Optimal transplantation strategies are uncertain in primary hyperoxaluria (PH) due to potential for recurrent oxalosis. Outcomes of different transplantation approaches were compared using life‐table ...methods to determine kidney graft survival among 203 patients in the International Primary Hyperoxaluria Registry. From 1976–2009, 84 kidney alone (K) and combined kidney and liver (K + L) transplants were performed in 58 patients. Among 58 first kidney transplants (32 K, 26 K + L), 1‐, 3‐ and 5‐year kidney graft survival was 82%, 68% and 49%. Renal graft loss occurred in 26 first transplants due to oxalosis in ten, chronic allograft nephropathy in six, rejection in five and other causes in five. Delay in PH diagnosis until after transplant favored early graft loss (p = 0.07). K + L had better kidney graft outcomes than K with death‐censored graft survival 95% versus 56% at 3 years (p = 0.011). Among 29 year 2000–09 first transplants (24 K + L), 84% were functioning at 3 years compared to 55% of earlier transplants (p = 0.05). At 6.8 years after transplantation, 46 of 58 patients are living (43 with functioning grafts). Outcomes of transplantation in PH have improved over time, with recent K + L transplantation highly successful. Recurrent oxalosis accounted for a minority of kidney graft losses.
The International Primary Hyperoxaluria Registry (IPHR) was queried, demonstrating improvement in kidney transplant outcomes over time despite the challenge of oxalosis recurrence in renal allografts.
Abstract The International Society for Clinical Densitometry (ISCD) periodically convenes Position Development Conferences (PDCs) in order to establish standards and guidelines for the assessment of ...skeletal health. The most recent Adult PDC was held July 20–22, 2007, in Lansdowne, Virginia, USA; the first Pediatric PDC was June 20–21, 2007 in Montreal, Quebec, Canada. PDC topics were selected according to clinical relevancy, perceived need for standardization, and likelihood of achieving agreement. Each topic area was assigned to a task force for a comprehensive review of the scientific literature. The findings of the review and recommendations were presented to adult and pediatric international panels of experts. The panels voted on the appropriateness, necessity, quality of the evidence, strength, and applicability (worldwide or variable according to local requirements) of each recommendation. Those recommendations that were approved by the ISCD Board of Directors become Official Positions. This is a review of the methodology of the PDCs and selected ISCD Official Positions.
We present a multiple-instance-learning-based scheme for detecting coeliac disease, an autoimmune disorder affecting the intestine, in histological whole-slide images (WSIs) of duodenal biopsies. We ...train our model to detect 2 distinct classes, normal tissue and coeliac disease, on the patch-level, and in turn leverage slide-level classifications. Using 5-fold cross-validation in a training set of 1841 (1163 normal; 680 coeliac disease) WSIs, our model classifies slides as normal with accuracy (96.7±0.6)%, precision (98.0±1.7)%, and recall (96.8±2.5)%, and as coeliac disease with accuracy (96.7±0.5)%, precision (94.9±3.7)%, and recall (96.5±2.9)% where the error bars are the cross-validation standard deviation.
We apply our model to 2 test sets: one containing 191 WSIs (126 normal; 65 coeliac) from the same sources as the training data, and another from a completely independent source, containing 34 WSIs (17 normal; 17 coeliac), obtained with a scanner model not represented in the training data. Using the same-source test data, our model classifies slides as normal with accuracy 96.5%, precision 98.4% and recall 96.1%, and positive for coeliac disease with accuracy 96.5%, precision 93.5%, and recall 97.3%. Using the different-source test data the model classifies slides as normal with accuracy 94.1% (32/34), precision 89.5%, and recall 100%, and as positive for coeliac disease with accuracy 94.1%, precision 100%, and recall 88.2%. We discuss generalising our approach to screen for a range of pathologies.
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•Automated detection of coeliac disease.•Localisation of disease features in histological images.•WSI classification.•Inter-scanner/source generalisation.
