SNF472, a novel inhibitor of vascular calcification, could be administered during hemodialysis to attain potentially therapeutic phytate levels.

BACKGROUND: Cardiovascular calcification (CVC) is a major concern in hemodialysis (HD) and the loss of endogenous modulators of calcification seems involved in the process. Phytate is an endogenous crystallization inhibitor and its low molecular mass and high water solubility make it potentially dialyzable. SNF472 (the hexasodium salt of phytate) is being developed for the treatment of calciphylaxis and CVC in HD patients. We aimed to verify if phytate is lost during dialysis, and evaluate SNF472's behaviour during dialysis. METHODS: Dialyzability was assessed in vitro using online-hemodiafiltration and high-flux HD systems in blood and saline. SNF472 was infused for 20 min and quantified at different time points. RESULTS: Phytate completely dialyzed in 1 h at low concentrations (10 mg/l) but not when added at 30 or 66.67 mg/l SNF472. In bypass conditions, calcium was slightly chelated during SNF472 infusion but when the system was switched to dialysis mode the calcium in the bath compensated this chelation. CONCLUSION: Phytate dialyses with a low clearance. The administration of SNF472 as an exogenous source of phytate allows to attain supra-physiological levels required for its potential therapeutic properties. As SNF472 is infused during the whole dialysis session, the low clearance would not affect the drug's systemic exposure.

Relationship Between Vitamin D Blood Levels and Cancer Development in Renal Transplant Patients: A Case-Control Study.

BACKGROUND: Malignancy is one of the most common long-term complications in renal transplant patients, often related to immunosuppressive treatment although other factors could be considered. Vitamin D plays an important role in reducing cancer risk. After kidney transplantation (KT), 25-hydroxyvitamin D (25OH-D, or calcidiol) insufficiency concerns >85%. The main aim of the present study was to determine the relationship between calcidiol blood levels and cancer development in KT recipients. METHODS: This was a retrospective observational case-control study including patients who received transplants in our hospital from 2003 to 2009 with a follow-up period to 2015. A total of 738 patients were included; 94 of them developed malignancy process, 80 of whose tumor data were analyzed in the cancer group, and the rest composed the control group. At the moment of cancer presentation, age, sex, primary kidney disease, time after surgery, immunosuppressant schedule, and 25OH-D blood levels were collected. RESULTS: The mean patient age was 57 years. The percentages of man and women were 59.5% and 41.5%. The predominant etiology of kidney disease was chronic glomerulonephritis in 31.9%. There were no significant differences between sex, primary kidney disease, immunosuppressant schedule, or incidence of neoplasm in each group of patients. There were no significant differences in 25OH-D blood levels. The incidence of cancer was 7.1%-13.7% per year. The mean time between the graft surgery and the event was 5.6 years. CONCLUSIONS: In patients with functioning KT, we found no correlation between blood levels of calcidiol and the incidence of cancer.

Desensitization in ABO-Incompatible Kidney Transplantation With Low ABO Iso-Agglutinin Titers.

BACKGROUND: In ABO-incompatible (ABOi) kidney transplantation (KT) with low iso-agglutinin (IG) titers (IGT), standard pre-conditioning treatment might be excessive. To try to answer this question, we evaluated the pre-conditioning requirements of a group of ABOi KT with low ABO IGT in our center. Our main objective was to assess desensitization requirements for ABOi KT with low IGT (<16) at Hospital Clinic of Barcelona from 2006 to 2014. METHODS: A retrospective study of desensitization (rituximab and plasma exchange [PE]) requirements for ABOi KT with IGT <16 was conducted. RESULTS: One and 5 years after KT, patient survival was 100%. Renal graft survival was 90% at 1 and 5 years after KT. Mean PE performed before KT was 1.7 (standard deviation [SD], 1.703); 50% of the patients did not receive PE after transplantation, 30% received 2 sessions of PE, and 20% received only 1. The average is 0.8 (SD, 0.91).Follow-up IG determinations remained with low titers (≤8/8). No rebounds of titers were observed during the first 4 to 6 months after transplantation. CONCLUSIONS: Recipients with IGT ≤8 required none or only 1 PE session to reach acceptable titers (titers ≤4) to perform ABOi KT safely. This information is useful to assess the possibility of a minimized desensitization protocol in ABOi KT donors with low titers of IG to reduce adverse effects, reduce cost, and simplify pre-transplant logistics.

Pre-Emptive Retransplantation in Patients With Chronic Kidney Graft Failure.

INTRODUCTION: The aim of this study was to compare the group of patients receiving a new kidney transplant before starting dialysis again (pre-reTR) with a group of patients receiving a new kidney transplant after restarting dialysis (reTR). METHODS: This retrospective cohort included all the kidney retransplantations (second transplantations) between 2000 and 2012 performed at our center and their follow-up until July 2014. We analysed graft and patient survival, rejection rates, and immunologic parameters of these patients. RESULTS: We studied 18 patients who had pre-reTR and 83 who had reTR. In the pre-reTR group no patient had panel-reactive assay (PRA) >10% at any time. In the reTR group 26.5% had PRA >10% at the time of transplantation (P = .014) and 54.2% had a historical highest PRA >10% (P < .001). The rejection rate was 11.1% in the pre-reTR group and 27.7% in the reTR group during the first year post-retransplantation (P = .227). Patient survival rate was 100% in the pre-reTR group at 5 years of follow-up, whereas in the reTR group at 1 year it was 95.2% and 85.9% at 5 years after retransplantation. Allograft survival at 1 and 5 years was 88% and 89%, respectively, in the pre-reTR group. On the other hand, in the reTR group it was 89% after the first year and 65% at 5 years post-retransplantation. CONCLUSION: Pre-emptive renal retransplantation is a feasible option that should be assessed in patients with kidney graft failure and may help to minimize the morbidity associated with dialysis reinitiation.

