Risk factors of one year increment of coronary calcifications and survival in hemodialysis patients.

BACKGROUND: Heart and coronary calcifications in hemodialysis patients are of very common occurrence and linked to cardiovascular events and mortality. Several studies have been published with similar results. Most of them were mainly cross-sectional and some of the prospective protocols were aimed to evaluate the results of the control of altered biochemical parameters of mineral disturbances with special regard to serum calcium, phosphate and CaxP with the use of calcium containing and calcium free phosphate chelating agents. The aim of the present study was to evaluate in hemodialysis patients classic and some non classic risk factors as predictors of calcification changes after one year and to evaluate the impact of progression on survival. METHODS: 81 patients on hemodialysis were studied, with a wide age range and HD vintage. Several classic parameters and some less classic risk factors were studied like fetuin-A, CRP, 25-OHD and leptin. Calcifications, as Agatston scores, were evaluated with Multislice CT basally and after 12-18 months. RESULTS: Coronary artery calcifications were observed in 71 of 81 patients. Non parametric correlations between Agatston scores and Age, HD Age, PTH and CRP were significant. Delta increments of Agatston scores correlated also with serum calcium, CaxP, Fetuin-A, triglycerides and serum albumin. Logistic regression analysis showed Age, PTH and serum calcium as important predictors of Delta Agatston scores. LN transformation of the not normally distributed variables restricted the significant correlations to Age, BMI and CRP. Considering the Delta Agatston scores as dependent, significant predictors were Age, PTH and HDL. A strong association was found between basal calcification scores and Delta increment at one year. By logistic analysis, the one year increments in Agatston scores were found to be predictors of mortality. Diabetic and hypertensive patients have significantly higher Delta scores. CONCLUSIONS: Progression of calcification is of common occurrence, with special regard to elevated basal scores, and is predictive of survival. Higher predictive value of survival is linked to the one year increment of calcification scores. Some classic and non classic risk factors play an important role in progression. Some of them could be controlled with appropriate management with possible improvement of mortality.

Asymmetric dimethylarginine, vascular calcifications and parathyroid hormone serum levels in hemodialysis patients.

BACKGROUND: Asymmetric dimethylarginine (ADMA)is an endogenous amino acid similar to l-arginine and able to inhibit the enzyme endothelial nitric oxide synthase (eNOS). It is a factor of impaired nitric oxide (NO) synthesis. Serum levels of ADMA in chronic kidney disease (CKD) increase due to defective inactivation and excretion. High ADMA levels are associated with endothelial dysfunction and cardiovascular damage. A linkage between ADMA levels and vascular calcifications of CKD can therefore be hypothesized. This study explores also a possible relation between ADMA and parathyroid hormone (PTH) serum levels, which are known to be linked to increased rates of cardiovascular death. METHODS: The study was carried out in 79 patients on hemodialysis (HD), mean age 59.25 +/- 12 years. In all patients, serum ADMA, PTH, Ca, P, bone alkaline phosphatase (BALP), cholesterol and albumin were measured. In addition, the patients were subjected to multislice computed tomography for heart calcification evaluation. RESULTS: Correlation analysis of ADMA showed a significant relation with total and coronary calcium volumes, HD vintage, body mass index (BMI), cholesterol, serum albumin, PTH, natural logarithm of PTH (LnPTH) and BALP. Multiple regression analysis selected HD vintage, albumin and PTH as predictive variables for coronary calcium volume, while ADMA was excluded. With LnPTH as dependent variable, ADMA, serum calcium and BMI were predictive variables with R2 of 0.37. ADMA as dependent variable was also predicted by PTH, HD vintage, albumin and BMI. CONCLUSIONS: Despite the results of bivariate analysis showing a linkage between ADMA and cardiac and coronary calcifications, regression analysis showed only a spurious association. The strong positive correlation between ADMA and LnPTH, validated by the regression analysis, may suggesta link between ADMA and PTH-derived vascular damage. ADMA levels could be influenced by the severity of hyperparathyroidism and contribute to cardiovascular death linked to PTH of hemodialysis patients.

