Circulating osteoprotegerin in women during GnRH-agonist treatment and their relationships with mineral components and biomarkers of bone turnover

A novel cytokine termed osteoprotegerin (OPG) that is also called osteoclastogenesis-inhibitory factor, which inhibits osteoclast maturation and activity, was recently isolated. In order to determine the influence of estrogen deficiency on the levels of circulating OPG in women, we studied the changes in the levels of circulating OPG in 10 Japanese women ages 25-49 (mean +/- SD, 34.0 +/- 6.9) years with endometriosis receiving gonadotropin-releasing hormone agonists (GnRH-a) therapy. We further analyzed whether the levels of circulating OPG have relations with the levels of the biomarkers of bone turnover or those of circulating mineral components in these patients during GnRH-a treatment. The patients were treated with a monthly injection of 3.75 mg leuprolide acetate depot for 6 months. In all patients, the concentrations of serum estradiol decreased after 6 months of GnRH-a treatment. The bone mineral density of the lumber spines in these patients significantly (P < 0.01) decreased (percentage change: mean +/- SD, -5.4 +/- 2.1%), while circulating OPG levels significantly (P < 0.01) increased after 6 months of treatment. The values of circulating OPG had significant correlations with those of urinary pyridinoline (r = 0.59, P < 0.01), urinary deoxypylridinoline (Dpd) (r = 0.46, P < 0.05), and serum alkaline phosphatase (r = 0.66, P < 0.01) but not with those of serum carboxy-terminal propeptide of type I procollagen during GnRH-a treatment. The values of circulating OPG also correlated significantly with those of serum calcium (Ca) and phosphorus (P) (r = 0.65 and 0.72, P < 0.01). Further analyses revealed that the percentage change in the value of circulating OPG had a significant correlation with that of urinary Dpd (r = 0.84, P < 0.01). These results suggest that circulating OPG levels rise against the increase in osteoblastic bone resorption and circulating Ca levels in the case of estrogen deficiency, possibly as a compensatory mechanism serving to limit circulating Ca levels and bone density.     

Variations along the 24-hour cycle of circulating osteoprotegerin and soluble RANKL: a rhythmometric analysis

Summary The variability of serum osteoprotegerin (OPG) and soluble RANKL (sRANKL) along the 24-h cycle was assessed in 20 healthy women. No rhythmic variations of serum OPG, sRANKL or sRANKL/OPG ratio were detected as a group phenomenon. Timing of sampling is unlikely to influence the results of measurements of circulating OPG and sRANKL. Introduction Physiological bone turnover shows diurnal variations. The aim of the study was to assess variability of OPG and sRANKL serum levels along the 24-h cycle. Methods Blood was collected from 20 healthy women (median age 31 years, range 25–65 years) at 4-h intervals between 08:00 and 24:00 and at 2-h intervals between 24:00 and 08:00. Serum albumin, cortisol, osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX), OPG and total sRANKL were measured. Temporal variations were assessed by the COSINOR model. Results Circadian rhythms of cortisol and albumin documented a normal synchronization within the circadian structure. Serum OC and CTX showed rhythmic variations, peaking at night-time. Rhythmic variations of serum OPG, sRANKL and sRANKL/OPG ratio were not detected as a group phenomenon. On an individual basis, rhythmic changes were detected in ten patients for OPG and eight patients for sRANKL, with very small amplitudes and heterogeneous acrophases. Conclusions The absence of consistent rhythmic variations of circulating OPG and sRANKL levels may reflect the absence of rhythmic variations of their expression in the bone microenvironment. Were this the case, the nocturnal rise of bone resorption should be accounted for by different, not RANKL/OPG-mediated factors. Since circulating OPG and sRANKL may derive from sources other than bone, rhythmicity could be masked by non-rhythmic or non-synchronized rhythmic expression in these sources. Timing of sampling is unlikely to influence the results of measurements of circulating OPG and sRANKL. Andrea Dovio and Daniele Generali contributed equally to the study.     