Summary
This study compared the effects of pediatric acne treatment with two isotretinoin formulations on bone mineral density. We demonstrated no difference in the effect of the two formulations. No ...effect on pediatric bone mineral density was identified for either formulation.
Introduction
Isotretinoin (13-cis-retinoic acid) is a treatment for recalcitrant nodular acne with a purported effect on bone mineral density (BMD). The side effects of isotretinoin on vertebral bone were evaluated to assess the safety of a new FDA-approved isotretinoin formulation: Lidose-isotretinoin (Cip-Iso).
Methods
This double-blind, randomized, phase III, active control, parallel-group, multicenter study compared the safety, efficacy, and non-inferiority of CIP-Iso to a marketed reference product, Accutane®, in severe recalcitrant nodular acne subjects. Three hundred fifty-eight pediatric male and female subjects aged between 12 and 17 years underwent 20 weeks of treatment with PA lumbar spine dual X-ray absorptiometry (DXA) measurements obtained for bone mineral density (BMD) and Z-scores, 5.5 months apart on visits 1 and 8. One hundred sixty-eight of 358 subjects had height adjusted Z-scores (HAZ) calculated.
Results
There was no difference in the least squares (LS) mean Z-score or HAZ of the two drugs at visit 1 or 8. The mean and LS mean Z-score and HAZ were greater than zero at visits 1 and 8 for both drugs. The change in the LS mean spine Z-score, but not HAZ, between visits, was statistically significant for both drugs. There was a mean increase in BMD (g/cm
2
) for both products between visits.
Conclusions
There is no difference in the effect of two formulations of isotretinoin on spine bone density after 6 months of treatment. BMD increased and the small change in spine Z-score over treatment disappeared after height adjustment. Mean positive Z-scores and HAZ in the study were likely due to the exclusion of low and inclusion of high Z-score subjects.
Summary
Osteoporosis treatment of patients with hip fractures is necessary to prevent subsequent fractures. Secondary causes for bone loss are present in more than 80% of patients with hip fractures, ...and therefore, assessment of Vitamin D status, disorders in calcium absorption and excretion, monoclonal gammopathies, and renal function should be performed. Identifying and managing these disorders will improve detection and enhance treatment aimed at reducing the risk of recurrent fractures in older adults.
Introduction
The purpose of this study was to determine the prevalence of disorders affecting bone and mineral metabolism in individuals with osteoporotic hip fractures.
Methods
Community dwelling individuals with hip fractures (HFx) 50 years of age and older. Assessment for vitamin D, renal and parathyroid status, calcium absorption, and plasma cell disorders.
Results
Of 157 HFx, mean age 70 ± 10 years, HFx had higher creatinine (p = 0.002, 95% C.I. −0.09, 0.05); lower 25 OH vitamin D (p = 0.019, 95% C.I. 6.5, 2.7), albumin (p = 0.007, 95% C.I. 0.36, 0.009), and 24-h urine calcium (p = 0.024, 95% CI 51, 21) as compared to controls. More than 80% of HFx had at least one previously undiagnosed condition, with vitamin D insufficiency (61%), chronic kidney disease (16%) (CKD), monoclonal gammopathy (6%), and low calcium absorption (5%) being the most common. One case each of multiple myeloma and solitary plasmocytoma were identified.
Conclusions
Osteoporosis treatment of HFx is necessary to prevent subsequent fractures. Secondary causes for bone loss are remarkably common in HFx; therefore, assessment of vitamin D status, disorders in calcium absorption and excretion, protein electrophoresis, and renal function should be performed. Identifying and correcting these disorders will improve detection and enhance treatment aimed at reducing the risk of recurrent fractures in older adults.
An activating mutation of the receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) was recently found in a patient with Jansens's metaphyseal chondrodysplasia, a ...rare form of short-limbed dwarfism associated with hypercalcemia and normal or low serum concentrations of the two hormones. To investigate this and other activating mutations and to refine the classification of this unusual disorder, we analyzed genomic DNA from six additional patients with Jansen's disease.
