Inverse Association Between Serum Osteoprotegerin and Bone Mineral Density in Renal Transplant Recipients.

BACKGROUND: Osteoprotegerin (OPG) has pleiotropic effects on bone metabolism as well as endocrine function. Our aim was to evaluate the relationship between bone mineral density (BMD) and serum OPG concentration in renal transplant recipients. METHODS: Fasting blood samples were obtained from 69 renal transplant recipients. BMD was measured in lumbar vertebrae (L2-L4) by dual-energy X-ray absorptiometry. Eight patients (11.6%) had BMD values indicative of osteoporosis, 28 patients (40.6%) had BMD values indicative of osteopenia, and 33 patients had normal BMD values. Increased serum OPG levels (P < .001), decreased body mass index (BMI) (P = .033), and decreased body weight (P = .010) were significantly correlated with low lumbar T-score cut-off points between groups (normal, osteopenia, and osteoporosis). RESULTS: Women had significantly lower lumbar BMD values than men (P = .013). Menopause (P = .005), use of tacrolimus (P = .020), and use of cyclosporine (P = .046) were associated with lower lumbar BMD in renal transplant recipients. Univariate linear regression analysis revealed that lumbar BMD was positively correlated with height (P = .016), body weight (P = .001), and BMI (P = .015) and negatively correlated with age (P = .039) and log-OPG (P = .001). Multivariate linear regression analysis revealed that log-OPG (ß: -0.275, R(2) change = 0.154, P = .014), body weight (ß: 0.334, R(2) change = 0.073, P = .004), and age (ß: -0.285, R(2) change = 0.079, P = .008) were independent predictors of lumbar BMD values in renal transplant recipients. CONCLUSIONS: Serum OPG concentration correlated negatively with lumbar BMD values in renal transplant recipients.

Hyperleptinemia Is a Risk Factor for the Development of Central Arterial Stiffness in Kidney Transplant Patients.

BACKGROUND: Arterial stiffness could cause adverse outcomes in kidney transplant (KT) patients. Leptin has a role in influencing vascular smooth muscle that may contribute to atherosclerosis. The aim of this study was to evaluate the relationship between fasting serum leptin concentration and carotid-femoral pulse wave velocity (cfPWV) in KT patients. MATERIALS AND METHODS: Fasting blood samples were obtained from 55 KT patients and 65 subjects from the outpatient department were enrolled as the control group. The cfPWV values of >10 m/s were used to define as the high arterial stiffness group and <10 m/s as the low arterial stiffness group. The predictive ability of leptin for arterial stiffness of KT was assessed using receiver operating characteristic (ROC) curve and multivariate logistic regression analyses. RESULTS: Kidney transplant patients had lower hemoglobin, but higher blood urea nitrogen, creatinine, total cholesterol, diastolic blood pressure, intact parathyroid hormone levels, and leptin levels than controls. Although cfPWV levels were higher in KT patients, there is no difference of cfPWV levels between KT patients and control (P = .595). Fifteen KT patients (27.3%) were defined in the high arterial stiffness group, and serum leptin level was higher in the high arterial stiffness group compared with the low arterial stiffness group in KT patients (P < .001). Multivariate logistic regression analysis showed that leptin (odds ratio: 1.044, 95% confidence interval [CI]: 1.016-1.072, P = .002) was an independent predictor of arterial stiffness in KT patients. The sensitivity, specificity, positive predictive value, negative predictive value, and area under the ROC curve predicting arterial stiffness in KT patients were 73.33%, 87.5%, 68.7%, 89.7%, and 0.828 (95% CI: 0.703-0.917, P < .001), and the leptin cut-off value was 74.14 ng/mL. CONCLUSION: Serum fasting leptin level could predict the development of central arterial stiffness of KT patients.

N-terminal pro-B-type natriuretic peptide is inversely related to bone mineral density in renal transplant recipients.

