Parathyroidectomy: still the best choice for the management of severe secondary hyperparathyroidism / Paratireoidectomia: ainda a melhor escolha para o tratamento do hiperparatireoidismo secundário grave

Abstract Introduction: Management of secondary hyperparathyroidism (SHPT) is a challenging endeavor with several factors contruibuting to treatment failure. Calcimimetic therapy has revolutionized the management of SHPT, leading to changes in indications and appropriate timing of parathyroidectomy (PTX) around the world. Methods: We compared response rates to clinical vs. surgical approaches to SHPT in patients on maintenance dialysis (CKD 5D) and in kidney transplant patients (Ktx). A retrospective analysis of the one-year follow-up findings was carried out. CKD 5D patients were divided into 3 groups according to treatment strategy: parathyroidectomy, clinical management without cinacalcet (named standard - STD) and with cinacalcet (STD + CIN). Ktx patients were divided into 3 groups: PTX, CIN (cinacalcet use), and observation (OBS). Results: In CKD 5D we found a significant parathormone (PTH) decrease in all groups. Despite all groups had a higher PTH at baseline, we identified a more pronounced reduction in the PTX group. Regarding severe SHPT, the difference among groups was evidently wider: 31%, 14% and 80% of STD, STD + CIN, and PTX groups reached adequate PTH levels, respectively (p<0.0001). Concerning the Ktx population, although the difference was not so impressive, a higher rate of success in the PTX group was also observed. Conclusion: PTX still seems to be the best treatment choice for SHPT, especially in patients with prolonged diseases in unresourceful scenarios.

Resumo Introdução: O manejo do hiperparat-ireoidismo secundário (HPTS) é uma tarefa desafiadora com diversos fatores que contribuem para o fracasso do tratamento. A terapia calcimimética revolucionou o manejo do HPTS, levando a alterações nas indicações e no momento apropriado da paratireoidectomia (PTX) em todo o mundo. Métodos: Comparamos taxas de resposta às abordagens clínica vs. cirúrgica do HPTS em pacientes em diálise de manutenção (DRC 5D) e pacientes transplantados renais (TxR). Foi realizada uma análise retrospectiva dos achados de um ano de acompanhamento. Pacientes com DRC 5D foram divididos em 3 grupos de acordo com a estratégia de tratamento: paratireoidectomia, manejo clínico sem cinacalcete (denominado padrão - P) e com cinacalcete (P + CIN). Os pacientes com TxR foram divididos em 3 grupos: PTX, CIN (uso de cinacalcete) e observação (OBS). Resultados: Na DRC 5D, encontramos uma redução significativa do paratormônio (PTH) em todos os grupos. Apesar de todos os grupos apresentarem um PTH mais elevado no início do estudo, identificamos uma redução mais acentuada no grupo PTX. Com relação ao HPTS grave, a diferença entre os grupos foi evidentemente maior: 31%, 14% e 80% dos grupos P, P + CIN e PTX atingiram níveis adequados de PTH, respectivamente (p< 0,0001). Com relação à população TxR, embora a diferença não tenha sido tão impressionante, também foi observada uma taxa maior de sucesso no grupo PTX. Conclusão: A PTX ainda parece ser a melhor escolha de tratamento para o HPTS, especialmente em pacientes com doenças prolongadas em cenários sem recursos.

Parathyroidectomy: still the best choice for the management of severe secondary hyperparathyroidism.

