (CI 16.1 to 24.7). CONCLUSION: The progression of hyperparathyroidism is slower in predialysis patients with BB genotypes than in the other genotypes. Also, calcitriol levels are less reduced in the BB genotype, which may act to lessen the severity of secondary hyperparathyroidism.     

Parathyroid function as a determinant of the response to calcitriol treatment in the hemodialysis patient.

BACKGROUND: Bolus calcitriol (CTR) is used for the treatment of secondary hyperparathyroidism in dialysis patients. Although CTR treatment reduces parathyroid hormone (PTH) levels in many dialysis patients, a significant number fail to respond. METHODS: To learn whether or not an analysis of parathyroid function could further illuminate the response to CTR, a PTH-calcium curve was performed before and after at least two months of CTR treatment in 50 hemodialysis patients with a predialysis intact PTH of greater than 300 pg/ml. RESULTS: For the entire group (N = 50), CTR treatment resulted in a 24% reduction in predialysis (basal) PTH from 773 +/- 54 to 583 +/- 71 pg/ml (P < 0.001), whereas ionized calcium increased from 1.10 +/- 0.02 to 1.22 +/- 0.02 mM (P < 0.001); however, maximal and minimal PTH did not change from pre-CTR values. Based on whether or not the basal PTH decreased by 40% or more during CTR treatment, patients were divided into responders (Rs, N = 25) and nonresponders (NRs, N = 25). Before CTR, the NR group was characterized by a greater basal (959 +/- 80 vs. 586 +/- 51 pg/ml, P < 0.001) and maximal (1899 +/- 170 vs. 1172 +/- 108 pg/ml, P < 0. 001) PTH and serum phosphorus (6.14 +/- 0.25 vs. 5.14 +/- 0.34 mg/dl, P < 0.01). Logistical regression analysis showed that the pre-CTR basal PTH was the most important predictor of the post-CTR basal PTH, and a pre-CTR basal PTH of 750 pg/ml represented a 50% probability of a response. Basal PTH correlated with the ionized calcium in the NR group (r = 0.59, P = 0.002) but not in the R group (r = 0.06, P = NS). In the R group, an inverse correlation was present between ionized calcium and the basal/maximal PTH ratio, an indicator of whether calcium is suppressing basal PTH secretion relative to the maximal secretory capacity (maximal PTH) r = -0.55, P = 0.004; in the NR group, this correlation approached significance but was positive (r = 0.34, P = 0.09). After CTR treatment, serum calcium increased in both groups, and despite marked differences in basal PTH (Rs, 197 +/- 25 vs. NRs, 969 +/- 85 pg/ml), an inverse correlation between ionized calcium and basal/maximal PTH was present in both groups (Rs, r = -0.61, P = 0.001, and NRs, r = -0.60, P = 0.001). CONCLUSIONS: (a) Dynamic testing of parathyroid function provided insights into the pathophysiology of PTH secretion in hemodialysis patients. (b) The magnitude of hyperparathyroidism was the most important predictor of the response to CTR. (c) Before CTR treatment, PTH was sensitive to calcium in Rs, and serum calcium was PTH driven in NRs, and (d) after the CTR-induced increase in serum calcium, calcium suppressed basal PTH relative to maximal PTH in both groups.     

Association of increased active PTH(1–84) fraction with decreased GFR and serum Ca in predialysis CRF patients: modulation by serum 25-OH-D

Summary As the serum calcium and glomerular filtration rate decreased, the proportion of active PTH(1–84) molecules in PTH immunoreactivity increased in serum from predialysis uremic patients, particularly those with vitamin D insufficiency. Introduction The PTH(1–84) fraction was altered in predialysis patients with chronic renal failure (CRF). Methods Serum PTH in predialysis CRF patients without any medication was measured by PTH(1–84)-specific whole PTH assay and intact PTH assay cross-reacting with N-truncated PTH. Results In CRF patients, the glomerular filtration rate (GFR) correlated positively with serum Ca and 1,25-dihydroxyvitamin D (1,25(OH)₂D), and inversely with serum Pi, log intact PTH, and log whole PTH. In multiple regression analysis, including age, gender, body mass index, GFR, Ca, and Pi and 1,25(OH)₂D as independent variables, serum Ca and GFR associated significantly with serum log whole PTH and intact PTH. Serum log whole PTH/intact PTH ratio, which increased as serum Ca and GFR decreased, retained a negative correlation in those with serum 25-hydroxyvitamin D levels below 20 ng/ml, but not in those above 20 ng/ml. The ratio also correlated positively with serum log tartrate-resistant acid-phosphatase-5b, log cross-linked N-telopeptide of type-I collagen, and log bone alkaline-phosphatase. Conclusion As GFR declined with suppression of serum Ca, the proportion of active PTH molecules increased in predialysis CRF patients, particularly those with vitamin D insufficiency.     

