Musculoskeletal Health Worsened from Carnitine Supplementation and Not Impacted by a Novel Individualized Treadmill Training Protocol.

INTRODUCTION: Chronic kidney disease (CKD) negatively affects musculoskeletal health, leading to reduced mobility, and quality of life. In healthy populations, carnitine supplementation and aerobic exercise have been reported to improve musculoskeletal health. However, there are inconclusive results regarding their effectiveness and safety in CKD. We hypothesized that carnitine supplementation and individualized treadmill exercise would improve musculoskeletal health in CKD. METHODS: We used a spontaneously progressive CKD rat model (Cy/+ rat) (n = 11-12/gr): (1) Cy/+ (CKD-Ctrl), (2) CKD-carnitine (CKD-Carn), and (3) CKD-treadmill (CKD-TM). Carnitine (250 mg/kg) was injected daily for 10 weeks. Rats in the treadmill group ran 4 days/week on a 5° incline for 10 weeks progressing from 30 min/day for week one to 40 min/day for week two to 50 min/day for the remaining 8 weeks. At 32 weeks of age, we assessed overall cardiopulmonary fitness, muscle function, bone histology and architecture, and kidney function. Data were analyzed by one-way ANOVA with Tukey's multiple comparisons tests. RESULTS: Moderate to severe CKD was confirmed by biochemistries for blood urea nitrogen (mean 43 ± 5 mg/dL CKD-Ctrl), phosphorus (mean 8 ± 1 mg/dL CKD-Ctrl), parathyroid hormone (PTH; mean 625 ± 185 pg/mL CKD-Ctrl), and serum creatinine (mean 1.1 ± 0.2 mg/mL CKD-Ctrl). Carnitine worsened phosphorous (mean 11 ± 3 mg/dL CKD-Carn; p < 0.0001), PTH (mean 1,738 ± 1,233 pg/mL CKD-Carn; p < 0.0001), creatinine (mean 1 ± 0.3 mg/dL CKD-Carn; p < 0.0001), cortical bone thickness (mean 0.5 ± 0.1 mm CKD-Ctrl, 0.4 ± 0.1 mm CKD-Carn; p < 0.05). Treadmill running significantly improves maximal aerobic capacity when compared to CKD-Ctrl (mean 14 ± 2 min CKD-TM, 10 ± 2 min CKD-Ctrl; p < 0.01). CONCLUSION: Carnitine supplementation worsened CKD progression, mineral metabolism biochemistries, and cortical porosity and did not have an impact on physical function. Individualized treadmill running improved maximal aerobic capacity but did not have an impact on CKD progression or bone properties. Future studies should seek to better understand carnitine doses in conditions of compromised renal function to prevent toxicity which may result from elevated carnitine levels and to optimize exercise prescriptions for musculoskeletal health.

Effects of ferric citrate and intravenous iron sucrose on markers of mineral, bone, and iron homeostasis in a rat model of CKD-MBD.

BACKGROUND: Anemia and chronic kidney disease-mineral and bone disorder (CKD-MBD) are common and begin early in CKD. Limited studies have concurrently compared the effects of ferric citrate (FC) versus intravenous (IV) iron on CKD-MBD and iron homeostasis in moderate CKD. METHODS: We tested the effects of 10 weeks of 2% FC versus IV iron sucrose in rats with moderate CKD (Cy/+ male rat) and untreated normal (NL) littermates. Outcomes included a comprehensive assessment of CKD-MBD, iron homeostasis and oxidative stress. RESULTS: CKD rats had azotemia, elevated phosphorus, parathyroid hormone and fibroblast growth factor-23 (FGF23). Compared with untreated CKD rats, treatment with FC led to lower plasma phosphorus, intact FGF23 and a trend (P = 0.07) toward lower C-terminal FGF23. FC and IV iron equally reduced aorta and heart calcifications to levels similar to NL animals. Compared with NL animals, CKD animals had higher bone turnover, lower trabecular volume and no difference in mineralization; these were unaffected by either iron treatment. Rats treated with IV iron had cortical and bone mechanical properties similar to NL animals. FC increased the transferrin saturation rate compared with untreated CKD and NL rats. Neither iron treatment increased oxidative stress above that of untreated CKD. CONCLUSIONS: Oral FC improved phosphorus homeostasis, some iron-related parameters and the production and cleavage of FGF23. The intermittent effect of low-dose IV iron sucrose on cardiovascular calcification and bone should be further explored in moderate-advanced CKD.