Economic analysis of the treatment of end-stage renal disease treatment: living-donor kidney transplantation versus hemodialysis.

INTRODUCTION: End-stage renal disease (ESRD) is a major public health problem in the Spanish health system. Kidney transplantation is the treatment of choice, offering better survival and cost-effectiveness than other alternatives. This study aimed to compare the cost of living-donor kidney transplantation (LDKT) during the first year after transplantation with that of hemodialysis (HD). METHOD: A prospective, descriptive study of cost and efficacy was performed in the Hospital Clinic in Barcelona from January to December 2011. We included 106 patients (57 undergoing HD and 49 receiving a LDKT). The costs of LDKT (donor and recipient) and HD were calculated based on our economic database program. RESULTS: The mean age of recipients and donors was 46 ± 15 and 52 ± 10 years, respectively, and 67% of the recipients were men. In HD patients, the mean age was 67 ± 11 years and 62% were men. The total cost of LDKT was €29,897.91 (€8,128.44 for donors and €21,769.47 for recipients). The total cost of HD was €43,000.88 (€37,917 for HD and related procedures plus €5,082 for transport). LDKT represented a savings of €13,102.97 per patient/year and the payback period was less than 1 year. Quality-adjusted life years were higher in LDKT than in HD patients. CONCLUSION: LDKT is cost effective during the first year after transplantation and is associated with enhanced quality of life. From both the medical and economic points of view, pre-emptive LDKD should be encouraged in Spain to reduce the health budget for ESRD.

Efficacy of a simple dosage scheme to convert from shorter-acting erythropoiesis-stimulating agent to continuous erythropoietin receptor activator in kidney transplantation patients.

INTRODUCTION: Anemia after kidney transplantation (KT) has a negative impact on graft and patient survival. Anemia management includes iron supplements and erythropoiesis-stimulating agents (ESAs). Most ESAs require short frequency of administration and conversion to ESAs with longer half-life are complex. OBJECTIVE: This study was performed to assess the efficacy of continuous erythropoietin receptor activator (CERA) in hemoglobin (Hb) maintenance after conversion from shorter-acting ESAs with a simple conversion scheme in kidney transplant recipients. METHOD: This is an open-label, prospective, single-arm, single-center, 12-month follow-up study including 77 anemic KT patients with stable renal function. Baseline and monthly measurements of Hb, iron, and creatinine were performed. The conversion scheme from darbepoetin alfa or epoetin was as follows: <30 µg or 5000 IU/week was switched to 75 µg/mo; between 30-50 or 5000-8000 was switched to 100 µg/mo; >50 µg or 8000 IU was changed to 150 µg/month of CERA. Dose adjustments were performed to maintain Hb levels between 10 g/dL and 12 g/dL. RESULTS: The mean age was 57 ± 19 years. The mean time of conversion after KT was 61 ± 49 months. Before conversion, 62.9% of patients were administered epoetin and 37.1% with darbepoetin alfa. Baseline Hb is noted at 10.6 ± 1.3 g/dL. Thirteen percent of patients started receiving CERA at doses of 50 µg/mo, 66% at 75 µg/mo, 13% at 100 µg/mo, and 8% at 150 µg/mo. During the first month, 21% required dose adjustment (6% were increased, 15% were decreased). The final Hb was 11.2 ± 0.8 g/dL. Iron and creatinine levels remained stable during the follow-up examination. CONCLUSION: We propose a simple scheme of conversion from short-acting ESAs to a once-monthly dose of CERA that provides sustained Hb levels within the recommended target with small dose adjustments and low CERA doses.

A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism.

Persistent hyperparathyroidism (HPT) after kidney transplantation (KTx) is associated with hypercalcemia, hypophosphatemia and abnormally high levels of parathyroid hormone (PTH). In this randomized trial, cinacalcet was compared to placebo for the treatment of hypercalcemia in adult patients with persistent HPT after KTx. Subjects were randomized 1:1 to cinacalcet or placebo with randomization stratified by baseline corrected total serum calcium levels (≤11.2 mg/dL [2.80 mmol/L] or >11.2 mg/dL [2.80 mmol/L]). The primary end point was achievement of a mean corrected total serum calcium value<10.2 mg/dL (2.55 mmol/L) during the efficacy period. The two key secondary end points were percent change in bone mineral density (BMD) at the femoral neck and absolute change in phosphorus; 78.9% cinacalcet- versus 3.5% placebo-treated subjects achieved the primary end point with a difference of 75.4% (95% confidence interval [CI]: 63.8, 87.1), p<0.001. There was no statistical difference in the percent change in BMD at the femoral neck between cinacalcet and placebo groups, p=0.266. The difference in the change in phosphorus between the two arms was 0.45 mg/dL (95% CI: 0.26, 0.64), p<0.001 (nominal). No new safety signals were detected. In conclusion, hypercalcemia and hypophosphatemia were effectively corrected after treatment with cinacalcet in patients with persistent HPT after KTx.

Long-term follow-up after conversion from tacrolimus to cyclosporin in renal transplant patients with new-onset diabetes mellitus after transplantation.