Serum levels of calcification inhibition proteins and coronary artery calcium score: comparison between transplantation and dialysis.

Vascular calcifications in CKD are now linked to serum alterations of both divalent ions and calcification inhibitory proteins. Due to possible biochemical differences between dialysis (D) and transplantation (Tx), we examined the entity and severity of these biochemical modifications and of coronary artery calcium score separately in these two populations. We assayed, besides standard markers of inflammation, divalent ions and serum levels of fetuin, matrix Gla protein (MGP) and osteoprotegerin (OPG), in 51 Tx patients (age 45 +/- 12 years; 30 males, 21 females; previous D duration 4.8 +/- 4.2 years; Tx since 6.6 +/- 5.5 years; Cr 1.8 +/- 0.6 mg/dl) and in 49 D patients (age 49 +/- 14 years; 30 males,19 females; D duration 5.6 +/- 4.8 years). Additionally, coronary calcium score (AS) was evaluated by cardiac multi-slice CT. Compared with D patients, Tx patients had better values of divalent ions and inflammation markers, and lower prevalence (65 vs. 86%; p < 0.02) and severity (AS = 570 +/- 1,637 vs. 1,311 +/- 3,128; p < 0.008) of coronary calcification. In addition, a tendency toward normalization for all of the three calcification inhibitory proteins was evident. In both Tx and D, AS correlated with age and OPG (Tx: r(s) = 0.439, p < 0.001, and r(s) = 0.510, p < 0.0001; D: r(s) = 0.471, p < 0.001, and r(s) = 0.403, p < 0.005, respectively); in D patients, a correlation was present also with D duration (r(s) = 0.435; p < 0.002), other markers of inflammation and, notably, fetuin (r(s) = -0.442; p < 0.002). Regression analysis selected previous time on D in Tx patients (r(m) = 0.400; p < 0.004), and C-reactive protein and OPG in D patients (r(m) = 0.518; p < 0.004) as the most predictive parameters of AS. Discriminant analysis confirmed the major role of age and D duration in the appearance of AS and evidenced male gender as a distinct risk condition. At variance, Tx duration was never associated with AS. In conclusion, as compared to D, renal Tx patients show serum levels of calcification inhibition proteins and of divalent ions closer to normal. As this is associated with a lower prevalence and severity of AS, it is suggested that Tx antagonize the accelerating role of D in the progression of vascular calcification. Assessment of both coronary calcifications and serum levels of calcification inhibitory proteins may be of value to identify those subjects at higher risk of development and progression of vascular lesions, among whom males have the highest rate.

Effects of the administration of corticosterone, parathyroid hormone, or both, and of their withdrawal, on rat bone and cartilage histomorphometric parameters, and on osteoprotegerin and RANKL mRNA expression and proteins.

We have studied the effects of the treatment with corticosterone (CORT), parathyroid hormone (PTH), or both (CORT + PTH), and of their withdrawal (CORT-rec and CORT + PTH-rec), on the osteoprotegerin (OPG) and receptor activator of nuclear factor-kB ligand (RANKL) localization and expression and on histomorphometric parameters in primary and secondary spongiosa of rat femur and tibia metaphyses. In the secondary spongiosa of the CORT group, the bone remodeling and the OPG/RANKL mRNA ratio decreased. In the PTH group, the bone turnover and the structural and connectivity indices increased, and the OPG/RANKL mRNA ratio fell; this ratio rose, however, in the primary spongiosa. In the CORT + PTH group, remodeling values intermediate between those of the CORT and PTH groups, were detected in the secondary spongiosa, where OPG and RANKL mRNA rose. Return towards control values was found in the recovery groups. The Cartilage Growth Plate Width was reduced in the CORT and CORT + PTH groups and returned to normal values in the recovery groups, while it was not affected by PTH. Independently of treatments, both OPG and RANKL mRNA and proteins were co-localized in the same cartilage and bone cells and in several bone marrow cells. In conclusion, the catabolic effects induced by CORT treatment occur together with an OPG fall and a RANKL rise. In the PTH group in which the bone turnover increase, the OPG and RANKL mRNA expressions differ in the primary and secondary spongiosa, confirming that the bone tissue in these sites can have different metabolic trends.

