Pablo Urena

2009 EANM parathyroid guidelines

The present guidelines were issued by the Parathyroid Task Group of the European Association of Nuclear Medicine. The main focus was imaging of primary hyperparathyroidism. Dual-tracer and single-tracer parathyroid scintigraphy protocols were discussed as well as the various modalities of image acquisition. Primary hyperparathyroidism is an endocrine disorder with high prevalence, typically caused by a solitary parathyroid adenoma, less frequently (about 15%) by multiple parathyroid gland disease (MGD) and rarely (1%) by parathyroid carcinoma. Patients with MGD may have a double adenoma or hyperplasia of three or all four parathyroid glands. Conventional surgery has consisted in routine bilateral neck exploration. The current trend is toward minimally invasive surgery. In this new era, the success of targeted parathyroid surgery depends not only on an experienced surgeon, but also on a sensitive and accurate imaging technique. Recognizing MGD is the major challenge for pre-operative imaging, in order to not direct a patient towards inappropriate minimal surgery. Scintigraphy should also report on thyroid nodules that may cause confusion with a parathyroid adenoma or require concurrent surgical resection. The two main reasons for failed surgery are ectopic glands and undetected MGD. Imaging is mandatory before re-operation, and scintigraphy results should be confirmed with a second imaging technique (usually US for a neck focus, CT or MRI for a mediastinal focus). Hybrid SPECT/CT instruments should be most helpful in this setting. SPECT/CT has a major role for obtaining anatomical details on ectopic foci. However, its use as a routine procedure before target surgery is still investigational. Preliminary data suggest that SPECT/CT has lower sensitivity in the neck area compared to pinhole imaging. Additional radiation to the patient should also be considered. The guidelines also discuss aspects related to radio-guided surgery of hyperparathyroidism and imaging of chronic kidney disease patients with secondary hyperparathyroidism.

Effects of vitamin D supplementation on the calcium–phosphate balance in renal transplant patients

Low serum levels of 25-hydroxy vitamin D frequently occur after renal transplantation, but few studies have evaluated the effects of normalizing this on serum parathyroid hormone and calcium levels or urinary calcium excretion. To determine this we compared the outcomes of 94 renal transplant patients with low 25-hydroxy vitamin D and normal serum calcium levels who were either treated or not with cholecalciferol every 2 weeks for 2 months (intensive phase) followed by an every other month maintenance phase. The biological characteristics of the two equally divided patient groups did not differ before treatment. After the intensive phase, serum 25-hydroxy vitamin D levels were normalized in all but 3 patients and the serum parathyroid hormone decreased and calcium levels increased with no severe adverse effects. During the maintenance phase, the serum 25-hydroxy vitamin D level decreased but remained significantly higher than in controls. In the control group, the serum 25-hydroxy vitamin D concentration increased slightly but became normal in only three patients. Serum 25-hydroxy vitamin D levels were significantly higher and parathyroid hormone levels were lower in treated patients compared to controls one year following transplant. Hence, cholecalciferol treatment significantly increased serum 25-hydroxy vitamin D and decreased parathyroid hormone levels with no adverse effects in 25-hydroxy vitamin D-deficient renal transplant patients.

Serum Erythropoietin and Erythropoiesis in Primary and Secondary Hyperparathyroidism: Effect of Parathyroidectomy

