Osteoporosis in chronic kidney disease.
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Adult↗
Biomedical subjects
John Cunningham
Publications and source records attributed to John Cunningham.
Achieving therapeutic targets in the treatment of secondary hyperparathyroidism.
Disturbances in the control of extracellular ionized calcium and phosphorus concentrations, and vitamin D metabolism, in patients with chronic kidney disease (CKD) are associated with prolonged stimulation of the parathyroid glands. This results in increased synthesis and release of parathyroid hormone (PTH) and parathyroid hyperplasia-secondary hyperparathyroidism (SHPT). SHPT is in turn a major driver of the skeletal disturbance that characterizes renal osteodystrophy and is associated with vascular and other soft tissue calcification. Current therapeutic strategies based on vitamin D compounds and calcium-containing phosphate binders are difficult to implement effectively because both agents are associated with substantial, and often dose-limiting, calcaemic actions that prevent the attainment of treatment targets. Calcimimetics are novel agents that increase the sensitivity of calcium-sensing receptors in the parathyroid glands. Consequently, they allow simultaneous reduction of both PTH and extracellular calcium concentrations, thus differing from currently available vitamin D therapies. Reduction of the calcium-phosphorus product (Ca x P) is a consistent feature of calcimimetic therapy and may facilitate the achievement of SHPT treatment targets.
Cinacalcet↗
Renal function and risk stratification in acute coronary syndromes.
In this prospective cohort study we analyzed the impact of admission renal function on the hospital course of 2,503 patients with unstable angina pectoris (UAP) and acute myocardial infarction (AMI). The patients were stratified into quartile groups (Q1 to Q4) defined by baseline corrected creatinine clearance (cCrCl) values of 51.4, 63.8, and 76.8 mg/min/72 kg. The proportions of patients with a discharge diagnosis of AMI increased with declining cCrCl, from 35.5% in Q4 to 46.0% in Q1 (p <0.0001). The frequency of left ventricular (LV) failure (Q4 4.5%, Q1 31.0%, p <0.0001) and cardiac death (Q4 0.5%, Q1 9.5%, p <0.0001) also increased linearly with decreasing cCrCl, with no evidence that the prognostic impact of renal dysfunction was different in AMI or UAP (p for interaction 0.15). Logistic regression analysis confirmed the independent effects of cCrCl on outcome, with odds of LV failure and cardiac death for patients in Q4 being 0.34 (95% confidence intervals 0.16 to 0.72) and 0.14 (95% confidence intervals 0.03 to 0.74), respectively, relative to patients in Q1. No threshold was detected for the adverse effects of renal dysfunction on outcomes; the log odds of LV failure and cardiac death against quartiles of cCrCl both showed significant linear trends (p <0.0001) with each change in quartile, resulting in risk reductions of 55% (odds [SE] 0.45 [0.03]) and 65% (odds [SE]: 0.35 [0.05]), respectively. In conclusion, renal function showed a graded association with LV failure and hospital death that was independent of diagnosis (UAP or AMI) and other baseline variables. There was no detectable threshold of renal dysfunction for these adverse prognostic effects.
Aged↗
Modulating action of the new polymorphism L436F detected in the GLB1 gene of a type-II GM1 gangliosidosis patient.
We report the modulating action of the L436F new polymorphism identified in the GLB1 gene of a patient affected by GM1 gangliosidosis with onset at 17 months and rapidly progressive psychomotor deterioration. Sequencing analysis and familial restriction studies revealed that the maternal allele of this patient carried the L436F polymorphism in cis with the known R201C mutation. The new mutation R68W was identified in his paternal allele. Since the GLB1 activity of the patient's leukocytes was very low and compatible with both the type-I and the type-II form of the disease, the potential impact of each mutation was investigated by expression studies in COS1 cells, and Western blots. Expression study of the R68W mutated allele resulted in no GLB1 activity. Transfection with a vector carrying the R201C mutation gave rise to a residual GLB1 activity, which, interestingly, was severely reduced in transfection with the L436F/R201C allele. These expression studies, together with co-transfection experiments, suggest that the R201C/L436F GLB1 "complex allele" leads to this patient's clinical and biochemical findings. The type-II phenotype of the disease is subdivided into late infantile and juvenile forms. The clinical and molecular characterization of this patient as late-infantile GM1 gangliosidosis is in keeping with a clear-cut division between the two sub forms of the type-II phenotype. The modulating role of the L436F polymorphism should be stressed as a cause of this patient's condition. This model suggests that the combination of missense mutations or polymorphisms should be evaluated when diagnosing inherited genetic disorders.