INTRODUCTION: The relationship between anticalcineurin (CNI) drugs and the development new-onset diabetes mellitus after kidney transplantation (NODAT) is well established. Among these agents cyclosporine shows lesser diabetogenicity than tacrolimus. It has been described that conversion from tacrolimus to cyclosporine improves glycemic control; however, there are no studies showing whether this reduced risk is maintained upon long-term follow-up. OBJECTIVE: To evaluate whether CNI drugs conversion from tacrolimus to cyclosporine helps to maintain better glycemic control. MATERIALS AND METHODS: We retrospectively evaluated the evolution of glucose metabolism at 5 years after conversion from tacrolimus to cyclosporine in eight patients (six men) with NODAT. Mean age was 42.8 ± 15 years, and time after transplantation to conversion 128 ± 40 months. We analyzed fasting serum glucose, lipid metabolism, renal function, and cyclosporine levels at 0, 6, 12, 24, 36, 48, and 60 months after conversion. RESULTS: At 6 months after conversion, improved glucose metabolism was observed (268 ± 161 versus 121 ± 31 mg/dL; P < .01) although it was minimal in one case with persistent high blood glycemic levels. Only two patients maintained a normal glucose at the end of follow-up. Five subjects showed increased glycemia at 12 to 24 months after conversion requiring antidiabetic therapy: three patients, insulin and two oral antidiabetic agents. Two patients lost their allografts due to chronic rejection at 32 and 50 months respectively. Among the other six patients, renal function remained stable (1.9 ± 0.6 versus 2.11 ± 0.97 mg/dL; P = NS). There was no significant differences among the other variables. Cyclosporine levels remained stable during the follow-up. CONCLUSION: Conversion of renal transplant patients with NODAT from tacrolimus to cyclosporine improves glucose metabolism in the short term but glycemia increases thereafter.

Cinacalcet treatment for stable kidney transplantation patients with hypercalcemia due to persistent secondary hyperparathyroidism: a long-term follow-up.

BACKGROUND: Cinacalcet is an effective treatment for hypercalcemia due to persistent hyperparathyroidism (HPT) in patients who have undergone kidney transplantation (KT). Few data are available about their long-term follow-up. OBJECTIVE: We aimed to evaluate the long-term efficacy of cinacalcet in functioning stable KT subjects with hypercalcemia secondary to persistent HPT. MATERIAL AND METHODS: Twenty-three patients (6 men) with a stable KT showed persistent hypercalcemia (>12 months) secondary to HPT (parathyroid hormone by radioimmunoassay [iPTH] > 150 pg/mL). The mean age was 54 ± 13 years. Time after KT to beginning cinacalcet treatment was 36.5 ± 37.9 (range 12 to 172) months. Initial cinacalcet doses were 30 mg/d. Median follow-up was 53 ± 7.4 months (range 42 to 60 months). We determined serum calcium, phosphorus, alkaline phosphatase, iPTH, creatinine, and immunosuppressant concentrations at baseline as well as 3, 6, and 12 months and after every 6 months thereafter. RESULTS: Initial serum calcium was 11 ± 0.65 mg/dL and mean calcium during treatment, 10.25 ± 0.81 mg/dL (P < .001). Initial serum phosphorus was 2.8 ± 0.58 mg/dL and mean value serum phosphorus during the treatment period, 3.13 ± 0.6 mg/dL (P = 0.015). Initial iPTH was 260 ± 132 pg/mL and during the treatment period; 237 ± 131 pg/mL (P = ns). There was no change in renal function nor in immunosuppressant blood levels. Doses of cinacalcet at the end of the follow-up were 40.4 ± 18.9 mg/d. CONCLUSION: Cinacalcet was effective for long-term control of hypercalcemia related to persistent HPT for patients with stable KT.

Cinacalcet de novo in persistent hypercalcemia after kidney transplantation secondary to hyperparathyroidism: long-term follow-up and effect of withdrawal.

BACKGROUND: Secondary hyperparathyroidism that persists after kidney transplantation (KT), is the main cause of hypercalcemia. Cinacalcet has been used to control hypercalcemia in KT patients. OBJECTIVE: The aim of this study was to evaluate the effect of de novo cinacalcet in KT patients with hypercalcemia and the evolution after its withdrawal. METHODS: This observational study included 41 KT patients (17 men) with persistent hypercalcemia (>6 months), defined as serum calcium (sCa) ≥10.5 mg/dL, and a mean age of 51.1 ± 13.3 years with a functional allograft for >12 months. The time after surgery to begin cinacalcet was 33 months (range, 12.5-81.3). The initial dose of cinacalcet was 30 mg/d. In a subgroup of 14 patients cinacalcet was stopped after 1 year. We studied the evolution of serum levels of calcium, phosphorus, intact pathyroid hormone (iPTH), and serum creatinine. RESULTS: Calcemia normalized in all patients (sCa <10.2 mg/dL). iPTH decreased (basal 267 ± 212 pg/mL vs final: 219 ± 160 pg/mL; P = ns) Serum phosphorus increased (basal 2.85 ± 0.48 mg/dL vs final 3.16 ± 0.50 mg/dL; P = ns). Renal function remained stable (basal creatinine 1.49 ± 0.48 vs final 1.47 ± 0.32 mg/dL; P = ns). After stopping cinacalcet, in group 1 calcemia persisted at normal levels in 50% (n = 7), but the drug had to be reintroduced in the other 50% after 10 ± 7.9 months. No adverse events were documented. CONCLUSIONS: Cinacalcet is an effective alternative for the treatment of hypercalcemia in patients with persistent hyperparathyroidism after KT. Once the treatment is started, there is presently no invice to disclose to who tolerate its withdrawal or the time to do so.

Withdrawal of cinacalcet at the time of renal transplantation is not a risk factor for allograft calcifications in the early posttransplantation period.