Primary as well as secondary hyperparathyroidism may be associated with anemia, and parathyroidectomy (PTx) may improve or even heal it. The precise link between the two conditions is still matter of discussion. The purpose of the present study was to investigate possible effects of PTx on serum immunoreactive erythropoietin (iEPO) in secondary (group I, n = 23), and primary (group II, n = 16) hyperparathyroidism patients, and in 3 patients undergoing cervicotomy for thyroid mass removal (group III). In group I patients, circulating iEPO levels rose from 23.1 +/- 4.8 mU/ml before PTx to 28.2 +/- 5.0 and 245 +/- 125 mU/ml (mean +/- SEM) at day 7 (p = NS) and 14 after PTx (p less than 0.003), respectively. Reticulocyte count increased 2 weeks after PTx: from 61,000 +/- 13,317 to 86,533 +/- 13,462/mm3 (p less than 0.05, n = 23). In 4 of these patients serum iEPO levels could be measured again 12-24 months after PTx. They were slightly higher than those determined before PTx: 37.0 +/- 8.4 versus 31.8 +/- 13.5 mU/ml. Their hematocrits were also higher than before PTx: 12.8 +/- 0.9 versus 11.0 +/- 0.9 g/dl. In group II patients, serum iEPO levels remained unchanged after PTx: 17.5 +/- 2.0 mU/ml before PTx and 20.0 +/- 3.0 mU/ml 14 days PTx. The reticulocyte count, however, increased significantly 2 weeks after PTx: from 25,103 +/- 3,000 to 40,827 +/- 4,080/mm3 (p less than 0.01). In group III patients, serum iEPO, reticulocyte count, and hemoglobin remained stable after surgery. Since all group I patients had received vitamin D supplementation after PTx, we studied an additional group of 14 chronic dialysis patients (group IV) who received either calcitriol (1 micrograms/day, n = 7) or placebo (n = 7) during 14 days. The patients on calcitriol treatment, but not those on placebo, had a significant decrease of serum iEPO: 18.6 +/- 4.9 versus 16.0 +/- 4.2 mU/ml (p less than 0.03). In conclusion, PTx led to a striking increase of serum iEPO and blood reticulocytes in uremic patients with secondary hyperparathyroidism, and an increase of reticulocyte count, but not of iEPO, in patients with primary hyperparathyroidism. Marked changes of circulating PTH, extra-or intracellular calcium and phosphorus concentrations as well as of tissue sensitivity to EPO after PTx could all be responsible. In contrast, the surgical procedure and the therapeutic increase in plasma calcitriol do not appear to be involved.

Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) Guidelines: a European Renal Best Practice (ERBP) commentary statement

Under the auspices of the European Renal Best Practice, a group of European nephrologists, not serving on the Kidney Disease Improving Global Outcomes (KDIGO) working group, but with significant clinical and research interests and expertise in these areas, was invited to examine and critique the Chronic Kidney Disease-Mineral and Bone Disorder KDIGO document published in August 2009. The final form of this paper in Nephrology Dialysis Transplantation, as a commentary, not as a position statement, reflects the fact that we have had no more evidence to review, discuss and debate available to us than was available to the KDIGO working group. However, we have felt that we were able to comment on specific areas where we feel that further clinical guidance would be helpful, thereby going beyond the KDIGO position as reflected in their document. This present paper, we hope, will be of most use to the practising kidney specialist and those allied to the clinical team.

Pitfalls of Measuring Total Blood Calcium in Patients with CKD

Disorders of mineral and bone metabolism are prevalent in patients with chronic kidney disease (CKD). The recent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend that blood calcium (Ca) be regularly measured in patients with stages 3 to 5 CKD. The Kidney Disease: Improving Global Outcomes (KDIGO) position states that the measurement of ionized Ca (iCa) is preferred and that if total Ca (tCa) concentration is used instead, then it should be adjusted in the setting of hypoalbuminemia. In 691 consecutive patients with stages 3 to 5 CKD, we compared the ability of noncorrected and albumin-corrected tCa concentration to identify low, normal, or high iCa concentration. The agreement between noncorrected or albumin-corrected tCa and iCa was only fair. The risk for underestimating ionized calcium was independently increased by a low total CO(2) concentration when either noncorrected or albumin-corrected Ca was used and by a low albumin concentration only when noncorrected tCa was used. The risk for overestimating iCa was increased by a low albumin concentration only when albumin-corrected Ca was used. In conclusion, albumin-corrected tCa does not predict iCa better than noncorrected tCa. Moreover, both noncorrected and albumin-corrected tCa concentrations poorly predict hypo- or hypercalcemia in patients with CKD.

PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilage growth plate of uraemic rats

PTH/PTHrP receptor mRNA is down-regulated in epiphyseal cartilage growth plate of uraemic rats. Growth retardation, hypocalcaemia, hyperphosphataemia, and skeletal resistance to the action of PTH are well known features of advanced chronic renal failure (CRF). It has been suggested that the downregulation of renal and skeletal PTH receptors (PTH/PTHrP-R) could play an important role in the occurrence of these abnormalities. In the present study, four uraemic (4 weeks after 5/6 nephrectomy) and four control (sham-operated) rats were analysed for PTH/PTHrP-R mRNA expression at the proximal femoral and tibial growth plates by in situ hybridization. Uraemic rats had plasma biochemical abnormalities of advanced CRF including high creatinine, phosphate, and PTH, and low calcium and calcitriol levels. The femoral and tibial bones of uraemic animals were shorter in length than those of control rats, and had reduced width and cellularity of the epiphyseal cartilage growth plate. Mean (+/- SD) tibia growth plate width was 152 +/- 30 microns in uraemic rats, compared with 170 +/- 35 microns in control rats. The difference was mostly due to a marked reduction of the zone expressing PTH/PTHrP-R (mature chondrocytes) which was 30 +/- 5 microns in tibias from uraemic versus 44 +/- 10 microns in tibias from control rats. The hybridization signals of PTH/PTHrP-R per individual cell were quantified on dark field images using a computer-assisted image analysis system. The number of grains in PTH/PTHrP-R positive cells was also decreased in uraemic rats, 103 +/- 13 compared with 123 +/- 14 arbitrary units (dark pixel density)/cell in control rats (P < 0.005). In conclusion, these data indicate that rats with severe CRF and secondary hyperparathyroidism have reduced epiphyseal cartilage PTH/PTHrP-R mRNA expression. This alteration may be relevant in the pathogenesis of growth retardation in uraemia.

Preoperative imaging of parathyroid glands with technetium-99m-labelled sestamibi and iodine-123 subtraction scanning in secondary hyperparathyroidism.

BACKGROUND Parathyroidectomy is unsuccessful in 10-30% of uraemic patients operated on for secondary hyperparathyroidism. We investigated the usefulness of preoperative radionuclide imaging, with simultaneous recording of the distribution images of iodine-123 and technetium-99m-labelled sestamibi. METHODS 11 patients with secondary hyperparathyroidism underwent prospective imaging and parathyroidectomy. Plasma concentrations of intact parathyroid hormone (PTH) were measured in all patients before and 6 months after subtotal parathyroidectomy. FINDINGS Preoperative scanning showed 42 hot-spots suggesting enlarged parathyroid glands. 45 glands were discovered at surgery, and the parathyroidectomy was deemed successful in ten patients. Among the latter, one patient had a supernumerary parathyroid gland detected by scanning and resected from the left thymus. Another patient showed ectopic uptake corresponding to a large parathyroid gland in the upper mediastinum, and another had a parathyroid gland well above the thyroid. No false-positive scan findings were documented. In the patient for whom parathyroidectomy failed, preoperative scanning suggested five enlarged parathyroid glands, though the surgeon found only four glands, in their normal positions. Hyperparathyroidism persisted (intact PTH 527 ng/L, 6 months after surgery). A second scan confirmed the preoperative scan, showing a fifth parathyroid gland in the middle of the right thyroid lobe. INTERPRETATION Simultaneous recording of 99mTc-sestamibi and 123I improved the imaging of parathyroid glands in secondary hyperparathyroidism. The technique can identify ectopic and supernumerary parathyroid glands.

Recent findings in phosphate homeostasis.

Purpose of reviewWe summarize the most recent findings on the proteins that interact with sodium/inorganic phosphate (Na/Pi) cotransporters, the factors that regulate Pi homeostasis and their role in pathology. Recent findingsStudies in animal models and cell lines identified proteins mandatory to correct trafficking of the kidney-specific Na/Pi cotransporter NPT2a and its control by the parathyroid hormone. Expression of the intestinal cotransporter NPT2b is controlled by calcitriol, the ubiquitin ligase Nedd-4 and the serum glucocorticoid inducible kinase. Recent data confirm that fibroblast growth factor 23 plays a central role in the control of Pi homeostasis. Mice disrupted for or overexpressing this gene exhibit significant alteration of Pi transport and calcitriol metabolism. In humans, fibroblast growth factor 23 mutations are responsible for autosomal hypophosphataemic rickets or tumoral calcinosis. This gene also seems to be involved in hyperparathyroidism in patients with chronic kidney disease. Several new phosphaturic factors have been identified. Moderate increases in serum Pi concentration may have deleterious effects on lifespan in humans with chronic kidney disease. Disruption of the Klotho gene in mice is associated with hyperphosphataemia and decreased lifespan. Polymorphisms in this gene, in humans and in mice, influence vascular calcification and survival. SummaryPi homeostasis depends on the activity of Na/Pi cotransporters in intestine and kidney. Na/Pi transporter activity is regulated by cellular and endocrine factors, among which fibroblast growth factor 23 plays a central role. Adequate control of Pi homeostasis is crucial, as a moderate increase in serum Pi concentration and polymorphisms in genes involved in Pi metabolism may influence the aging process and lifespan.