Direct effect of the correction of acidosis on plasma parathyroid hormone concentrations, calcium and phosphate in hemodialysis patients: a prospective study

BACKGROUND: Metabolic acidosis contributes to renal osteodystrophy and together with hyperphosphatemia, hypocalcemia and altered vitamin D metabolism may result in increased levels of intact parathyroid hormone (iPTH) and metastatic calcifications. However, the impact of the correction of metabolic acidosis on iPTH levels and calcium-phosphate metabolism is still controversial. STUDY DESIGN: The effects of the correction of metabolic acidosis on serum concentrations of iPTH, calcium (Ca), phosphate (PO(4)) and alkaline phosphatase were prospectively studied. Twelve uremic patients on maintenance hemodialysis (HD) for 49 months (median; range 6-243 months) with serum bicarbonate levels < or =20 mmol/l were studied before and after 3 months of oral sodium bicarbonate supplementation. Predialysis serum bicarbonate, arterial pH, ionized calcium, plasma sodium, plasma potassium, serum creatinine, hemoglobin, K(t)/V, postdialysis body weight, predialysis systolic and diastolic blood pressure were also evaluated before and after correction. RESULTS: Serum bicarbonate levels and arterial pH increased respectively from 19.3 +/- 0.6 to 24.4 +/- 1.2 mmol/l (p < 0.0001) and 7.34 +/- 0.03 to 7.40 +/- 0.02 (p < 0.001). iPTH levels decreased significantly from 399 +/- 475 to 305 +/- 353 pg/ml (p = 0.026). No changes in total serum Ca, plasma PO(4), serum akaline phosphatase, K(t)/V, serum creatinine, hemoglobin, body weight, predialysis systolic and diastolic blood pressures were observed. iCa decreased significantly. CONCLUSIONS: Our study demonstrates that the correction of metabolic acidosis in chronic HD patients reduces iPTH concentrations in HD patients with secondary hyperparathyroidism possibly by a direct effect on iPTH secretion.     

Effect of a low calcium dialysate on parathyroid hormone secretion in diabetic patients on maintenance hemodialysis.

Diabetic patients on maintenance dialysis often are characterized by a relative parathyroid hormone (PTH) deficiency and a form of renal osteodystrophy with low bone turnover known as adynamic bone. The goal of the present study was to determine whether a reduction in the dialysate calcium concentration would increase the predialysis (basal) PTH and maximal PTH level. Thirty-three diabetic maintenance hemodialysis patients with basal PTH values less than 300 pg/ml were randomized to be dialyzed with either a regular (3.0 mEq/liter or 3.5 mEq/liter, group I) or low (2.25 mEq/liter or 2.5 mEq/liter, group II) calcium dialysate for 1 year. At baseline and after 6 months and 12 months of study, low (1 mEq/liter) and high (4 mEq/liter) calcium dialysis studies were performed to determine parathyroid function. At baseline, basal (I, 126+/-20 vs. II, 108+/-19 pg/ml) and maximal (I, 269 pg/ml+/-40 pg/ml vs. II, 342 pg/ml+/-65 pg/ml) PTH levels were not different. By 6 months, basal (I, 98+/-18 vs. II, 200+/-34 pg/ml, p = 0.02) and maximal (I, 276 pg/ml+/-37 pg/ml vs. II, 529 pg/ml+/-115 pg/ml; p = 0.05) PTH levels were greater in group II. Repeated measures analysis of variance (ANOVA) of the 20 patients who completed the entire 12-month study showed that only in group II patients were basal PTH (p = 0.01), maximal PTH (p = 0.01), and the basal/maximal PTH ratio (p = 0.03) different; by post hoc test, each was greater (p < 0.05) at 6 months and 12 months than at baseline. When study values at 0, 6, and 12 months in all patients were combined, an inverse correlation was present between basal calcium and both the basal/maximal PTH ratio (r = -0.59; p < 0.001) and the basal PTH (r = -0.60; p < 0.001). In conclusion, in diabetic hemodialysis patients with a relative PTH deficiency (1) the use of a low calcium dialysate increases basal and maximal PTH levels, (2) the increased secretory capacity (maximal PTH) during treatment with a low calcium dialysate suggests the possibility of enhanced parathyroid gland growth, and (3) the inverse correlation between basal calcium and both the basal/maximal PTH ratio and the basal PTH suggests that the steady-state PTH level is largely determined by the prevailing serum calcium concentration.     