The contribution of serum osteoprotegerin to bone mass and vertebral fractures in postmenopausal women

Regulation of osteoclastic activity is critical for understanding bone loss associated with the postmenopausal period. In vitro and animal studies have revealed the role of OPG as a decoy receptor that neutralizes the effect of RANKL on the differentiation and activation of osteoclasts. However, the role of the OPG-RANKL system in postmenopausal osteoporosis is controversial. Thus, the aim of this study was to investigate the relationship among circulating levels of OPG, RANKL, bone turnover markers (BTM), bone mineral density (BMD) and vertebral fractures in postmenopausal women. We determined anthropometric parameters, circulating OPG and RANKL, BTM, estradiol, BMD by dual X-ray absorptiometry at the lumbar spine (LS) and femoral neck (FN), and pre-existing vertebral fractures in 206 ambulatory postmenopausal women of a mean age of 62 years (SD 7). Circulating OPG was significantly related to age ( r =0.158; P =0.023), years since menopause ( r =0.167; P =0.016) and BMD (LS Z-score: r =0.240; P =0.001, FN Z-score: r =0.156; P =0.025). Over half of the women had undetectable RANKL ( n =113; 54.9%). There were no significant differences in clinical variables, BTM or BMD among women with detectable vs. undetectable RANKL. OPG was found to be independently associated with osteoporosis (OR: 2.9, 1.4–5.9) and prevalent vertebral fractures (OR: 2.5, 1.2–5.4). We conclude that serum OPG levels are independently associated with bone mass and prevalent vertebral fractures in postmenopausal women.     

Hepatitis C-associated osteosclerosis (HCAO): report of a new case with involvement of the OPG/RANKL system

We report a new case of hepatitis C-associated osteosclerosis (HCAO). The clinical presentation of the patient was an acquired deep severe bone pain with increased serum bone alkaline phosphatase activity (up to 12 times the upper limit of normal), and generalized bone sclerosis, temporally related to the hepatitis C-virus (HCV) infection. We documented in this patient an increase of circulating osteoprotegerin (OPG), and a concentration of circulating receptor activator for nuclear factor-kB ligand (RANKL) below the lower limit of the reference range. The observed abnormalities of the OPG/RANKL system may contribute to the maintenance of the positive balance of bone remodeling that characterizes patients with HCAO.     

核因子κB受体活化因子及其配体在5/6肾切除大鼠肾脏中表达及缬沙坦对其影响

目的 探讨核因子κB受体活化因子(RANK)及其配体(RANKL)在5/6肾切除大鼠(STNx)残肾中表达的意义,以及血管紧张素受体拮抗剂(ARB)缬沙坦对其表达的影响。方法 制备5/6肾切除的SD大鼠动物模型, 分为未给药组、治疗组及假手术组。治疗组在5/6肾切除后即给予缬沙坦治疗,大鼠分别于第4、8、12 周杀检。第12 周时用ELISA方法检测大鼠血清中骨保护蛋白(OPG)及RANKL水平;显微镜观察肾脏病理变化;免疫组化方法及Western印迹方法分析RANK/RANKL/OPG蛋白表达;RT-PCR检测RANK/RANKL/OPG的mRNA表达。结果 (1)第12周时假手术组尿蛋白量为(6.1±0.6) mg/24 h;未给药组为(19.0±1.5) mg/24 h;治疗组为(13.4±1.2) mg/24 h,3 组间的差异有统计学意义(P均 < 0.01)。(2)第12周时未给药组及治疗组肾脏均有明显硬化,但治疗组硬化程度较未给药组轻。(3)未给药组RANK及RANKL蛋白及mRNA的表达均高于治疗组及假手术组,3 组间的差异有统计学意义(P均 < 0.01)。OPG蛋白及mRNA的表达在3 组间无显著性差异。(4)血清中OPG及RANKL含量在3 组间的差异亦无统计学意义。结论 在5/6肾切除大鼠残肾中表达上调的RANK和RANKL可能参与了肾小球硬化的发生发展。抑制RANK和RANKL的表达可能是缬沙坦延缓肾小球硬化的原因之一。     

Osteoprotegerin Levels in Primary Hyperparathyroidism: Effect of Parathyroidectomy and Association with Bone Metabolism