BACKGROUND: Secondary hyperparathyroidism is a relevant problem in patients on dialysis. Cinacalcet in regular clinical practice increases the percentage of patients achieving treatment targets for PTH, Ca and P. We evaluated allograft calcification in serial protocol biopsies after transplantation among patients receiving Cinacalcet on dialysis but discontinued after surgery. METHODS: This retrospective single-centre study included kidney allograft recipients who were receiving Cinacalcet for more than 6 months before surgery and had it withdrawn thereafter. The 46 patients including 17 women showed a mean overall age of 54 ± 30 years. Protocol graft biopsy was performed at 3 and at 12 months. Biochemical analyses at the time of biopsy included blood levels of creatinine, phosphorus, calcium, alkaline phosphatases, iPTH, and proteinuria. RESULTS: Any biopsy showed nephrocalcinosis either intratubular calcifications, or in the parenchyma. There were no changes in calcemia (10.22 ± 0.7 to 10.27 ± 0.7 mg/dL), in alkaline phosphatase (259 ± 119.6 to 255 ± 122.3 mg/dL) nor in iPTH (317 ± 220.2 to 320 ± 168.8 pg/mL) between 3 and 12 months respectively. There was a slight but non-significant increase in serum phosphorus (2.79 ± 0.8 to 3.22 ± 0.9 mg/dL), serum creatinine (1.53 ± 0.6 to 1.84 ± 1.2 mg/dL) and proteinuria (528 ± 603 to 879 ± 1398 mg/24h) between 3 and 12 months respectively. CONCLUSIONS: Withdrawal of Cinacalcet at the time of renal transplantation was not a risk factor for allograft calcifications in the early post-transplant period.

Efficacy of low doses of pamidronate in osteopenic patients administered in the early post-renal transplant.

UNLABELLED: This study evaluates the efficacy of low doses of pamidronate after renal transplantation to prevent bone loss in osteopenic patients. Results show that pamidronate is safe and significantly reduced spinal bone loss when administered immediately after renal transplantation. INTRODUCTION: The purpose of this work is to evaluate the efficacy of two intravenous infusions of pamidronate in the immediate post-transplant period in a renal transplant (RT) population. METHODS: In this 12-month, randomized, double-blind, multicenter trial, 39 kidney recipients with diagnosed osteopenia received two doses of 30 mg of disodium pamidronate (n = 24) or placebo (n = 15), at surgery and 3 months post-RT. All patients received calcium and vitamin D. Bone density of the lumbar spine and total femur was measured by dual-energy X-ray absorptiometry (DXA) and X-rays were performed at RT, 6 and 12 months post-RT. Biochemical and hormonal determinations were performed before and after treatment. RESULTS: Pamidronate significantly reduced spinal bone loss, but no significant benefit was found for the incidence of fractures. Elevated baseline intact parathyroid hormone (iPTH) and bone remodeling markers returned to normal levels 3 months post-RT. However, normal procollagen type I N propeptide (PINP) concentrations were only maintained in the pamidronate group. After RT, a comparable graft function was observed in both groups according to creatinine values, 25-hydroxyvitamin-D (25-OH-D) levels were improved, and serum calcium levels normalized after a transient fall during the first 3 months. CONCLUSION: A low dose of pamidronate prevents bone loss in osteopenic patients when administered immediately after RT.

Dinámica in vitro de la secreción de hormonaparatiroidea regulada por calcio y efecto sobre el ciclo celular: adenoma frente a hiperplasiaparatiroidea / In vitro dynamics of parathyroid hormone secretion regulated by calcium and effects on the cell cycle: parathyroid hyperplasia versus adenoma

Objetivo: Comparar in vitro la dinámica de la secreción de hormona paratiroidea (PTH) regulada por calcio y su relación con el ciclo celular en adenomas frente a hiperplasia de paratiroides. Material y métodos: Ocho adenomas de paratiroides y 23 glándulas hiperplásicas procedentes de 8 pacientes con hiperparatiroidismo primario y 7 pacientes con hiperparatiroidismo secundario, respectivamente. Para el estudio de la dinámica de secreción, pequeños fragmentos de tejido paratiroideo se transfirieron secuencialmente a intervalos de una hora a pocillos con concentraciones variables de calcio: 0,4, 0,6, 0,8, 1,0, 1,25, y 1,35 o 1,5 mM. Se determinaron las concentraciones de iPTH en el medio. Células paratiroides se aislaron sin el uso de enzimas y el ciclo celular paratiroideo se analizó por el método de Vindelov. El núcleo se adquirió por citometría de flujo y se analizó usando un software CELLFIT. Resultados: En los tejidos paratiroideos de las glándulas hiperplásicas, el aumento del calcio extracelular produjo una disminución de la secreción de PTH manifestada con valores de calcio de0,8 mM y una inhibición máxima de secreción de PTH con un calcio de 1,25 mM. Por el contrario, en los tejidos de los adenomas de paratiroides se requirieron concentraciones de Ca de 1,2 mM para provocar una mínima disminución de la secreción de PTH. En los adenomas no hubo correlación entre las fases del ciclo celular y la calcemia o el set point (r = 0,914; p <0,005) y el calcio sérico basal (r = 0,862; p <0,02). Conclusiones: La regulación de la secreción de PTH por el calcio extracelular in vitro es menos sensible en adenomas que en glándulas hiperplásicas paratiroideas. En hiperplasia paratiroidea la proliferación celular parece es- tar regulada por la concentración de calcio extracelular (a mayor calcemia menor proliferación) (AU)

