A prospective study of the influence of the skeleton on calcium mass transfer during hemodialysis.

BACKGROUND: Calcium gradient, the difference between serum calcium and dialysate calcium d[Ca], is the main contributor factor influencing calcium transfer during hemodialysis. The impact, however, of bone turnover, on calcium mass transfer during hemodialysis is still uncertain. METHODS: This prospective cross-sectional study included 10 patients on hemodialysis for a 57.6±16.8 months, with severe hyperparathyroidism. Patients were submitted to 3 hemodialysis sessions using d[Ca] of 1.25, 1.5 and 1.75 mmol/l in three situations: pre-parathyroidectomy (pre-PTX), during hungry bone (early post-PTX), and after stabilization of clinical status (late post-PTX). Biochemical analysis and calcium mass transfer were evaluated and serum bone-related proteins were quantified. RESULTS: Calcium mass transfer varied widely among patients in each study phase with a median of -89.5, -76.8 and -3 mmol using d[Ca] 1.25 mmol/L, -106, -26.8 and 29.7 mmol using d[Ca] 1.50 mmol/L, and 12.8, -14.5 and 38 mmol using d[Ca] 1.75 mmol/L during pre-PTX, early post-PTX and late post-PTX, respectively, which was significantly different among d[Ca] (p = 0.0001) and among phases (p = 0.040). Ca gradient and delta of Ca also differed among d[Ca] and phases (p<0.05 for all comparisons), whether ultrafiltration was similar. Serum Osteocalcin decreased significantly in late post-PTX, whereas Sclerostin increased earlier, in early post-PTX. CONCLUSIONS: The skeleton plays a key role in Ca mass transfer during dialysis, either by determining pre-dialysis serum Ca or by controlling the exchangeable Ca pool. Knowing that could help us to decide which d[Ca] should be chosen in a given patient.

Parathyroidectomy Improves Restless Leg Syndrome in Patients on Hemodialysis.

BACKGROUND: Restless leg syndrome (RLS) is a sleep disorder with high prevalence among patients on hemodialysis. It has been postulated that high phosphate and high parathyroid hormone may be implicated in its pathogenesis. Standard international criteria and face-to-face interview are not always applied. METHODS: this was an interventional prospective study in which 19 patients (6 men, aged 48±11 years) with severe hyperparathyroidism were evaluated. RLS diagnosis and rating scale were accessed based on the International RLS Study Group pre- and post-parathyroidectomy. Patients also underwent standard polysomnography. RESULTS: At baseline, RLS was present in 10 patients (52.6%), and pain was the most reported symptom associated with the diagnosis. Patients with RLS had higher serum phosphate (p = 0.008) that remained independently associated with RLS in a logistic regression model, adjusted for hemoglobin, age and gender (HR = 7.28;CI = 1.14-46.3, p = 0.035). After parathyroidectomy, there was a reduction of serum parathyroid hormone, phosphate, calcium and alkaline phosphatase, and an increase of 25(OH)-vitamin D, and Fetuin-A. Parathyroidectomy alleviated RLS (from 52% to 21%; p = 0.04), which was accompanied by a decrease in severity scale, in association with relief of pain and pruritus. Polysomnography in these patients showed an improvement of sleep parameters as measured by sleep efficiency, sleep latency and percentage of REM sleep. CONCLUSION: RLS is associated with high levels of phosphate in patients with severe secondary hyperparathyroidism on hemodialysis. Pain is most reported complain in these patients. Parathyroidectomy provided an opportunity to relief RLS. Whether the reduction of serum phosphorus or parathyroid hormone contributed to this improvement merits further investigation.

Repression of osteocyte Wnt/ß-catenin signaling is an early event in the progression of renal osteodystrophy.

Chronic kidney disease-mineral bone disorder (CKD-MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft-tissue calcification. Emerging evidence suggests that features of CKD-MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild-type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD-MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild-type mice. To capture the early molecular and cellular events in the progression of CKD-MBD we examined cell-specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor-Ser33/37-ß-catenin was observed both in mouse and human bones. Overall repression of Wnt/ß-catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF-κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late-stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD-MBD and suggest that repression of the Wnt/ß-catenin pathway is involved in the pathogenesis of renal osteodystrophy.