The effect of parathyroid hormone (PTH) on the production of osteoprotegerin (OPG) remains controversial. Most in vitro studies indicate that PTH decreases OPG secretion by the osteoblast, but in vivo observations are conflicting. In primary hyperparathyroidism (PHPT), hypersecretion of PTH leads to enhanced bone resorption and formation with increased risk of fracture. Patients with PHPT are cured by surgery, resulting in normalization of PTH levels and bone metabolism, but the concomitant effects on OPG production are not known. The hypothesis of the present study was that the circulating level of OPG is diminished in patients with PHPT and increases with successful parathyroidectomy. We also speculated that serum OPG may determine the magnitude of bone loss up to the time of surgery. In the present study, 20 patients (17 women and 3 men, mean age 62 y) with PHPT who were candidates for surgical cure were examined before and 12 months after surgery. Bone turnover markers decreased and BMD increased significantly after surgery. Serum OPG did not correlate with PTH before surgery (r = 0.07, P = 0.77) and was not affected by parathyroidectomy (P = 0.79). After normalization of PTH, bone formation markers showed significant (P1NP) and near-significant (osteocalcin) correlations with serum OPG. In conclusion, serum OPG is not decreased in patients with PHPT, nor is serum OPG to any demonstrable extent regulated by PTH pre- or postoperatively.     

Plasma osteoprotegerin, arterial stiffness, and mortality in normoalbuminemic Japanese hemodialysis patients

Summary  

A high circulating osteoprotegerin (OPG) level may be a risk factor for vascular calcification and mortality in hemodialysis patients. OPG and pulse wave velocity (PWV) were measured at baseline in 151 normoalbuminemic, long-term (>3 years) Japanese hemodialysis patients who were prospectively followed for 6 years. In long-term normoalbuminemic Japanese hemodialysis patients, OPG levels were strongly linked with both arterial stiffness and worse outcome.     

Imbalance of the osteoprotegerin/RANKL ratio in bone marrow microenvironment after allogeneic hemopoietic stem cell transplantation

BACKGROUND: Bone loss is a common complication after allogeneic stem cell transplantation. Osteoprotegerin (OPG) plays a critical role in bone remodeling by neutralizing the effect of receptor activator of nuclear factor-kappaB ligand (RANKL) on differentiation and activation of osteoclasts. We investigated OPG and RANKL in serum and marrow plasma in transplanted patients. MATERIALS AND METHODS: In 36 patients and 36 controls, the relationships among bone mineral density, circulating OPG, RANKL, interferon-gamma, and interleukin-6 levels were investigated; in addition, OPG and RANKL were measured in marrow plasma and in conditioned medium of long-term cultures of marrow mesenchymal-derived osteogenic cells. RESULTS: Lumbar and femoral bone mineral density were lower in patients than in controls (P<0.01). Serum OPG (sOPG) and interferon-gamma were significantly higher in patients than in controls (P<0.05). Patients' interferon-gamma correlated with sOPG levels (r=0.4; P=0.03). Interleukin-6 did not differ between patients and controls. By contrast, OPG levels were lower in patients than in controls in marrow plasma (P<0.001) and in conditioned media after one (P=0.035) and three months (P=0.003) of culture of marrow mesenchymal-derived osteogenic cells. RANKL was similar in patients and controls. The OPG/RANKL ratio "in situ" was significantly lower in patients than in controls (P<0.05). There was no correlation between sOPG and marrow OPG, RANKL levels, densitometric values, and chronic graft-versus-host disease. CONCLUSION: Our findings suggest that after allogeneic stem cell transplantation: 1) sOPG bear no relationship with OPG in the bone marrow; 2) increased sOPG can be the result of its enhanced production in extra bone tissues triggered by inflammatory cytokines; 3) low bone marrow OPG levels may be partly related to the persistent quantitative and qualitative deficit of osteoblastic precursors; and 4) reduced OPG/RANKL ratio in bone microenvironment may increase bone remodeling by promoting bone resorption.     

Juvenile Paget's disease: the second reported, oldest patient is homozygous for the TNFRSF11B "Balkan" mutation (966_969delTGACinsCTT), which elevates circulating immunoreactive osteoprotegerin levels.