[The role of intraoperative parathyroid hormone assay in the surgical management of hyperparathyroidism]. / Il ruolo del dosaggio del PTH intraoperatorio nella terapia chirurgica dell'iperparatiroidismo.

BACKGROUND: Intraoperative parathyroid hormone (iPTH) assay (QPTH) in combination with preoperative localization, permits a less invasive operative approach in the treatment of hyperparathyroidism. A 50% reduction of the intraoperative PTH level, mesured within 15 minutes with an immunochemestry system of III generation (ICMA), shows the completeness of the hypersecretive tissues surgical removal. PATIENTS AND METHODS: From June 2003 to December 2005 a series of 39 patients underwent target parathyroidectomy with intraoperative parathyroid hormone assay for parathyroid disease. Intraoperative PTH was measured before, 5-10 and 20 minutes after parathyroidectomy. 79.5% of patients had secondary hyperparathyroidism, 29.5% had primary disease. In 38 patients (97,4%) the intraoperative PTH levels declined more than 70% and in only one patient (2,6%) intraoperative PTH levels declined less than 50%. RESULTS AND CONCLUSIONS: QPTH has deeply modified the surgical approach to the treatment of hyperparathyroidism. Intraoperative measurement of iPTH is useful in prediction the complete removal of all parathyroid tissue after surgery for parathyroid disease, thus avoiding persistence or recurrence of disease and surgical failures. In well-studied cases QPTH can be considered a valid alternative to the intraoperative hystological examination.

Renal osteodystrophy: alpha-Heremans Schmid glycoprotein/fetuin-A, matrix GLA protein serum levels, and bone histomorphometry.

BACKGROUND: Fetuin-A of hepatic origin circulates in large amounts in serum, but also is expressed in bone, where it is an inhibitor of transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) proteins. Together with matrix GLA protein (MGP), fetuin-A is able to make up a complex with calcium and phosphate that is more soluble than calcium and phosphate alone, preventing its deposition in extraskeletal tissues. Experimental results suggested that this complex is made at bone tissue level. The aim of this study is to evaluate whether serum fetuin-A and MGP are influenced by type of renal osteodystrophy, they correlate with bone histomorphometric and histodynamic parameters, and/or serum levels may influence bone turnover. METHODS: Thirty-eight hemodialysis patients who volunteered to undergo a bone biopsy were studied. Patients (27 men, 11 women) had a mean age of 55.2 +/- 11.8 years and dialysis vintage of 75.7 +/- 57.4 months. They were not administered vitamin D or drugs connected with mineral metabolism. They underwent transiliac bone biopsy after tetracycline labeling. Biopsies were performed for histological, histomorphometric, and histodynamic evaluation and aluminum histochemistry. Serum fetuin-A and MGP were measured by using enzyme-linked immunosorbent assay kits. RESULTS: Serum fetuin-A levels were significantly less than normal, whereas MGP levels were less than the normal average. Fetuin-A levels in patients with hyperparathyroidism, mixed osteodystrophy, and low-turnover osteodystrophy were 0.219 +/- 0.1, 0.27 +/- 0.1, and 0.197 +/- 0.1 ng/mL, respectively (P = not significant). Fetuin-A level significantly correlated inversely with values for several histomorphometric parameters, such as osteoid volume (OV/BV), osteoblastic surface (Ob.S/BS), osteoid surface (OS/BS), and osteoclastic surface (Oc.S/BS). Logistic regression showed odds ratios of 5.3 and 4.9 for the association of high fetuin-A levels with low values for OS/BS and Ob.S/BS, respectively. Results of multiple regression analysis with intact parathyroid hormone and fetuin-A levels as independent variables and OV/BV and Ob.S/BS as dependent variables showed that independent variables correlated significantly with dependent variables, positively for intact parathyroid hormone levels and inversely for fetuin-A levels. MGP levels in patients with hyperparathyroidism, mixed osteodystrophy, and low-turnover osteodystrophy were not significantly different (3.94 +/- 0.86, 3.40 +/- 0.99, and 5.64 +/- 2.4 nmol/L, respectively). By dividing MGP serum values into tertiles, mean values for OV/BV were different (analysis of variance, P < 0.04), with a greater value in the higher MGP tertile. By exclusion of 3 extravariant cases (>3 SDs greater than the mean), 1 case for each type of osteodystrophy, a significant correlation between bone formation rate and MGP serum level was found (P < 0.05). In addition, a significant correlation was found between MGP level and trabecular thickness. CONCLUSION: Fetuin-A and MGP levels correlated with bone formation parameters. This association could be caused by an effect of these proteins on bone formation, presumably mediated by the TGF-beta/BMP system. Fetuin-A, as opposed to MGP, is known to inhibit the TGF-beta/BMP complex, a protein-cytokine system that appears to be an important regulator of bone formation and probably a factor with an important role in renal osteodystrophy.

