RESUMEN
INTRODUCTION: Hyperphosphatemia is a frequent complication of chronic kidney disease and is associated with increased mortality. Despite side effects, risk of accumulation and high costs, phosphate binders (PBs) have become the crucial cornerstone of therapy. The iron-containing PB sucroferric oxyhydroxide (SO) and ferric citrate hydrate (FCH) have entered the market and other candidates are prior market entry. AREAS COVERED: A literature search was performed using MEDLINE and EMBASE databases to identify references on iron-containing PB with particular regard to efficacy, safety and potential benefits. Additional hand searches were conducted along with a full-text review of any citation that appeared relevant. EXPERT OPINION: On the highly competitive market, where the 'ideal' PB is still unknown, novel substances that offer clear benefits over available drugs are desired. Although SO and FCH showed similar efficacy and safety compared to sevelamer, head-to-head studies with lanthanum carbonate are absent. Clinical 1-year data in a limited patient cohort suggested improved adherence for SO and a large randomized controlled trial showed significant reduction in hospitalizations and costs for FCH. Additional large randomized controlled trials have now to prove these possible advantages. Cost-effectiveness in comparison to other PB and the exclusion of significant harms under long-term treatment will determine the future use of both drugs.
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Compuestos Férricos/uso terapéutico , Hiperfosfatemia/tratamiento farmacológico , Insuficiencia Renal Crónica/complicaciones , Animales , Carbonatos/uso terapéutico , Ensayos Clínicos como Asunto , Combinación de Medicamentos , Humanos , Hiperfosfatemia/sangre , Hiperfosfatemia/etiología , Hierro/uso terapéutico , Lantano/uso terapéutico , Magnesio/uso terapéutico , Fosfatos/sangre , Sevelamer/uso terapéutico , Almidón/uso terapéutico , Sacarosa/uso terapéuticoRESUMEN
BACKGROUND: Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) is a well defined risk factor for subsequent bacteremia and death in various groups of patients, but its impact on outcome in patients receiving long-term hemodialysis (HD) is under debate. METHODS: This prospective interventional cohort study (performed 2004 to 2010) enrolled 289 HD outpatients of an urban dialysis-unit. Nasal swab cultures for MRSA were performed in all patients upon first admission, at transfer from another dialysis facility or readmission after hospitalisation. Nasal MRSA carriers were treated in a separate ward and received mupirocin nasal ointment. Concomitant extra-nasal MRSA colonization was treated with 0.2% chlorhexidine mouth rinse (throat) or octenidine dihydrochloride containing antiseptic soaps and 2% chlorhexidine body washes (skin). Clinical data and outcome of carriers and noncarriers were systematically analyzed. RESULTS: The screening approach identified 34 nasal MRSA carriers (11.7%). Extra-nasal MRSA colonization was observed in 11/34 (32%) nasal MRSA carriers. History of malignancy and an increased Charlson Comorbidity Index were significant predictors for nasal MRSA carriers, whereas traditional risk factors for MRSA colonization or markers of inflammation or malnutrition were not able to discriminate. Kaplan-Meier analysis demonstrated significant survival differences between MRSA carriers and noncarriers. Mupirocin ointment persistently eliminated nasal MRSA colonization in 26/34 (73.5%) patients. Persistent nasal MRSA carriers with failure of this eradication approach had an extremely poor prognosis with an all-cause mortality rate >85%. CONCLUSIONS: Nasal MRSA carriage with failure of mupirocin decolonization was associated with increased mortality despite a lack of overt clinical signs of infection. Further studies are needed to demonstrate whether nasal MRSA colonization represents a novel predictor of worse outcome or just another surrogate marker of the burden of comorbid diseases leading to fatal outcome in HD patients.