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.     

Moderate metabolic acidosis and its effects on serum parameters in hemodialysis patients

We screened the laboratory data of 50 chronic hemodialysis patients selected randomly over a 21-month period to generate 158 data points which identified two groups: (1) those with a predialysis total CO(2) concentration less than or equal to 19 mEq/l (data A; n = 57) and (2) those with a predialysis total CO(2) concentration greater than 19 mEq/l (data B; n = 101). Then, both groups were compared for the following parameters: predialysis blood urea nitrogen (BUN), serum phosphorus, uric acid, creatinine, and albumin concentrations, Kt/V, urea reduction ratio, normalized protein catabolic rate, dry weight, ultrafiltration, blood flow and dialysis flow rates, duration of dialysis treatment, and blood pressure. Group data A had significantly higher predialysis BUN, phosphorus, and uric acid concentrations than group data B. There were significant inverse correlations between predialysis serum bicarbonate and predialysis BUN, phosphorus, and uric acid concentrations. Although it is not clear what the long term side effects of moderate metabolic acidosis are, we recommend its correction.     

Parathormone, calcitonin, and vitamin D metabolites during normal fracture healing in geriatric patients

In order to study the role of calcium-regulating hormones during callus formation in elderly patients, serum levels of parathormone (PTH), calcitonin (CT), 25-hydroxyvitamin D [25-OH-D], 1,25-dihydroxyvitamin D [1,25(OH)2D], 24,25-dihydroxyvitamin D [24,25(OH)2D], and calcium (Ca) were determined in 41 patients with fractures of long bones, primarily hip fractures. The parameters were measured on admission and after eight weeks. There were almost no changes in hormone serum levels during bone repair, except for a decrease in serum levels of 1,25(OH)2D from 25.3 +/- 2.3 pg/ml on admission to 21.0 +/- 2.0 pg/ml eight weeks later (p less than .001). Patients with fractures compared to normal elderly humans have lower serum levels of PTH (0.99 +/- 0.06 ng/ml versus 1.88 +/- 0.34 ng/ml; p less than .001), 25-OH-D (10.7 +/- 1.0 ng/ml versus 17.1 +/- 1.8 ng/ml; p less than .001), and Ca (9.1 +/- 0.1 mg% versus 9.7 +/- 0.1 mg%; p less than .001) and higher serum levels of 1,25(OH)2D (25.3 +/- 2.3 pg/ml versus 17.1 +/- 2.3 pg/ml; p less than .001). Female patients have lower serum levels of 24,25(OH)2D compared to males (1.65 +/- 0.15 ng/ml versus 2.06 +/- 0.29 ng/ml; p less than .05). A similar trend was noted in serum CT levels during callus formation (0.12 +/- 0.02 ng/ml versus 0.16 +/- 0.02 ng/ml; p less than .05). Patients with subcapital fractures of the femur have significantly lower serum levels of all vitamin D metabolites on admission, compared with patients suffering from extracapsular fractures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Demographic, dietary, and serum factors and parathyroid hormone in the National Health and Nutrition Examination Survey

Summary

Many determinants of parathyroid hormone (PTH) are unknown. In the National Health and Nutrition Examination Survey (NHANES), numerous factors not classically associated with calcium–phosphorus homeostasis, such as uric acid and smoking, are independently associated with PTH in adults without chronic kidney disease. Associations between serum phosphorus and PTH may vary by race.

Introduction

Although PTH may be an important biomarker for osteoporosis and cardiovascular disease, many determinants of PTH are unknown. We investigated associations between demographic, dietary, and serum factors and PTH level.

Methods

We studied 4,026 white, 1,792 black, and 1,834 Mexican-American adult participants without chronic kidney disease from the 2003–2004 and 2005–2006 NHANES.