Alleles↗
Long-term effects on bone mineral density of pamidronate given at the time of renal transplantation.
BACKGROUND: Fracture rate after renal transplantation is substantially increased, is a source of morbidity and mortality, and correlates with osteopenia. The rate of bone loss after transplantation is time dependent. While we recorded marked bone loss during the first year after renal transplantation, bone loss in long-term recipients (>24 months) was found to be similar to expected age-related decline. We have previously shown that treatment with pamidronate at the time of transplantation protected the skeleton over a 1-year study period. METHODS: We have reexamined patients who participated in our original study, all of whom had been randomized to receive either placebo or pamidronate (0.5 mg/kg) at the time of transplantation and 1 month later. We now report 4-year data from 17 of the 26 original cohort. All patients received immunosuppression, comprising prednisolone, cyclosporine, and azathioprine. RESULTS: We found that without prophylaxis bone loss at 4 years was substantial and significant at the femoral neck (mean loss was -12.3%) but was not significant at the lumbar spine (mean loss was -4.64%). Patients who received two doses of pamidronate experienced no statistically significant bone loss at either the femoral neck or the lumbar spine. Patient characteristics of the placebo and treatment groups were similar with the exception of serum parathyroid hormone concentrations, which remained higher at 4 years in the pamidronate-treated patients (15.8 +/- 3.7 pmol/L vs. 9.8 +/- 1.8 pmol/L, P < 0.05). CONCLUSION: Without prophylaxis, most patients who continue to receive low dose glucocorticoids as part of maintenance immunosuppression manifest a substantial deficit in bone mineral density (BMD) at the femoral neck. In contrast, two doses of pamidronate given at the time of transplantation and 1 month later protected the skeleton from significant bone loss over the 4 years after transplantation.
Adult↗
Etiology and outcome of graft failure in pediatric hematopoietic stem cell transplant recipients.
PURPOSE: To determine the incidence, etiology and outcome of graft failure in pediatric allogeneic bone marrow transplant (BMT) recipients. PATIENTS AND METHODS: Patients with primary or secondary graft failure were identified by database review. A retrospective chart review was performed. Etiologic factors were identified and assessed for statistical significance. RESULTS: 309 children underwent allogeneic BMT during the time interval studied. Four cases of primary graft failure and 7 cases of secondary graft failure occurred. Nonmalignant diagnosis, lower total nucleated cell (TNC) dose, and conditioning without total body irradiation were associated with a higher incidence of graft failure. Donor source, donor/recipient CMV status, CD34+ cell dose, and alloimmunization were not associated with graft failure. CONCLUSIONS: Graft failure is a relatively uncommon occurrence in pediatric patients. Autologous reinfusion may allow time to prepare the patient for a second transplant and decrease complications associated with aplasia. More immunosuppressive conditioning regimens may decrease the incidence of graft failure, particularly in patients with non-malignant diseases or those with lower stem cell doses. More frequent monitoring of chimerism by VNTR analysis may detect late graft failure earlier and allow for more rapid intervention.
Bone Marrow Transplantation↗
Effects of 'non-calcaemic' vitamin D analogues on 24-hydroxylase expression in MG-63 osteoblast-like cells.