Detection of osteoprotegerin (OPG) and its ligand (RANKL) mRNA and protein in femur and tibia of the rat.

Osteoprotegerin (OPG) and the receptor activator of nuclear factor (NF)-kB ligand (RANKL) are key regulators of osteoclastogenesis. The present study had the main aim of showing the localization of OPG and RANKL mRNA and protein in serial sections of the rat femurs and tibiae by immunohistochemistry (IHC) and in situ hybridization (ISH). The main results were: (1) OPG and RANKL mRNA and protein were co-localized in the same cell types, (2) maturative/hypertrophic chondrocytes, osteoblasts, lining cells, periosteal cells and early osteocytes were stained by both IHC and ISH, (3) OPG and RANKL proteins were mainly located in Golgi areas, and the ISH reaction was especially visible in active osteoblasts, (4) immunolabeling was often concentrated into cytoplasmic vacuoles of otherwise negative proliferative chondrocytes; IHC and ISH labeling increased from proliferative to maturative/hypertrophic chondrocytes, (5) the newly laid down bone matrix, cartilage-bone interfaces, cement lines, and trabecular borders showed light OPG and RANKL immunolabeling, (6) about 70% of secondary metaphyseal bone osteocytes showed OPG and RANKL protein expression; most of them were ISH-negative, (7) osteoclasts were mostly unstained by IHC and variably labeled by ISH. The co-expression of OPG and RANKL in the same bone cell types confirms their strictly coupled action in the regulation of bone metabolism.

PTH 1-84 and PTH "7-84" in the noninvasive diagnosis of renal bone disease.

BACKGROUND: The intact parathyroid hormone (PTH) assay evaluates levels of serum 1-84 PTH and other N-terminally truncated PTH fragments, mainly PTH "7-84." This PTH molecule has been found experimentally to interfere with biological activity of PTH 1-84, perhaps through its binding to the PTH receptor complex. Therefore, assuming that high levels of PTH 7-84 are a cause of bone resistance to PTH, it has been hypothesized that a decreased 1-84 to 7-84 PTH ratio caused by a relative increase in PTH 7-84 level might help in the noninvasive diagnosis of low-turnover osteodystrophy (LTO). METHODS: This study was performed in 35 patients with chronic renal failure on hemodialysis therapy who underwent bone biopsy for a histological, histomorphometric, and histodynamic study. In addition, blood samples were obtained for intact PTH, 1-84 PTH, and total PTH assays. PTH 7-84 level was obtained from the difference between total and 1-84 PTH assay results. RESULTS: Nine patients had LTO (8 patients, adynamic bone disease; 1 patient, osteomalacia), 12 patients had hyperparathyroidism (HP), and 14 patients had mixed osteodystrophy (MO). On average, 1-84 PTH levels were approximately 60% of mean values for intact PTH. The two assays were strictly correlated. Average 1-84 to 7-84 PTH ratios were 1.57 +/- 0.85, 1.73 +/- 1.31, and 1.95 +/- 2.1 in the three histological groups (LTO, HP, and MO, respectively), with no significant difference. CONCLUSION: Contrary to previous expectations, results do not favor the hypothesis of a role of 7-84 PTH in bone resistance in renal osteodystrophy. The 1-84 to 7-84 PTH ratio is not a marker of LTO and is of no use in noninvasive histological diagnosis.