Aim: To compare the dynamics of calcium-regulated PTH secretion in vitro from adenomatous versus hyperplastic glands and to investigate the relationship between the parathyroid cell cycle and the calcium-regulated PTH secretion in these glands. Materials and methods: A total of31 parathyroid glands (8 adenomatous and 23 hyperplastic) from 8 patients with primary hyperparathyroidism and7 with secondary hyperparathyroidism respectively were studied. For the evaluation of calcium-regulated PTH secretion, small parathyroid pieces of 1 mm were sequentially transferred to wells with varying Ca concentrations:0.4, 0.6, 0.8, 1, 1.25 and 1.35 or 1.5 mM. PTH concentrations were determined in the medium. For the parathyroid cell cycle studies, parathyroid cells were isolated without the use of enzymes and cell cycle was analyzed using the method described by Vindelov. The nuclei were acquired by flow cytometer and analyzed using the CELL- FIT software. Results: In parathyroid tissues from hyper- plastic glands, the increase in extracellular calcium pro- duced a decrease in PTH secretion which was apparent with a calcium level as low as 0.8 mM and the maximal in- hibition of PTH secretion was obtained with a calcium of 1.25 mM, by the contrary, adenomatous glands required a calcium of 1.2 mM to produce a minimal decrease in PTH secretion. In hyperplastic parathyroid glands but not in parathyroid adenomas there was a significant correlation between the percentage of cells in G0/G1 phase with the set point (r = 0.914; P <0.005) and the basal serum Ca (r = 0.862; P <0.02). Conclusions: The control of the extracellu- lar calcium-PTH release in vitro is less sensitive in parathy- roid adenomas than hyperplasic parathyroid glands. In parathyroid hyperplasia the cell proliferation may be reg- ulated by the extracellular calcium concentration (higher calcemia less proliferation) (AU)

[In vitro dynamics of parathyroid hormone secretion regulated by calcium and effects on the cell cycle: parathyroid hyperplasia versus adenoma]. / Dinámica in vitro de la secreción de hormona paratiroidea regulada por calcio y efecto sobre el ciclo celular: adenoma frente a hiperplasia paratiroidea.

AIM: To compare the dynamics of calcium-regulated PTH secretion in vitro from adenomatous versus hyperplastic glands and to investigate the relationship between the parathyroid cell cycle and the calcium-regulated PTH secretion in these glands. MATERIALS AND METHODS: A total of 31 parathyroid glands (8 adenomatous and 23 hyperplastic) from 8 patients with primary hyperparathyroidism and 7 with secondary hyperparathyroidism respectively were studied. For the evaluation of calcium-regulated PTH secretion, small parathyroid pieces of 1 mm were sequentially transferred to wells with varying Ca concentrations: 0.4, 0.6, 0.8, 1, 1.25 and 1.35 or 1.5 mM. PTH concentrations were determined in the medium. For the parathyroid cell cycle studies, parathyroid cells were isolated without the use of enzymes and cell cycle was analyzed using the method described by Vindelov. The nuclei were acquired by flow cytometer and analyzed using the CELLFIT software. RESULTS: In parathyroid tissues from hyperplastic glands, the increase in extracellular calcium produced a decrease in PTH secretion which was apparent with a calcium level as low as 0.8 mM and the maximal inhibition of PTH secretion was obtained with a calcium of 1.25 mM, by the contrary, adenomatous glands required a calcium of 1.2 mM to produce a minimal decrease in PTH secretion. In hyperplastic parathyroid glands but not in parathyroid adenomas there was a significant correlation between the percentage of cells in G0/G1 phase with the set point (r = 0.914; P < 0.005) and the basal serum Ca (r = 0.862; P < 0.02). CONCLUSIONS: The control of the extracellular calcium-PTH release in vitro is less sensitive in parathyroid adenomas than hyperplasic parathyroid glands. In parathyroid hyperplasia the cell proliferation may be regulated by the extracellular calcium concentration (higher calcemia less proliferation).

[Use of bisphosphonates in chronic kidney disease]. / Uso de bifosfonatos en la enfermedad renal crónica.

Bisphosphonates are synthetic compounds similar to organic pyrophosphates. The bioavailability of intravenous preparations is 100%, whereas the availability of oral therapy ranges from 1 to 5%. About 50% to 80% of free bisphosphonates are incorporated into bone. Because of their urinary elimination, bisphosphonates must be carefully administered in chronic kidney disease (CKD) patients. In spite of this, bisphosphonates can safely be used in all CKD stages, including dialysis and kidney transplant. The renal toxicity seems different among these compounds, and it is due basically to their protein binding and the average lifespan in renal tissues. In practice, renal toxicity have been associate to the infusion velocity and excessive dosage In patients with CKD, it is very relevant to maintain the time of infusion and in haemodialysis patients we recommend the administration during the haemodialysis session. When bisphosphonates are given to 4-5 CKD patients it seems reasonable to reduce the dose to 50%. No renal pathology has been associated to oral administration. The indications of bisphosphonates in CKD include: hypercalcemia episodes, prevention of bone loss after renal transplantation, treatment of low bone mineral density in all CKD stage including transplantation. They are too a promising therapy of calciphylaxis and to prevent vascular calcifications. When suppressed bone turnover is suspected, bone biopsy is mandatory before bisphosphonates therapy.

