Integral pharmacological management of bone mineral disorders in chronic kidney disease (part I): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification.

INTRODUCTION: Chronic kidney disease-mineral and bone disorders (CKD-MBD), involving a triad of laboratory and bone abnormalities, and tissue calcifications, are associated with dismal hard-outcomes. AREAS COVERED: In two comprehensive articles, we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (this part 1) and hyperparathyroidism (part 2), taking into account CKD-accelerated atheromatosis/atherosclerosis and/or cardiovascular calcification (CVC) processes. EXPERT OPINION: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Individualization of treatment with P-binders and combinations of anti-parathyroid agents may improve biochemical control with lower incidence of undesirable effects. Isolated biochemical parameters do not accurately reflect calcium or P load or bone activity and do not stratify high cardiovascular risk patients with CKD. Initial guidance is provided on reasonable therapeutic strategies which consider the presence of CVC. This part reflects that although there is not an absolute evidence, many studies point to the need to improve P imbalance while trying to, at least, avoid progression of CVC by restriction of Ca-based P-binders if economically feasible. The availability of new drugs (i.e. inhibitors of intestinal transporters), and studies including early CKD should ultimately lead to clearer and more cost/effective clinical targets for CKD-MBD.

Integral pharmacological management of bone mineral disorders in chronic kidney disease (part II): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification.

INTRODUCTION: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are associated with costly complications and dismal hard-outcomes. AREAS COVERED: In two comprehensive articles we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (part 1) and hyperparathyroidism (this part 2), taking into account CKD-accelerated cardiovascular calcification (CVC) processes. EXPERT OPINION: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Here, initial guidance to control hyperparathyroidism is provided, taking into account the presence/absence of CVC. We include also measures for patients at risk of adynamic bone disease or suffering from calciphylaxis. Many epidemiological studies (relating to vitamin D) and thorough analyses of recent randomized clinical trials (of cinacalcet) point towards benefits of attempting to improve biochemical parameters while trying to, at least, avoid progression of CVC by more rational use of intestinal P-binders and low-dose vitamin D derivatives and/or calcimimetics. This approach does not seem to be far away from significantly improving hard-outcomes, at least in the dialysis population. The availability of new drugs and the performance of randomized clinical trials should ultimately lead to define earlier, clearer, and more cost-effective patient stratification and biochemical targets with consequent significant clinical improvements.

Clinical Uses of 1,25-dihydroxy-19-nor-vitamin D(2) (Paricalcitol).

The activation of vitamin D receptors (VDR) - (including activation by 25-hydroxyvitamin D) - seems to have not only mineral-metabolism beneficial effects but also important extra-skeletal actions. Paricalcitol is a synthetic vitamin D2 agonist of the VDR approved for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD). As a result of its selectivity, paricalcitol provides a wider therapeutic window for PTH suppression, minimizing deleterious effects of high serum calcium and/or phosphate concentrations. Paricalcitol also shares, and sometimes improves pleiotropic vitamin-D related systemic effects. For instance, paricalcitol has been repeatedly shown to decrease calcium and phosphate deposition in vessels and to decrease the expression of osteogenic factors preventing the active transformation of smooth muscle vascular cells into osteoblast-like cells in experimental models. In patients, paricalcitol has been associated with improved survival of dialysis patients and it may improve residual albuminuria in diabetic patients. Consequently, paricalcitol may enhance the standard of care in these high-risk patients. Although it seems reasonable to use these potential advantages to guide the individual and integral management of the complex CKD-mineral and bone disorder, it is necessary to recognize that many of these observations have not been proven nor confirmed in prospective clinical trials.

Role of vitamin D receptor activators in peritoneal dialysis.

Chronic kidney disease (CKD), including patients on peritoneal dialysis (PD), is linked to an important increase in mortality risk. Within the new systemic term CKD-MBD, alterations in vitamin D metabolism are also included. Many adverse events have been associated with vitamin D deficiency or lack of vitamin D receptor (VDR) activation both in the general population and CKD patients, and these associations seem to be maintained in PD patients. Particularities of PD in vitamin D metabolism, calcium balance, low PTH levels and the high prevalence of adynamic bone disease are discussed. We also review the associations of clinical or survival benefits with vitamin D supplementation, VDR or selective VDR activation, although they are low-graded and most of them obtained from HD databases. Nevertheless, we think that the combined approach to secondary hyperparathyroidism seems also to be appropriate in PD patients, and vitamin D (native plus VDR or selective VDR activation) seem an important part of the required integral approach. The later may provide additional benefits but definitive prove is still lacking.

Trasplante renal de donante vivo en paciente VIH positivo / Living donor kidney transplatation in a HIV patient

La infección por el virus de la inmunodeficiencia humana (VIH) ha dejado de ser una contraindicación absoluta para el trasplante renal desde la introducción del tratamiento antirretroviral de gran actividad (TARGA). Se han establecido unos criterios consensuados para seleccionar a los pacientes VIH positivo candidatos a un trasplante: no haber sufrido enfermedades definitorias de SIDA (criptosporidiosis intestinal, leuco encefalopatía multifocal progresiva o sarcoma de Kaposi sistémico), tener una cifra de linfocitos CD4 mayor de 200 células/ µL, tener una carga viral indetectable y estar con tratamiento antirretroviral de gran actividad. Cumpliendo estos criterios, individualizando el tratamiento antirretroviral y con una pauta inmunosupresora óptima, la supervivencia del injerto renal al año es comparable a la de los pacientes VIH negativo. Presentamos el primer trasplante renal de donante vivo en un paciente VIH realizado en la Fundación Puigvert (AU)

