Digital radiography as an alternative method in the evaluation of bone density in uremic rats / Radiografia digital como método alternativo na avaliação da densidade óssea em ratos urêmicos

ABSTRACT Introduction: Digital radiography (DRx) may provide a suitable alternative to investigate mineral and bone disorder (MBD) and loss of bone density (BD) in rodent models of chronic kidney disease (CKD). The objective of this study was to use DRx to evaluate BD in CKD rats, and to evaluate the correlation between DRx findings and serum MBD markers and bone histomorphometry. Methods: Uremia was induced by feeding Wistar rats an adenine-enriched diet (0.75% for 4 weeks/0.10% for 3 weeks); outcomes were compared to a control group at experimental weeks 3, 4, and 7. The following biochemical markers were measured: creatinine clearance (CrC), phosphate (P), calcium (Ca), fractional excretion of P (FeP), alkaline phosphatase (ALP), fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH). DRx imaging was performed and histomorphometry analysis was conducted using the left femur. Results: As expected, at week 7, uremic rats presented with reduced CrC and higher levels of P, FeP, and ALP compared to controls. DRx confirmed the lower BD in uremic animals (0.57±0.07 vs. 0.68 ± 0.06 a.u.; p = 0.016) compared to controls at the end of week 7, when MBD was more prominent. A severe form of high-turnover bone disease accompanied these biochemical changes. BD measured on DRx correlated to P (r=-0.81; p = 0.002), ALP (r = -0.69, p = 0.01), PTH (r = -0.83, p = 0.01), OS/BS (r = -0.70; p = 0.02), and ObS/BS (r = -0.70; p = 0.02). Conclusion: BD quantified by DRx was associated with the typical complications of MBD in CKD and showed to be viable in the evaluation of bone alterations in CKD.

RESUMO Introdução: A radiografia digital (RxD) pode representar uma alternativa adequada para investigar o distúrbio mineral e ósseo (DMO) e a perda de densidade óssea (DO) em modelos de roedores da doença renal crônica (DRC). O objetivo deste estudo foi utilizar a RxD para avaliar a DO em ratos com DRC, e avaliar a correlação entre os achados da RxD e marcadores séricos de DMO e histomorfometria óssea. Métodos: A uremia foi induzida pela alimentação de ratos Wistar com dieta enriquecida com adenina (0,75% por 4 semanas/0,10% por 3 semanas); os resultados foram comparados com um grupo controle nas semanas experimentais 3, 4 e 7. Os seguintes marcadores bioquímicos foram medidos: clearance de creatinina (CCr), fosfato (P), cálcio (Ca), fração excretada de P (FeP), fosfatase alcalina (ALP), fator de crescimento de fibroblastos-23 (FGF-23) e paratormônio (PTH). A imagem da RxD foi obtida e a análise histomorfométrica foi realizada com o fêmur esquerdo. Resultados: como esperado, na semana 7, os ratos urêmicos apresentaram redução do CCr e níveis mais altos de P, FeP e ALP em comparação aos controles. A RxD confirmou a menor DO em animais urêmicos (0,57 ± 0,07 vs. 0,68 ± 0,06 u.a.; p = 0,016) em comparação aos controles no final da semana 7, quando a DMO foi mais proeminente. Uma forma grave de doença óssea de alta renovação celular acompanhou essas mudanças bioquímicas. A DO, medida na RxD foi correlacionada a P (r = -0,81; p = 0,002), ALP (r = -0,69, p = 0,01), PTH (r = -0,83, p = 0,01), OS/BS (r = -0,70 p = 0,02) e Ob.S/BS (r = -0,70; p = 0,02). Conclusão: A DO quantificada por RxD esteve associada às complicações típicas da DMO na DRC e mostrou-se viável na avaliação de alterações ósseas na DRC.

Digital radiography as an alternative method in the evaluation of bone density in uremic rats.

INTRODUCTION: Digital radiography (DRx) may provide a suitable alternative to investigate mineral and bone disorder (MBD) and loss of bone density (BD) in rodent models of chronic kidney disease (CKD). The objective of this study was to use DRx to evaluate BD in CKD rats, and to evaluate the correlation between DRx findings and serum MBD markers and bone histomorphometry. METHODS: Uremia was induced by feeding Wistar rats an adenine-enriched diet (0.75% for 4 weeks/0.10% for 3 weeks); outcomes were compared to a control group at experimental weeks 3, 4, and 7. The following biochemical markers were measured: creatinine clearance (CrC), phosphate (P), calcium (Ca), fractional excretion of P (FeP), alkaline phosphatase (ALP), fibroblast growth factor-23 (FGF-23), and parathyroid hormone (PTH). DRx imaging was performed and histomorphometry analysis was conducted using the left femur. RESULTS: As expected, at week 7, uremic rats presented with reduced CrC and higher levels of P, FeP, and ALP compared to controls. DRx confirmed the lower BD in uremic animals (0.57±0.07 vs. 0.68 ± 0.06 a.u.; p = 0.016) compared to controls at the end of week 7, when MBD was more prominent. A severe form of high-turnover bone disease accompanied these biochemical changes. BD measured on DRx correlated to P (r=-0.81; p = 0.002), ALP (r = -0.69, p = 0.01), PTH (r = -0.83, p = 0.01), OS/BS (r = -0.70; p = 0.02), and ObS/BS (r = -0.70; p = 0.02). CONCLUSION: BD quantified by DRx was associated with the typical complications of MBD in CKD and showed to be viable in the evaluation of bone alterations in CKD.