INTRODUCTION: Management of secondary hyperparathyroidism (SHPT) is a challenging endeavor with several factors contruibuting to treatment failure. Calcimimetic therapy has revolutionized the management of SHPT, leading to changes in indications and appropriate timing of parathyroidectomy (PTX) around the world. METHODS: We compared response rates to clinical vs. surgical approaches to SHPT in patients on maintenance dialysis (CKD 5D) and in kidney transplant patients (Ktx). A retrospective analysis of the one-year follow-up findings was carried out. CKD 5D patients were divided into 3 groups according to treatment strategy: parathyroidectomy, clinical management without cinacalcet (named standard - STD) and with cinacalcet (STD + CIN). Ktx patients were divided into 3 groups: PTX, CIN (cinacalcet use), and observation (OBS). RESULTS: In CKD 5D we found a significant parathormone (PTH) decrease in all groups. Despite all groups had a higher PTH at baseline, we identified a more pronounced reduction in the PTX group. Regarding severe SHPT, the difference among groups was evidently wider: 31%, 14% and 80% of STD, STD + CIN, and PTX groups reached adequate PTH levels, respectively (p<0.0001). Concerning the Ktx population, although the difference was not so impressive, a higher rate of success in the PTX group was also observed. CONCLUSION: PTX still seems to be the best treatment choice for SHPT, especially in patients with prolonged diseases in unresourceful scenarios.

Iron-based phosphorus chelator: Risk of iron deposition and action on bone metabolism in uremic rats.

Phosphate chelators are frequently used in patients with chronic kidney disease (CKD). New iron-based chelators remain understudied and offer a promising therapeutic option for the control of bone and mineral disorders of chronic kidney disease (BMD-CKD). We assessed the effect of the phosphorus chelator, chitosan-iron III (CH-FeCl), compared to calcium carbonate (CaCO3) in BMD-CKD and the potential iron overload in uremic rats. Thirty-two animals were divided into four groups, namely the control, CKD, CKD/CH-FeCl, and CKD/CaCO3 groups. CKD was induced by adding 0.75% (4 weeks) and 0.1% (3 weeks) adenine to the diet. The chelators were administered from week 3 through week 7. The renal function, BMD-CKD markers, and histomorphometry of the femur were assessed at week 7. The CKD group showed a significant increase in creatinine (83.9 ± 18.6 vs. 41.5 ± 22.1 µmol/L; P = 0.001), phosphate (3.5 ± 0.8 vs. 2.2 ± 0.2 mmol/L; P = 0.001), fractional excretion of phosphorus (FEP) (0.71 ± 0.2 vs. 0.2 ± 0.17; P = 0.0001), and FGF23 (81.36 ± 37.16 pg/mL vs. 7.42 ± 1.96; P = 0.011) compared to the control group. There was no accumulation of serum or bone iron after the use of CH-FeCl. The use of chelators reduced the FEP (control: 0.71 ± 0.20; CKD/CH-FeCl: 0.40 ± 0.16; CKD/CaCO3 0.34 ± 0.15; P = 0.001), without changes in the serum FGF23 and parathyroid hormone levels. Histomorphometry revealed the presence of bone disease with high remodeling in the uremic animals without changes with the use of chelators. The CH-FeCl chelator was efficient in reducing the FEP without iron accumulation, thereby paving the way for the use of this class of chelators in clinical settings in the future.

Parathyroid hormone levels after parathyroidectomy for secondary hyperparathyroidism.

OBJECTIVE: The parathormone level after parathyroidectomy in dialysis patients are of interest. Low levels may require cryopreserved tissue implantation; however, the resection is necessary in case of recurrence. We analyzed post parathyroidectomy parathormone levels in renal hyperparathyroidism. METHODS: Prospective observation of postoperative parathormone levels over defined periods in a cohort of dialysis patients that underwent total parathyroidectomy and immediate forearm autograft from 2008 to 2010, at a single tertiary care hospital. RESULTS: Of 33 patients, parathormone levels until 36 months could be divided into four patterns. Patients with stable function (Pattern 1) show relatively constant levels after two months (67% of the cases). Early function and later failure (Pattern 2) were an initial function with marked parathormone reduction before one year (18%). Graft recurrence (Pattern 3) showed a progressive increase of parathormone in four cases (12%). Complete graft failure (Pattern 4) was a nonfunctioning implant at any period, which was observed in one patient (3%). Parathormone levels of Pattern 3 became statistically different of Pattern 1 at 36 months. CONCLUSIONS: Patients that underwent the total parathyroidectomy and autograft present four different graft function patterns with a possible varied therapeutic management.