Serum leptin in dialysis renal osteodystrophy.

BACKGROUND: The hormone leptin is considered to have a role in the prevention of osteoporosis and probably acts on bone tissue through inhibition of osteoclasia. Its action has been attributed to interference in osteoprotegerin (OPG)/OPG-ligand equilibrium. Contradictory data also have been reported, casting doubts on the positive effect on bone mass of the hormone, at least in males. To date, the relation between serum leptin levels of dialysis patients and renal osteodystrophy, defined by histomorphometric and histodynamic parameters of bone, has not been studied. METHODS: The study included 46 hemodialysis patients (32 men, 14 women; age, 57.2 +/- 11.4 years). A transiliac bone biopsy after double-tetracycline labeling was performed for histological, histomorphometric, and histodynamic studies. Blood samples were drawn for leptin, intact parathyroid hormone (PTH), whole PTH (PTH1-84), OPG, bone alkaline phosphatase, calcium, phosphate, 25-hydroxycholecalciferol, and calcitriol. Serum leptin was measured by means of a radioimmunoassay. RESULTS: Eighteen patients had mixed osteodystrophy (MO); 17 patients, hyperparathyroidism; 9 patients, adynamic bone disease (ABD); and 2 patients, osteomalacia. Aluminum histochemistry results were positive in 1 patient with ABD and 1 patient with MO. A sex difference was found in serum leptin levels (48.9 +/- 38 ng/mL in women and 12.2 +/- 13.2 ng/mL in men; P < 0.0002). In the entire population, lnleptin correlated significantly with body mass index (BMI; P < 0.01). SD score (SDS) leptin (adjusted for BMI, sex, and age) correlated inversely with PTH1-84 level and osteoclastic surface (OcS/BS; P < 0.05) and had a borderline correlation with bone formation rate. Correlations between leptin levels and other parameters were enhanced in men. SDS leptin correlated inversely with OcS/BS (P < 0.01), osteoclastic number (P < 0.01), and mineral apposition rate (P < 0.01). In addition, SDS leptin had a borderline inverse correlation with osteoblast surface (P < 0.06) and significant correlation with OPG level (P < 0.05). No difference was found in serum leptin levels between histological groups. CONCLUSION: The reported data confirm the finding of a positive relation between serum leptin level and BMI and greater levels in women compared with men. Serum leptin level is connected to bone resorption and also bone formation, both inversely related to serum leptin levels. The decrease in osteoclasia that accompanies increasing serum leptin levels does not seem to be related to an enhanced OPG effect because it was accompanied by decreased OPG levels. Low-turnover bone disease does not appear to be caused by increased serum leptin levels. The nature of the interrelation between serum leptin and PTH1-84 levels requires further study.

Atherosclerotic renal artery stenosis: one year outcome of total and separate kidney function following stenting.

BACKGROUND: Renal artery stenosis (RAS) is a known cause of hypertension and ischemic nephropathy. Stenting of the artery is a valid approach, in spite of cases of unexpected adverse evolution of renal function. METHODS: In this study, 27 patients with unilateral RAS were subjected to stenting and followed for a period of one year, while 19 patients were observed while on medical treatment only. The group of 27 patients, 67.33 +/- 6.8 years of age, creatinine of 2.15 +/- 0.9 mg/dl, following stenting, were followed at intervals with biochemical tests, renal scintigraphy and doppler ultrasonography. The control group (70.0 +/- 6.1 years, creatinine 1.99 +/- 0.7 mg/dl) was also followed for one year. RESULT: One year after stenting mean creatinine clearance (Ccr) increased from 36.07 +/- 17.2 to 40.4 +/- 21.6 ml/min (NS). Arterial BP, decreased after 1,3,6, and 12 months (p < 0.05). The number of antihypertensive drugs also decreased (p < 0.05). A significant increase in proteinuria was also observed. In the control group both Ccr, BP and proteinuria did not show significant changes. Based on renal scintigraphy and Ccr at subsequent times, it was possible to evaluate the timecourse of renal function in both kidneys of the stented patients. In the stented kidneys Ccr increased significantly. On the controlateral kidney a decrease of renal function (p < 0.05) was observed. Resistance index appeared to be a risk factor of the functional outcome. CONCLUSIONS: Stenting of RAS due to atherosclerosis is followed by stabilization or improvement of Ccr, mainly at the stented kidney, while contralateral renal function showed a decrease.