INTRODUCTION: Bone mineral density (BMD) was significantly lower in heart failure patients. Our aim was to evaluate the relationship between BMD and fasting serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration in renal transplant recipients. METHODS: Fasting blood samples were obtained from 69 renal transplant recipients. BMD was measured by dual energy x-ray absorptiometry in lumbar vertebrae (L2-L4). Serum NT-proBNP levels were measured by electrochemiluminescence immunoassay. RESULTS: Among the renal transplant recipients, 8 patients (11.6%) had osteoporosis and 28 (40.6%) had osteopenia; 33 had a normal BMD. Increased serum NT-proBNP (P < .001) and decreased body mass index (P = .033) and body weight (P = .010) were significantly correlated with low lumbar T-score cutoff points between groups (normal, osteopenia, and osteoporosis). Women had lower lumbar BMD than did men (P = .013). Menopause in women (P = .005), use of tacrolimus (P = .020), and use of cyclosporine (P = .046) among renal transplant recipients were associated with lower lumbar BMD. Multivariate forward stepwise linear regression analysis of the significant variables revealed that log-transformed NT-proBNP (ß, -0.545; R(2) = 0.331; P < .001), and body weight (ß, 0.273, R(2) = 0.104; P = .005) were independent predictors of lumbar BMD values among the renal transplant recipients. CONCLUSIONS: Serum NT-proBNP concentrations correlate negatively with lumbar BMD values among renal transplant recipients and may be an alternative to energy x-ray absorptiometry for identifying at risk of osteoporosis in renal transplant recipients.

Serum leptin levels positively correlate with peripheral arterial stiffness in kidney transplantation patients.

BACKGROUND: Leptin is a protein predominantly produced by adipocytes that plays a pathophysiologic role in the pathogenesis of hypertension and cardiovascular diseases. The aim of this study was to evaluate the relationship between fasting serum leptin levels and peripheral arterial stiffness among kidney transplant (KT) patients. METHODS: Fasting blood samples were obtained from 74 KT patients. Brachial-ankle pulse wave velocity (baPWV) was measured in the right or left brachial artery to the ankle segments using an automatic pulse wave analyzer (VaSera VS-1000). Plasma leptin levels were measured using a commercial enzyme-linked immunosorbent assay kit. In this study, left or right baPWV values of less than 14.0 m/s were used to define the high arterial stiffness group. RESULTS: Forty KT patients (54.1%) were defined in high arterial stiffness group. Hypertension (P < .010), diabetes (P < .010), age (P = .010), KT duration (P = .013), triglyceride levels (P = .016), systolic blood pressure (P < .001), waist circumference (P = .031), and leptin level (P < .001) were higher, whereas serum high-density lipoprotein cholesterol level (P = .030) was lower in the high arterial stiffness group compared with the low arterial stiffness group. Multivariate logistic regression analysis showed that leptin (odds ratio, 1.033; 95% CI, 1.004-1.062; P = .023), KT duration (odds ratio, 1.023; 95% CI, 1.004-1.044; P = .020), and high-density lipoprotein cholesterol level (odds ratio, 0.925; 95% CI, 0.872-0.982; P = .010) were the independent predictors of peripheral arterial stiffness in KT patients. CONCLUSIONS: Serum fasting leptin level was positively associated with peripheral arterial stiffness among KT patients.

Fasting long-acting natriuretic peptide correlates inversely with metabolic syndrome in kidney transplant patients.