Reversing cortical porosity: Cortical pore infilling in preclinical models of chronic kidney disease.

PURPOSE: Chronic kidney disease (CKD) patients have a high incidence of fracture due in part to cortical porosity. The goal of this study was to study cortical pore infilling utilizing two rodent models of progressive CKD. METHODS: Exp 1: Female C57Bl/6J mice (16-week-old) were given dietary adenine (0.2%) to induce CKD for 10 weeks after which calcium water supplementation (Ca-H2O; 1.5% and 3%) was given to suppress PTH for another 4 weeks. Exp 2: Male Cy/+ rats were aged to ~30 weeks with baseline porosity assessed using in vivo µCT. A second in vivo scan followed 5-weeks of Ca-H2O (3%) supplementation. RESULTS: Exp 1: Untreated adenine mice had elevated blood urea nitrogen (BUN), parathyroid hormone (PTH), and cortical porosity (~2.6% porosity) while Ca-H2O lowered PTH and cortical porosity (0.5-0.8% porosity). Exp 2: Male Cy/+ rats at baseline had variable porosity (0.5%-10%), but after PTH suppression via Ca-H2O, cortical porosity in all rats was lower than 0.5%. Individual pore dynamics measured via a custom MATLAB code demonstrated that 85% of pores infilled while 12% contracted in size. CONCLUSION: Ca-H2O supplementation causes net cortical pore infilling over time and imparted mechanical benefits. While calcium supplementation is not a viable clinical treatment for CKD, these data demonstrate pore infilling is possible and further research is required to examine clinically relevant therapeutics that may cause net pore infilling in CKD.

Kidney Disease Progression Does Not Decrease Intestinal Phosphorus Absorption in a Rat Model of Chronic Kidney Disease-Mineral Bone Disorder.

The Cy/+ rat has been characterized as a progressive model of chronic kidney disease-mineral bone disorder (CKD-MBD). We aimed to determine the effect of kidney disease progression on intestinal phosphorus absorption and whole-body phosphorus balance in this model. A total of 48 Cy/+ (CKD) and 48 normal littermates (NL) rats were studied at two ages: 20 weeks and 30 weeks, to model progressive kidney function decline at approximately 50% and 20% of normal kidney function. Sodium-dependent and sodium-independent intestinal phosphorus absorption efficiency were measured by the in situ jejunal ligated loop method using 33 P radioisotope. Our results show that CKD rats had slightly higher sodium-dependent phosphorus absorption compared to NL rats, and absorption decreased from 20 to 30 weeks. These results are in contrast to plasma 1,25OH2 D, which was lower in CKD rats. Gene expression of the major intestinal phosphorus transporter, NaPi-2b, was not different between CKD and NL rats in the jejunum but was lower in CKD rats versus NL rats in the duodenum. Jejunal ligated loop phosphorus absorption results are consistent with percent net phosphorus absorption results obtained from metabolic balance: higher net percent phosphorus absorption values in CKD rats compared with NL, and lower values in 30-week-olds compared with 20-week-olds. Phosphorus balance was negative (below zero) in CKD rats, significantly lower in 30-week-old rats compared with 20-week-old rats, and lower in CKD rats compared with NL rats at both ages. These results demonstrate no reduction in intestinal phosphorus absorption with progression of CKD despite lower 1,25OH2 D status when assessed by an in situ ligated loop test, which is in contrast to the majority of in vitro studies, and if confirmed in further studies, could challenge the physiological relevance of in vitro findings. © 2019 American Society for Bone and Mineral Research.

Effect of Advanced Glycation End-Products (AGE) Lowering Drug ALT-711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKD-MBD.

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification, and bone. We hypothesized that the accumulation of advanced glycation end-products (AGEs) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKD-MBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALT-711), or with calcium in the drinking water to mimic calcium phosphate binders for 10 weeks. These animals were compared to normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated blood urea nitrogen (BUN), PTH, FGF23 and phosphorus. Treatment with ALT-711 had no effect on kidney function or PTH, but 3 mg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALT-711, with parallel decreases in left ventricular hypertrophy. ALT-711 (3 mg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3 mg/kg ALT-711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKD-MBD with an AGE breaker ALT-711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALT-711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKD-MBD. © 2019 American Society for Bone and Mineral Research.

