Opposite actions of urotensin II and relaxin-2 on cellular expression of fibronectin in renal fibrosis: A preliminary experimental study.

Our aim was to evaluate the role of urotensin II, urantide (urotensin II receptor antagonist) and relaxin-2 on the cellular expression of fibronectin as a surrogate marker for renal fibrosis. We employed LLC-PK1 renal tubular epithelial cells and assessed the influence on the fibrotic process of the above-mentioned substances by using anti-fibronectin antibodies in western blot analysis. The addition of urotensin II increased fibronectin expression. Urantide reduced the positivity for fibronectin caused by urotensin II (P<.05). The anti-fibrotic action was more evident for relaxin-2 (P<.01). Also in the model of TGF-ß1-induced fibrosis, urantide and, to a greater extent, relaxin-2 were able to significantly lessen fibronectin expression (respectively, P<.05 and P<.01). In conclusion, relaxin-2 may reduce urotensin II-induced renal fibrosis.

The relationship between coping, emotion regulation, and quality of life of patients on dialysis.

Previous studies have investigated constructs that facilitate adaptation to chronic disease and improve quality of life and constructs that lead to psychopathological complications. The purpose of this research is to investigate the impact of coping and emotional regulation on the quality of life of patients on dialysis. Three questionnaires were administered to 78 patients on dialysis: Coping Orientations to Problems Experienced, Short Form (36), and Cognitive Emotion Regulation Questionnaire. Regressions analyses indicated that age, Rumination, Positive Refocusing, Avoidance Strategies, Approach to the Problem, and Transcendent Orientation predicted Physical Health. With regard to Mental Health, the predictors were gender, Self-Blame, Acceptance, Rumination, Positive Reappraisal, Catastrophizing, Avoidance Strategies, and Transcendent Orientation. This study confirms the relationship between emotional regulation, coping, and quality of life. The results highlight the need for total care of the patients, including an assessment of both physical state and psychological functioning in order to promote total well-being.

Semaphorin 3A serum levels are influenced by haemodialysis: what clinical significance?

AIM: Semaphorin 3A urinary levels represent an early, predictive biomarker of acute kidney injury and positively correlate with albumin-to-creatinine ratio and serum creatinine in hypertensive patients with chronic kidney disease. Our purpose has been to evaluate semaphorin 3A serum levels in a cohort of haemodialysis (HD) patients, the influence of a single HD session on its concentrations, and the potential correlation with clinical and biochemical parameters. METHODS: We enrolled 18 patients receiving HD with Acetate-Free Biofiltration technique and 16 healthy subjects as controls. Peripheral venous blood samples were obtained from patients at different intervals: start of dialysis (pre-HD), middle, and end of the treatment (post-HD). We also collected dialysate samples by the Quantiscan monitoring system (Hospal, Bologna, Italy). RESULTS: Semaphorin 3A was significantly lower in HD patients at baseline compared to controls (median 19.50 (interquartile range 1.00-65.00) versus 97.50 (23.50-161.00) ng/mL, P = 0.0237). A statistically significant reduction was seen during a single HD session (from 19.50 (1.00-65.00) to 0.86 (0.82-4.21) ng/mL, P < 0.0001), with a reduction ratio of 65.92 ± 33.51%. The median concentration in dialysate was 54.00 (15.00-102.00) ng/mL. Pre-HD values were directly related to serum vitamin D (r = 0.872; P = 0.001) and inversely correlated with calcium levels (r = -0.426; P = 0.012) and calcium × phosphate product (r = -0.422; P = 0.0252). CONCLUSION: Semaphorin 3A removal during HD may be clinically relevant due to its involvement in different aspects of cell physiology and in bone remodelling. Semaphorin 3A both inhibits osteoclastic bone reabsorption and increases osteoblastic new bone formation, thus playing a dual osteoprotective role.

Vitamin D receptor polymorphism in chronic kidney disease patients with complicated cardiovascular disease.