Asunto(s)
Atención Ambulatoria , Portador Sano/diagnóstico , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Mucosa Nasal/microbiología , Diálisis Renal , Infecciones Estafilocócicas/diagnóstico , Anciano , Portador Sano/terapia , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Diálisis Renal/mortalidad , Factores de Riesgo , Infecciones Estafilocócicas/mortalidad , Infecciones Estafilocócicas/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: Ubiquitous mitochondrial creatine kinase (uMtCK) accumulates as macroenzyme creatine kinase type 2 (macro CK2) in the serum of HIV-infected patients under a tenofovir disoproxil fumarate (TDF)-containing antiretroviral regimen. The genesis and clinical significance of this finding is unclear. METHODS: A prospective observational 5-year follow-up study was performed on those patients in which macro CK2 appearance was initially described ('TDF switch study' cohort). In addition, tenofovir (TFV), its prodrug TDF and its active, intracellular derivative TFV diphosphate (TDP) were tested in vitro for their effects on different key properties of uMtCK to clarify possible interactions of uMtCK with TFV compounds. RESULTS: In just under 5 years of continuous TDF treatment, only 4/12 (33%) patients remained macro CK2-positive, whereas 8/12 (66%) originally positive patients were macro CK2-negative at the end of follow-up. Prospective clinical follow-up data indicate that macro CK2 appearance under TDF is not associated with significant cell damage or occurrence of malignancies. A trend towards grade 1 hypophosphataemia suggests subclinical proximal tubular dysfunction in macro-CK2-positive patients, although it was not associated with a significant decrease in estimated glomerular filtration rate. In vitro, TFV, TDF and TDP did not interfere with uMtCK enzyme activity as competitive inhibitors or pseudo-substrates, but TFV and TDF stabilized the native uMtCK octameric structure in dilute solutions. CONCLUSIONS: Appearance of octameric uMtCK as macro CK2 in the serum of TDF-treated patients is suggested to result from a combination of low-level mitochondrial damage caused by subclinical renal tubular dysfunction together with possible compensatory uMtCK overexpression and a putative concomitant stabilization of uMtCK octamers by higher levels of TFV in proximal tubules.
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Adenina/análogos & derivados , Fármacos Anti-VIH/farmacología , Forma Mitocondrial de la Creatina-Quinasa/metabolismo , Infecciones por VIH/metabolismo , Organofosfonatos/farmacología , Multimerización de Proteína , Adenina/farmacología , Adenina/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Catálisis/efectos de los fármacos , Forma Mitocondrial de la Creatina-Quinasa/sangre , Forma Mitocondrial de la Creatina-Quinasa/química , Estabilidad de Enzimas , Estudios de Seguimiento , Tasa de Filtración Glomerular/efectos de los fármacos , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Humanos , Hipofosfatemia/sangre , Organofosfonatos/uso terapéutico , Multimerización de Proteína/efectos de los fármacos , TenofovirRESUMEN
Anemia is a prevalent and premature comorbidity in chronic kidney disease (CKD) and associated with multiple adverse clinical consequences including increased mortality. Today Erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the cornerstones of therapy for correcting anemia in CKD patients. As no generally accepted dosing algorithms for these agents exist, current recommendations prefer a partial but not complete anemia correction thereby favoring a more conservative and individualized ESA and iron dosing. Here we discuss in detail current evidence derived from large randomized trials about the proposed hemoglobin targets to aim at in CKD and End-Stage renal disease patients and report recent data from the thriving European market of biosimilar erythropoietins. We summarize promising investigational strategies including peginesatide and prolyl hydroxylase inhibitors for stabilization of the hypoxia inducible factor and provide a clinical review of novel high dose iron formulations like ferumoxytol or iron (III)-carboxymaltose. Taking these findings together, treatment strategies for anemia of CKD have got considerably more complicated so that a careful balance between maximization of patient`s quality of life while minimizing all risks associated with anemia treatment has become a major task of current nephrology.
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Anemia/sangre , Anemia/tratamiento farmacológico , Hematínicos/uso terapéutico , Insuficiencia Renal Crónica/sangre , Ensayos Clínicos como Asunto , Femenino , Hemoglobinas/metabolismo , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
PURPOSE OF REVIEW: Left-ventricular hypertrophy (LVH) represents an important marker of cardiovascular morbidity and mortality. Numerous noninterventional studies in patients with chronic kidney disease (CKD) revealed a consistent relationship of LVH with modifiable risk factors attributable to failing renal function, particularly anemia and hypertension. RECENT FINDINGS: Given the clear role for anemia in initiating or accelerating LVH, it seems imperative to correct renal anemia with erythropoiesis-stimulating agents (ESAs). A few nonrandomized studies have described a regression of LVH with correction of anemia, but prospective randomized trials showed no evidence that ESA treatment is able to improve cardiac prognosis in the CKD patient. Current data alert physicians that normalization of hemoglobin in patients with advanced CKD is harmful. Recent studies are now trying to clarify the mechanisms for harm focussing on the influence of comorbidities, ESA doses, and hemoglobin variability. The pathogenesis of hypertension in CKD is multifactorial and only a small percentage of CKD patients have controlled their blood pressure, indicating poor medication adherence, insufficient control of volume overload and undertreatment. SUMMARY: This review provides an update of ESA treatment, hypertension and LVH in the CKD patient, indicating that pathogenesis of LVH in this population is currently not completely understood. In addition, the impact of pharmacological interventions targeted to prevent or reduce LVH in anemic or hypertensive CKD patients is not well defined. As adoption of the Framingham approach seems not feasible in the CKD patient, evidence from large-scale randomized clinical trials is mandatory to resolve this dilemma.