The oldest person (60 yr) with juvenile Paget's disease is homozygous for the TNFRSF11B mutation 966_969delTGACinsCTT. Elevated circulating levels of immunoreactive OPG and soluble RANKL accompany this genetic defect that truncates the OPG monomer, preventing formation of OPG homodimers. INTRODUCTION: Juvenile Paget's disease (JPD), a rare autosomal recessive disorder, features skeletal pain, fracture, and deformity from extremely rapid bone turnover. Deafness and sometimes retinopathy also occur. Most patients have diminished osteoprotegerin (OPG) inhibition of osteoclastogenesis caused by homozygous loss-of-function defects in TNFRSF11B, the gene that encodes OPG. Circulating immunoreactive OPG (iOPG) is undetectable with complete deletion of TNFRSF11B but normal with a 3-bp in-frame deletion. MATERIALS AND METHODS: We summarize the clinical course of a 60-yr-old Greek man who is the second reported, oldest JPD patient, including his response to two decades of bisphosphonate therapy. Mutation analysis involved sequencing all exons and adjacent mRNA splice sites of TNFRSF11B. Over the past 4 yr, we used ELISAs to quantitate his serum iOPG and soluble RANKL (sRANKL) levels. RESULTS: Our patient suffered progressive deafness and became legally blind, although elevated markers of bone turnover have been normal for 6 yr. He carries the same homozygous mutation in TNFRSF11B (966_969delTGACinsCTT) reported in a seemingly unrelated Greek boy and Croatian man who also have relatively mild JPD. This frame-shift deletes 79 carboxyterminal amino acids from the OPG monomer, including a cysteine residue necessary for homodimerization. Nevertheless, serum iOPG and sRANKL levels are persistently elevated. CONCLUSIONS: Homozygosity for the TNFRSF11B "Balkan" mutation (966_969delTGACinsCTT) causes JPD in the second reported, oldest patient. Elevated circulating iOPG and sRANKL levels complement evidence that this deletion/insertion omits a cysteine residue at the carboxyterminus needed for OPG homodimerization.     

Immunological characterization of circulating osteoprotegerin/osteoclastogenesis inhibitory factor: increased serum concentrations in postmenopausal women with osteoporosis.

Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) is a soluble member of the tumor necrosis factor receptor family of proteins and plays an important role in the negative regulation of osteoclastic bone resorption. Whether OPG/OCIF circulates in human blood and how its level changes under pathological conditions is not known. To address these issues, a panel of monoclonal antibodies was generated against recombinant OPG/OCIF and screened for reactivity with solid-phase monomeric and homodimeric forms of the recombinant protein. Antibodies that showed high affinity for both forms of OPG/OCIF and those that selectively recognized the homodimer were identified, enabling development of two types of sensitive enzyme-linked immunosorbent assay (ELISA): one that detects both forms of OPG/OCIF equally and one specific for the homodimer. Characterization of circulating OPG/OCIF with these ELISAs revealed that the protein exists in human serum mainly in the monomeric form. The serum concentration of OPG/OCIF increased with age in both healthy Japanese men and women, and was significantly higher in postmenopausal women with osteoporosis than in age-matched controls. Within the osteoporotic group, serum OPG/OCIF concentrations were higher in patients with low bone mass. Serum OPG/OCIF concentrations were also significantly increased in those postmenopausal women with a high rate of bone turnover, as determined by increased serum bone-specific alkaline phosphatase and urinary excretion of pyridinoline and deoxypyridinoline. The results suggested that circulating OPG/OCIF levels are regulated by an age-related factor(s) and that the increased serum concentration may reflect a compensative response to enhanced osteoclastic bone resorption and the resultant bone loss rather than a cause of osteoporosis.     

Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis.

BACKGROUND: Osteoporosis is a well known side-effect of long-term treatment with glucocorticoids. However, the precise mechanism of this disorder is unclear. Recently, osteoprotegerin (OPG) [osteoclastogenesis inhibitory factor (OCIF)] has been identified as a novel cytokine, which inhibits differentiation and activation of osteoclast. In the present study, in order to clarify the roles of OPG in the development of glucocorticoid-induced osteoporosis, we measured circulating OPG before and after glucocorticoid therapy. METHODS: The study subjects were 12 patients (five males, seven females, 53.4 +/- 4.8 [SE] years) with various renal diseases that required glucocorticoid therapy. All patients received glucocorticoids for the first time. Treatment was initiated at an average dose of 32.5 +/- 3.0 mg per day. Serum OPG was measured using enzyme-linked immunosorbent assay (ELISA). Laboratory data, markers of bone metabolism and circulating OPG were compared before and after treatment for 4 weeks. RESULTS: Serum OPG prior to glucocorticoid therapy was positively and independently correlated with serum creatinine. Serum OPG decreased significantly (P: < 0.0001) from 1.03 +/- 0.14 to 0.77 +/- 0.12 ng/ml after short-term administration of glucocorticoids. Furthermore, serum osteocalcin as a marker of bone formation was also reduced markedly (P: = 0.001). On the other hand, there were no remarkable changes in serum calcium, total alkaline phosphatases, creatinine and intact parathyroid hormone in response to glucocorticoid administration. CONCLUSION: These findings indicate that short-term administration of glucocorticoids significantly suppresses serum OPG and osteocalcin. It might participate in the development of glucocorticoid-induced osteoporosis via an enhancement of bone resorption and suppression of bone formation.     