Results

The mean serum PTH level was 38.3?pg/ml for whites, 42.6?pg/ml for blacks, and 41.3?pg/ml for Mexican-Americans. After adjusting for diet, body mass index, serum levels of calcium, phosphorus, 25-hydroxyvitamin D, creatinine, and other factors, smokers compared to non-smokers had lower PTH, ranging from ?4.2?pg/ml (95% confidence interval (CI) ?7.3 to ?1.1) in Mexican-Americans to ?6.1?pg/ml (95% CI ?8.7 to ?3.5) in blacks. After multivariate adjustment, PTH was higher in females compared to males, ranging from 1.1?pg/ml (95% CI ?1.2 to 3.4) in Mexican-Americans to 4.5?pg/ml (95% CI 1.9 to 7.0) in blacks, and in older (>60?years) compared to younger participants (<30?years), ranging from 3.7?pg/ml (95% CI 1.3 to 6.1) in Mexican-Americans to 8.0?pg/ml (95% CI 5.4 to 10.7) in blacks. Higher uric acid was associated with higher PTH. In whites only, lower serum phosphorus and lower serum retinol were associated with higher PTH.

Conclusions

Numerous factors not classically associated with calcium–phosphorus homeostasis are independently associated with PTH and should be considered in future studies of PTH and chronic disease. Additional research is needed to elucidate mechanisms underlying identified associations with PTH and to explore possible racial differences in phosphorus handling.     

Effect of calcitriol treatment and withdrawal on hyperparathyroidism in haemodialysis patients with hypocalcaemia.

BACKGROUND: Calcitriol is used to treat secondary hyperparathyroidism in dialysis patients. For similarly elevated parathyroid hormone (PTH) levels, the PTH response to calcitriol treatment is believed to be better in hypocalcaemic dialysis patients than in dialysis patients with higher serum calcium values. Furthermore, few studies have evaluated the rapidity of the rebound in serum PTH values after prolonged treatment with calcitriol. Our goal was to evaluate (i) the PTH response to calcitriol treatment in hypocalcaemic haemodialysis patients, (ii) the rapidity of rebound in PTH after calcitriol treatment was stopped, and (iii) whether the effect of calcitriol treatment on PTH levels could be separated from those produced by changes in serum calcium and phosphate values. METHODS: Eight haemodialysis patients (29+/-3 years) with hypocalcaemia and hyperparathyroidism were treated thrice weekly with 2 microg of intravenous calcitriol and were dialysed with a 3.5 mEq/l calcium dialysate. Parathyroid function (PTH-calcium curve) was determined before and after 30 weeks of calcitriol treatment and 15 weeks after calcitriol treatment was stopped. RESULTS: Pretreatment PTH and ionized calcium values were 907+/-127 pg/ml and 3.89+/-0.12 mg/dl (normal, 4.52+/-0.07 mg/dl). During calcitriol treatment, one patient did not respond, but basal (predialysis) PTH values in the other seven patients decreased from 846+/-129 to 72+/-12 pg/ml, P<0.001 and in all seven patients, the decrease exceeded 85%. During the 15 weeks after calcitriol treatment was stopped, a slow rebound in basal PTH values in the seven patients was observed, 72+/-12 to 375+/-44 pg/ml. Covariance analysis was used to evaluate the three tests of parathyroid function (0, 30, and 45 weeks), and showed that calcitriol treatment was associated with reductions in maximal PTH values while reductions in basal PTH were affected by ionized calcium and serum phosphate. The basal/maximal PTH ratio and the set point of calcium were associated with changes in ionized calcium. CONCLUSIONS: In haemodialysis patients with hypocalcaemia, (i) moderate to severe hyperparathyroidism responded well to treatment with calcitriol, (ii) reductions in maximal PTH were calcitriol dependent while reductions in basal PTH were affected by the ionized calcium and serum phosphate concentrations, (iii) changes in the basal/maximal PTH ratio and the set point of calcium were calcium dependent, and (iv) the delayed rebound in basal PTH levels after withdrawal of calcitriol treatment may have been due to the long duration of treatment and the marked PTH suppression during treatment.     

Vasodilating prostaglandins attenuate ischemic renal injury only if thromboxane is inhibited.