Skeletal levels of bisphosphonate in the setting of chronic kidney disease are independent of remodeling rate and lower with fractionated dosing.

BACKGROUND: Chronic kidney disease (CKD) results in a dramatic increase in skeletal fracture risk. Bisphosphates (BP) are an effective treatment for reducing fracture risk but they are not recommended in advanced CKD. We have recently shown higher acute skeletal accumulation of fluorescently-tagged zoledronate (ZOL) in the setting of CKD but how this accumulation is retained/lost over time is unclear. Furthermore, it is unknown if alternative dosing approaches can modulate accumulation in the setting of CKD. METHODS: To address these two questions normal (NL) and Cy/+ (CKD) rats were divided into control groups (no dosing), a single dose of a fluorescent-tagged ZOL (FAM-ZOL), a single dose of non-labelled zoledronate (ZOL) or ten weekly doses of FAM-ZOL each at 1/10th the dose of the single dose group. Half of the CKD animals in each group were provided water with 3% calcium in drinking water (CKD + Ca) to suppress PTH and remodeling. At 30 or 35 weeks of age, serum, tibia, ulna, radius, vertebra, femora, and mandible were collected and subjected to assessment methods including biochemistry, dynamic histomorphometry and multi-spectral fluorescence levels (using IVIS SpectrumCT). RESULTS: FAM-ZOL did not significantly reduce bone remodeling in either NL or CKD animals while Ca supplementation in CKD produced remodeling levels comparable to NL. At five- and ten-weeks post-dosing, both CKD and CKD + Ca groups had higher levels of FAM-ZOL in most, but not all, skeletal sites compared to NL with no difference between the two CKD groups suggesting that the rate of remodeling did not affect skeletal retention of FAM-ZOL. Fractionating the FAM-ZOL into ten weekly doses led to 20-32% less (p < 0.05) accumulation/retention of compound in the vertebra, radius, and ulna compared to administration as a single dose. CONCLUSIONS: The rate of bone turnover does not have significant effects on levels of FAM-ZOL accumulation/retention in animals with CKD. A lower dose/more frequent administration paradigm results in lower levels of accumulation/retention over time. These data provide information that could better inform the use of bisphosphonates in the setting of CKD in order to combat the dramatic increase in fracture risk.

What Role Does Positive Psychology Play in Understanding Pain Intensity and Disability Among Patients with Hand and Upper Extremity Conditions?

BACKGROUND: A large body of research shows that psychologic distress and ineffective coping strategies substantially contribute to more severe pain and increased physical limitations among patients with orthopaedic disorders. However, little is known about the relationship between positive psychology (constructs that enable individuals to thrive and adapt to challenges) and pain and physical limitations in this population. QUESTIONS/PURPOSES: (1) Which positive-psychology factors (satisfaction with life, gratitude, coping through humor, resilience, mindfulness, and optimism) are independently associated with fewer upper-extremity physical limitations after controlling for the other clinical and demographic variables? (2) Which positive-psychology factors are independently associated with pain intensity after controlling for relevant clinical and demographic variables? METHODS: In a cross-sectional study, we recruited patients presenting for a scheduled appointment with an orthopaedic surgeon at a hand and upper-extremity clinic of a major urban academic medical center. Of 125 approached patients, 119 (44% men; mean age, 50 ± 17 years) met screening criteria and agreed to participate. Patients completed a clinical and demographic questionnaire, the Numerical Rating Scale to assess pain intensity, the Patient-reported Outcomes Measurement Information System (PROMIS) Upper Extremity Physical Function computerized adaptive test to assess physical limitations, and six measures assessing positive-psychology constructs: The Satisfaction with Life Scale, the Gratitude Questionnaire, the Coping Humor Scale, the Brief Resilience Scale, the Cognitive and Affective Mindfulness Scale-Revised, and the Life Orientation Test-Revised. We first examined bivariate associations among physical limitations, pain intensity, and all positive-psychology factors as well as demographic and clinical variables. All variables that demonstrated associations with physical limitations or pain intensity at p < 0.05 were included in two-stage multivariable hierarchical regression models. RESULTS: After controlling for the potentially confounding effects of prior surgical treatment and duration since pain onset (step1; R total = 0.306; F[7,103] = 6.50), the positive-psychology variables together explained an additional 15% (R change = 0.145, F change [5, 103] = 4.297, p = 0.001) of the variance in physical limitations. Among the positive-psychology variables tested, mindfulness was the only one associated with fewer physical limitations (ß = 0.228, t = 2.293, p = 0.024, 4% variance explained). No confounding demographic or clinical variables were found for pain intensity in bivariate analyses. All positive-psychology variables together explained 23% of the variance in pain intensity (R = 0.23; F[5,106] = 6.38, p < 0.001). Among the positive-psychology variables, satisfaction with life was the sole factor independently associated with higher intensity (ß = -0.237, t = -2.16, p = 0.033, 3% variance explained). CONCLUSIONS: Positive-psychology variables explained 15% of the variance in physical limitations and for 23% of the variance in pain intensity among patients with heterogenous upper extremity disorders within a hand and upper extremity practice. Of all positive-psychology factors, mindfulness and satisfaction with life were most important for physical limitations and pain intensity, respectively. As positive-psychology factors are more easily modifiable through skills-based interventions than pain and physical limitations, results suggest implementation of such interventions to potentially improve outcomes in this population. Skills-based interventions targeting mindfulness and satisfaction with life may be of particular benefit. LEVEL OF EVIDENCE: Level II, prognostic study.