Parathyroid hormone levels after parathyroidectomy for secondary hyperparathyroidism

SUMMARY OBJECTIVE: The parathormone level after parathyroidectomy in dialysis patients are of interest. Low levels may require cryopreserved tissue implantation; however, the resection is necessary in case of recurrence. We analyzed post parathyroidectomy parathormone levels in renal hyperparathyroidism. METHODS: Prospective observation of postoperative parathormone levels over defined periods in a cohort of dialysis patients that underwent total parathyroidectomy and immediate forearm autograft from 2008 to 2010, at a single tertiary care hospital. RESULTS: Of 33 patients, parathormone levels until 36 months could be divided into four patterns. Patients with stable function (Pattern 1) show relatively constant levels after two months (67% of the cases). Early function and later failure (Pattern 2) were an initial function with marked parathormone reduction before one year (18%). Graft recurrence (Pattern 3) showed a progressive increase of parathormone in four cases (12%). Complete graft failure (Pattern 4) was a nonfunctioning implant at any period, which was observed in one patient (3%). Parathormone levels of Pattern 3 became statistically different of Pattern 1 at 36 months. CONCLUSIONS: Patients that underwent the total parathyroidectomy and autograft present four different graft function patterns with a possible varied therapeutic management.

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.

A Randomized Trial of Zoledronic Acid to Prevent Bone Loss in the First Year after Kidney Transplantation.

BACKGROUND: Bone and mineral disorders commonly affect kidney transplant (KTx) recipients and have been associated with a high risk of fracture. Bisphosphonates may prevent or treat bone loss in such patients, but there is concern that these drugs might induce adynamic bone disease (ABD). METHODS: In an open label, randomized trial to assess the safety and efficacy of zoledronate for preventing bone loss in the first year after kidney transplant, we randomized 34 patients before transplant to receive zoledronate or no treatment. We used dual-energy x-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HR-pQCT), and bone biopsies to evaluate changes in bone in the 32 evaluable participants between the time of KTx and 12 months post-transplant. RESULTS: Both groups of patients experienced decreased bone turnover after KTx, but zoledronate itself did not affect this outcome. Unlike previous studies, DXA showed no post-transplant bone loss in either group; we instead observed an increase of bone mineral density in both lumbar spine and total hip sites, with a significant positive effect of zoledronate. However, bone biopsies showed post-transplant impairment of trabecular connectivity (and no benefit from zoledronate); HR-pQCT detected trabecular bone loss at the peripheral skeleton, which zoledronate partially attenuated. CONCLUSIONS: Current immunosuppressive regimens do not contribute to post-transplant central skeleton trabecular bone loss, and zoledronate does not induce ABD. Because fractures in transplant recipients are most commonly peripheral fractures, clinicians should consider bisphosphonate use in patients at high fracture risk who have evidence of significantly low bone mass at these sites at the time of KTx.

Bone biopsy in nephrology practice.

Renal osteodystrophy (ROD), a group of metabolic bone diseases secondary to chronic kidney disease (CKD), still represents a great challenge to nephrologists. Its management is tailored by the type of bone lesion - of high or low turnover - that cannot be accurately predicted by serum biomarkers of bone remodeling available in daily clinical practice, mainly parathyroid hormone (PTH) and alkaline phosphatase (AP). In view of this limitation, bone biopsy followed by bone quantitative histomorphometry, the gold-standard method for the diagnosis of ROD, is still considered of paramount importance. Bone biopsy has also been recommended for evaluation of osteoporosis in the CKD setting to help physicians choose the best anti-osteoporotic drug. Importantly, bone biopsy is the sole diagnostic method capable of providing dynamic information on bone metabolism. Trabecular and cortical bones may be analyzed separately by evaluating their structural and dynamic parameters, thickness and porosity, respectively. Deposition of metals, such as aluminum and iron, on bone may also be detected. Despite of these unique characteristics, the interest on bone biopsy has declined over the last years and there are currently few centers around the world specialized on bone histomorphometry. In this review, we will discuss the bone biopsy technique, its indications, and the main information it can provide. The interest on bone biopsy should be renewed and nephrologists should be capacitated to perform it as part of their training during medical residency.