Ischemia-induced renal injury is prevented by inhibition of thromboxane (Tx) synthesis. This protection was believed to be secondary to a high prostaglandin (PG)/TxA2 ratio. This study tests whether increasing the PG/Tx ratio by administration of vasodilating PGs protects the reperfused ischemic kidney. Anesthetized rats underwent right nephrectomy and 45 minutes of left renal pedicle clamping. Beginning 10 minutes before clamp release, animals were treated intravenously with the following: saline placebo (n = 10); the cyclooxygenase inhibitor ibuprofen (Ibu), 12.5 mg/Kg in a bolus (n = 8); a stable analogue of prostacyclin (PGI2), 500 ng/kg/minute for 2 hours (n = 9); PGE1, 400 ng/kg/minute for 2 hours (n = 8); the combination Ibu and PGI2 (n = 8) or PGE1 (n = 8). In saline treated ischemic controls, 5 minutes after reperfusion plasma, thromboxane (TxB2) and 6-keto-PGF1 levels were 2537 and 317 pg/ml, respectively--higher than the TxB2 and 6-keto-PGF1 levels of 750 and 80 pg/ml, respectively, in nephrectomized but nonischemic sham controls (n = 7) (p less than 0.05). In ischemic control animals at 24 hours, creatinine levels were 4.6 mg/dl, relative to 0.9 ml/dl in sham animals (p less than 0.05); the weight of the left (L) ischemic kidney relative to the right (R) normal kidney was 118%, compared with 99% in sham animals (p less than 0.05); and renal histology of ischemic control animals at 24 hours showed acute tubular necrosis (ATN) relative to normal findings in sham animals. Pretreatment with Ibu led to: TxB2 and 6-keto-PGF1 levels of 116 and 40 pg/ml, lower than those of sham animals (p less than 0.05); creatinine levels of 4.6 mg/dl, L/R renal weight of 119%; and ATN similar to that of ischemic controls. Treatment with a PGI2 analogue or PGE1 was not protective and led to increases in TxB2, 6-keto-PGF1, creatinine, L/R renal weight, and ATN similar to that of ischemic controls. The combination of Ibu and either PGI2 or PGE1 led to: reduced levels of TxB2 and 6-keto-PGF1 (p less than 0.05); attenuated increases in creatinine to 2.2 and 2.3 mg/dl, respectively (p less than 0.05); and limited ATN (p less than 0.05). These data indicate that the vasodilating PG protect the ischemic reperfused kidney only when Tx is inhibited.     

A new assay method that detects only intact osteocalcin. Two-step non-invasive diagnosis to predict adynamic bone disease in haemodialysed patients.

BACKGROUND: We studied the usefulness of a new assay method that detects only the intact human osteocalcin molecule in haemodialysed patients. METHODS: Iliac bone biopsy specimens obtained from 62 haemodialysed patients were analysed. RESULTS: Bone formation rates (BFR/BS) correlated positively with serum intact osteocalcin concentrations (n=62), osteocalcin concentrations assayed by a conventional method (n=31), parathyroid hormone (PTH) concentrations (n=62), and total alkaline phosphatase concentrations (r=0.602, 0. 588, 0.650, and 0.401 respectively). Based on ROC curve and Youden index analysis, the optimal cut-off value to distinguish adynamic bone disease from a mild lesion was 195 pg/ml of serum PTH concentration (Youden index=0.233) or 30 ng/ml of serum intact osteocalcin concentration (Youden index=0.628). The optimal cut-off value to distinguish between hyperparathyroid bone and a mild lesion was 455 pg/ml of serum PTH level (Youden index=0.63) or 50 ng=ml of serum intact osteocalcin concentration (Youden index=0.634). Since both ROC curve and Youden index suggested that the serum PTH concentration was not a good marker to distinguish adynamic bone from a mild lesion or hyperparathyroid bone, we designed a two-step procedure. The first step was the diagnosis of adynamic bone (cut-off: 65 pg/ml) or hyperparathyroid bone (cut-off: 455 pg/ml) according to serum PTH concentration. In a second step, we assessed serum intact osteocalcin concentration in patients with serum PTH concentrations between 65 and 455 pg/ml. The cut-off values for adynamic and hyperparathyroid bone in this diagnostic approach were 30 and 70 ng/ml respectively. As a result, 49 out of 62 patients were diagnosed properly. The Youden index of this two-step diagnosis was 0.527 and 0.661 for adynamic bone and hyperparathyroid bone respectively. Sensitivity markedly improved to 94.4% and 96.2% for adynamic bone and hyperparathyroid bone respectively, without sacrificing specificity (84.0 and 88.8% respectively). CONCLUSION: Measurement of serum intact osteocalcin concentration is useful for the diagnosis of adynamic bone in haemodialysed patients. A two-step procedure involving also simultaneous measurement of serum PTH concentration further improved the sensitivity of each individual marker while maintaining specificity.     