Several studies indicate a relationship between vitamin D and cardiovascular disease. Pleiotropic actions of vitamin D and its analogs are mediated by vitamin D receptor (VDR). VDRs have been identified in almost all tissues, including vascular smooth muscle cells, cardiomyocytes, and endothelial cells. The FokI and BsmI polymorphisms of the VDR gene are regarded as strong markers of disturbed vitamin D signaling pathway. Studies investigating the relationship between VDR genotypes and left ventricular hypertrophy revealed a highly significant association with the BsmI Bb heterozygous genotype. There are conflicting data on the action of vitamin D in left ventricular hypertrophy. Experimental as well as observational studies and small clinical trials have suggested that vitamin D administration may favorably influence left ventricular hypertrophy, whereas large randomized clinical trials have shown negative results. However, a beneficial effect on the left atrial volume index and the duration of hospitalization were observed in patients treated with vitamin D analogs. Larger clinical trials with robust clinical end points are needed to confirm that vitamin D is effective in preventing cardiovascular disease in chronic kidney disease patients and in general population.

Proteinuric effect of transcranial magnetic stimulation in healthy subjects and diabetic patients with stage 3-4 CKD.

BACKGROUND: Many authors have investigated the numerous connections between the nervous system and kidneys, and recent literature has indicated that these similar systems are interconnected. Recent scientific works have shown that there is similarity between the cerebral cortex 'viscera representation' and the 'motor omunculus'. We studied the connection between the brain and kidney in vivo using repetitive transcranial magnetic stimulation (rTMS). Proteinuria and albuminuria were used as markers of renal response in patients with diabetes (DP) and in a group of healthy subjects (HSs) who received rTMS for 5 consecutive days. METHODS: The study population consists of the following four groups: Group A (HS stimulated), Group B (HS sham), Group C (DP stimulated) and Group D (DP sham). All subjects in Groups A and C underwent rTMS delivered at a frequency corresponding to 90% of the threshold at rest for 5 consecutive days. All subjects in Groups B and D underwent rTMS delivered with the coil placed on the scalp without delivering electromagnetic stimuli, while another coil at a distance of ∼2 m emitted stimuli at a very low intensity. This strategy ensured that brain stimulation would not occur, so that the subjects felt the vibrations produced by the click of the TMS coil. The proteinuria and albuminuria of 24 h and creatinine clearance were measured at time 0 (T0), after the first session (T1), at the end of the treatment (T5) and 24 h after the last stimulation (Post 24 h). RESULTS: In Group A, there was a statistically significant increase in albuminuria (5.65 ± 0.52 versus 12 ± 0.55 mg/24 h, P = 0.0001) and proteinuria (6.05 ± 0.48 versus 13.1 ± 0.60 mg/24 h, P = 0.0001) at the end of the treatment (T5) compared with the baseline values (T0). In Group C, the albuminuria was statistically higher at T5 than the baseline T0 (416.22 ± 181 versus 677.25 ± 280 mg/24 h, P = 0.04), as was proteinuria (561.37 ± 86 versus 865.125 ± 104 mg/24 h, P = 0.0001); in Group C, the increase in albuminuria (T0 versus post 24 h, P = 0.02) and proteinuria (T0 versus 24 h post, P = 0.0002) persisted at 24 h post. In Groups B and D, statistically significant changes were not found in proteinuria (Group B T0 versus T5, P = 0.61; Group D: T0 versus T5, P = 0.66) and albuminuria (Group B T0 versus T5, P = 0.15; Group D T0 versus T5, P = 0.44) measured at the same times. CONCLUSIONS: Consecutive rTMS is able to induce a statistically significant increase in albuminuria and proteinuria in HS and DP. A functional link between the brain and kidney is possible. For the first time, the results have indicated an increase of proteinuria in subjects undergoing transcranial stimulation.

New insights on the role of vitamin D in the progression of renal damage.

Several studies indicate a relationship between hypovitaminosis D, survival, vascular calcification and inflammation. In addition to its central role in the regulation of bone mineral metabolism, vitamin D also contributes to other systems, including the immune, cardiovascular and endocrine systems. Vitamin D analogs reduces proteinuria, in particular through suppression of the renin-angiotensin-aldosterone system (RAAS) and exerts anti-inflammatory and immunomodulatory effects. In particular vitamin D deficiency contribute to an inappropriately activated RAAS, as a mechanism for progression of chronic kidney disease (CKD) and/or cardiovascular disease. Human and sperimental models of CKD showed that vitamin D may interact with B and T lymphocytes and influence the phenotype and function of the antigen presenting cells and dendritic cells, promoting properties that favor the induction of tolerogenic T regulators rather than T effectory. Interstitial fibrosis may be prevented through vitamin D supplementation. Renal myofibroblast, an activated fibroblast with expression of a molecular hallmark α-smooth muscle actin (α-SMA), is generally considered the principal matrix-producing effector cells that are responsible for the excess production of extracellular matrix (ECM) components in the fibrotic tissues. It turns out that calcitriol effectively blocks myofibroblast activation from interstitial fibroblasts, as evidenced by suppression of TGF-ß1-mediated α-SMA expression.