Atherosclerotic ischemic renal disease. Diagnosis and prevalence in an hypertensive and/or uremic elderly population.

BACKGROUND: Atherosclerotic ischemic renal disease is a frequent cause of end-stage renal failure leading to dialysis among the elderly; Its prevalence is inferred from autopsy or retrospective arteriographic studies. This study has been conducted on 269 subjects over 50 with hypertension and/or CRF, unrelated to other known causes of renal disease. METHODS: All 269 patients were studied either by color-flow duplex sonography (n = 238) or by renal scintigraphy (n = 224), and 199 of the 269 patients were evaluated using both of these techniques. 40 patients, found to have renal artery stenosis (RAS), were subjected to 3D-contrast enhancement Magnetic Resonance Angiography (MRA) and/or Selective Angiography (SA). An additional 23 cases, negative both to scintigraphy and to ultrasound study, underwent renal angiography (MRA and/or SA). RESULTS: Color-duplex sonography, carried out in 238 patients, revealed 49 cases of RAS. MR or SA was carried out in 35 of these 49 patients, and confirmed the diagnosis in 33. Color-duplex sonography showed a PPV value of 94.3% and NPV of 87.0% while renal scintigraphy, carried out in 224 patients, had a PPV of 72.2% and a NPV of 29.4%. Patients with RAS showed a higher degree of renal insufficiency compared to non stenotic patients while there were no differences in proteinuria. RAS, based on color-duplex sonography studies, was present in 11% of patients in the age group 50-59, 18% in the 60-69 and 23% at age 70 and above. CONCLUSIONS: A relatively large percentage of the elderly population with renal insufficiency and/or hypertension is affected by RAS and is at risk of developing end-stage renal failure. Color-duplex ultrasonography is a valid routine method of investigation of population at risk for renal artery stenosis.

Peripheral artery calcifications evaluated by histology correlate to those detected by CT: relationships with fetuin-A and FGF-23.

BACKGROUND: Calcification of arteries is a frequent occurrence in hemodialysis (HD) patients and is linked to mortality. This study was conducted to evaluate the correspondence between coronary calcification scores and calcifications observed histologically in peripheral arteries in HD patients. In addition the association of humoral parameters including fetuin-A and fibroblast growth factor 23 (FGF-23) with arterial calcifications was studied. PATIENTS AND METHODS: HD patients (n=44) were studied with multislice computed tomography (CT) and histological quantification of arterial calcifications in the lower epigastric artery sampled at the time of renal transplant. In addition, humoral assays were performed including fetuin-A and FGF-23. RESULTS: There was a significant correlation between medial calcification of the artery and Agatston scores. Natural logarithm (Ln) FGF-23 significantly correlated to Ln Agatston score but not to Ln medial calcification. A significant negative correlation between fetuin-A and Ln FGF-23 was observed, changing to borderline significance after correction for age and Ln HD age. Ln Agatston score in a multiregression analysis was predicted by Ln FGF-23 and age. CONCLUSIONS: The association found between histologically evaluated calcification of the media of a peripheral artery in HD and the multislice CT Agatston scores is in favor of a generalized arterial calcification, either intimal or of tunica media, when calcium deposits are found in the coronary arteries. The association of FGF-23 with coronary calcification score, already reported, and less so with histological medial calcification is in favor of a link between the protein and intimal more than the medial calcification. FGF-23 may be considered a potential biomarker of arterial calcification in HD patients. The negative association between fetuin-A and FGF-23 may suggest a linkage between these humoral substances, vascular calcifications and mortality. The nature of this linkage requires further studies.

25-hydroxyvitamin D levels and bone histomorphometry in hemodialysis renal osteodystrophy.