Evaluation of prevalence, biochemical profile, and drugs associated with chronic kidney disease-mineral and bone disorder in 11 dialysis centers.

INTRODUCTION: The diagnosis and treatment of mineral and bone disorder of chronic kidney disease (CKD-MBD) is a challenge for nephrologists and health managers. The aim of this study was to evaluate the prevalence, biochemical profile, and drugs associated with CKD-MBD. METHODS: Cross-sectional study between July and November 2013, with 1134 patients on dialysis. Sociodemographic, clinical, and laboratory data were compared between groups based on levels of intact parathyroid hormone (iPTH) (< 150, 150-300, 301-600, 601-1000, and > 1001 pg/mL). RESULTS: The mean age was 57.3 ± 14.4 years. The prevalence of iPTH < 150 pg/mL was 23.4% and iPTH > 601 pg/mL was 27.1%. The comparison between the groups showed that the level of iPTH decreased with increasing age. Diabetic patients had a higher prevalence of iPTH < 150 pg/mL (27.6%). Hyperphosphatemia (> 5.5 mg/dL) was observed in 35.8%. Calcium carbonate was used by 50.5%, sevelamer by 14.7%, 40% of patients had used some form of vitamin D and 3.5% used cinacalcet. Linear regression analysis showed a significant negative association between iPTH, age, and diabetes mellitus and a significant positive association between iPTH and dialysis time. CONCLUSION: The prevalence of patients outside the target for iPTH was 50.5%. There was a high prevalence of hyperphosphatemia (35.8%), and the minority of patients were using active vitamin D, vitamin D analogs, selective vitamin D receptor activators, and cinacalcet. These data indicate the need for better compliance with clinical guidelines and public policies on the supply of drugs associated with CKD-MBD.

Evaluation of prevalence, biochemical profile, and drugs associated with chronic kidney disease-mineral and bone disorder in 11 dialysis centers / Avaliação da prevalência, perfil bioquímico e drogas associadas ao distúrbio mineral ósseo-doença renal crônica em 11 centros de diálise

ABSTRACT Introduction: The diagnosis and treatment of mineral and bone disorder of chronic kidney disease (CKD-MBD) is a challenge for nephrologists and health managers. The aim of this study was to evaluate the prevalence, biochemical profile, and drugs associated with CKD-MBD. Methods: Cross-sectional study between July and November 2013, with 1134 patients on dialysis. Sociodemographic, clinical, and laboratory data were compared between groups based on levels of intact parathyroid hormone (iPTH) (< 150, 150-300, 301-600, 601-1000, and > 1001 pg/mL). Results: The mean age was 57.3 ± 14.4 years. The prevalence of iPTH < 150 pg/mL was 23.4% and iPTH > 601 pg/mL was 27.1%. The comparison between the groups showed that the level of iPTH decreased with increasing age. Diabetic patients had a higher prevalence of iPTH < 150 pg/mL (27.6%). Hyperphosphatemia (> 5.5 mg/dL) was observed in 35.8%. Calcium carbonate was used by 50.5%, sevelamer by 14.7%, 40% of patients had used some form of vitamin D and 3.5% used cinacalcet. Linear regression analysis showed a significant negative association between iPTH, age, and diabetes mellitus and a significant positive association between iPTH and dialysis time. Conclusion: The prevalence of patients outside the target for iPTH was 50.5%. There was a high prevalence of hyperphosphatemia (35.8%), and the minority of patients were using active vitamin D, vitamin D analogs, selective vitamin D receptor activators, and cinacalcet. These data indicate the need for better compliance with clinical guidelines and public policies on the supply of drugs associated with CKD-MBD.