Satisfaction with life moderates the indirect effect of pain intensity on pain interference through pain catastrophizing.

OBJECTIVE: Satisfaction with life buffers the effect of stress on health, but its role in the mechanism through which pain may impact engagement in activities of daily living is not known. We tested whether satisfaction with life protects against engaging in pain catastrophizing and through this explains individual differences in the extent to which pain interferes with activities of daily living. METHOD: One-hundred and 42 patients with upper extremity musculoskeletal illness participated in this cross-sectional study and completed the PROMIS pain intensity, PROMIS pain interference, pain catastrophizing scale (PCS), satisfaction with life scale (SWLS), and demographic variables. RESULTS: A simple mediation model confirmed that the indirect effect of pain intensity on pain interference through PCS was 35.9% of the total effect. A moderated mediation analysis showed that the indirect effect of pain intensity on pain interference through PCS was differentially moderated by SWLS after controlling for relevant covariates. As satisfaction with life increased from low to moderate to high, a smaller proportion of the effect of pain intensity on pain interference (41.6%, 26.1%, and 10.5%) was carried through PCS, such that at the highest satisfaction with life, the indirect effect becomes completely nonsignificant. CONCLUSIONS: Satisfaction with life appears to buffer the effect of pain in individuals with upper extremity musculoskeletal illness. If replicated through longitudinal designs, results suggest that clinical interventions focused on increasing satisfaction with life, such as acceptance and commitment therapy, mindfulness training, gratitude, and other positive psychology skills, may improve outcomes in this population. (PsycINFO Database Record

Does a Brief Mindfulness Exercise Improve Outcomes in Upper Extremity Patients? A Randomized Controlled Trial.