Bone biopsy in nephrology practice / Biópsia óssea na prática nefrológica

Abstract Renal osteodystrophy (ROD), a group of metabolic bone diseases secondary to chronic kidney disease (CKD), still represents a great challenge to nephrologists. Its management is tailored by the type of bone lesion - of high or low turnover - that cannot be accurately predicted by serum biomarkers of bone remodeling available in daily clinical practice, mainly parathyroid hormone (PTH) and alkaline phosphatase (AP). In view of this limitation, bone biopsy followed by bone quantitative histomorphometry, the gold-standard method for the diagnosis of ROD, is still considered of paramount importance. Bone biopsy has also been recommended for evaluation of osteoporosis in the CKD setting to help physicians choose the best anti-osteoporotic drug. Importantly, bone biopsy is the sole diagnostic method capable of providing dynamic information on bone metabolism. Trabecular and cortical bones may be analyzed separately by evaluating their structural and dynamic parameters, thickness and porosity, respectively. Deposition of metals, such as aluminum and iron, on bone may also be detected. Despite of these unique characteristics, the interest on bone biopsy has declined over the last years and there are currently few centers around the world specialized on bone histomorphometry. In this review, we will discuss the bone biopsy technique, its indications, and the main information it can provide. The interest on bone biopsy should be renewed and nephrologists should be capacitated to perform it as part of their training during medical residency.

Resumo A osteodistrofia renal (OR), um grupo de doenças ósseas metabólicas secundárias à doença renal crônica (DRC), ainda representa um grande desafio para os nefrologistas. Seu manejo é individualizado de acordo com o tipo de lesão óssea - de alto ou baixo remodelamento - cujo diagnóstico não pode ser prevista com precisão pelos biomarcadores séricos de remodelação óssea disponíveis na prática clínica diária, principalmente o paratormônio (PTH) e a fosfatase alcalina (FA). Em vista dessa limitação, biópsia óssea seguida de histomorfometria óssea quantitativa, método padrão-ouro para o diagnóstico de OR, ainda é considerado um procedimento de grande importância. A biópsia óssea também é recomendada na avaliação da osteoporose em indivíduos com DRC, a fim de auxiliar na escolha do melhor medicamento anti-osteoporótico. É importante observar que a biópsia óssea é o único método diagnóstico capaz de proporcionar informações dinâmicas sobre o metabolismo ósseo. Os ossos trabecular e cortical podem ser analisados separadamente por meio da avaliação de seus parâmetros estruturais e dinâmicos, espessura e porosidade, respectivamente. A deposição óssea de metais como alumínio e ferro também pode ser detectada. Apesar de suas características singulares, o interesse pela biópsia óssea diminuiu nos últimos anos. Poucos centros em todo o mundo são especializados em histomorfometria óssea. A presente revisão discute a técnica de biópsia óssea, suas indicações e as principais informações que ela pode oferecer. O interesse pela biópsia óssea deve ser renovado e os nefrologistas devem ser capacitados a realizá-la durante o período de residência médica.

Effect of cross-linked chitosan iron (III) on vascular calcification in uremic rats.

