Serum phosphate modifies the vascular response to vitamin D receptor activation in chronic kidney disease (CKD) patients.

BACKGROUND AND AIMS: Vitamin D receptor activation (VDRA) ameliorates endothelial dysfunction in CKD patients but also increases phosphate and FGF-23, which may attenuate the beneficial effect of VDRA on endothelial function. METHODS AND RESULTS: This is a pre-specified secondary analysis of the PENNY trial (NCT01680198) testing the effect of phosphate and FGF-23 on the flow mediated vasodilatory (FMD) response to paricalcitol (PCT, 2 µg/day) and placebo over a 12-weeks treatment period. Eighty-eight stage G3-4 CKD patients were randomized to PCT (n = 44) and Placebo (n = 44). Endothelial function was assessed by measuring endothelium dependent forearm blood flow (FBF) response to ischemia. The FMD response was by the 61% higher in PCT treated patients than in those on placebo (P = 0.01). Phosphate (+11%, P = 0.039), calcium (+3%, P = 0.01) and, particularly so, FGF23 (+164%, P < 0.001) increased in PCT treated patients. Changes in FMD by PCT associated inversely with phosphate (r = -0.37, P = 0.01) but were independent of FGF-23, calcium and PTH changes. The response to PCT was maximal in patients with no changes in phosphate (1st tertile), attenuated in those with mild-to-moderate rise in phosphate (2nd tertile) and abolished in those with the most pronounced phosphate increase (3rd tertile) (effect modification P = 0.009). No effect modification by FGF-23 and other variables was observed. CONCLUSIONS: The beneficial effect of PCT on endothelial function in CKD is maximal in patients with no or minimal changes in phosphate and it is abolished in patients with a pronounced phosphate rise. These findings generate the hypothesis that the endothelium protective effect by VDRA may be potentiated by phosphate lowering interventions.

The Dark Side of Blocking RAS in Diabetic Patients with Incipient or Manifested Nephropathy.

Renin-angiotensin system (RAS) inhibitors are currently advocated as the first line approach for diabetic patients with high blood pressure, particularly if early signs of renal damage are manifest. This mostly relies on the supposed benefits of these drugs, either achieved indirectly by blood pressure lowering or directly by pleiotropic effects, on cardiovascular and renal outcomes. Yet, data from large randomized controlled trials and independent meta-analyses seem to raise some concerns on the compelling use of RAS-inhibitors in the whole diabetic population as improvements in cardiovascular and renal endpoints may not be as definite as generally believed. Furthermore, the risk of adverse events, such as hyperkalemia, deserves more attention in diabetic patients.In this brief review we aimed at summarizing the most relevant available evidence on "negative" or "null" effects of RAS-inhibitors on clinical outcomes in diabetic patients, providing reasons for a "personalized" rather than generalized use of these drugs according to individual characteristics.

Glitazones in chronic kidney disease: potential and concerns.

AIMS: Glitazones rank now among the most used hypoglycemic agents in patients with type-2 diabetes. This systematic review focuses on the cardiovascular and renal outcomes in chronic kidney disease (CKD) patients treated with these drugs. DATA SYNTHESIS: Data from randomized clinical trials and a meta-analysis indicate that glitazones (particularly rosiglitazone) may increase the risk of myocardial infarction, heart failure and cardiovascular death in type-2 diabetics. Observational studies looking at survival and cardiovascular outcomes in diabetic patients with kidney failure show controversial results. Studies in experimental models and clinical studies suggest that glitazones may have favorable effects on renal disease progression, because these drugs coherently reduce urinary albumin excretion and proteinuria in diabetic and non-diabetic nephropathies. No clinical trial based on clinical end-points like kidney failure has until now tested the effect of glitazones on the evolution of chronic renal failure in these patients. CONCLUSIONS: Whether the use of glitazones has a positive or a negative impact upon major cardiovascular and renal outcomes in diabetic patients remains an open, unanswered question. Specific studies are needed to assess the efficacy and safety of glitazones in a high risk population like type-2 diabetics with chronic kidney disease.

A new therapy for kidney injury: regeneration.