RESUMO Introdução: O diagnóstico e tratamento do distúrbio mineral ósseo-doença renal crônica (DMO-DRC) é um desafio para os nefrologistas e gestores de saúde. O objetivo deste estudo foi avaliar a prevalência, perfil bioquímico, e drogas associadas a DMO-DRC. Métodos: Estudo transversal entre julho e novembro de 2013, em 11 centros com 1134 pacientes em diálise. Dados sociodemográficos, clínicos, e laboratoriais foram comparados entre os grupos, com base em níveis do paratormônio intacto (PTHi) (< 150,151-300, 301-600,601-1000, e > 1001 pg/mL). Resultados: A idade média foi de 57,3 ± 14,4 anos, 1071 pacientes estavam em hemodiálise, e 63 em diálise peritoneal. A prevalência de PTHi < 150 pg/mL foi 23,4% e PTHi > 601 pg/mL foi de 27,1%. A comparação dos grupos mostrou que o nível de PTHi diminuiu com o aumento da idade. Pacientes diabéticos apresentaram uma maior prevalência de PTHi < 150 pg/mL (27,6%). Carbonato de cálcio foi usado por 50,5%, Sevelamer por 14,7%, 40% dos pacientes utilizaram alguma forma de vitamina D, e 3,5% utilizaram cinacalcet. A hiperfosfatemia (> 5,5mg/dL) foi observada em 35,8%. A análise de regressão linear mostrou uma associação negativa significativa entre PTHi, idade, e diabetes mellitus e uma associação positiva significativa com o tempo em diálise. Conclusão: A prevalência de pacientes fora do alvo para PTHi foi de 50,5%. Houve uma alta prevalência de hiperfosfatemia e um baixo uso de vitamina D ativa, análogos da vitamina D, ativadores seletivos da vitamina D, e cinacalcet. Estes dados chamam a atenção para a necessidade de uma maior conformidade com as diretrizes e políticas públicas sobre o fornecimento de medicamentos associados à DMO-DRC.

Renal osteodystrophy in the obesity era: Is metabolic syndrome relevant?

BACKGROUND: Observational studies have shown a beneficial effect of obesity on bone health; however, most of those studies were not based on bone biopsies. Metabolic syndrome (MetS) could have an effect on bone remodeling. However, there are no data on the effects of MetS in the presence of renal osteodystrophy. OBJECTIVE: The aim of this study was to investigate associations between MetS and renal osteodystrophy using the bone histomorphometric turnover-mineralization-volume (TMV) classification. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: This observational cross-sectional study included 55 hemodialysis patients (28 women/27 men) who were evaluated for MetS and bone histomorphometry. Biochemical parameters included calcium, phosphorus, alkaline phosphatase, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, free serum leptin, fibroblast growth factor 23 (FGF23), intact osteocalcin, sclerostin (Scl), glucose, insulin, and thyroid hormones. Robust models of multivariate linear regressions were used for the statistical analyses. RESULTS: Females had higher iPTH levels (1,143 vs. 358, p = 0.02). Patients with normal bone volume (BV/TV) had a higher prevalence of MetS (73.6% vs. 41.7%, p = 0.02) and higher serum phosphorus, C-terminal FGF23 and insulin levels. The multivariate regression analysis showed that low-density lipoprotein cholesterol (LDL) was positively correlated with bone formation rate (BFR/BS) and negatively associated with mineralization lag time. Bone volume was negatively associated with age but positively associated with MetS. Body mass index (BMI) was not correlated with any of the bone histomorphometric parameters. CONCLUSION: Our results suggest that MetS is not a risk factor for low bone volume in hemodialysis patients. Furthermore, BMI alone was not related to bone volume in this population.

The complexity of chronic kidney disease-mineral and bone disorder across stages of chronic kidney disease.

Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (CKD-MBD) is a complex disease that is not completely understood. However, some factors secreted by the osteocytes might play an important role in its pathophysiology. Therefore, we evaluated the bone expression of proteins in a group of patients with CKD 2-3, CKD 4, and CKD 5 on dialysis and healthy individuals. We also tested several bone remodeling markers, and correlated these levels with bone biopsy findings. As expected, as serum calcium decreased, serum phosphate, alkaline phosphatase, fibroblast growth factor-23 (FGF-23), parathyroid hormone, and osteoprotegerin increased, as CKD progressed. Additionally, there was a gradual increase in bone resorption associated with a decrease in bone formation and impairment in bone mineralization. Bone expression of sclerostin and parathyroid hormone receptor-1 seemed to be increased in earlier stages of CKD, whereas FGF-23 and phosphorylated ß-catenin had increased expression in the late stages of CKD, although all these proteins were elevated relative to healthy individuals. Immunohistochemical studies showed that FGF-23 and sclerostin did not co-localize, suggesting that distinct osteocytes produce these proteins. Moreover, there was a good correlation between serum levels and bone expression of FGF-23. Thus, our studies help define the complex mechanism of bone and mineral metabolism in patients with CKD. Linkage of serum markers to bone expression of specific proteins may facilitate our understanding and management of this disease.

Peritoneal dialysis per se is a risk factor for sclerostin-associated adynamic bone disease.

Chronic kidney disease--mineral bone disorder (CKD-MBD) is a complex syndrome influenced by various factors, such as age, CKD etiology, uremic toxins, and dialysis modality. Although extensively studied in hemodialysis (HD) patients, only a few studies exist for peritoneal dialysis (PD) patients. Since most of these older studies contain no bone biopsy data, we studied the pattern of renal osteodystrophy in 41 prevalent PD patients. The most common presentation was adynamic bone disease (49%). There was a significant inverse association between serum sclerostin (a Wnt/ß-catenin pathway inhibitor that decreases osteoblast action and bone formation) and the bone formation rate. Bone alkaline phosphatase had the best sensitivity and specificity to detect both high- and low-turnover diseases. The comparison between nondiabetic PD and HD patients, matched by age, gender, parathyroid hormone level, and length of dialysis, revealed low 25-hydroxyvitamin D levels, worse bone mineralization, and low bone turnover in the nondiabetic PD group. Thus, adynamic bone disease was the most frequent type of renal osteodystrophy in PD patients. Sclerostin seems to participate in the pathophysiology of adynamic bone disease and bone alkaline phosphatase was the best serum marker of bone turnover in these patients.