Sevelamer hydrochloride, a phosphate binder, protects against deterioration of renal function in rats with progressive chronic renal insufficiency.

BACKGROUND: Dietary phosphate restriction prevents renal function deterioration in animal models. This study examined whether sevelamer hydrochloride (Renagel(R); 'sevelamer' hereafter), a non-calcaemic phosphate binder could slow deterioration of renal function in rats with progressive renal insufficiency. METHODS: Wistar Kyoto male rats were singly injected with normal rabbit serum or rabbit anti-rat glomerular basement membrane serum. Three days later, rats were fed a powder diet containing 0, 1 or 3% sevelamer for 58 days. Time course changes of serum levels of blood urea nitrogen (BUN), creatinine, calcium, phosphorus and parathyroid hormone (PTH) were measured throughout, and creatinine clearance (CCr), kidney calcium content and renal histology examined at the end of the study. RESULTS: Sevelamer partially inhibited elevation of BUN and serum creatinine, and completely inhibited increases in serum phosphorus, PTH and calcium xphosphorus product. Sevelamer significantly prevented the decrease in CCr and kidney calcium content elevation. Kidney calcium content and BUN and serum creatinine were strongly positively correlated, and kidney calcium content and CCr strongly negatively correlated. Kidney calcium content correlated well with serum phosphorus, serum calcium x phosphorus product and PTH, but not serum calcium. Sevelamer treatment partly prevented histological deterioration of both glomerular and tubulointerstitial lesions of the kidney. CONCLUSIONS: The results suggest that sevelamer protects against renal function deterioration by maintaining kidney calcium at a low level as a result of reducing serum phosphorus and PTH.     

Serum antioxidant activity in uremic patients

Serum antioxidant activity (AOA) was examined in 35 healthy subjects and 111 patients with chronic renal failure (CRF), consisting of 13 patients in the predialysis stage, 11 requiring the start of regular dialysis therapy (RDT) and 87 undergoing RDT. Serum AOA was determined by assaying serum activity to inhibit malondialdehyde (MDA) generation. AOA levels were significantly lower in CRF patients, and the lowest levels were noticed in patients with uremic symptoms requiring the start of RDT. These levels were restored to a subnormal level during RDT. Defective serum AOA appears to be an endogenous metabolic consequence in uremia. Sera with low AOA tended to show high MDA levels, indicating that patients with low serum AOA were susceptible to cellular injury by lipid peroxidation. It is proposed that defective serum AOA may contribute to a certain uremic toxicity through peroxidative cell damage.     

Decreased renal transplant function after parathyroidectomy.

BACKGROUND: Persistent secondary hyperparathyroidism after renal transplantation may require parathyroidectomy (PTX). Clinical experience suggests that these patients commonly develop decreased renal function thereafter. METHODS: To test this notion, we evaluated 76 transplant patients who underwent pararhyroidectomy between 1997 and 2003. RESULTS: In half the patients (47%), creatinine clearance decreased >20% (before vs after PTX, 57 +/- 21 vs 38 +/- 17 ml/min, P = 0.001). The patients with decreased creatinine clearance had higher parathyroid hormone (PTH) concentrations before and lower values after PTX compared with those who did not (594 +/- 392 vs 447 +/- 234 pg/ml before PTX, P = 0.03; 35 vs 123 pg/ml thereafter, P = 0.002). They also had lower serum calcium concentrations after PTX (2.0 vs 2.2 mmol/l, P = 0.005) and they required more calcium and vitamin D analogues. These patients also more commonly underwent total PTX with autotransplantation, compared with subtotal (75 vs 50%, P = 0.03). However, in multivariate analysis, only the delta PTH decline (%) after PTX was a significant predictor of deteriorating renal function (P = 0.005) and was correlated with the creatinine clearance decrease (R = 0.369, P = 0.001). Prospectively measured inulin and para-amino-hippuric acid (PAH) clearance decreased significantly after PTX in a subgroup of 19 patients (inulin before vs after PTX 67 vs 55 ml/min/1.73 m(2), P = 0.001; PAH 360 vs 289 ml/min/1.73 m(2), P = 0.001). Transplant biopsies revealed calcification in 70% of biopsied cases. CONCLUSION: Since PTH has a known positive regulatory effect on renal perfusion and glomerular filtration rate, we conclude that relative hypoparathyroidism after PTX is the main mechanism contributing to decreased renal function in these patients. There was no difference in 10-year-graft survival between the deteriorating and the non-deteriorating group.     