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Anemia/tratamiento farmacológico , Hematínicos/uso terapéutico , Hipertensión/etiología , Hipertrofia Ventricular Izquierda/etiología , Fallo Renal Crónico/complicaciones , Anemia/sangre , Anemia/etiología , Antihipertensivos/uso terapéutico , Presión Sanguínea , Progresión de la Enfermedad , Hemoglobinas/metabolismo , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/prevención & control , Pronóstico , Medición de Riesgo , Factores de RiesgoRESUMEN
Mitochondrial diseases are a heterogeneous group of syndromes caused by genetic defects in mitochondrial DNA (mtDNA) or nuclear-encoded mitochondrial genes. They present with a wide range of clinical phenotypes. Myopathy may be the sole or main sign, or merely an incidental finding occurring in the late course of a multisystemic illness. Although mitochondrial disorders are increasingly being recognized, confirming a specific diagnosis remains a great challenge due to the clinical heterogeneity of the diseases. Several well-defined clinical syndromes associated with specific mutations have been described. Thus, suspicion of mitochondrial diseases among patients with multiple, seemingly unrelated neuromuscular and multisystem disorders should be confirmed by the finding of deleterious mutations in genes involving mitochondrial biogenesis and function. This case report describes a 58-year-old patient with a 40-year course of a multisystemic illness representing the diagnostic challenges of mitochondrial disease.
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Fallo Renal Crónico/genética , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Síndrome MELAS/diagnóstico , Análisis Mutacional de ADN , ADN Mitocondrial/genética , Diagnóstico Tardío , Estudios de Seguimiento , Humanos , Síndrome MELAS/genética , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/diagnósticoRESUMEN
IMPORTANCE OF THE FIELD: The incidence and prevalence of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT) continues to grow worldwide. ESRD causes significant morbidity and mortality and has enormous financial and personal costs. AREAS COVERED IN THIS REVIEW: Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched from 1989 to September 2009 to summarize current pharmacotherapy of ESRD-associated complications in adults receiving maintenance dialysis (hemodialysis or continuous ambulatory peritoneal dialysis). Current guidelines for the treatment of ESRD (e.g., NKF-K/DOQI, KDIGO, and the ERA-EDTA's European Renal Best Practice Guidelines) were included. WHAT THE READER WILL GAIN: Commonly used pharmacological treatment strategies for chronic arterial hypertension, anemia, iron management, dyslipidemia, hyperglycemia, and for disturbances of bone and mineral metabolism, including hyperphosphatemia and secondary hyperparathyroidism in ESRD, are presented. In addition, the reader will learn that nonadherence to oral medication in ESRD can contribute significantly to excess morbidity and mortality of the dialysis population. TAKE HOME MESSAGE: Improvements in pharmacotherapy of ESRD may be at least in part counteracted by continuously increasing age and comorbid disease of the dialysis population. Individualized and tailor-made pharmacological management of the ESRD patient remains a challenge for the future.