The metabolic syndrome (MetS) is a risk factor for posttransplant diabetes mellitus, chronic graft dysfunction, graft loss, occurrence of atherosclerotic events, and patient death among kidney transplantation patients. Long-acting natriuretic peptide (LANP) is among the peptide hormones in atrial natriuretic peptide prohormone. Low levels of natriuretic peptide may lead to reduced lipolysis and excessive weight gain in obese patients. This study was undertaken to evaluate the relationship between MetS and fasting serum LANP concentration among kidney transplanted patients. Fasting blood samples were obtained from 69 kidney recipients. The MetS and its components were defined using the diagnostic criteria of the International Diabetes Federation. Fasting LANP levels were measured using a commercial enzyme immunoassay kit. The prevalence rate of MetS was 20.3% (14/69). Fasting LANP level negatively correlated with MetS among these patients (P = .010). Using univariate linear regression analysis, serum LANP values were negatively correlated with hemoglobin (r = -0.252; P = .037), and positively correlated with blood urea nitrogen (r = 0.254; P = .035) and creatinine (r = 0.311; P = .009). Multivariate forward stepwise linear regression analysis of the significant variables revealed that creatinine (R(2) change = 0.097; P = .009) was an independent predictor of fasting serum LANP concentration among kidney transplanted patients. Serum LANP concentration correlates inversely with MetS; for these patients, creatinine is an independent predictor of the serum LANP value.

Influence of Alzheimer pathology on clinical diagnostic accuracy in dementia with Lewy bodies.

OBJECTIVE: To determine whether AD neurofibrillary pathology influences clinical diagnostic accuracy in dementia with Lewy bodies (DLB). BACKGROUND: Pathologic diagnosis of DLB mandates Lewy bodies but also allows for AD pathology in the form of plaques and tangles. Because clinical diagnostic accuracy of DLB remains low, the authors questioned whether the severity of AD pathology in the form of tangles might affect the clinician's ability to correctly diagnose DLB in life. DESIGN/METHODS: Ninety-eight subjects with autopsy-proven DLB who had been evaluated annually at the University of California San Diego AD Research Center were identified. The clinical diagnosis used was the last diagnosis before death. Pathologic diagnosis of DLB was made according to Consensus guidelines, and Braak staging was used to assess the degree of neurofibrillary AD pathology. The clinical characteristics of subjects with DLB with low vs high Braak stages were compared and the clinical diagnostic accuracy for subjects stratified according to Braak stage was determined. RESULTS: Only 27% of the subjects with DLB demonstrated both visual hallucinations and spontaneous extrapyramidal signs (EPS). The low Braak stage (0 to 2, n = 24) subjects had a higher frequency of visual hallucinations (65%) than did subjects with DLB with higher (3 to 6, n = 66) Braak stages (33%, p = 0.008), and showed a slightly greater but not significant degree of EPS. Although clinical diagnostic accuracy for DLB was relatively low (49%), it was higher for subjects with low (75%) compared to high (39%) Braak stages (p = 0.0039). CONCLUSIONS: The degree of concomitant AD tangle pathology has an important influence on the clinical characteristics and, therefore, the clinical diagnostic accuracy of DLB.

Cognitive profiles differ in autopsy-confirmed frontotemporal dementia and AD.

BACKGROUND: Frontotemporal dementia (FTD) is currently distinguished from AD primarily on the basis of behavioral features because studies of cognition have shown negligible or inconsistent differences. However, the poor discriminability of cognitive measures may relate to reliance on imprecise clinically diagnosed groups. Therefore, a retrospective examination of neuropsychological test performance in autopsy-confirmed patients is warranted. OBJECTIVE: To compare the pattern of cognitive deficits exhibited by patients with autopsy-confirmed FTD and AD. METHODS: The profiles of cognitive deficits exhibited by patients with neuropathologic diagnosis of FTD (n = 14) or AD (n = 28) were compared. The Mattis Dementia Rating Scale (MDRS), letter and category fluency tests, Wechsler Intelligence Scale for Children-Revised block design test, Boston naming test, and clock drawing test were administered. RESULTS: Multivariate analysis of covariance controlling for age, education, and level of dementia revealed that patients with FTD performed significantly worse than patients with AD on letter and category fluency tests but significantly better on the MDRS memory subscale, block design test, and clock drawing test. A logistic regression model, validated in an independent clinical sample, used letter fluency, MDRS memory, and block design scores to correctly classify 91% of AD patients and 77% of FTD patients. CONCLUSIONS: A double dissociation in the pattern of cognitive deficits exhibited by FTD and AD patients was demonstrated. The FTD patients were more impaired than AD patients on word generation tasks (i.e., verbal fluency) that are sensitive to frontal lobe dysfunction but less impaired on tests of memory and visuospatial abilities sensitive to dysfunction of medial temporal and parietal association cortices.