BACKGROUND: The importance of 25-hydroxyvitamin D (25-OHD) serum levels in hemodialysis chronic renal failure has not been so far histologically evaluated. Information still lacking relate to the effect of 25-OHD deficiency on serum parathyroid hormone (PTH) levels and on bone and its relationship with calcitriol levels. METHODS: This retrospective study has been performed on a cohort of 104 patients on hemodialysis from more than 12 months, subjected to transiliac bone biopsy for histologic, histomorphometric, and histodynamic evaluation. The patients, 61 males and 43 females, mean age 52.9 +/- 11.7 years, hemodialysis length 97.4 +/- 61.4 months, were treated with standard hemodialysis and did not receive any vitamin D supplementation. Treatment with calcitriol was not underway at the time of the biopsy. Transiliac bone biopsies were performed after double tetracycline labels. In addition, serum intact PTH (iPTH), alkaline phosphatase, and 25-OHD were measured. Calcitriol serum levels was also measured in a subset of patients (N= 53). The patients were divided according to serum 25-OHD levels in three groups: (1) 0 to 15 (15 patients), (2) 15 to 30 (38 patients), and (3) >30 ng/mL (51 patients). RESULTS: There was no significant difference in average age, hemodialysis age, serum PTH [490 +/- 494, 670 +/- 627, and 489 +/- 436 pg/mL, respectively (mean +/- SD)], alkaline phosphatase, and calcitriol between the three groups. The parameters double-labeled surface, trabecular mineralizing surface, and bone formation rate were significantly lower in group 1 than in the other groups (P < 0.03, < 0.03, and < 0.02, respectively). Osteoblast surface and adjusted apposition rate were borderline significantly lower in group 1 (P < 0.06 and < 0.10). There was no statistical difference in the biochemical and bone parameters between groups 2 and 3. A positive significant correlation was found between several bone static and dynamic parameters and 25-OHD levels in the range 0 to 30 ng/mL, showing a vitamin D dependence of bone turnover at these serum levels. However, actual evidence of an effect on bone of 25-OHD deficiency was found at serum levels below 20 ng/mL. With increasing 25-OHD levels beyond 40 ng/mL, a downslope of parameters of bone turnover was also observed. CONCLUSION: Since PTH serum levels are equally elevated in low and high 25-OHD patients, while calcitriol levels are constantly low, an effect of 25-OHD deficiency (group 1) on bone, consisting of a mineralization and bone formation defect, can be hypothesized. The effect of vitamin D deficiency or bone turnover is found below 20 ng/mL. The optimal level of 25-OHD appears to be in the order of 20 to 40 ng/mL. Levels of the D metabolite higher than 40 ng/mL are accompanied by a reduction of bone turnover.

In vivo assessment of intact parathyroid hormone adsorption by different dialysis membranes during hemodialysis.

BACKGROUND: Different parathyroid hormone (PTH) behavior during hemodialysis with different types of dialysis membranes has been reported. The behavior of intact parathyroid hormone (iPTH) adsorption using different dialysis membranes was assessed in 12 dialysis patients with secondary hyperparathyroidism. METHODS: The study was performed according to a longitudinal scheme comprising three treatment modalities, each lasting 2 weeks, for 6 weeks altogether. The first treatment consisted of standard bicarbonate dialysis with low-flux polysulfone, followed by acetate-free biofiltration with high-flux-polysulfone or with polyacrylonitrile-AN69. In the first week of each period, dialysis was delivered by using a 1.3 m(2) surface area and subsequently, a 1.8 m(2) surface area. Intact parathyroid hormone was assayed on the blood and dialysate samples to calculate iPTH adsorption. RESULTS: The results showed that polyacrylonitrile-AN69 and high-flux polysulfone induce a significantly larger drop in PTH serum levels as compared with low-flux-polysulfone, particularly in the first half of the dialysis session, while the ionized calcium increase is comparable in all different hemodialysis treatments. The measurement of iPTH in the dialysate showed lower values than those disappearing on the blood side, thus suggesting the presence of an adsorptive mechanism in the different dialysis membranes. CONCLUSION: High-flux polysulfone is endowed with a comparable adsorptive capacity per surface unit compared to polyacrylonitrile-AN69, although it seems to show a different behavior, as polyacrylonitrile-AN69 saturates early in the first hour of dialysis corresponding to its maximum adsorption power, while high-flux-polysulfone displays a more lasting adsorptive capacity. Thus, iPTH changes during hemodialysis also depend on dialyzer characteristics and the dialysis membrane adsorption.