High osteoprotegerin levels predict MACCE in STEMI patients,but are not associated with myocardial salvage

Objectives. High circulating levels of osteoprotegerin (OPG) carry prognostic impact in cohorts with various cardiovascular diagnoses. With the present study, we aim to investigate the role of OPG within the scale of myocardial damage. Design. This study includes 219 consecutive patients with acute ST-elevation myocardial infarction randomized to primary percutaneous coronary intervention (pPCI) or pPCI and remote ischemic per-conditioning. Salvage index via myocardial single-photon emission CT assessment (data available in 61% of the patients) was performed, and derived from Day 1 (myocardial area at risk) and Day 30 (final infarct size). Plasma OPG levels were measured using an in-house immunoassay. A combined end-point of all-mortality, myocardial infarction, stroke, readmission for heart failure and ischemic stroke/transient ischemic attack (Major Adverse Cardiac and Cerebrovascular Events [MACCE]) was used for follow-up; 45 (38–48 months). Results. High OPG levels were associated with the severity of cardiovascular disease. During follow-up, OPG was a predictor of MACCE (unadjusted, HR: 2.1, 95% CI: 1.14–3.85, P = 0.017). Adjustments for age, gender, and body mass index preserved the independent predictive power of OPG. However, OPG levels were neither associated with salvage index nor with the final infarct size. Remote ischemic per-conditioning had no effect on OPG levels. Conclusion. Despite absent association between OPG levels and the scale of myocardial damage, high OPG levels predict a significantly increased risk of MACCE.     

Osteoprotegerin and fractures in men and women with chronic kidney disease

Fractures are common in men and women with chronic kidney disease (CKD) but the best tool to identify those at high risk is unknown. Increased circulating osteoprotegerin (OPG) is associated with fractures in postmenopausal women. We determined if serum OPG was associated with prevalent fractures (self-reported low-trauma fractures since 40 years of age and/or prevalent vertebral fractures identified by radiographs) in men (n = 97) and women (n = 67) with stage 3–5 CKD. Analyses were performed unadjusted and adjusted for stage of CKD. Results are expressed as mean ± standard deviation (SD), and as odds ratio (OR) per SD increase in OPG with 95 % confidence intervals (CI). The mean age was 62.7 ± 16.3 years, and mean weight was 78.9 ± 18.7 kg. Compared to those without fractures, those with fractures (n = 55) were older (p < 0.01). Serum OPG increased as kidney function decreased, and OPG was higher in those with fractures compared to those without (9.42 ± 4.08 vs 8.06 ± 3.11 pmol/L, p = 0.02). After adjusting for stage of CKD, increased OPG was associated with an increased fracture risk (OR 1.13, 95 % CI 1.02–1.25); however, OPG did not discriminate fracture status well (area under the receiver operating characteristic curve 0.61, 95 % CI 0.52–0.70). OPG is associated with fractures in men and women with stage 3–5 CKD; however, the ability of OPG to discriminate fracture status is poor and cannot be used in isolation to assess fracture risk. Further studies should examine the ability of OPG in combination with other risk factors to better discriminate fracture status in men and women with CKD.     