Aspecto histológico normal à microscopia óptica comum não prognostica o funcionamento do tecido paratiréoideo criopreservado / Normal hystology on optical microscopy does not predict cryopreserved parathyroid tissue function

Introdução: Efetuado o tratamento cirúrgico do hiperparatireoidismo secundário, pode sobrevir hipoparatireoidismo. Um recurso terapêutico corrente é auto-implantar fragmentos paratireóideos criospreservados. A função do tecido criopreservado não é bem compreendida e preditores de função são de interesse. Objetivo: Analisar a relação entre o aspecto morfológico do tecido criopreservado à microscopia óptica e a função subseqüente deste tecido auto-implantado. Métodos: Análise retrospectiva do aspecto observado à microscopia óptica de alguns fragmentos de tecido implantado em pacientes com hipoparatireoidismo após paratireoidectomia total feita para tratamento de hiperplasia secundária. As imagens observadas foram correlacionadas à função do implante em dois grupos: um com microscopia normal e outro com autólise. Os níveis de hormônio da paratireóide (PTH) foram analisados um ano após o implante. O auto-implante de tecido criopreservado foi considerado funcional quando os níveis sistêmicos de PTH eram maiores que 15pg/ml. Resultados: Quinze pacientes foram incluídos no estudo. Desses, a função do implante pode ser demonstrada em seis (40%). A autólise foi achada em dois casos, ambos sem sinal de funcionamento. Em 13 pacientes, o tecido implantado era normal à microscopia óptica. Apesar dessa morfologia normal, em sete (53,8%) casos não havia funcionamento mesmo após um ano após a operação; apenas seis (46,2%) estão funcionais. Conclusões: A microscopia óptica convencional parece ter valor limitado para predizer a eventual função do tecido paratireóideo criopreservado após seu auto-implante. A autólise pode ser um indicador de má função.

Introduction: Hypoparathyroidism may ensue after the surgical treatment of secondary hyperparathyroidism. Implantation of cryopreserved parathyroid tissue is an option to revert the state of hypoparathyroidism after total parathyroidectomy for secondary hyperplasia. The function of cryopreserved tissue is not fully understood and function predictors are of interest. Objective: To analyze the relationship between optical microscopy aspect of cryopreserved tissue and its subsequent function after autograft. Methods: We analyzed retrospectively the optical microscopy findings of some fragments of implanted tissue in patients with hypoparathyroidism after total parathyroidectomy for secondary hyperplasia. These findings were correlated to the graft function. They were divided in one group with normal optical microscopy and another one with the presence of autolysis. PTH levels were analyzed one year after implant. Function of the cryopreserved graft was considered when systemic levels of PTH were greater than 15pg/ml. Results: Fifteen patients were included in this study. Of those, graft function was demonstrable in six (40%). Autolysis was found in two cases, without any sign of PTH secretion on both. In 13 patients, optical microscopy was normal. Despite this gross morphological normality, seven (53.8%) implants did not work after one year and only six (46.2%) are working. Conclusion: Conventional optical microscopy seems to play a limited role in predicting the outcome of parathyroid autografts. Autolysis may be a bad sign for future autograft function.

Proteínas ósseas envolvidas na calcificação vascular de ratos urêmicos, paratireoidectomizados, alimentados com dieta rica e pobre em fósforo associada à infusão fixa de paratormônio / Correlation of chemokine ligands and its receptors with lymph node metastasis in head and neck squamous cell carcinoma

Bone tissue alterations and vascular calcification (VC) are commonly found in patients with chronic renal failure (CKD). The importance of phosphorus (P) and parathyroid hormone (PTH) is not clear, yet. An in vitro study showed that inorganic phosphate was able to transform vascular smooth muscle cells (VSMC) into calcifying cells confirmed for up-expression of Runx2 in these cells. Besides, it has been demonstrated the in vivo expression of Runx2 in intimal and medial VSMC in calcified arteries of CKD patients. We evaluated the effect of phosphorus (P) and parathyroid hormone (PTH) on bone remodeling and on the expression of bone proteins (Runx2, Osteoprotegerin, type I Collagen, Osteocalcin, Osteopontin and NF?B) in aortic valve and heart in experimental uremia. Wistar rats were submitted to parathyroidectomy, nephrectomy (Nx) and continuous infusion of 1-34 rat PTH in physiologic or 5 times the normal values. The diet was identical, however the P content was low (LP: 0,2%) or high (HP: 1,2%). We performed biochemical, histomorphometric, imuno-histochemistry and RT-PCR analysis. Rats submitted to Nx developed renal failure. The P overload contributed to loss bone volume independent of uremia. Besides Nx animals that received high PTH doses bone loss was slight probably because of the anabolic effect of PTH, which was attenuated by the phosphorus overload toxic. VC was only observed in Nx animals that received high PTH doses independently of P overload. However, the P overload with physiologic PTH doses induced phenotypic changes in VSMC that was confirmed for the up-expression of Runx2 on aorta of these animals. The high concentrations of P and PTH promoted histological changes on expression of osteoprotegerin and type I Collagen in calcified arteries and heart. This study does not established ideal levels of PTH sufficient for the maintenance of the bone integrity and also to prevent VC when animal are submitted to different P overload.