Uso de bifosfonatos en la enfermedad renal crónica / Use of bisphosphonates in chronic kidney disease

Los bifosfonatos son compuestos sintéticos análogos de los pirofosfatos. Mientras que la biodisponibilidad de una dosis intravenosa es del 100%, la biodisponibilidad oral es del1 al 5%. Aproximadamente el 50-80% del bifosfonato disponible es captado por el hueso. En pacientes con deterioro de función renal debemos ser cautelosos, fundamentalmente porque son eliminados por el riñón (se filtran por el glomérulo y secretan en el túbulo). Su diferente toxicidad renal puede deberse a factores como diferente capacidad de unión a proteínas, distinta vida media en tejido renal y diferente toxicidad renal acumulada. No obstante, la toxicidad se debe a la administración rápida y a dosis excesivas. En pacientes con filtrado glomerular inferior a 30 ml/min es aconsejable reducir la dosis a la mitad. Con la administración intravenosa es importante mantener el tiempo de infusión y en hemodiálisis, administrar el fármaco durante la sesión. Con el ibandronato, hasta el momento actual, no se ha descrito patología renal y con las formas orales de cualquiera de ellos tampoco. Los bifosfonatos han demostrado ser eficaces en la prevención de la pérdida ósea posterior al trasplante, en el tratamiento de la calcifilaxis y en la prevención de las calcificaciones vasculares. En los pacientes con enfermedad renal crónica (ERC) avanzada o en sometidos a diálisis, los bifosfonatos estarían indicados, sobre todo, ante la presencia de franca disminución de la masa ósea y la existencia de factores de riesgo de osteoporosis junto con alto remodelado óseo. Se debe sopesar con cuidado su indicación en pacientes en quienes se sospeche la existencia de una enfermedad ósea adinámica, en cuyo caso sería obligada la realización de una biopsia ósea (AU)

Bisphosphonates are synthetic compounds similar to organic pyrophosphates. The bioavailability of intravenous preparations is 100%, whereas the availability of oral therapy ranges from 1 to 5%. About 50% to 80% of free bisphosphonates are incorporated into bone. Because of their urinary elimination, bisphosphonates must be carefully administered in chronic kidney disease (CKD)patients. In spite of this, bisphosphonates can safely be used in all CKD stages, including dialysis and kidney transplant. The renal toxicity seems different among these compounds, and it is due basically to their protein binding and the average lifespan in renal tissues. In practice, renal toxicity have been associate to the infusion velocity and excessive dosage In patients with CKD, it is very relevant to maintain the time of infusion and in haemodialysis patients were commend the administration during the haemodialysis session. When bisphosphonates are given to 4-5 CKD patients it seems reasonable to reduce the dose to 50%. No renal pathology has been associated to oral administration. The indications of bisphosphonates in CKD include: hypercalcemia episodes, prevention of bone loss after renal transplantation, treatment of low bone mineral density in all CKD stage including transplantation. They are too a promising therapy of calciphylaxis and to prevent vascular calcifications. When suppressed bone turnover is suspected, bone biopsy is mandatory before bisphosphonates therapy (AU)

Utilidad de las técnicas de imagen en el hiperparatiroidismo secundario / Usefulness of imaging techniques in secondary hyperparathyroidism

En los pacientes con enfermedad renal crónica que desarrollan hiperparatiroidismo secundario (HPTS), las técnicas de imagen pueden ser de utilidad, fundamentalmente para valorarla localización, el tamaño y el funcionalismo de las glándulas paratiroides. Esta revisión valora las técnicas de imagen de las que se dispone actualmente para evaluar las glándulas paratiroides en el contexto del HPTS. Se hace referencia a: 1)ecografía cervical (modo B, Doppler, Doppler-color y power-Doppler); 2) estudios gammagráficos (talio, 99mTc-MIBI y99mTc-tetrofosmin), incluyendo técnicas especiales de adquisición de imágenes (Pinhole, SPECT); 3) estudios PET (tomografía por emisión de positrones); 4) tomografía computarizada(TC) y resonancia magnética, y 5) escáneres híbridos(SPECT/TC y PET/TC). Nuestra recomendación es practicar, en todos los pacientes con HPTS que no responden inicial y fácilmente al tratamiento médico, una gammagrafía con 99mTc-MIBI que puede complementarse con un Eco-Doppler color. Si la gammagrafía es positiva y, tras gradación de la intensidad de captación, alguna de las glándulas (no ectópicas) presenta un índice intenso, aunque se puede intentar intensificar el tratamiento, debería pensarse en la realización de una paratiroidectomía. Si la gammagrafía es positiva y, tras gradación de la intensidad de captación, ninguna de las glándulas (no ectópicas) presenta un índice intenso, debería intentarse la intensificación del tratamiento, y si no existe buena respuesta, considerar la paratiroidectomía. Si la gammagrafía es negativa, debería practicarse un PET si se dispone de dicha prueba. En caso de no disponer de PET, lo aconsejable sería realizar una resonancia magnética (AU)

For patients with chronic renal failure who develop secondary hyperparathyroidism (SHPT), imaging techniques can be useful, especially to evaluate the location, size and functional status of parathyroidg lands. This review analyzes all available imaging procedures in the context of SHPT. We evaluate: 1)Cervical ultrasound (B-mode, Doppler, colour-Doppler and power-Doppler), 2) Scintigraphic studies (Tallium,99mTc-MIBI and 99mTc-tetrofosmin), including nonstandard image acquisition techniques (Pinhole, SPECT),3) Positron emission tomography (PET), 4) Computed tomography (CT) and magnetic resonance imaging(MRI) and 5) hybrid scanners (SPECT/CT and PET/CT).Our recommendation is that SHPT patients who are initially non responders to medical therapy should be investigated using parathyroid scintigraphy and cervical ultrasound. 99mTc-MIBI uptake can be graded in a semiquantitative scale. Intense uptake indicates a low probability of success using medical treatment and parathyroidectomy should be considered. A moderate to faint uptake indicates that a more intensive medical therapy would probably be beneficial. In the case of noup take of 99mTc-MIBI, PET should be performed. Where this is not available, MRI could be a possible alternative (AU)

Combined liver-kidney transplantation in patients with cirrhosis and chronic kidney disease.