Since the introduction of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV) infection is no longer an absolute contraindication for renal transplantation. Selection criteria have been established for selecting HIV patients as a candidates for a transplant: not having suffered AIDS-defining disease (intestinal cryptosporidiosis, progressive multifocal leukoencephalopathy or systemic Kaposi sarcoma), to have a CD4 T-cell count greater than 200 cells/mL, undetectable viral load and being under treatment with highly active antiretroviral therapy. Fulfilling these criteria, individualizing antiretroviral therapy and with optimal immunosuppressive regimen, graft survival rates are similar to those reported for patients without HIV. We present the first Kidney transplantation from living donor in HIV patient performed at Fundació Puigvert (AU)

Oclusiónes intestinales altas por hematomas yeyunales intramurales espontáneos en tratamiento dicumarínico / Small bowel obstruction due to intramural hematoma during anticoagulant therapy

Los accidentes oclusivos y suboclusivos en el inicio del uso de los tratamientos prolongados con anticoagulantes se cifraban entre el 1-2%, disminuyendo paulatinamente gracias al mejor conocimiento de los mecanismos de la hemostasia. La presencia de dolor abdominal y cuadro suboclusivo/oclusivo en pacientes bajo tratamiento anticoagulante con dicumarínicos representa un problema diagnóstico para el cirujano, al emular un abdomen quirúrgico. Hasta la aparición de la ecografía y sobre todo de la tomografía axial computerizada, fue difícil su diagnóstico y proporcionándonos éstas, datos precisos tanto para su estudio como por la información sobre su evolución. Su tratamiento inicialmente es médico y no requiriendo intervención quirúrgica, excepto en los casos de perforación. Presentamos dos casos que no requirieron intervención quirúrgica (AU)

Small bowel obstruction caused by intramural haemorrhage secondary to anti-coagulant therapy is estimated at 1-2%, gradually decreasing due to better understanding of the mechanisms of haemostasis. The presence of abdominal pain and occlusive box / occlusion in patients under anticoagulant therapy with Coumadin is a diagnostic problem for the surgeon, a surgical abdomen emulate. Until the advent of ultrasound and especially computerized tomography, it was difficult to diagnose and supplying them, so accurate data for study and for the information on its progress. Their initial treatment is medical and not requiring surgical intervention, except in cases of perforation. We present two cases treated conservatively (AU)

Complicaciones de aterosclerosis de grandes vasos / Complications of large vessel atherosclerosis

La enfermedad renal ateroembólica es consecuencia del desprendimiento y migración a vasos distales de microémbolos de colesterol, procedentes de placas de ateroma de grandes arterias. Estos émbolos pueden ocluir pequeños vasos en el riñón, retina, cerebro, páncreas, músculos y piel. Se produce en pacientes con arterioesclerosis tras procesos endovasculares o bien se puede producir espontáneamente. Por ello ante un deterior de función renal inexplicable, en paciente con signos de arterioesclerosis, se debe sospechar siempre una enfermedad ateroembólica y buscar manifestaciones extrarrenales. En estos casos, puede ser necesaria la confirmación histológica para el diagnóstico definitivo. No existe tratamiento específico, debiendo tomar algunas medidas como, suspender los anticoagulantes, las manipulaciones aórticas y reducir la PA. De ello dependerá la evolución, ya que ésta puede ser muy variable siendo, desde formas leves, hasta potencialmente mortales. Por otro lado es conveniente remarcar; que a pesar del control estricto de los factores de riesgo vascular, la enfermedad aterosclerótica es una enfermedad progresiva, como se desprende del caso que presentamos y aconsejamos en pacientes de este tipo, con alto riesgo vascular, la toma periódica de la PA en ambas extremidades (AU)

Atheroembolic renal disease is a consequence of the detachment and migration of microemboli distal vessels of cholesterol from atherosclerotic plaques of large arteries. These emboli can occlude small vessels in the kidney, retina, brain, pancreas, muscles and skin. It occurs in patients with atherosclerosis after endovascular procedures or it may occur spontaneously. Therefore, before an unexplained deterioration of renal function, in patients with signs of atherosclerosis, an atherosclerotic disease should always be suspected and seek for extra renal manifestations. In these cases, histological confirmation may be required for definitive diagnosis. There is non specific treatment and certain measures should be taken such as suspending anticoagulants, aortic manipulation and reducing the blood pressure. The evolution will depend on this, as it can vary from being mild to life-threatening forms. On the other band, it is advisable to note, that in despite the strict control of vascular risk factors, atherosclerotic disease is a progressive disease, as shown in the case reported, and in such patients, with high vascular risk, we advise monitoring their BP regularly in both extremities (AU)

Dietary and pharmacological control of calcium and phosphate metabolism in dialysis patients.

Chronic kidney disease-mineral and bone disorder is a new term defining a complex syndrome which underlines the need of a systemic approach to disturbances of calcium and phosphate metabolism in patients with renal failure. In recent years, the availability of new phosphorus binders and the appearance of new selective vitamin D receptor activators and calcimimetics have increased our current armamentarium and have changed previous paradigms. All these drugs can be used in combination, acting in distinct yet complementary pathways, with a resultant improvement in their individual clinical profile and reduction in secondary effects, while enhancing the achievement of clinical guideline targets. On the other hand, we should be aware that treatment costs are increasing and most of our knowledge is opinion-based. In this article, we shall consider rational recommendations on the control of calcium, phosphorus and parathyroid hormone while awaiting new evidence. We shall also briefly review some important related issues such as vascular calcification, adynamic bone disease, osteoporosis and the need of parathyroidectomy. Future guidelines may modify current recommendations, but we believe that the lack of an absolute evidence is not equivalent to the lack of awareness of the important problem which chronic kidney disease-mineral and bone disorder represents.