[Diagnostic accuracy study comparing total alkaline phosphatase with intact parathyroid hormone 1-84 for the diagnosis of high turnover renal osteodystrophy in chronic renal failure on hemodialysis]. / Estudio de exactitud diagnóstica que compara fosfatasa alcalina total con paratohormona intacta 1-84 para el diagnóstico de osteodistrofia renal de alto recambio en la insuficiencia renal crónica en hemodiálisis.

INTRODUCTION: High turnover renal osteodystrophy (HTRO) is a highly prevalent complication in patients with chronic kidney disease and mineral bone disease (CKD-MBD), causing pain and significant fracture-associated morbidity and mortality. The diagnostic gold standard test is bone biopsy but there are other, more widely available screening tests such as 1-84 intact parathormone (1-84 iPTH) and nonspecific markers such as total alkaline phosphatase (tALP). PURPOSE: To determine the diagnostic value (ROC curve, predictive values and likelihood ratios) of 1-84 iPTH and tALP for HTRO screening. METHODS: A diagnostic accuracy study was performed on a sample of CKD-MDB patients, grouping them according to bone biopsy results and analyzing the results of the diagnostic tests as descriptive variables. RESULTS: The study group comprised 188 patients with CKD-MDB, 36 of which had biopsy-confirmed HTRO (19.15%). The average age was 50.2 years in the biopsy group, and 53.4 years in the non-biopsy group (p=0.2385), most were male (63.8%) and diabetic (80.5%). The mean time in dialysis was 5.02 years in the biopsy group, and 2.61 years for the non-biopsy group (p<0.001). The mean Kt/V was 1.44 in the biopsy group, and 1.40 in the non-biopsy group (p=0.5354). The mean tALP was 398.02 IU/L in the group with HTRO versus 141.76 IU/L in the group without HTRO (p<0.001). The best cut-off value for tALP was 300-350 IU/L with a near 80% post-test probability, but also with a 15-20% probability for HTRO if the test is negative. The mean 1-84 iPTH was 1248.01 pg/ml in the group with HTRO versus 350.76 pg/ml in the group without HTRO (p<0.001). The 1-84 iPTH cut-off reference value of 300 pg/ml was associated with a post-test probability of 30% for HTRO diagnosis and had a lower overall performance. The best cut-off value for iPTH 1-84 was 600 pg/ml with a post-test probability for HTRO of 70% if positive and less than 5% if the test results are negative. DISCUSSION: Both markers show good correlation with bone biopsy findings. tALP elevation detects presence of HTRO in selected patients but does not rule it out. tALP does not perform as well as 1-84 iPTH as a screening test for HTRO.

INTRODUCCIÓN: La osteodistrofia renal de alto recambio es una complicación altamente prevalente en pacientes con insuficiencia renal crónica y desorden mineral óseo, determinando dolor importante y morbimortalidad importante asociada a fracturas. El gold estándar para su diagnóstico es mediante biopsia ósea. Sin embargo, su pesquisa es mediante la elevación de paratohormona intacta 1-84 (iPTH 1-84) y otros marcadores más inespecíficos como fosfatasa alcalina total (FAT). OBJETIVOS: Determinar las propiedades diagnósticas (curva ROC, valores predictivos y likelihood ratios) de paratohormona intacta 1-84 y fosfatasa alcalina total para la sospecha de osteodistrofia renal de alto recambio. MÉTODOS: Estudio de exactitud diagnóstica tomando muestra de pacientes con insuficiencia renal crónica y desorden mineral óseo, clasificándolos según resultado de biopsia ósea y evaluando resultados de test diagnóstico señalados así como variables descriptivas de interés. RESULTADOS: De los 188 pacientes con insuficiencia renal crónica y desorden mineral óseo, 36 presentaron osteodistrofia renal de alto recambio confirmada por biopsia (19,15%). La edad promedio fue de 50,2 años en el grupo con biopsia y 53,4 en el grupo sin biopsia (p=0,2385); la mayoría fueron hombres (63,8%) y diabéticos 80,5%. El tiempo promedio en diálisis fue de 5,02 años para el grupo con biopsia y 2,61 para el grupo sin biopsia (p<0,001). Kt/V promedio 1,44 en el grupo con biopsia y 1, 40 en el grupo sin biopsia (p=0,5354). Fosfatasa alcalina total promedio 398,02 UI/L en grupo con osteodistrofia renal de alto recambio versus 141,76 UI/L en grupo sin osteodistrofia renal de alto recambio (p<0,001). El mejor valor de corte para fosfatasa alcalina total fue de ≥ 300 - 350 UI/L, determinando probabilidad post test de osteodistrofia renal de alto recambio cercana a 80% con test positivo y de 15 a 20% en caso de resultado negativo. La paratohormona intacta 1-84 promedio fue 1248,01 pg/ml en grupo con osteodistrofia renal de alto recambio versus 350,76 pg/ml en grupo sin osteodistrofia renal de alto recambio (p<0,001). El valor de corte de referencia para paratohormona intacta 1-84 ≥ 300 pg/ml se asoció a una probabilidad post test de osteodistrofia renal de alto recambio de 30% y mal rendimiento en general. El mejor valor de corte fue de ≥ 600 pg/ml con probabilidad post test de osteodistrofia renal de alto recambio del 70% con test positivo y menor a 5% con test negativo. CONCLUSIONES: Ambos marcadores estudiados muestran correlación con los hallazgos de biopsias óseas. La elevación de fosfatasa alcalina total detecta presencia de osteodistrofia renal de alto recambio en pacientes seleccionados, pero no la descarta. En rendimiento es inferior a la paratohormona intacta 1-84 como test de tamizaje.