Because of progressive population ageing and epidemic diffusion of type 2 diabetes mellitus in industrialized Countries, we are attending a growing incidence of end stage renal disease. This phenomenon has induced researchers to study potential alternative methods of renal function replacement. Actually, only dialytic methodics and renal transplant make possible survival of patients with terminal uremia, but both these therapeutic approaches show important limitations. The ideal solution would be represented by the possibility to "regenerate" the injured organ. This is the purpose of Regenerative Nephrology, a new medical domain which tries to develop new therapies through stimulation and induction in humans of regenerative processes already observed in other species, like reptiles and fishes. Such an ambitious and fascinating purpose requires a deep knowledge of the intricate networks which regulate the production of the hormones and mediators involved in the tissue regenerative processes. In this field the kidney embryonic development phases can represent a fundamental study model to acquire information about the reparative mechanisms of the structure and function of this excretory organ.

From kidney to cardiovascular diseases: NGAL as a biomarker beyond the confines of nephrology.

Neutrophil gelatinase-associated lipocalin (NGAL), a small 25 kDa stress-protein released from injured tubular cells after various damaging stimuli, is already known by nephrologists as one of the most promising biomarkers of incoming Acute Kidney Injury. Moreover, recent studies seem to suggest a potential involvement of this factor also in the genesis and progression of chronic kidney diseases. This brief review explores the new interesting involvement of NGAL in the experimental and clinical field of cardiovascular diseases, such as the pathogenesis and clinical manifestations of atherosclerosis, acute myocardial infarction and heart failure. It does not seem difficult that, in the next future, NGAL may become a new missing link between the kidney and the cardiovascular system.

Acute cardiovascular complications of hemodialysis.

In patients with chronic renal failure undergoing dialysis the mortality rate from cardiovascular conditions is 10 to 100 fold than in general population. The higher mortality rate is due not only to the influence of traditional risk factors, such as hypertension, diabetes, obesity, dyslipidemia and cigarette smoking, but also to specific factors of uremic patients. Acute complications commonly take place during routine hemodialysis treatments (HD) due to unsteadiness in the cardiovascular system balance. We will review most important cardiovascular complications during HD from hypotension to ventricular hypertrophy, from arrhythmias to sudden death, and finally myocardial ischemia. A large number of structural and functional peripheral vascular and cardiac abnormalities including electrolyte imbalance, hemodynamic instability and neuro-humoral stress exert an overwork on myocardium and lead to occurring of a single cardiovascular complication but are always strictly correlated events.

The erythropoietin and regenerative medicine: a lesson from fish.

BACKGROUND: Erythropoietin (EPO), the main haematopoietic growth factor for the proliferation and differentiation of erythroid progenitor cells, is also known for its angiogenic and regenerative properties. MATERIALS AND METHODS: In this study, we aimed to test the regenerative effects of EPO administration in an experimental model of Sea bass (Dicentrarchus labrax) subjected to amputation of the caudal fin. RESULTS: Erythropoietin-treated fishes (3000 UI of human recombinant EPO-alpha immediately after cutting and after 15 days) showed an increased growth rate of their fins compared with those untreated (anova variance: P: 0.01 vs. P: 0.04). By analysing fin length at established times (15 and 30 days after cut), EPO-treated fishes always showed an increased length compared with untreated ones (T-15: 1.1 +/- 0.2 vs. 0.7 +/- 0.2 cm, P: 0.03; T-30: 1.9 +/- 0.3 vs. 1.2 +/- 0.2 cm, P: 0.01). Moreover, exogenous EPO administration induced an enormous increase in EPO-blood levels at each observation time (T-15: 2240 +/- 210 vs. 16.7 +/- 1.8 mU mL(-1), P < 0.001; T-30: 2340 +/- 190 vs. 17.1 +/- 1.9 mU mL(-1), P < 0.001), whereas these levels remained quite unmodified in untreated fishes. Immunochemical analyses performed by confocal laser scanning microscopic observations showed an increased expression of EPO-receptors and PECAM-1 (an endothelial surface marker of vessels sprout) in the regenerating tissue, whereas no signs of inflammation or fibrosis were recognisable. CONCLUSIONS: All these findings confirm EPO as a new factor involved in regenerative processes, also suggesting a potential, future utility for new therapeutical applications in the field of human regenerative medicine.

A case-by-case protocol of membranous nephropathy treatment with endovenous infusion of high doses of human immunoglobulins.