Insulin-like growth factor binding protein-1 is pre-synaptic at mouse neuromuscular synapses and is transported in nerve.

In a previous study, we localized insulin-like growth factor binding protein 1 (IGFBP-1) to mouse neuromuscular junctions, and intramuscular nerves. To determine if pre-synaptic accumulation of IGFBP-1 occurred, we used double ligation of sciatic nerve in adult mice at different time points. IGFBPs were detected by Western ligand blot (WLB) with 125I-IGF-I. WLB and Western immunoblot (WIB) analysis of extracts from double-ligated nerves showed a delayed (6 days) increase of IGFBP-1 in the soluble fraction between the ligatures and distal to the distal ligature. For comparison we evaluated transport of neurofilament components, using WIB and confirmed the primarily anterograde transport of these intraaxonal proteins. These data suggest that expression of IGFBP-1 is both by activated Schwann cells as well as retrograde axonal transport with likely entry into the axon at the synapse.

Insulin-like growth factor binding protein-1 at mouse neuromuscular synapses.

The insulin-like growth factor (IGF) signaling system includes the growth factors and their cell surface receptors, along with circulating IGF binding proteins (IGFBPs) that may alter and modulate the action of these neurotrophic hormones. These IGFBPs, along with IGFs and receptors, have been detected in various tissues including the brain. In this study, using polyclonal antibody to human IGFBP-1 or bovine IGFBP-2, we found that mouse muscle extracts contain similar-sized proteins that cross-react with these antibodies on Western immunoblots. After establishing that these antibodies reacted with the homologous murine IGFBPs, we performed immunocytochemistry to demonstrate the localization of IGFBP-1 at the neuromuscular junction, a model nicotinic, cholinergic synapse, as well as within intramuscular nerves. IGFBP-2, a distinct macromolecule, is present on the surface of muscle fibers and is not present within synapses or nerves.

Cross-linking of beta-amyloid protein precursor catalyzed by tissue transglutaminase.

Alzheimer's disease is characterized by progressive dementia, cortical atrophy with synaptic loss, and the accumulation of neurofibrillary tangles and senile plaques containing beta-amyloid. The beta-amyloid protein precursor (beta-APP), may normally be involved in cell adhesion related to synaptic maintenance. Loss of synapses correlates with dementia, suggesting that synaptic deficits may underlie the disease. Synapse stability may depend on the action of tissue transglutaminase (tTG), an enzyme capable of crosslinking large, multi-domain extracellular glycoproteins, that is active and present at synapses. We now show that beta-APP is a substrate for tTG in vitro that results in dimers and multimers by silver staining and immunoblotting. This novel post-translational modification suggests further roles for beta-APP in synaptic function as well as in Alzheimer's disease.

Extravascular proteolysis and the nervous system: serine protease/serpin balance.

Widely recognized as components of the blood coagulation cascade, serine proteases and their natural inhibitors, specific serpins known as the protease nexins, also regulate the maintenance of normal function in the nervous system. Increasingly, evidence has accumulated as to regulation of their synthesis and functional roles within both the CNS and peripheral nervous system. Our review focuses on the localization and activity of TH and PN I in the nervous system, as well as on the impact of the protease/inhibitor balance for the pathogenesis of neurodegenerative disorders such as AD.

Serine proteases and their serpin inhibitors in Alzheimer's disease.

Our article documents recent studies in the proteolytic processing of the Alzheimer's beta-amyloid protein precursor (beta-APP), as well as the role of thrombin and its potent inhibitor, protease nexin I in Alzheimer's disease (AD). Since synapse loss correlates best with cognitive decline in AD, we also present in detail, our model of synapse formation and elimination, reviewing recent findings related to the subject as well as our own original data. Recent exciting findings concerning the involvement of thrombin-like activity in synapse elimination, which we feel to be important in neural plasticity are also discussed.