La osteodistrofia renal y la paratohormona supresora de la remodelación ósea / Renal osteodystrophy and supressor paratohormone in bone remodeling

El Hiperparatiroidismo juega un rol central en la Osteodistrofia Renal (ODR) en pacientes con Insuficiencia Renal Crónica (IRC). Las primeras determinaciones de paratohormona (PTH) sérica aplicadas a la clínica en los años 1960, se basaban en métodos de radioinmunoanálisis (RIA) que usaban un solo anticuerpo contra la región carboxiterminal o la región media de la hormona. En 1987 se introdujo un método inmunométrico (IMA) basado en 2 anticuerpos, denominada en sandwich o PTH intacta, rutinariamente usado hasta hoy en la Investigación y Guías de manejo de la Osteodistrofia. A fines de la década del 90, autores detectaron 2 picks inmunoreactivos al usar el método tradicional, uno de ellos comigraba con la PTH intacta 1-84, en tanto que el 2º pick comigraba con la fracción 7-84, sugiriendo que un importante fragmento inactivo era incluido en las mediciones IMA, sobreestimando el real valor de la PTH, y exponiendo al paciente a tratamientos con altas dosis de vitamina D activa. Este método permitió separar la fracción biológicamente activa, denominada CAP-PTH, de una fracción supresora del metabolismo óseo, la CIP-PTH, y ha sido asociado a la falta de correlación entre la histomorfometría ósea y la PTH intacta 1-84. El importante aumento de la forma adinámica de ODR y las calcificaciones vasculares en los adultos urémicos, se han relacionado a elevadas dosis de vitamina D, calcio y fósforo, terapias que hasta hoy eran orientadas por los niveles de PTH plasmática. El actual manejo de la ODR debe ser reevaluado a la luz del conocimiento actual, y de futuras investigaciones que permitirán un mejor control de esta complicación de la Insuficiencia Renal Crónica.

Serum markers of low-turnover bone disease in Mexican children with chronic kidney disease undergoing dialysis.

BACKGROUND: The frequency of low-turnover bone disease (LTBD) in patients with chronic kidney disease (CKD) has increased in past years. This change is important because LTBD is associated with bone pain, growth delay, and higher risk for bone fractures and extraosseous calcifications. LTBD is a histological diagnosis. However, serum markers such as parathyroid hormone (PTH) and calcium levels offer a noninvasive alternative for diagnosing these patients. OBJECTIVE: To describe the prevalence of LTBD in pediatric patients with renal failure undergoing some form of renal replacement therapy, using serum calcium and intact PTH levels as serum markers. METHODS: In this cross-sectional study, 41 children with CKD undergoing dialysis treatment (31 on continuous ambulatory peritoneal dialysis and 10 on hemodialysis) were included. There were no inclusion restrictions with respect to gender, cause of CKD, or dialysis modality. The children were studied as outpatients. The demographic data, CKD course, time on dialysis, phosphate-binding agents, and calcitriol prescription were registered, as well as weight, height, Z-score for height, linear growth rate, and Z-score for body mass index. Serum calcium, phosphorus, aluminum, PTH, alkaline phosphatase, osteocalcin, glucose, creatinine, urea, cholesterol, and triglycerides were measured. RESULTS: There were 20 (48.8%) children with both PTH < 150 pg/mL and corrected total calcium >10 mg/dL who were classified as having LTBD[(+)]; the remaining 21 (51.2%) children were classified as having no LTBD[(-)]. The LTBD(+) patients were younger (11.2 +/- 2.7 vs 13.2 +/- 2.4 years, p < 0.01) but they had no differences regarding Z-scores for height. Linear growth in 6 months was less than expected in both groups (-0.15 +/- 0.23 cm/month), but the difference between expected and observed growth was higher in the LTBD(+) group (-0.24 +/- 0.14 vs -0.07 +/- 0.28 cm/mo, p < 0.03). LTBD(+) patients also had lower serum creatinine (8.69 +/- 2.75 vs 11.19 +/- 3.17 mg/dL, p < 0.01), higher serum aluminum levels [median (range) 38.4 (9 - 106) vs 28.1 (9 - 62) microLg/L, p < 0.05], and lower systolic blood pressure (112.0 +/- 10.3 vs 125.0 +/-1 2.9 mmHg, p < 0.015) and diastolic blood pressure (76.0 +/- 9.7 vs 84.5 +/- 8.2 mmHg, p < 0.017). A significant correlation was found between PTH and alkaline phosphatase (r = 0.68, p < 0.001), but not between PTH and aluminum. CONCLUSION: The LTBD(+) biochemical profile was found in 48.8% of the children and was associated with impaired linear growth. Aluminum contamination, evidenced by higher serum aluminum levels, may have had a pathogenic role in these disorders. Higher systolic and diastolic blood pressure levels may be related to higher serum PTH levels.

Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function, and bone in rats with renal failure.

BACKGROUND: Hyperphosphatemia and disturbances in calcium or parathyroid hormone (PTH) metabolism contribute to the high incidence of cardiovascular disease and renal osteodystrophy in chronic renal failure (CRF). We evaluated the effect of hyperphosphatemia on the cardiovascular system, on renal function, and on bone in experimental uremia. METHODS: Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx) with minipump implantation, delivering 1-34 rat PTH (physiologic rate), or were sham-operated and received vehicle. Only phosphorus content (low-phosphorus (LP) 0.2%; high-phosphorus (HP) 1.2%) differentiated diets. We divided the groups as follows: PTx +Nx +LP; sham + LP; PTx + Nx + HP; and sham + HP. Tail-cuff pressure and weight were measured weekly. After 2 months, biochemical, arterial, and myocardial histology and bone histomorphometry were analyzed. RESULTS: Heart weight normalized to body weight (heart weight/100 g body weight) was higher in PTx + Nx + HP rats (PTx + Nx + HP = 0.36 +/- 0.01 vs. sham + HP = 0.29 +/- 0.01, PTx + Nx + LP = 0.32 +/- 0.01, sham + LP = 0.28 +/- 0.01) (P < 0.05). Serum creatinine levels were higher in PTx + Nx + HP rats than in PTx + Nx + LP rats (1.09 +/- 0.13 vs. 0.59 +/- 0.03 mg/dL) (P < 0.05). Levels of PTH did not differ significantly between the groups. Myocardial and arterial histology detected no vascular calcification or fibrosis. Bone histomorphometry revealed an association, unrelated to uremia, between HP diets and decreased trabecular connectivity. CONCLUSION: Myocardial hypertrophy, impaired renal function, and adverse effects on bone remodeling were associated with hyperphosphatemia and were not corrected by PTH replacement. Although no vascular calcification was observed in this model, we cannot rule out an adverse effect of hyperphosphatemia on the vascular bed. Our finding underscores the importance of phosphorus control in reducing morbidity and mortality in CRF patients.

[Whole PTH and 1-84/84 PTH ratio for the non invasive determination of low bone turnover in renal osteodysthrophy]. / Utilidad de la determinación de PTH entera y del cociente PTH 1-84/7-84 en el diagnóstico no invasivo de osteodistrofia de bajo recambio.

The conventional intact PTH assays detect not only PTH 1-84 but also inactive fragments (as PTH 7-84) that accumulate in renal failure. There has been a recent development of a new PTH assay that measures only true 1-84 PTH (Whole PTH or CAP assay, Scantibodies). As 7-84 PTH fragment is antagonistic on bone effects of 1-84 PTH, Moniere-Faugere has suggested that 1-84/7-84 PTH ratio less than 1 is predictive of low turnover. We evaluated the usefulness of CAP assay and the 1-84/7-84 PTH ratio as markers of bone turnover in a groups of 24 patients in peritoneal dialysis (PD). Patients were classified as having low bone turn over if they had a Total PTH (similar to intact PTH) of less than 100 pg/ml. We also measured serum CrossLaps (CTX) as another serum resorption marker. Patients had a mean Whole PTH of 95.5 pg/ml and a mesan total PTH of 155.4 pg/l (range 9 to 900). Whole PTH represented 69.1% of total PTH. Fifteen patients (62.5%) had a total PTH of less than 100. These patients had a 1-84/7-84 relationship of 1.9 +/- 1.8 while 9 patients with Total PTH more than 100 had a relationship of 1.29 +/- 0.6 (p = NS). There was a tight correlation between Whole PTH and total PTH (r = 0.98; p < 0.0001) and with serum CTX (r = 0.78; p < 0.0001). We conclude that 1-84/7-84 ratio does not seem useful in the prediction of low bone turnover and that Whole PTH does not seem to be more useful than intact PTH in the prediction of bone turnover in this population. Future studies should correlate this markers with direct measurements of bone turnover in bone biopsies to demonstrate their usefulness in the prediction of the type of renal osteodystrophy.