BACKGROUND: New 'non-calcaemic' analogues of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) are entering the clinical arena and some of them have been shown to have differential effects in bone. This may have a bearing on the evolution of bone lesions in uraemic patients receiving vitamin D therapies. A potential mechanism for differential effects of analogues lies in their target cell inactivation. METHODS: Using a human osteoblastic cell line, MG-63, three analogues, 22-oxacalcitriol (OCT), 19-nor-1,25-dihydroxyvitamin D2 (paricalcitol) and 1alpha,25-dihydroxydihydrotachysterol2(1,25(OH)2DHT2), were compared with 1,25(OH)2D3 for (1) their affinity for the vitamin D receptor (VDR) by competitive displacement of tritiated 1,25(OH)2D3 from calf thymus VDR; (2) effects on 24-hydroxylase mRNA expression using comparative RT-PCR, and (3) rates of metabolism, using high performance liquid chromatography, over a 24-hour time course. RESULTS: Relative VDR-binding affinities (IC50) were 1,25(OH)2D3 (100%), OCT (25%), paricalcitol (14%) and 1,25(OH)2DHT2 (0.3%). A > or =3-fold increase in 24-hydroxylase mRNA expression was observed for all compounds at 2 h peaking at 7- to 8-fold above control levels by 12 h, with no significant difference between the analogues and 1,25(OH)2D3. Differences in their rates of metabolism were observed [calculated t(1/2) values = OCT (1.2 h) > paricalcitol (2.3 h) > 1,25(OH)2D3 (2.6 h) > 1,25(OH)2DHT2 (3.4 h)], with OCT having a significantly shorter half-life. CONCLUSION: In MG-63 cells these analogues up-regulate 24-hydroxylase mRNA expression with similar potency, in each case accelerating ligand inactivation, despite significant differences in VDR affinity. VDR affinity did not correspond to either 24-hydroxylase mRNA expression or the rates of ligand disappearance, suggesting cellular metabolism is one of several factors that determine the analogue specificity of these agents in bone.
Animals↗
Functional amelioration of murine galactosialidosis by genetically modified bone marrow hematopoietic progenitor cells.
Protective protein/cathepsin A (PPCA), a lysosomal carboxypeptidase, is deficient in the neurodegenerative lysosomal disorder galactosialidosis (GS). PPCA(-/-) mice display a disease course similar to that of severe human GS, resulting in nephropathy, ataxia, and premature death. Bone marrow transplantation (BMT) in mutant animals using transgenic BM overexpressing the corrective enzyme in either erythroid cells or monocytes/macrophages has proven effective for the improvement of the phenotype, and encouraged the use of genetically modified BM cells for ex vivo gene therapy of GS. Here, we established stable donor hematopoiesis in PPCA(-/-) mice that received hematopoietic progenitors transduced with a murine stem cell virus (MSCV)-based, bicistronic retroviral vector overexpressing PPCA and the green fluorescent protein (GFP) marker. We observed complete correction of the disease phenotype in the systemic organs up to 10 months after transplantation. PPCA(+) BM-derived cells were detected in all tissues, with the highest expression in liver, spleen, BM, thymus, and lung. In addition, a lysosomal immunostaining was seen in nonhematopoietic cells, indicating efficient uptake of the corrective protein by these cells and cross-correction. Expression in the brain occurred throughout the parenchyma but was mainly localized on perivascular areas. However, PPCA expression in the central nervous system was apparently sufficient to delay the onset of Purkinje cell degeneration and to correct the ataxia. The long-term expression and internalization of the PPCA by cells of systemic organs and the clear improvement of the neurologic phenotype support the use of this approach for the treatment of GS in humans. (Blood. 2002;99:3169-3178)
Animals↗
Long-term outcome in patients with benign biliary strictures treated endoscopically with multiple stents.