The outcome of patients with cirrhosis and chronic kidney disease treated with combined liver-kidney transplantation (CLKT) is not well known because most series of patients treated with CLKT include not only patients with cirrhosis but also patients with inherited diseases without cirrhosis. To evaluate to what extent the combined kidney transplantation impairs posttransplantation outcome compared to liver transplantation (LT) alone, the outcome of patients with cirrhosis and chronic kidney disease treated with CLKT (n = 20) was compared to that of a group of patients with cirrhosis without chronic kidney disease treated with LT alone matched by age, sex, year of transplantation and severity of cirrhosis (n = 60). The primary end point of the study was survival, and secondary end points were outcome of renal function and complications within 6 months of transplantation. Patients with CLKT had a higher incidence of bacterial infections and transfusion requirements compared to LT patients. The incidence of acute renal failure during the first 6 months was similar, yet the severity of renal failure was greater in patients with CLKT. Hospital and intensive care unit (ICU) stays were longer in the CLKT group. One- and three-year survival probabilities in patients treated with CLKT were 80 and 75% compared to 97 and 88%, respectively, in patients treated with LT. In conclusion, CLKT for patients with cirrhosis and chronic kidney disease is associated with a relatively high frequency of postoperative complications that moderately impairs short-term survival. However, 3-year survival of patients with cirrhosis treated with CLKT is excellent.

Trasplante renal ABO incompatible: de un sueño a una realidad. Experiencia del Hospital Clínic de Barcelona / ABO incompatible living donor kidney transplantation: a dream come true. Experience of Hospital Clínic of Barcelona

Introducción: En los últimos años se ha mantenido estable el número de pacientes en lista de espera para un trasplante renal. El trasplante renal de donante vivo representa actualmente una vía para aumentar el pool de donantes, pero hay un grupo de pacientes que presentan incompatibilidad de grupo sanguíneo ABO, lo que contraindicaba hasta ahora que pudiera llevarse a cabo el trasplante. Nuestro objetivo consiste en describir nuestra experiencia con el programa de trasplante renal de donante vivo con incompatibilidad de grupo ABO. Material y métodos: Se trata de un estudio de retrospectivo-descriptivo de los primeros 11 pacientes sometidos a trasplante renal de donante vivo ABO incompatible en el Hospital Clínic de Barcelona desde octubre de 2006 a enero de 2009. Se utilizó un protocolo de acondicionamiento basado en inmunoadsorción específica (con número sesiones necesarias hasta conseguir títulos de isoaglutininas aceptables pretrasplante), inmunoglobulina policlonal inespecífica y anticuerpo monoclonal anti-CD20, seguido del tratamiento inmunosupresor adaptado a cada receptor. Se determinaron títulos de isoaglutininas antes del tratamiento de acondicionamiento, pretrasplante y postrasplante durante las primeras 2 semanas. La valoración inmunológica, médica y quirúrgica fue la habitual en el programa de trasplante renal de donante vivo. Resultados: La edad media de los donantes y receptores fue de 47,8 ± 12,4 y 44,4 ± 14,1 años, respectivamente. Un 90,1% de los donantes fue mujer y un 72,7% de los receptores, hombres. El tiempo de seguimiento medio fue de 10,2 ± 10,2 meses. Hermanos y esposos fueron las relaciones más frecuentes (n = 4, 36,4%, respectivamente), al igual que la causa de nefropatía fueron la glomerulopatía, poliquistosis y el síndrome de Alport (n = 2, 18,2% para cada enfermedad renal primaria). Todos los pacientes adquirieron un título de isoaglutininas correctos pretrasplante (<8) y requirieron 5,54 ± 2,6 sesiones de inmunoadsorción pretrasplante y 2,82 sesiones postrasplante. Un paciente no requirió ninguna sesión de inmunoadsorción (única con incompatibilidad anti-B) y otro requirió recambios plasmáticos, en vez de inmunoadsorciones, por tratarse de un potencial receptor hipersensibilizado con crossmatch por citometría de flujo positivo. Los títulos de isoaglutininas postrasplante se mantuvieron a títulos bajos. Dos pacientes presentaron un episodio de rechazo agudo celular (Banff IA e IB), con buena respuesta al tratamiento. La supervivencia de paciente y del injerto fue de un 90,9% en el primer año y se mantuvo estable a lo largo del seguimiento. Únicamente se registró una pérdida del injerto por fallecimiento en relación con una complicación hemorrágica en las primeras 72 horas sin relación con la incompatibilidad de grupo ABO. La función de injerto renal al año es excelente, con valores de creatinina sérica de 1,3 ± 0,8 mg/dl, con aclaramiento de creatinina ajustado a superficie corporal 62,6 ml/min/1,73 m2 y proteinuria de 244,9 mg/orina de 24 horas. Conclusiones: El trasplante renal de donante vivo con incompatibilidad de grupo sanguíneo representa una alternativa eficaz y segura en determinados pacientes en lista de espera de trasplante renal, obteniendo resultados excelentes de supervivencia de paciente e injerto y con una buena función de injerto renal (AU)