Inhibition of thromboxane (Tx) synthesis by free radical scavengers

Treatment with thromboxane (Tx) synthase inhibitors or free radical scavengers has been shown to afford protection from renal ischemia. Since free radicals are closely associated with thromboxane (Tx) synthesis, this study examines the thesis that free radical scavengers inhibit formation of Tx. Anesthetized rats (n = 42) underwent right nephrectomy. By random choice, before 45 min of left renal pedicle clamping, rats received: 0.5 ml dextrose placebo IV (n = 6); the hydroxyl radical scavenger dimethyl-thiourea (DMTU), 500 mg/kg IV (n = 10); or the superoxide scavenger superoxide dismutase (SOD), 24,000 Sigma Units (SU)/kg IV (n = 12). This dose of SOD was repeated before release of the clamp. Treatment with DMTU and SOD decreased plasma TxB2 levels following 5 min of reperfusion from 2,480 pg/ml in dextrose treated controls to 1,155 pg/ml (p less than 0.01) and 1,419 pg/ml (p less than 0.03), respectively. At 24 hr, DMTU and SOD therapy decreased creatinine from 3.0 mg/dl in controls to 1.6 mg/dl (p less than 0.01) and 2.1 mg/dl (p less than 0.05), respectively. At 24 hr, DMTU but not SOD decreased left renal weight from 113 to 94% (p less than 0.0003) of the weight of the previously removed right kidney, and histologically prevented acute tubular necrosis (p less than 0.05). In nephrectomized but nonischemic sham control rats (n = 7) plasma TxB2 and 6-keto-PGF1 alpha concentrations were 757 pg/ml and 82 pg/ml, creatinine level 0.9 mg/dl and kidney weight 94% of the previously removed right kidney.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fibroblast growth factor-23 is regulated by 1alpha,25-dihydroxyvitamin D.

Serum FGF-23 regulation was studied in patients with hypoparathyroidism or pseudohypoparathyroidism treated with calcitriol. Serum FGF-23 levels changed in parallel in response to changes in serum 1,25-D, suggesting that FGF-23 may be regulated by 1,25-D. In addition, the phosphaturic effect of FGF-23 may be diminished in the absence of PTH action on the kidney. INTRODUCTION: Fibroblast growth factor (FGF)-23 is a recently described hormone that has been shown to be involved in the regulation of phosphate and vitamin D metabolism. The physiologic role of FGF-23 in mineral metabolism and how serum FGF-23 levels are regulated have yet to be elucidated. Three patients with mineral metabolism defects that allowed for the investigation of the regulation of FGF-23 were studied. MATERIALS AND METHODS: Patient 1 had postsurgical hypoparathyroidism and Munchausen's syndrome and consumed a pharmacologic dose of calcitriol. Patient 2 had postsurgical hypoparathyroidism and fibrous dysplasia of bone. She was treated with increasing doses of calcitriol followed by synthetic PTH(1-34). Patient 3 had pseudohypoparathyroidism type 1B and tertiary hyperparathyroidism. She underwent parathyroidectomy, which was followed by the development of hungry bone syndrome and hypocalcemia, requiring treatment with calcitriol. Serum FGF-23 and serum and urine levels of mineral metabolites were measured in all three patients. RESULTS: Patient 1 had an acute and marked increase in serum FGF-23 (70 to 670 RU/ml; normal range, 18-108 RU/ml) within 24 h in response to high-dose calcitriol administration. Patient 2 showed stepwise increases in serum FGF-23 from 117 to 824 RU/ml in response to increasing serum levels of 1alpha,25-dihydroxyvitamin D (1,25-D). Finally, before parathyroidectomy, while hypercalcemic, euphosphatemic, with low levels of 1,25-D (10 pg/ml; normal range, 22-67 pg/ml), and with very high serum PTH (863.7 pg/ml; normal range, 6.0-40.0 pg/ml), patient 3 had high serum FGF-23 levels (217 RU/ml). After surgery, while hypocalcemic, euphosphatemic, and with high serum levels of serum 1,25-D (140 pg/ml), FGF-23 levels were higher than preoperative levels (305 RU/ml). It seemed that the phosphaturic effect of FGF-23 was diminished in the absence of PTH or a PTH effect. CONCLUSIONS: Serum FGF-23 may be regulated by serum 1,25-D, and its phosphaturic effect may be less in the absence of PTH.     