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Fallo Renal Crónico/terapia , Diálisis Peritoneal Ambulatoria Continua , Preparaciones Farmacéuticas/administración & dosificación , Diálisis Renal , Anemia/tratamiento farmacológico , Anemia/etiología , Anemia/fisiopatología , Bases de Datos Bibliográficas , Dislipidemias/tratamiento farmacológico , Dislipidemias/etiología , Dislipidemias/fisiopatología , Humanos , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/etiología , Hiperglucemia/fisiopatología , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/etiología , Hiperparatiroidismo Secundario/fisiopatología , Hiperfosfatemia/tratamiento farmacológico , Hiperfosfatemia/etiología , Hiperfosfatemia/fisiopatología , Hipertensión/tratamiento farmacológico , Hipertensión/etiología , Hipertensión/fisiopatología , Compuestos de Hierro/administración & dosificación , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/fisiopatología , Guías de Práctica Clínica como AsuntoRESUMEN
Surgical removal of enlarged parathyroid glands is the treatment of choice in most cases of tertiary renal hyperparathyroidism. Complications of this surgical procedure are rare. We report two cases of patients who developed acute hyperthyroidism after total parathyroidectomy with parathyroid autotransplantation for refractory tertiary hyperparathyroidism. The patients had no history or biochemical or radiologic evidence of thyroid disease. They were not taking drugs affecting thyroid function. Thyroid function (thyroid stimulating hormone, free T(3) and free T(4)) was measured preoperatively, immediately after surgery and again three months later. Total parathyroidectomy was successful in both patients. Circulating levels of parathyroid hormone were at the lower limit of normal values. Postoperative thyroid function tests demonstrated acute hyperthyroidism with a rapid increase in free T(3) and T(4) levels above normal and a drop in thyroid stimulating hormone below normal in both patients. The course of hyperthyroidism was short (normalization of fT(3) and fT(4) values within 14-21 days). Neither patient had symptoms of thyrotoxicosis. Transient hyperthyroidism may be an under-recognized complication of total parathyroidectomy for tertiary hyperparathyroidism. These patients should be monitored with thyroid function tests and assessed for clinical signs attributable to thyrotoxicosis.
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Hiperparatiroidismo Secundario/cirugía , Hipertiroidismo/etiología , Paratiroidectomía , Complicaciones Posoperatorias/etiología , Adulto , Humanos , Hiperparatiroidismo Secundario/sangre , Hipertiroidismo/sangre , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Complicaciones Posoperatorias/sangre , Diálisis Renal , Hormonas Tiroideas/sangreRESUMEN
BACKGROUND: Mycophenolate mofetil (MMF) is a routinely used immunosuppressive agent that selectively blocks T- and B-lymphocyte proliferation. The present study was designed to investigate the effects of this drug on human leukocyte(HLA) antibody production in general and donor-specific antibody (DSA) formation in particular in 154 recipients of renal allografts. PATIENTS AND METHODS: Renal allograft recipients were subdivided into three groups. Group 1 patients (n = 60) had received MMF since transplantation in combination with either cyclosporin A or tacrolimus and steroids. Group 2 patients (n = 29) had received an MMF-free immunosuppressive regimen initially followed by addition of MMF some time later. Group 3 patients (n = 65) had received no MMF. Cyclosporin A or tacrolimus in combination with azathioprine and/or steroids were used for immunosuppression. DSA were demonstrated by enzyme-linked immunosorbent assay (ELISA) for detection of panel-reactive antibodies of HLA class I and II specificity. RESULTS: The HLA antibodies were found in 16.7%, 27.6% and 30.8% of transplant recipients in groups 1, 2 and 3, respectively. DSA were found in 8.3%, 17.2% and 20.0%, and non-DSA in 10.0%, 20.7% and 24.6%, of patients in groups 1, 2 and 3, respectively. CONCLUSION: The MMF reduces anti-HLA class I and II antibody production and consequently DSA production in renal allograft recipients. Our data indicate this effect to be more pronounced in patients given MMF immediately after transplantation than in those in whom MMF is introduced some time later. The presence of DSA in the serum of renal allograft recipients is associated with poorer graft function (higher serum creatinine and more rejection episodes).