Circulating amounts of osteoprotegerin and RANK ligand: genetic influence and relationship with BMD assessed in female twins

Osteoprotegerin (OPG) is a circulating receptor that inhibits osteoclastogenesis by binding to RANK ligand (RANKL). OPG knock-out animals develop severe osteoporosis. Treatment with OPG lowers bone resorption and increases BMD. OPG production is influenced by a wide range of hormones and cytokines. The influence of genetic factors on circulating amounts of OPG and RANKL is not known. BMD has been demonstrated to have a high heritability and there is evidence also that bone turnover and bone loss rates are controlled at least in part by genetic factors. OBJECTIVE: Assessing the genetic impact on serum OPG and RANKL in women and estimation of the relative contribution of this inheritance to the total heritability of BMD. METHODS: 188 female twins (52 DZ and 42 MZ pairs) from the Danish Twin Registry were included in the study. Mean age was 35 years (range 19-64 years), average spine BMD was 1.04 +/- 0.11 g/cm2. Serum levels of OPG and RANKL were measured by ELISA (Biomedica, Vienna, Austria). This register covers twins born in Denmark since 1870. Heritability and environmental influence was assessed using a maximum-likelihood model for genetic pleiotropy. RESULTS: RANKL levels showed a negative correlation with age and lower values in smokers. OPG levels were higher in postmenopausal women. Heritability (h(2)) was 85% for spine BMD and 52% for serum RANKL after adjustment for age, smoking and BMI. By contrast, there was no significant genetic influence on OPG levels (h(2) = 0, 95% CI: 0 to 0.31). Serum OPG was determined almost exclusively by individual environment (e(2) = 0.79), with a small, non-significant contribution from shared environment (c(2) = 0.21). Restricting analyses to the 158 premenopausal twins did not alter the findings. CONCLUSIONS: Serum OPG and RANKL levels have only a weak relation to BMD in healthy women. Phenotype correlations indicate that the genes that contribute to twin similarity for BMD are not genes regulating serum levels of RANKL or OPG. The weak correlation with BMD appears to consist in shared environmental factors.     

The haemodynamic response to submaximal exercise during isovolaemic haemodialysis.

Sir, We read with interest the article of Banerjee et al. on thehaemodynamic response to short intermittent submaximal exerciseduring haemodialysis [1]. The authors observed rapid haemoconcentrationduring intra-dialytic exercise. Since haemoconcentration isgenerally interpreted as a decrease of the circulating bloodvolume (BV), the authors express concern that exercise may compromisecardiovascular stability during haemodialysis. Although     

Correlates of Osteoprotegerin Levels in Women and Men

Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kB ligand (RANK-L). OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD). Thus, we measured serum OPG levels in an age-stratified, random sample of men (n= 346 age range, 23–90 years) and women (n= 304; age range 21–93 years) and related them to sex steroid levels, bone turnover markers and BMD. Serum OPG levels increased with age in both men (R= 0.39, p<0.001) and women (R= 0.18, p<0.01). Premenopausal women had higher OPG levels than men under age 50 years (171 ± 6 pg/ml vs 134 ± 6 pg/ml, respectively, p<0.001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 ± 7 pg/ml vs 188 ± 7 pg/ml, respectively, p= 0.179). OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R=–0.27, p<0.001), but no associations were present with either estrogen or testosterone levels in the women. In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD. Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro. Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss. Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency. Received: 14 August 2001 / Accepted: 20 November 2001     

Epithelial cell polarity and improved early outcomes in delayed graft function: a pilot study of polyclonal vs monoclonal antibodies

Background. Polyclonal antibody preparations contain antibodiesthat bind not only to molecules on circulating lymphocytes butalso to other sites that bear similar antigens. We hypothesizedthat this extra-antibody effect would increase the number ofintact tubular epithelial cells in organs at high risk for delayedgraft function (DGF). Methods. We used immunohistochemistry to examine serial biopsysamples (time 0 and 7–10 days after transplantation) in18 kidney transplant recipients with DGF. These individualsreceived either polyclonal rabbit antithymocyte sera or a monoclonalhumanized anti-CD25 antibody as induction immunosuppression.We also examined their early clinical course over 6 months. Results. Individuals treated with the polyclonal preparationdemonstrated greater preservation of kidney epithelial cellpolarity manifested by more intense and more localized basolateraldistribution of E-cadherin (P = 0.016), ß-catenin(P = 0.008) and Na-K ATPase (P = 0.02). These individuals werealso more likely to maintain greater estimated glomerular filtrationrates (eGFRs) at follow-up than patients treated with an anti-CD25monoclonal antibody (6 month eGFR polyclonal: 55.5±7.12ml/min vs monoclonal: 43.33±6.48 ml/min; P = 0.002). Conclusion. Though a pilot study, these data suggest that apurified polyclonal antibody preparation may help conserve functionalkidney mass during DGF with potential benefits on transplantfunction overall.     