[Biochemical and histological spectrum of renal osteodystrophy in Argentina]. / Espectro bioquímico e histológico de la osteodistrofia renal en Argentina.

Between 1994-2001 we have performed 57 bone biopsies for diagnostic purposes in symptomatic CRF patients. We analyzed here 52 samples where the material was optimal for study, and divided them into 2 periods according to when the biopsy was performed: 1994-1996 and 1997-2001, to verify changes in the spectrum of renal osteodystrophy. Mean serum values were: serum calcium 9.9 +/- 1.8 mg/dl, phosphate 5.8 +/- 3.2 mg/dl, alkaline phosphatase 693.9 +/- 968.9 Ul/L, iPTH 562.0 +/- 598.5 pg/ml, serum aluminum 65.7 +/- 79.3 ug/L and bone aluminum 22.8 +/- 22.4 ug/g. Hyperparathyroidism was the most common histological diagnosis as severe in 13 patients (25%), or as mild in 14 (27%). Ten patients had osteomalacia (19%), adynamic bone disease was diagnosed in 5 (9.6%) and mixed renal osteodystrophy in 10 (19.2%). Low bone turnover patients showed higher bone and serum aluminum than high bone turnover patients. We observed a relative increment in high turnover bone disease in the later period (1997-2001) without changes in low turnover bone disease. These data showed a high prevalence of hyperparathyroidism and aluminum-related low turnover bone disease, with no significant changes between the two time-periods analyzed here.

[Importance of the "adequate blood phosphorus" concept as a risk factor for hyperphosphatemia]. / Importancia del concepto "fosfatemia adecuada" como factor de riesgo de hiperfosfatemia.

Hyperphosphatemia is an important risk factor of secondary hyperparathyroidism and extraosseous calcifications in chronic renal failure patients. In this study our hypothesis is that physicians misconception of adequate phosphatemia is a risk factor for hyperphosphatemia. In 1999 GEMOR sent a renal osteodystrophy inquiry to different hemodialysis centers in Argentina. It included 80 dialysis centers in 17 Argentinian provinces. The enquire had 33 questions about renal osteodystrophy. Here we report the section related to phosphorous metabolism. We obtained responses from 80 dialysis centers (4,512 dialysis patients), which represents about 24% of Argentinian dialysis centers. Physicians considered phosphorous levels between 4.5 to 5.5 mg/dl in 83.5% of centers as adequate, and between 5.5 to 6.5 mg/dl in 10.1%. Five out of 77 centers reported that they had no patients with hyperphosphatemia. The percentage of hemodialysis patients that had more than 6 mg/dl in each center was 28.8 +/- 15.9%. Those centers that aimed for phosphatemia between 5.5 and 6.5 mg/dl, had a higher percentage of patients with phosphatemia above 6 mg/dl than those aiming for between 4.5 and 5.5 mg/dl (42.8 +/- 16.7 vs 27.1 +/- 15.2% respectively, p = 0.007), and had higher mean of phosphatemia (6.4 +/- 0.7 vs 5.3 +/- 0.7 mg/dl respectively, p = 0.0001), than the last group. In conclusion, a higher mean phosphate level was obtained in hemodialysis centers where physicians considered higher pre-dialysis target levels. Some centers had no patients with hyperphosphatemia (neglect or good control?).

Effects of in-center daily hemodialysis upon mineral metabolism and bone disease in end-stage renal disease patients.

CONTEXT: Alternative hemodialysis schedules have been proposed to improve the quality of the dialysis. Nonetheless, their influence upon mineral and bone disorders is unknown. OBJECTIVE: To report the impact of a daily hemodialysis schedule upon the lesions of renal osteodystrophy. TYPE OF STUDY: Prospective non-controlled study. SETTING: Public University Hospital. PARTICIPANTS: Five patients treated by daily hemodialysis for at least 24 months. INTERVENTION: Daily dialysis sessions were accomplished with non-proportional dialysis machines without an ultrafiltration control device, with blood flow of 300 ml/min, bicarbonate dialysate ([Ca]=3.5 mEq/L) at 500 ml/min, and low-flux membrane dialyzers. Sessions were started at 6:00 p.m. (except Sundays) and lasted 2 hours. MAIN MEASUREMENTS: Serum levels of Ca and P from the last 6 months on conventional hemodialysis for the same patients were used for comparison with each semester of daily hemodialysis. Bone biopsies and PTH levels were obtained at the end of the conventional hemodialysis period and then again after 2 years of daily hemodialysis. RESULTS: Mean serum calcium was significantly higher during the second and third semesters of daily dialysis [10.0 mg% (SD 0.6), and 10.0 mg% (SD 0.8), respectively] compared to standard dialysis [9.4 mg% (SD 0.8)], p < 0.05. Mean values for phosphorus were significantly lower during every semester of daily hemodialysis [6.3 mg% (SD 1.8), 5.8 mg% (SD 1.7), 6.0 mg% (SD 1.7), and 6.0 mg% (SD 1.8)] compared to standard dialysis [7.2 mg% (SD 2.7)], P < 0.05. Variations in mean Ca x P product followed the same pattern as for phosphorus [59.5 (SD 16.0), 57.1 (SD 16.3), 59.8 (SD 17.7), and 58.31 (SD 20.9) vs. 68.6 (SD 27.3), P < 0.05]. After 2 years on daily hemodialysis, 2 patients who had aplastic lesion were found to have mild bone disorder. In addition, one patient with mixed bone lesion and moderate bone aluminum accumulation had osteitis fibrosa with no aluminum. Intact PTH values at the beginning of study and after 2 years on daily hemodialysis did not differ [134 pg/ml (SD 66) vs. 109 pg/ml (SD 26), P = 0.60, respectively]. CONCLUSIONS: Patients treated using daily hemodialysis had better control of serum phosphorus and perhaps a lower risk of metastatic calcifications. Daily hemodialysis also seemed to be beneficial to low turnover bone disease and bone aluminum deposition.