Sporadic aluminum osteomalacia: identification of patients at risk

Chronic dialysis patients at risk for aluminum osteomalacia in areas of low water-aluminum content are not well identified. We, therefore, studied retrospectively a cohort of 59 patients who underwent bone biopsy at two hospital-based dialysis centers in Montreal (water aluminum content less than 10 micrograms/L). Overall, 25% of patients biopsied had aluminum-related osteomalacia defined by aluminum staining of more than 30% of the trabecular surface and low levels of bone formation as measured by tetracycline labeling. Multiple linear regression analysis showed high predialysis serum creatinine (P less than .05) and the amount of aluminum prescribed per month (P less than .05) as the most important determinants of aluminum staining. We conclude that aluminum-related osteomalacia can be a frequent disease entity in areas of low water-aluminum content. Our findings also suggest predialysis serum creatinine and the amount of aluminum prescribed per month are risk factors for the development of aluminum-related osteomalacia. Though the relationship between serum creatinine and aluminum staining of trabecular bone is unclear, serum creatinine is probably a marker for adequacy of dialysis in these patients.     

Comparison of the effects of calcitriol and maxacalcitol on secondary hyperparathyroidism in patients on chronic haemodialysis: a randomized prospective multicentre trial.

BACKGROUND: To identify differences between the effects of calcitriol and the calcitriol analogue, maxacalcitol, on parathyroid hormone (PTH) and bone metabolisms, we conducted a randomized prospective multicentre study on patients on chronic haemodialysis. METHODS: We randomly assigned 91 patients with secondary hyperparathyroidism [intact PTH (iPTH) > or =150 pg/ml] to have either calcitriol (47 patients) or maxacalcitol (44 patients) therapy, for 12 months after a 1 month control period. Serum electrolytes, bone alkaline phosphatase (bAP), iPTH, total PTH and PTH(1-84) (whole PTH) levels were measured periodically. The first end point was a serum iPTH of <150 pg/ml, the second was the iPTH levels obtained. RESULTS: Treatment was discontinued for various reasons in nine patients in each group, but no serious side effects were observed in either group. The numbers of cases reaching the first end point were not significantly different between the two groups. Serum calcium concentration was significantly higher in the maxacalcitol than the calcitriol group during early treatment, but not at the end of treatment. Throughout the treatment period there were no significant differences between the two groups in serum iPTH, inorganic phosphate, the product of the serum calcium and inorganic phosphorus concentrations, bAP, or the ratio of whole PTH to total PTH minus whole PTH. Nor were the changes in these parameters significantly different between the two groups comparing the patients with moderate to severe hyperparathyroidism (basal iPTH > or =500 pg/ml). CONCLUSION: Calcitriol and maxacalcitol are equally effective on PTH and bone metabolism.     

Evaluation of IGF system component levels and mitogenic activity of uremic serum on normal human osteoblasts

To test the hypothesis that impairment in bone formation in renal osteodystrophy in adults with chronic renal failure (CRF) might be mediated in part by alterations in circulating levels of the insulin-like growth factor (IGF) system components, we compared serum levels of IGF-I, IGF-II, IGF-binding protein (IGFBP)-3, IGFBP-4 and IGFBP-5 in adults with CRF (CRF patients with parathyroid hormone (PTH) < 100 pg/ml, PTH > 300 pg/ml and end-stage renal failure (ESRF) patients) versus age-matched controls. To evaluate the biological significance of alterations in circulating level of IGF system components, we compared the mitogenic activity of the sera on proliferation of normal human osteoblasts in vitro by using [(3)H]thymidine incorporation. We found severalfold increased serum levels of IGFBP-3 (2-fold), IGFBP-4 (5-fold) and slightly increased IGF-II levels in ESRF patients as well as a 2.6-fold increase in free IGF-I in CRF patients with PTH < 100 pg/ml. The mitogenic activity was found to be increased in serum of kidney failure patients compared to controls. This was most pronounced in CRF patients with PTH < 100 pg/ml showing also a significant increase in free IGF-I and the lowest levels of the IGF-inhibitory IGFBP-4. Our data support the hypothesis that alterations in serum levels of stimulating (i.e. free IGF-I) and inhibitory IGF system components (i.e. IGFBP-4) may influence osteoblastic cell proliferation in renal osteodystrophy.