The treatment of membranous nephropathy is a highly controversial issue. As some patients may have spontaneous remission, in about 50% of cases the risk of treating patients with drugs that may have severe side effects is higher than the potential benefit of arresting disease progression. Some authors therefore propose exclusively symptomatic treatment; other authors use steroids and immunosuppressive drugs, alone or in association with high risk of adverse effects and often uncertain benefits. The intravenous administration of high doses of human immunoglobulins (IVIg) has been also extended to a growing number of kidney diseases including membranous nephropathy. The mechanisms through which IVIg carry out their therapeutic effect are still unclear. The present study is a retrospective and uncontrolled trial, the aim of which was firstly to verify if some patients could respond to extremely short treatment protocols, stopped when they appear to have a stable remission, thereby avoiding expensive continuation of treatment. Secondly, we aimed to verify if some patients, judged as nonresponders to a classical protocol of IVIg therapy, could respond to a more prolonged treatment.

[Therapy with vasopressin receptor antagonists: the aquaretics]. / La terapia con gli antagonisti della vasopressina: gli acquaretici.

Aquaretic drugs, by definition, can induce an increase in urinary volume and urinary free water associated with a decreased urinary osmolarity with a consequent increase in plasma sodium. This enhanced diuresis is not accompanied by an increased loss of electrolytes, whereas traditional diuretics have the opposite, so-called saluretic effect. Aquaretics belong to a family of vasopressin receptor antagonists, V2 in particular, that regulate tubular water reabsorption. Several studies have confirmed their utility in the treatment of hyponatremic states associated with water retention such as heart failure, cirrhosis related ascites and SIADH. Furthermore, new applications may include the treatment of arterial hypertension, polycystic kidney disease, glaucoma and Meniere's syndrome.

Pulmonary hypertension and erythropoietin.

Numerous uremic patients on hemodialysis have pulmonary hypertension attributable to the presence of arteriovenous fistulas, vascular calcification, and endothelial dysfunction due to alterations in the balance between vasoconstrictive and vasodilatory substances. For these reasons, the effects of recombinant human erythropoietin, a drug widely used in patients on dialysis, on the pulmonary circulation were studied. Some authors maintain that recombinant human erythropoietin has an antihypertensive effect, while others have observed that this hormone induces a reduction in pulmonary arterial pressure due to its vasoactive and stimulatory effects on endothelial and smooth muscle cell precursors.

[A brief "update" on renal effects of caffeine]. / Rene e caffeina: un breve "update"

Caffeine is one of the most frequently consumed substances worldwide. It is present in some common beverages such as tea and coffee and in a variety of drugs, particularly analgesics. Its main mechanisms of action include inhibition of phosphodiesterase enzyme and adenosine receptors; its effects involve the whole body. In recent years there has been a debate in the scientific literature over the relationship between caffeine and the kidney and its possible toxicity. Several experimental studies have demonstrated that caffeine may exacerbate some pathological conditions such as polycystic disease and proteinuria, while others have underlined its protective effects in specific situations. While awaiting new, in-depth studies that will help to solve the debate, we can conclude that there is currently no evidence contraindicating the consumption of moderate quantities of caffeine by healthy subjects or kidney patients.

From the oxygen to the organ protection: erythropoietin as protagonist in internal medicine.

Erythropoietin (EPO), already known as the stimulating hormone for erythropoiesis, has shown different and interesting pleiotropic actions. It does not only affect erythroid cells, but also myeloid cells, lymphocytes and megakaryocytes. This hormone can also enhance phagocytic function of the polymorphonuclear cells and reduce the activation of macrophages, thus modulating the inflammatory process.Moreover, hematopoietic and endothelial cells probably have the same cellular origin, and the discovery of erythropoietin receptors (EPO-R) also on mesangial and myocardial cells, smooth muscle fibrocells and neurons has prompted the study of the non-erythropoietic functions of this hormone.The interaction between EPO and VEGF may be of particular importance in neovascularization and wound healing. Different studies have demonstrated that EPO has an important direct hemodynamic and vasoactive action, which does not depend exclusively on any increase in hematocrit and viscosity. Moreover EPO showed protective effects on myocardial cells against apoptosis induced by ischemia/repefusion injury, but it could negatively affect pulmonary hypertension in patient with chronic cor pulmonale.This review aims to stress the importance of the increasing interest in EPO applications and the necessity of further studies to gain a deeper knowledge of this hormone and its pleiotropic and complex actions.