Different patterns of renal osteodystrophy in Iberoamerica.

The various forms of renal osteodystrophy are predominant hyperparathyroid bone disease, mixed uremic osteodystrophy, low turnover osteomalacia, and adynamic bone disease. The present study analyses a total number of 1,209 bone biopsies from 5 different countries (Brazil, Uruguay, Argentina, Portugal, and Spain). Low turnover osteomalacia and mixed uremic osteodystrophy were more common in Brazil, Uruguay, and Argentina than in Portugal and Spain whereas predominant hyperparathyroid bone disease was seen more often in Portugal and Spain. In all centers, independent of the aluminum staining technique used, the extent of aluminum deposited in bone was greater in patients presenting with low bone turnover, whether from low turnover osteomalacia or adynamic bone disease, than in the predominant hyperparathyroid bone disease. In summary, even though recent reports have indicated that, over the last decade, the incidence of aluminum-induced toxicity was reduced, aluminum still seems to be implicated in a great percentage of symptomatic low bone remodelling lesions in Iberoamerica.

Bone disease in patients with long-term renal transplantation and normal renal function.

Renal osteodystrophy may persist during the early years after renal transplantation. However, information on bone status after a successful long-term renal transplantation is limited. We examined biochemical parameters, bone mineral density (BMD), and bone histomorphometry in 25 asymptomatic men with normal renal function after 7.5 +/- 5.7 years of a renal transplantation. Serum calcium, phosphorus, alkaline phosphatase, and 1,25(OH)(2)D(3) levels and urinary calcium level and cyclic andenosine monophosphate excretion were within normal range in all patients. Serum intact parathyroid hormone (PTH) level was elevated in 11 subjects (133.6 +/- 78 pg/mL) and normal in the other 14 subjects (47.9 +/- 13.6 pg/mL). Mean BMD at the lumbar spine and femoral neck was low in the entire group. However, it progressively increased as time after transplantation increased, approaching normal values after 10 years. Bone histomorphometric analysis showed bone resorption, osteoid volume, and osteoid surface greater than normal range in the majority of patients. Bone formation rate and mineralization surface were low, and mineralization time was delayed in most patients. These lesions were more severe in patients after 3 to 4 years of transplantation but improved with time and approached normal values after a period of 10 years. PTH values did not correlate with bone histological characteristics or BMD. These results show that the bone alterations observed after long-term renal transplantation consist of a mixed bone disease in which features of high bone turnover coexist with altered bone formation and delayed mineralization. These findings may result from the combined effect of preexisting bone disease and immunosuppressive therapy.

The spectrum of bone disease in 200 chronic hemodialysis patients: a correlation between clinical, biochemical and histologic findings

Introduction: Renal osteodystrophy includes the complete range of mineral metabolism disordes that affect the skeleton in patients with chronic renal failure. Patients and Methods: 200 patients with end-stage renal disease and on dialysis were investigated regarding the clinical, biochemical and histological findings of bone disease. Results: The spectrum of renal osteodystrophy consisted mainly of high turnover bone lesions (74.5 percent), including osteitis fibrosa in 57.5 percent. Patients with mild bone disease were on dialysis for shorter periods of time and were mostly asymptomatic. Patients with aluminum-related bone disease (16.5 percent) had the greatest aluminum exposure, either orally or parenterally, and together with patients with high turnover mixed disease, were the most symptomatic. Although on a non-regular basis, the vast majority of the patients (82.5 percent) had been receiving vitamin D. The incidence of adynamic bone disease was high (n=8) among parathyroidectomized patients (n=12). Significantly higher serum levels of alkaline phosphatase were observed in osteitis fibrosa. Conclusions: The use calcitriol and phosphate-binding agents on a non-regular basis seems to be the reason for the apparent reduced response to the treatment of secondary hyperparathyroidism. Alkaline phosphatase has been shown to be a fair marker for bone turnover in patients with osteitis fiborsa. The severity of the clinical manifestations of bone disease correlates with the histological features of bone lesion and to the time spent on dialysis.