The Peroxisome Proliferator-Activated Receptor-γ Agonist Rosiglitazone Increases Bone Resorption in Women with Type 2 Diabetes: A Randomized, Controlled Trial

In previous studies, with up to 16 weeks of exposure to rosiglitazone or pioglitazone, circulating markers of bone formation [procollagen I N-terminal propeptide (P1NP), osteocalcin, and bone-specific alkaline phosphatase] decreased but no change in bone resorption markers was found. We examined the effect of rosiglitazone on bone resorption and formation markers when used for 24 weeks. This post-hoc analysis of a double-blind, placebo-controlled, randomized trial evaluated the effects of 6 months of rosiglitazone use versus placebo on circulating markers of bone turnover in 111 patients with type 2 diabetes and cardiovascular disease or additional cardiac risk factors. The principal end points for analysis were changes in bone formation and resorption markers, measured by P1NP and carboxy-terminal cross-links (CTX), respectively. There were 111 subjects who completed the study and had baseline and 6-month data; mean age was 56, including 41% women and 67% nonwhite (50 black, 18 Hispanic, and six other), and subjects were evenly distributed between placebo and rosiglitazone groups. Women treated with rosiglitazone had higher CTX levels (0.43 ng/mL) than those who received placebo (0.23 ng/mL) (P = 0.007), with no significant differences in P1NP or OPG. Overall, in stratified analyses of men and in stratified analyses among different ethnicities, there were no statistically significant differences observed in CTX, P1NP, OPG, PTH, or 25-OHD between the treatment groups. Women taking rosiglitazone had higher circulating markers of bone resorption, which is contrary to prior studies of shorter duration, where the principal observation was a decrease in markers of bone formation.     

Apolipoprotein (a) levels and phenotypes in NIDDM patients with microalbuminuria and albuminuria

This study was conducted to determine whether circulating levelsof lipoprotein (a), an independent risk factor of macrovasculardisease, are increased in non-insulin-dependent diabetes mellitus(NIDDM) patients with microalbuminuria who have an increasedrisk of cardiovascular mortality. Apolipoprotein (a) [apo(a)levels and phenotypes, and other circulating lipid levels weredetermined in 227 Chinese NIDDM patients with varying stagesof diabetic nephropathy. None was on lipid-lowering therapy.Apo(a) levels in normoalbuminuric (geometric mean 166 U/L; 95%confidence intervals 137, 200; n = 105) and microalbuminuricpatients (162; 132, 209; n = 77) were similar to values in controls(166; 143, 193, n = 168). Albuminuric patients, however, hadhigher apo(a) levels than both normoalbuminuric patients andcontrols (242; 184, 317; n = 45; p <0.05). The overall sizerange of the apo(a) phenotypes and the frequency of having atleast one small isoform, i.e. <700 kDa, were similar amongthe four groups of subjects. A positive correlation was foundbetween log apo(a) and log plasma creatinine levels (p<0.01).Compared to normoalbuminuric patients, both microalbuminuricand albuminuric patients were older (p<0.01) and had higherHbA1c (p<0.01), greater BMI (p<0.05) and longer diseaseduration (p< 0.05) compared to normoalbuminuric patients.Nevertheless, using multiple linear regression analysis, itwas found that the presence of nephropathy conferred an independentinfluence on increasing total cholesterol (p<0.001), triglyceride(p< 0.001) and apoB (p<0.01), and decreasing HDL cholesterol(p<0.05) levels even when only the normoalbuminuric and microalbuminuricgroups were analysed. The prevalence of macrovascular diseasewas significantly increased in microalbuminuric and albuminuricpatients (45.1 and 48.7% respectively vs 20.2% in normoalbuminuricpatients, p<0.01). It is concluded that circulating apo(a)levels were not increased in Chinese NIDDM patients with microalbuminuria.However, atherogenic changes in other lipid and lipoproteinlevels may contribute to an increased risk of macrovasculardisease in these patients.