BACKGROUND: Mindfulness-based interventions are useful in reducing psychologic distress and pain intensity in patients with chronic pain. However, most mindfulness-based interventions are resource-intensive, lengthy, and not feasible for busy orthopaedic surgical practices. QUESTIONS/PURPOSES: The purpose of this study was to determine if a 60-second personalized mindfulness-based video exercise is (1) associated with improved pain intensity, emotional distress, and state anxiety compared with an attention placebo control (a time-matched educational pamphlet about pain and stress); and (2) feasible and acceptable for patients with upper extremity injury in an orthopaedic practice. METHODS: This was a single-center, single-blind randomized controlled trial of the mindfulness-based video exercise (60 seconds duration, free online) versus an attention placebo control (an educational pamphlet about pain and stress presented to patients to read over 60 seconds). One hundred forty-nine patients presenting for a new or followup appointment at the office of one of two orthopaedic hand and upper extremity outpatient surgical practices at an urban academic hospital were invited to participate between September 2016 and December 2016. Of 149 patients screened, 125 patients were randomized and completed a demographic questionnaire, the Numeric Rating Scale to assess pain intensity, the State Anxiety subscale of the State Trait Anxiety Inventory to assess state anxiety, and Emotion Thermometers to assess anxiety, anger, and depression before and after the interventions. Postintervention, patients also completed the Client Satisfaction Questionnaire Scale-3 to assess the acceptability. A mean score of 21 or higher is considered acceptable. Feasibility was determined based on number of patients approached who refused participation. The intervention was defined as feasible if refusal rate was lower than 25%. Analysis of covariance was used to test comparative improved pain intensity on the NRS, psychologic distress on the Emotion Thermometers, and state anxiety on the State Anxiety Subscale of the State Trait Anxiety Index after controlling for respective baseline scores. A 1-point minimal clinically important difference (MCID) was used on the NRS for pain intensity. RESULTS: Adjusted for the baseline means, compared with patients who received the attention placebo control, patients who participated in the mindfulness-based video exercise demonstrated improved pain intensity (mindfulness-based video exercise: 3.03 ± 0.12; control: 3.49 ± 0.12; mean difference: 0.46 [0.12-0.80]; p = 0.008); state anxiety (mindfulness-based video exercise: 32.35 ± 0.59; control: 35.29 ± 0.59; mean difference: 2.94 [1.29-4.59]; p = 0.001); anxiety symptoms (mindfulness-based video exercise: 1.49 ± 0.19; control: 2.10 ± 0.19; mean difference: 0.61 [0.08-1.14]; p = 0.024); depression (mindfulness-based video exercise: 1.03 ± 0.10; control: 1.47 ± 0.11; mean difference: 0.44 [0.15-0.73]; p = 0.004); and anger (mindfulness-based video exercise: 0.76 ± 0.12; control: 1.36 ± 0.12; mean difference: 0.60 [0.26-0.94]; p = 0.001). However, the observed differences in pain intensity were below 1 point on the NRS, which is the MCID established in patients with chronic pain. No MCID is available for the other measures. The mindfulness-based video exercise was feasible based on a dropout rate of 0%, and acceptability reached the medium range with similar scores in both groups (mindfulness-based video exercise: 20.70 ± 5.48; control: 20.52 ± 6.42). CONCLUSIONS: A 60-second mindfulness-based video exercise is feasible to implement and acceptable to patients in busy orthopaedic practices. This video exercise is also effective in improving momentary pain, anxiety, depression, and anger in this population, but it is unclear whether these improved pain and distress levels are meaningful to patients who present with low levels of pain and psychologic distress. Future studies should seek to discern whether the improved pain and distress levels we observed are clinically important or whether the intervention delivers larger effects in subgroups of patients experiencing greater pain intensity and if the improved pain and distress levels are durable. Such studies might also assess cost-effectiveness, because this mindfulness-based tool takes little time and few resources to use, and the effects and durability of multiple sessions of a mindfulness-based video exercise. LEVEL OF EVIDENCE: Level II, therapeutic study.

Does Mindfulness Correlate With Physical Function and Pain Intensity in Patients With Upper Extremity Illness?

BACKGROUND: Mindfulness skills training interventions seem efficacious in increasing physical function and decreasing pain intensity in patients with chronic pain. The relationship of mindfulness and upper extremity complaints in patients presenting to orthopedic surgical practices is not known. The aim of this study was to assess if mindfulness has a relationship to physical function and pain intensity in patients with upper extremity illness. METHODS: In this cross-sectional study, a total of 126 patients with a nontraumatic upper extremity condition were asked to fill out questionnaires assessing the 5 facets of mindfulness, pain intensity, and upper extremity physical function, along with clinical and demographic variables prior to their visit with the surgeon. RESULTS: Nonreactivity to inner experiences was the only facet of mindfulness that was correlated with upper extremity physical function and pain intensity. The overall mindfulness score was correlated with pain intensity only. In multivariable analyses, mindfulness was not associated with either physical function or with pain intensity. Pain interference was the most important predictor of both pain intensity and physical function. CONCLUSIONS: Greater overall mindfulness was associated with lower pain intensity, and greater ability to be nonreactive to inner experiences was associated with both pain intensity and upper extremity physical function in bivariate but not multivariable analyses. Pain interference was the most important predictor of both pain intensity and upper extremity physical function. Psychosocial interventions focused on improving physical function and decreasing pain intensity in this population should focus primarily on reducing pain interference, and secondarily on teaching patients mindfulness skills.

Calcimimetic inhibits late-stage cyst growth in ADPKD.