Cross-linked chitosan iron (III) is a chitin-derived polymer with a chelating effect on phosphorus, but it is untested in vascular calcification. We evaluated this compound's ability to reduce hyperphosphatemia and its effect on vascular calcification in uremic rats using an adenine-based, phosphorus-rich diet for seven weeks. We used a control group to characterize the uremia. Uremic rats were divided according the treatment into chronic kidney disease, CKD-Ch-Fe(III)CL (CKD-Ch), CKD-calcium carbonate, or CKD-sevelamer groups. We measured creatinine, phosphorus, calcium, alkaline phosphatase, phosphorus excretion fraction, parathyroid hormone, and fibroblast growth factor 23. Vascular calcification was assessed using the aortic calcium content, and a semi-quantitative analysis was performed using Von Kossa and hematoxylin-eosin staining. At week seven, rats in the chronic kidney disease group had higher creatinine, phosphorus, phosphorus excretion fraction, calcium, alkaline phosphatase, fibroblast growth factor 23, and aortic calcium content than those in the Control group. Treatments with cross-linked chitosan iron (III) and calcium carbonate prevented phosphorus increase (20%-30% reduction). The aortic calcium content was lowered by 88% and 85% in the CKD-Ch and CKD-sevelamer groups, respectively. The prevalence of vascular changes was higher in the chronic kidney disease and CKD-calcium carbonate (62.5%) groups than in the CKD-Ch group (37.5%). In conclusion, cross-linked chitosan iron (III) had a phosphorus chelating effect similar to calcium carbonate already available for clinical use, and prevented calcium accumulation in the aorta. Impact statement Vascular calcification (VC) is a common complication due to CKD-related bone and mineral disorder (BMD) and is characterized by deposition of calcium in vessels. Effective therapies are not yet available but new phosphorus chelators can prevent complications from CV. We tested the effect of chitosan, a new phosphorus chelator, on the VC of uremic animals. It has recently been proposed that chitosan treatment may be effective in the treatment of hyperphosphataemia. However, its action on vascular calcification has not been investigated yet. In this study, we demonstrated that chitosan reduced the calcium content in the aorta, suggesting that this may be a therapeutic approach in the treatment of hyperphosphatemia by preventing CV.

Chitosan-Fe (III) Complex as a Phosphate Chelator in Uraemic Rats: A Novel Treatment Option.

Phosphate retention and hyperphosphataemia are associated with increased mortality in patients with chronic kidney disease (CKD). We tested the use of cross-linked iron chitosan III (CH-FeCl) as a potential phosphate chelator in rats with CKD. We evaluated 96 animals, divided equally into four groups (control, CKD, CH-FeCl and CKD/CH-FeCl), over 7 weeks. We induced CKD by feeding animals an adenine-enriched diet (0.75% in the first 4 weeks and 0.1% in the following 3 weeks). We administered 30 mg/kg daily of the test polymer, by gavage, from the third week until the end of the study. All animals received a diet supplemented with 1% phosphorus. Uraemia was confirmed by the increase in serum creatinine in week 4 (36.24 ± 18.56 versus 144.98 ± 22.1 µmol/L; p = 0.0001) and week 7 (41.55 ± 22.1 versus 83.98 ± 18.56 µmol/L; p = 0.001) in CKD animals. Rats from the CKD group treated with CH-FeCl had a 54.5% reduction in serum phosphate (6.10 ± 2.23 versus 2.78 ± 0.55 mmol/L) compared to a reduction of 25.6% in the untreated CKD group (4.75 ± 1.45 versus 3.52 ± 0.74 mmol/L, p = 0.021), between week 4 and week 7. At week 7, renal function in both CKD groups was similar (serum creatinine: 83.98 ± 18.56 versus 83.10 ± 23.87 µmol/L, p = 0.888); however, the CH-FeCl-treated rats had a reduction in phosphate overload measured by fractional phosphate excretion (FEPi) (0.71 ± 0.2 versus 0.4 ± 0.16, p = 0.006) compared to the untreated CKD group. Our study demonstrated that CH-FeCl had an efficient chelating action on phosphate.