Clonal Chromosomal Defects in the Molecular Pathogenesis of Refractory Hyperparathyroidism of Uremia

Indirect X chromosome-inactivation analyses have demonstrated that most parathyroid glands from patients with uremic refractory secondary/tertiary hyperparathyroidism are monoclonal neoplasms. However, little is known regarding the specific acquired genetic abnormalities that must underlie such clonal expansion or the molecular pathogenetic features of this disorder, compared with primary parathyroid adenomas. To address these issues in a uniquely powerful manner, both comparative genomic hybridization (CGH) and genome-wide molecular allelotyping were performed with a large group of uremia-associated parathyroid tumors. As indicated by CGH, one or more chromosomal changes were present in 24% of the tumors, which is markedly different from the value for common sporadic adenomas (72%). Two recurrent abnormalities that had not been previously described for sporadic parathyroid adenomas were noted with CGH, i.e., gains on chromosomes 7 (9%) and 12 (11%). Losses on chromosome 11 occurred in only one of the 46 uremia-associated tumors (2%); the tumor also contained a somatic mutation of the remaining MEN1 allele (221del18). A total of 13% of tumors demonstrated recurrent allelic loss on 18q, with 18q21.1-q21.2 being defined as the putative tumor suppressor-containing region. In conclusion, the powerful combination of genome-wide molecular allelotyping and CGH has identified recurrent clonal DNA abnormalities that suggest the existence and locations of genes important in uremic hyperparathyroidism. In addition, genome-wide patterns of somatic DNA alterations, including disparate roles for MEN1 gene inactivation, indicate that markedly different molecular pathogenetic processes exist for clonal outgrowth in severe uremic hyperparathyroidism versus common parathyroid adenomas.

Tumoral Calcifications in Hemodialysis Patients: Possible Role of Aluminum Intoxication

Uremic patients may develop extraskeletal calcifications. Among the latter, periarticular tumoral calcifications (TC) represent massive, multiloculated calcium-phosphate deposits. The aim of this report was to analyze a series of 10 cases of TC in hemodialysis patients who were admitted at the Necker Hospital between 1974 and 1988. They were all male. An increased plasma calcium x phosphorus product was observed in 8 of the 10 patients. Plasma calcium level was increased in only 2 patients. In contrast, hyperphosphatemia was a constant feature in all the patients, as was the absence of an increase in plasma alkaline phosphatase activity. Using the bone histomorphometry technique, osteitis fibrosa of mild degree was observed in 2 patients, of moderate degree in 2 and of severe degree in 2 others. Evidence of aluminum (Al) overload was found in the 8 patients in whom it was searched based on bone histomorphometry, bone histochemistry, bone Al content and increased serum Al levels either in the basal state or after a deferoxamine test. In addition, Al overload was strongly suspected in the 2 remaining patients because of prolonged exposure to Al-contaminated dialysate. Various treatment strategies, including parathyroidectomy (PTx), were undertaken that remained unsuccessful in modifying the course of TC to a significant extent. Remarkably, TC occurred for the first time after PTx in 1 patient and worsened after PTx in 2 others. In conclusion, overt secondary hyperparathyroidism appears not to be an essential prerequisite for TC development in hemodialysis patients, and PTx must not be performed in such patients on the sole basis of the presence of TC.(ABSTRACT TRUNCATED AT 250 WORDS)