Introduction: During the last years the number of patients on waiting list for kidney transplantation has been stable. Living donor kidney transplantation is nowadays a chance to increase the pool of donors. However, there are a group of patients with ABO incompatibility, making impossible the transplant until now. The aim of the present study is to describe the experience of Hospital Clinic Barcelona on ABO incompatible living transplantation. Material and methods: A retrospective-descriptive study was made based on 11 living donor kidney recipients with ABO incompatibility in Hospital Clinic of Barcelona from October’06 to January’09. Selective blood group, antibody removal with specific immunoadsortion, immunoglobulin and anti-CD20 antibody were made until the immunoglobulin (IgG) and isoaglutinine (IgM) antibody titters were 1/8 or lower. Immunosuppressive protocol was adjusted to particular recipient characteristics. Isoaglutinine titters were set before, during and post desensitization treatment and two weeks after transplant. Immunological, medical and surgical evaluation was the standard in living donor kidney transplant program. Results: Medium age of donors and recipients were 47.8 ±12.4 and 44.4 ± 14.1 years, respectively. 90% of donors were females and 73% of recipients males. Follow-up time was 10.2 ±10.2 months. Siblings and spouses were the most frequent relation (n = 4, 36.4%, respectively). Chronic glomerulonephritis, adult polycystic kidney disease and Alport syndrome, the most frequent cause of end-stage renal disease. All the patients acquire appropriate isoaglutinine titters pre transplant (<1/8), requiring 5.54 ± 2.6 immunoadsorption sessions pretransplant and 2.82 postransplant. One patient didn´t need any immunoadsorption session (incompatibility blood group B) and another patient plasma exchange instead of immunoadsorption for being hipersensitized with positive flow cytometry crossmath. Postransplant isoaglutinine titters remained low. Two patients had cellular acute rejection episode (type IA and IB of Banff classification) with good response to corticosteroid treatment. Patient and graft survival were 91% at first year and remain stable during the follow-up. A graft lost by death of patient in relation to haemorrhagic shock developed within the first 72 hours after transplantation. Renal graft function at first year was excellent with serum creatinina of 1.3 ± 0.8 mg/dl, creatinine clearance of 62.6 ml/min/1.73 m2 and proteinuria of 244.9 mg/U 24 h. Conclusion: ABO incompatible living donor kidney transplantation represent an effective and safe alternative in certain patients on waiting list for renal transplant, obtaining excellent results in patient and graft survival, with good renal graft function (AU)

Dinámica de la secreción de PTH regulada por calcio en el hiperparatiroidismo secundario: comparación de la respuesta in vivo frente a in vitro / Dynamics of calcium-regulated PTH secretion in secondary hyperparathyroidism: comparison between «in vivo» vs. «in vitro» responses

Objetivo: Comparar la dinámica de la secreción de calcio-PTH in vivo e in vitro de glándulas paratiroideas hiperplásicas. Materiales y métodos: Se estudiaron 7 pacientes con hiperparatiroidismo secundario y las 23 glándulas hiperplásicas obtenidas tras paratiroidectomía de estos mismos pacientes. Estudios in vivo de la curva de secreción de PTH se obtuvieron con inducción de hipocalcemia e hipercalcemia con infusiones intravenosas continuas de EDTA sódico y gluconato de calcio, respectivamente. Para los estudios in vitro se emplearon pequeñas piezas de paratiroides de 1 mm que se transfirieron secuencialmente a concentraciones de calcio variables: 0,4, 0,6, 0,8, 1, 1,25 y 1,50 mM, determinándose la concentración de PTHi en el medio. Resultados: Las curvas de secreción de PTH in vivo e in vitro fueron sigmoidales y similares, aunque el set point in vivo era más alto que el in vitro (1,57 ± 0,05 frente a 1,27 ± 0,07 mM; p <0,001). El grado de inhibición máxima de PTH fue similar en ambas circunstancias (30,5 ± 8,1 frente a 33,6 ± 5,4%; p = NS), con una correlación directa significativa (r = 0,901; p <0,01). El set point in vivo no se correlacionaba con las concentraciones de PTH basales, aunque se correlacionó significativamente con las concentraciones basales de calcio sérico (r = 0,62; p <0,02). Conclusiones: El set point in vivo del calcio está más relacionado con la concentración sérica de calcio que con la concentración basal de PTHi. Aunque hay diferencias entre el set point de calcio in vivo e in vitro, el grado máximo de inhibición de PTH y la curva sigmoidal fueron similares en las dos circunstancias (AU)

Aim: To compare the dynamics in vivo and in vitro calcium-PTH release of uremic patients with secondary hyperparathyroidism and their hyperplasic parathyroid glands after parathyroidectomy. Materials and methods: Seven patients with secondary HPT and their 23 hyperplasic glands obtained after surgical parathyroidectomy were evaluated. In vivo studies of the PTH secretion curve were obtained by induction of hypocalcemia and hypercalcemia with a continuous endovenous infusion of sodium EDTA and Ca gluconate, respectively. For the in vitro studies, small parathyroid pieces of 1 mm were sequentially transferred to wells with varying Ca concentrations: 0.4, 0.6, 0.8, 1, 1.25 and 1.5 mM. iPTH concentrations were determined in the medium. Results: The in vivo set point did not correlate with the basal, maximal or minimal PTH concentrations, although it correlated significantly with the basal serum Ca concentration (r = 0.62, p <0.02). Both in vivo and in vitro PTH secretion curves were sigmoidal, although the in vivo set point was higher than the in vitro (1.57 ± 0.05 vs. 1.27 ± 0.07 mM, p <0.001). The degree of maximal PTH inhibition were similar in both circumstances (30.5 ± 8.1 vs. 33.6 ± 5.4 %; p = NS) with a significant direct correlation (r = 0.901; p <0.01). Conclusions: The in vivo set point of calcium is more closely related to serum calcium concentration than to basal iPTH concentration. Although there are differences between the in vivo and in vitro calcium set point the maximal degree of PTH inhibition was similar in both circumstances (AU)