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Formación de Anticuerpos/efectos de los fármacos , Antígenos HLA/inmunología , IMP Deshidrogenasa/antagonistas & inhibidores , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Azatioprina/uso terapéutico , Transfusión Sanguínea , Ciclosporina/uso terapéutico , Femenino , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunosupresores/inmunología , Trasplante de Riñón/fisiología , Masculino , Persona de Mediana Edad , Ácido Micofenólico/inmunología , Reoperación , Esteroides/uso terapéutico , Tacrolimus/uso terapéuticoAsunto(s)
Cuidados Posteriores/métodos , Medicina Familiar y Comunitaria , Comunicación Interdisciplinaria , Trasplante de Riñón , Grupo de Atención al Paciente , Comorbilidad , Humanos , Pruebas de Función Renal , Nefrología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/terapiaRESUMEN
BACKGROUND: The CD40-CD40L (CD154) costimulatory pathway plays a critical role in the pathogenesis of kidney allograft rejection. In renal transplant biopsies, CD4+CD40L+ graft-infiltrating cells were detected during chronic rejection in contrast to acute rejection episodes. Using a rapid noninvasive FACS procedure, we were able to demonstrate CD40L upregulation in peripheral blood of patients with chronic renal allograft dysfunction. MATERIALS AND METHODS: Whole blood from recipients of renal allografts was stimulated with PMA and ionomycin and measured by flow cytometry. Patients were assigned to three groups based on transplant function. Group 1: 26 patients with excellent renal transplant function; group 2: 28 patients with impaired transplant function; group 3: 14 patients with chronic allograft dysfunction and group 4: 8 healthy controls. RESULTS: The median percentage +/- SEM of CD4+/CD40L+ cells stimulated ex vivo at 10 ng/ml PMA was as follows: group 1: 28.3 +/- 4.1%; group 2: 18.4 +/- 2.4%; group 3: 50.1 +/- 5.0% and group 4: 40.4 +/- 3.4%. Subdivisions of groups 2 and 3 resulted in different CD40L expression patterns. Patients with increased serum creatinine since the initial phase after transplantation (groups 2a and 3a) revealed a higher percentage of CD4+CD40L+ cells than patients showing a gradual increase over time (groups 2b and 3b). Consequently, patients of group 3a exhibited a significantly reduced transplant function compared with those of group 3b. CONCLUSION: After PMA + ionomycin stimulation, patients with excellent kidney graft function displayed significantly reduced expression of CD40L surface molecules on CD4+ cells early after transplantation. Those with a chronic dysfunction of the renal graft showed significantly more CD4+ cells expressing CD40L compared to the other transplanted groups. These results demonstrate that the percentage of CD4+CD40L+ cells stimulated ex vivo in peripheral blood may be a valuable marker for chronic allograft nephropathy.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/biosíntesis , Trasplante de Riñón/inmunología , Linfocitos B/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Ligando de CD40/inmunología , Femenino , Citometría de Flujo , Supervivencia de Injerto/inmunología , Humanos , Técnicas In Vitro , Ionomicina/farmacología , Riñón/fisiología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Estadísticas no Paramétricas , Acetato de Tetradecanoilforbol/farmacología , Regulación hacia ArribaRESUMEN
BACKGROUND: The number of inducible adhesion molecules known to be involved in cell-mediated allograft rejection is still increasing. In addition, recent data describe complement activation during acute humoral allograft rejection. The aim of this study was to assess whether specific molecules from either pathway are excreted into urine and whether they can provide useful diagnostic tools for the monitoring of renal transplant recipients. METHODS: Urinary concentrations of soluble adhesion molecules (sICAM-1, sVCAM-1) and of the complement degradation product C4d were determined by standardized ELISA technique in 75 recipients of renal allografts and 29 healthy controls. Patient samples were assigned to four categories according to clinical criteria: GROUP 1: acute steroid-sensitive rejection (ASSR, n = 14), GROUP 2: acute steroid-resistant rejection (ASRR, n = 12), GROUP 3: chronic allograft dysfunction (CAD, n = 20) and GROUP 4: stable graft function (SGF, n = 29). RESULTS: All patients with rejection episodes (groups 1-3) had significantly higher values of urinary sC4d compared with healthy controls and patients with stable graft function (p < 0.05). The urinary levels of sVCAM-1 were significantly higher in group 2 (ASRR) compared with all other groups (p < 0.001). Uniformly low amounts of s-VCAM-1 and complement-split product C4d were excreted by healthy controls (group 0). In contrast, urinary sICAM-1 concentration in healthy controls was almost as high as in group 2 (ASRR) whereas patients with a stable functioning graft (group 4) excreted significantly less sICAM-1 (p < 0.05). CONCLUSION: The evaluation of sVCAM-1 and sC4d excretion in urine can provide a valuable tool with regard to the severity and type of allograft rejection. With respect to long-term allograft survival, serial measurements of these markers should have the potential to detect rejection episodes and prompt immediate treatment.