Serum osteoprotegerin and renal osteodystrophy.

BACKGROUND: Numerous growth factors and cytokines are known to modulate bone turnover. An important, recently discovered complex involved in osteoclastogenesis is the osteoprotegerin/osteoprotegerin-ligand (OPG/OPGL) cytokine complex, which is produced by osteoblasts. Many factors, including parathyroid hormone (PTH), appear to affect bone turnover through this pathway. In this disorder, the role of the OPG/OPGL system in the pathogenesis of renal osteodystrophy, a disease with either low or high bone turnover, has not been investigated so far. METHODS: Thirty-nine chronic haemodialysis patients had bone biopsies, including histomorphometric and histodynamic examinations. In addition, the following serum biochemistry parameters were measured: serum OPG, intact PTH, PTH 1-84, total PTH, osteocalcin, total and bone alkaline phosphatases, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol. RESULTS: On average, serum OPG levels were above the normal range. They were lower in adynamic bone disease (ABD) patients, than in patients with predominant hyperparathyroidism (HP) or mixed osteodystrophy (MO). Significant negative correlations were found between serum OPG and PTH levels, and between serum OPG and parameters of bone resorption (ES/BS) and bone formation (ObS/BS and BFR/BS) in HP and MO patients with PTH values < or =1000 pg/ml. For intact PTH levels < or =300 pg/ml, serum OPG was significantly lower in the group with ABD than in those with HP or MO (P<0.05). CONCLUSION: In renal osteodystrophy the OPG/OPGL system is involved in the regulation of bone turnover induced by PTH. The determination of serum OPG levels could be of use in the diagnosis of low turnover bone disease, at least in association with PTH levels < or =300 pg/ml.

Renal osteodystrophy in predialysis and hemodialysis patients: comparison of histologic patterns and diagnostic predictivity of intact PTH.

BACKGROUND: Comparison of renal osteodystrophy in predialysis and hemodialysis has been rarely reported. Distinct patterns of renal osteodystrophy could be found in these conditions. In addition the use of parathyroid hormone (PTH) and other markers for noninvasive diagnosis may result in different predictive values in predialysis and hemodialysis patients. METHODS: 79 consecutive patients with conservative chronic renal failure and 107 patients on hemodialysis were studied. All patients were subjected to bone biopsy for histological and histomorphometric evaluation. The patients had no exposure to aluminium before dialysis and relatively low exposure while on hemodialysis. RESULTS: In the predialysis patients, bone biopsies showed 9 cases of adynamic bone disease (ABD) and 8 cases of osteomalacia (OM), 50 patients with mixed osteodystrophy and 2 cases of hyperparathyroidism. Among the hemodialysis patients 12 cases had ABD, 3 cases OM, 30 mixed osteodystrophy, and 61 patients hyperparathyroidism. In the predialysis patients with chronic renal failure, bone aluminium was on average 4.5 mg/kg dry weight, while in dialysis patients the average value was 35.4 mg/kg dry weight. Discriminant analysis of low turnover osteodystrophy (ABD and OM) by intact PTH showed higher accuracy in dialysis than in predialysis patients. Correlation studies of intact PTH versus bone formation rate, osteoblast surface/bone surface and osteoclast surface/bone surface showed significantly steeper slopes in dialysis than in predialysis patients, which indicates that bone resistance to PTH is more marked in predialysis patients. CONCLUSIONS: The prevalence of ABD and OM in the geographic area investigated is lower than in other reports. Aluminium exposure does not seem to be the cause of low turnover osteodystrophy in the present population. The predictive value of intact PTH in the noninvasive diagnosis of renal bone disease is higher in hemodialysis patients than in predialysis patients. Predialysis chronic renal failure, when compared to the dialysis stage, seems to be characterized by resistance of bone tissue to PTH.