In polycystic kidney disease (PKD), genetic mutations in polycystin 1 and 2 lead to defective intracellular trafficking of calcium, thereby decreasing intracellular calcium and altering cAMP signaling to favor proliferation. We hypothesized that calcimimetics, allosteric modulators of the calcium-sensing receptor, would reduce cyst growth by increasing intracellular calcium. We randomly assigned 20-wk-old male rats with a form of autosomal dominant PKD (heterozygote Cy/+) to one of four groups for 14 to 18 wk of treatment: (group 1) no treatment; (group 2) calcimimetic R-568 formulated in the diet; (group 3) R-568 plus calcium-supplemented drinking water (R-568 plus Ca); or (group 4) Ca-supplemented drinking water with a normal diet (Ca). Severity of PKD did not progress in any of the three treatment groups between 34 and 38 wk. Compared with no treatment, cyst growth was unaffected at 34 wk by all treatments, but cyst volume and fibrosis were lower at 38 wk, with both R-568-treated groups demonstrating a greater reduction than calcium alone. Between 34 and 38 wk, the total kidney weight increased by 78% in the control group (P < 0.001) and by 19% in the Ca group (P < 0.01), but did not increase in the R-568 or R-568 plus Ca groups, suggesting inhibition of disease progression despite equivalent suppression of parathyroid hormone. In summary, treatment of hyperparathyroidism halts late-stage progression of rodent cystic kidney disease. The benefit of R-568 alone suggests calcium-sensing receptor modulation may have additional inhibitory effects on late-stage cyst growth resulting from a direct modulation of intracellular calcium.

A rat model of chronic kidney disease-mineral bone disorder.

Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) is a newly defined syndrome encompassing patients with chronic kidney disease that have a triad of biochemical alterations in calcium, phosphorus and parathyroid hormone, vascular calcification, and bone abnormalities. Here we describe a novel Cy/+ rat model of slowly progressive kidney disease spontaneously developing the three components of CKD-MBD when fed a normal phosphorus diet. Since the renal disorder progressed 'naturally' we studied the effect of dietary manipulation during the course of the disease. Animals with early, but established, chronic kidney disease were fed a casein-based or a grain-based protein diet both of which had equivalent total phosphorus contents. The two different sources of dietary protein had profound effects on the progression of CKD-MBD, likely due to differences in intestinal bioavailability of phosphorus. Although both dietary treatments resulted in the same serum phosphorous levels, the casein-fed animals had increased urinary phosphorus excretion and elevated serum FGF23 compared to the grain-fed rats. This model should help identify early changes in the course of chronic kidney disease that may lead to CKD-MBD.

Analysis of transfusion predictors in shoulder arthroplasty.

BACKGROUND: We are not aware of any previous study that has examined predictive factors for blood transfusion after shoulder arthroplasty. We analyzed the association between clinical factors and the need for postoperative blood transfusion and documented the use and waste of predonated blood in a group of patients managed with shoulder arthroplasty. METHODS: A retrospective study of 119 patients who underwent 124 shoulder arthroplasties (including eighty-seven primary uncomplicated total shoulder arthroplasties, twenty-seven revision or complicated primary total shoulder arthroplasties, and ten hemiarthroplasties) from 2001 to 2004 was performed. Logistic regression analysis was conducted to determine which clinical variables were predictive of transfusion. RESULTS: A postoperative transfusion was received after thirty-one arthroplasties (25%). The strongest predictor of blood transfusion after shoulder arthroplasty was the preoperative hemoglobin level (likelihood ratio test = 37.8, p < 0.0001). Patients with a preoperative hemoglobin level of between 110 and 130 g/L had a five times greater estimated risk of transfusion than those with a level of >130 g/L (p < 0.001). Gender, body mass index, preoperative diagnosis, comorbid conditions, use of anticoagulants or aspirin, autologous predonation status, type of anesthesia, operative time, and decrease in hemoglobin or hematocrit were not predictors of blood transfusion. One hundred and two (78%) of the 131 predonated autologous units were discarded. Patients with a preoperative hemoglobin level of >130 g/L had the highest percentage of wasted units (90%; fifty-five of sixty-one). Preoperative autologous blood donation did not eliminate the risk of allogeneic blood transfusion in autologous donors. CONCLUSIONS: The preoperative hemoglobin level is the strongest predictor of blood transfusion after shoulder surgery, and individuals with a preoperative hemoglobin level of <110 g/L have the highest risk of transfusion. On the basis of these findings, we do not recommend autologous predonation for individuals with a preoperative hemoglobin level of >130 g/L, to avoid unnecessary expense and waste.

Phosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells.

BACKGROUND: Dialysis patients have accelerated atherosclerosis, with extensive calcification of both the intima and media. Cross-sectional studies have implicated hyperphosphatemia in this process, but the mechanism is unclear. METHODS: To test the hypothesis that hyperphosphatemia and/or uremia induces vascular calcification, bovine vascular smooth muscle cells (BVSMC) were treated with increasing concentrations of beta-glycerophosphate, a phosphate donor, in the presence or absence of inhibitors for sodium/phosphate (Na/Pi) co-transport (foscarnet) or alkaline phosphatase (levamisole) for 48 hours. BVSMC also were incubated for various times with DMEM plus 15% pooled uremic sera from patients with low (LP) or high serum phosphorus (HP), or from pooled healthy control serum. Calcification in BVSMC was examined by quantitation of calcium deposition. Osteopontin expression and alkaline phosphatase activity were assessed by Western blotting and a colorimetric assay. RESULTS: beta-glycerophosphate increased osteopontin expression and alkaline phosphatase activity in BVSMC. Inhibition of either alkaline phosphatase activity or Na/Pi co-transport abolished this effect. Compared to incubation with control human serum, BVSMC cultured with uremic sera had increased mineral deposition. Uremic sera also increased alkaline phosphatase activity and osteopontin expression in BVSMC. The addition of beta-glycerophosphate to uremic HP or LP sera did not further augment osteopontin expression. Blocking Na/Pi co-transport or alkaline phosphatase activity only partially inhibited uremic sera-induced osteopontin expression, indicating that other non-Na/Pi co-transport dependent mechanisms also are involved. CONCLUSION: beta-glycerophosphate and uremic sera induce calcification and osteopontin expression in BVSMC. The uremic sera-induced osteopontin expression in BVSMC is partially mediated through alkaline phosphatase activity and a Na/Pi co-transporter dependent mechanism. However, other non-Na/Pi dependent mechanisms also contribute to accelerated vascular calcification in patients with ESRD.

Medial artery calcification in ESRD patients is associated with deposition of bone matrix proteins.

BACKGROUND: In non-ESRD patients, recent studies have demonstrated that the process of vascular calcification resembles developmental osteogenesis. Patients with ESRD are known to have excessive vascular calcification, but this has previously been attributed to the non-cell-mediated process of metastatic calcification. METHODS: To determine if the calcification observed in patients with ESRD is related to a cell-mediated process, we removed a piece of inferior epigastric artery at the time of renal transplant. Calcium content of the entire vessel was quantified with spiral computed tomography (CT). The vessel was then examined histologically for calcification and the presence of bone matrix proteins by immunohistochemistry, and medial and intimal thickness quantified by histomorphometry. These findings were correlated with demographic, clinical and laboratory values. RESULTS: The proximal inferior epigastric artery was obtained from 41 patients undergoing renal transplantation, but two were inadequate for histologic examination. Twenty-seven of the remaining vessels had no evidence of calcification by MacNeal's or Alizarin red pH 4.2 staining, five vessels had mild/moderate calcification, and seven had severe calcification, all in the medial layer. Calcification assessed histologically was closely correlated with calcification score as assessed by spiral CT, normalized for vessel weight (P=0.027). Positive immunostaining for the bone matrix proteins osteopontin, type I collagen, bone sialoprotein, and alkaline phosphatase was strongly correlated with calcification (all P < or = 0.001), as was a history of coronary artery disease (P < 0.001), and diabetes (P=0.034). The calcification score by spiral CT correlated with these same factors and the serum phosphorus and calcium x phosphorus product (P=0.032 and 0.037). The location of immunostaining for the bone proteins was strongly associated with the presence of calcification. However, positive immunostaining also was observed in association with disorganization of the vascular smooth muscle cells in the medial layer due to deposition of a matrix-like substance, prior to overt calcification. CONCLUSIONS: In patients with ESRD undergoing renal transplantation, vascular calcification of the medial layer of the inferior epigastric artery is common (44%), can be detected by spiral CT, and is associated with deposition of bone matrix proteins. This implies an active cell-mediated process, raising hope that directed intervention can arrest this process.