Exons encoding the PTH-PTHrP receptor were amplified by the polymerase chain reaction (PCR), and the products were analyzed by gel electrophoresis or direct nucleotide-sequence analysis. Nucleotide changes were confirmed by restriction-enzyme digestion of genomic DNA or the PCR products.
The previously reported mutation, which changes a histidine at position 223 to arginine (H223R), was found in genomic DNA from three of the six patients but not in DNA from their healthy relatives or 45 unrelated normal subjects. A novel missense mutation that changes a threonine in the receptor's sixth membrane-spanning region to proline (T410P) was identified in another patient but not in 62 normal subjects. In two patients with radiologic evidence of Jansen's metaphyseal chondrodysplasia but less severe hypercalcemia, no receptor mutations were detected. In COS-7 cels expressing PTH-PTHrP receptors with the T410P or H223R mutation, basal cyclic AMP accumulation was four to six times higher than in cells expressing wild-type receptors.
The expression of constitutively active PTH-PTHrp receptors in kidney, bone, and growth-plate chondrocytes provides a plausible genetic explanation for mineral-ion abnormalities and metaphyseal changes in patients with Jansen's disease.
Objective
We tested the hypothesis that higher circulating levels of osteoprotegerin (OPG) are related to higher levels of coronary artery calcification (CAC) among women with systemic lupus ...erythematosus (SLE) compared with healthy controls (HCs).
Methods
Among 611 women in two age- and race-matched SLE case-control studies, OPG was assayed in stored blood samples (HEARTS: plasma, n cases/controls = 122/124, and SOLVABLE: serum, n cases/controls = 185/180) and CAC was measured by electron beam computed tomography.
Results
In both studies, SLE patients had higher OPG and CAC levels than HCs. Higher OPG was associated with high CAC (>100 vs.100) among SLE, and with any CAC (>0 vs. 0) among HCs. Multivariable-adjusted OR (95% CI) for OPG tertile 3 vs. 1 was 3.58 (1.19, 10.76), p trend = 0.01 for SLE, and 2.28 (1.06, 4.89), p trend = 0.04 for HCs. Associations were attenuated when age-adjusted, but remained significant for HC women aged ≥ 40 and SLE women aged ≥ 50. ROC analyses identified 4.60 pmol/l as the optimal OPG cutpoint for predicting high CAC (>100) among SLE patients with sensitivity = 0.74 and specificity = 0.61, overall, but 0.92 and 0.52, respectively, for SLE patients aged ≥ 50.
Conclusion
Our cross-sectional results suggest that higher OPG levels are related to higher CAC levels among women with SLE vs. healthy controls.
The International Society for Clinical Densitometry (ISCD) conducts Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines in the field of bone densitometry. ...Topics for consideration are selected according to clinical relevance, a perceived need for standardization, and the likelihood of achieving agreement. Questions regarding nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests for each topic area are assigned to task forces for a comprehensive review of the scientific literature. The findings of the review and recommendations are then presented to an international panel of experts at the PDC. The expert panel votes on potential Official Positions for appropriateness, necessity, quality of the evidence, strength of the recommendation, and applicability (worldwide or variable according to local requirements). Recommendations that are approved by the ISCD Board of Directors become Official Positions. The first Pediatric PDC was 20–21 June 2007 in Montreal, QC, Canada. The most recent Adult PDC was held 20–22 July 2007, in Lansdowne, VA, USA. This Special Report summarizes the methodology of the ISCD PDCs and presents selected Official Positions of general interest.
Plasma calcium oxalate supersaturation in children with primary hyperoxaluria and end-stage renal failure.
Children with primary hyperoxaluria type 1 (PH 1) are at great risk to develop systemic ...oxalosis in end-stage renal disease (ESRD), as endogenous oxalate production exceeds oxalate removal by dialytic therapy. As oxalate accumulates, calcium oxalate (CaOx) tissue deposition occurs. Children with other causes of ESRD, however, are not prone to CaOx deposition despite elevated plasma oxalate (POx) levels.