BACKGROUND: The long-term efficacy of sequential insertion of multiple plastic stents for benign biliary strictures is poorly defined. The aims of this study were to evaluate the long-term outcome (bile duct patency, complications) of this therapy and to identify predictors of a good outcome. METHODS: Retrospective review of 29 cases of benign biliary strictures treated with sequential plastic stent insertion in progressively increasing numbers and/or of increasing diameter. RESULTS: Stricture etiology was as follows: postoperative 19 (66%), chronic pancreatitis 9 (31%), and idiopathic 1 (3%). Therapy succeeded in 18 patients (62%) (mean follow-up 48.0 [11.56] months after stent removal). Therapy failed in 11 patients (38%) (mean interval to failure 11.59 [9.79] months after stent removal). The 2 groups of patients in which therapy failed had either a hilar stricture (n = 4, 25% success) or distal common bile duct stricture caused by chronic pancreatitis (n = 9, 44% success). In the remaining cases, therapy succeeded in 13 of 16 (81% success). The observed differences in success rate among subgroups were not statistically significant. There were no ERCP-related deaths. One episode of mild pancreatitis and 2 episodes of cholangitis developed during 126 ERCPs over a period of stent insertion of 36 patient years. CONCLUSIONS: In selected patients with benign biliary strictures, sequential endoscopic insertion of multiple biliary stents may lead to long-term success that could be equal to or superior to surgery with minimal morbidity. Hilar strictures and those caused by chronic pancreatitis appear to respond poorly to this therapy.
Adolescent↗
Summary of symposium: the future of stem cell transplantation for sickle cell disease.
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Anemia, Sickle Cell↗
Calcimimetics and calcilytics--fooling the calcium receptor.
CONTEXT: Just a decade after the the calcium-sensing receptor (CaR) was identified, pharmacological manipulation of the CaR is about to enter routine practice. For hyperparathyroid states, calcimimetics, which increase activation of the CaR, have been licensed in Europe and the USA. Calcilytics, which decrease CaR function and increase secretion of parathyroid hormone (PTH), might allow the anabolic effects of PTH on bone to be harnessed for the prevention and treatment of osteoporosis. STARTING POINT: In a multicentre randomised double-blind placebo-controlled study, Munro Peacock and colleagues recently confirmed the efficacy of the oral calcimimetic cinacalcet for achieving long-term reductions in serum calcium and PTH concentrations in primary hyperparathyroidism (J Clin Endocrinol Metab 2005; 90: 135-41). The arrival of a non-surgical option for this common disorder is important. WHAT NEXT? Study in primary and uraemic secondary hyperparathyroidism will indicate whether the efficacy of calcimimetic agents extends into the longer term. The extracellular relation between the CaR and its ligands and the intracellular signalling cascades that modify PTH gene transcription and secretion need further study. Drugs acting on the CaR might treat other disorders of bone remodelling, including osteoporosis. CaR expression in tissues beyond those involved in mineral ion homoeostasis should remain an important focus of research.
Bone Diseases, Metabolic↗
How should hyperphosphatemia be managed in dialysis patients?
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Calcium Compounds↗
Alcohol problems and interest in self-help: a population study of Alberta adults.
BACKGROUND: We quantified the prevalence of alcohol problems among Alberta adults and determined relationships between sociodemographic characteristics, problem drinking status, and interest in self-help materials to reduce alcohol use. METHODS: A computer-aided telephone interview was administered to a stratified random sample of 10,014 Albertans, 18 years of age or older (5,621 women and 4,393 men; M age = 43.3 years, SD = 16.0), with a response rate of 65.4%. Measures included: 1) current drinking status, 2) prior alcohol treatment, 3) problem drinking status (using the Alcohol Use Disorders Identification Test; AUDIT), and 4) interest in receiving free self-help materials to encourage safe drinking. Data were weighted to reflect age, sex, and regional Alberta population. RESULTS: Of the total sample, 19.3% abstained from drinking in the past year, 4.2% had received treatment for alcohol problems at some point in their lives, and 80.7% were current drinkers (i.e., consumed alcohol in the previous year). Some 15.2% (n = 1,193) of current drinkers were classified as having a drinking problem. Logistic regression analyses showed that problem drinkers had 3.5 times greater odds of being male and 2.3 times greater odds of being interested in self-help interventions, compared to other current drinkers. Being single, of younger age, and not being exposed to post-secondary education also significantly predicted problem drinking status. INTERPRETATION: Alcohol misuse is common among Alberta drinkers, but many of them are interested in receiving brief public health interventions designed to help them assert control over their behaviour.
Adolescent↗