Our study objective was to examine the potential mechanisms for these observations. We measured POx, sulfate, citrate, and calculated CaOx saturation (βCaOx) in 7 children with ESRD caused by PH 1 and in 33 children with non-PH–related ESRD. Maintenance hemodialysis (HD) was performed in 6 PH 1 and 22 non-PH patients: Pre- and post-HD levels were analyzed at this point and were repeated twice within 12 months in 5 PH 1 and 14 non-PH patients. Samples were obtained only once in 12 patients (one PH 1) on peritoneal dialysis (PD). After liver-kidney or kidney transplantation, plasma levels were measured repetitively.
The mean POx was higher in PH 1 (125.7 ± 17.9 μmol/liter) than in non-PH patients (44.2 ± 3.3 μmol/liter, P < 10-4). All other determined anions did not differ between the two groups. βCaOx was higher in PH 1 (4.71 ± 0.69 relative units) compared with non-PH children (1.56 ± 0.12 units, P < 10-4). POx and βCaOx were correlated in both the PH 1 (r = 0.98, P < 2 × 10-4) and the non-PH group (r = 0.98, P < 10-4). POx and βCaOx remained stable over time in the non-PH children, whereas an insignificant decline was observed in PH 1 patients after six months of more aggressive dialysis. βCaOx was supersaturated (more than 1) in all PH 1 and in 25 out of 33 non-PH patients. Post-HD βCaOx remained more than 1 in all PH 1, but in only 2 out of 22 non-PH patients. In non-PH children, POx and βCaOx decreased to normal within three weeks after successful kidney transplantation, whereas the levels still remained elevated seven months after combined liver-kidney transplantation in two PH 1 patients.
Systemic oxalosis in PH 1 children with ESRD is due to higher POx and βCaOx levels. As βCaOx remained supersaturated in PH 1 even after aggressive HD, oxalate accumulation increases, and CaOx tissue deposition occurs. Therefore, sufficient reduction of POx and βCaOx is crucial in PH 1 and might only be achieved by early, preemptive, combined liver-kidney transplantation or liver transplantation alone.
Primary hyperoxaluria (PH) is a heterogeneous disease with a variable age of onset and a variable progression into kidney failure. Early diagnosis is mandatory to avoid the damaging effects of ...systemic calcium oxalate deposition. In 1997, we initiated a nationwide survey of American nephrologists to ascertain epidemiological data and current practices. PH was reported in only 102 patients, with PH I in 79 and PH II in 9; 14 patients were not classified. Most patients were Caucasian (84%). Main symptoms at diagnosis were urolithiasis (54.4%) and nephrocalcinosis (30%). A significant delay of diagnosis was seen in 42% of patients and 30% of patients were diagnosed only at end-stage renal disease (ESRD). Diagnosis was usually based on history and urinary oxalate excretion. Glycolate and l-glyceric acid excretion were rarely determined. To determine the enzyme defect, a liver biopsy was performed in 40%. Even at ESRD, only 56% of patients received an adequate diagnostic work-up. Half of the patients showed 'good' or 'fair' pyridoxine sensitivity. In addition to B(6), most patients received either citrate or orthophosphate. Kidney transplantation (KTx) failed in 19 of 32 transplants ( n=27 patients) and was due to recurrent oxalosis in 8 transplants. Liver Tx was performed after KTx in 5 patients (1 patient died). Combined liver-kidney Tx in 21 patients (in 9 patients after failure of KTx) achieved good organ function in 13 patients; 7 patients, however, died shortly after transplantation. In conclusion, the time between first symptom and diagnosis of PH must be minimized, and the diagnostic procedures have to be improved. The cases of unclassified hyperoxaluria suggest the possibility of additional type(s) of PH. As isolated KTx failed in 59% of patients, combined liver-kidney Tx seems to be the better choice in place of isolated KTx as the primary transplant procedure.
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