A biotechnological T-shirt monitors the patient's heart during hemodialysis.

Uremic patients are characterized by a "pro-arrhythmic substrate." Arrhythmia appearance during hemodialysis (HD) is an unexpected event with a high incidence of mortality and morbidity and difficult to record in patients repeatedly checked using electrocardiogram (ECG). Furthermore the carrying out of this important examination by classical devices during HD is uncomfortable and sometimes stressful for the patient. It may be very useful to monitor the patient's cardiac activity during the whole HD session. We tried to overcome these difficulties using Whealthy(®) (Wearable Health Care System), a wearable system in a T-shirt composed of conductors and piezoresistive materials, integrated to form fibers and threads connected to tissular sensors, electrodes, and connectors. ECG and pneumographic impedance signals are acquired by the electrodes in the tissue, and the data are registered by a small computer and transmitted via GPRS or Bluetooth.

[From oxygen to erythropoietin, as a protagonist of the skin-brain-kidney axis]. / Dall'ossigeno all'EPO, protagonista dell'asse cute-cervello-rene.

Erythropoietin synthesis is one of the essential adaptive responses to a hypoxic environment. In mammals, a renal oxygen sensor capable of stimulating erythropoietic hormone synthesis through a transcriptional factor called HIF (hypoxia-inducible factor) has long been identified. Recent research has demonstrated that cerebral astrocytes and skin keratocytes can also produce erythropoietin as a response to different oxygen concentrations. Therefore, it is possible to hypothesize a skin-brain-kidney link which, through erythropoietin production, modulates the oxygen contribution to tissues. Moreover, the results are not so unambiguous and further research on the pleiotropic effects of erythropoetin would be opportune.

Acetate-free biofiltration to remove fibroblast growth factor 23 in hemodialysis patients: a pilot study.

AIM: Serum levels of 32 kDa-phosphaturic hormone fibroblast growth factor 23 (FGF23) rise early in renal failure in order to keep phosphatemia within the normal range; however, this compensatory mechanism itself contributes to chronic kidney disease-mineral bone disorder. High FGF23 is also associated to left ventricular hypertrophy, vascular calcifications and thus increased cardiovascular risk. The aim of this pilot pre-post study was to evaluate the effects of a single hemodiafiltration session with acetate-free biofiltration (AFB) on FGF23 serum levels. METHODS: Nine hemodialysis patients were enrolled; sessions were performed using the Integra® monitor (Hospal, Bologna, Italy) and a polyacrylonitrile membrane. Peripheral venous blood samples were taken before (pre-HD), at mid- and after treatment (post-HD); dialysate samples were collected by the Quantiscan™ monitoring system. FGF23 was measured by a human FGF-23 ELISA kit. Mid- and post-HD values were corrected for hemoconcentration. RESULTS: Pre-HD FGF23 levels positively correlated with dialysis vintage (r = 0.7192; p = 0.0443). They were significantly reduced by the hemodialysis session (from 2.38 ± 1.80 to 1.15 ± 1.21 ng/ml, p = 0.0171) with a reduction ratio of 52.55 ± 28.76%. FGF23 was detected in the dialysate samples. CONCLUSION: FGF23 underwent a significant reduction during AFB. Such removal was greater than that induced by conventional hemodialysis as reported in the literature (19%-decrease using modified cellulosic membranes). This difference may be attributed to the ability of AFB hemodiafiltration to efficiently remove middle molecules by convection. Whether a better clearance of FGF23 during hemodialysis may result in improved cardiovascular outcomes in the long term needs to be confirmed by randomized controlled trials.

Interplay of vitamin D, erythropoiesis, and the renin-angiotensin system.

For many years deficiency of vitamin D was merely identified and assimilated to the presence of bone rickets. It is now clear that suboptimal vitamin D status may be correlated with several disorders and that the expression of 1-α-hydroxylase in tissues other than the kidney is widespread and of clinical relevance. Recently, evidence has been collected to suggest that, beyond the traditional involvement in mineral metabolism, vitamin D may interact with other kidney hormones such as renin and erythropoietin. This interaction would be responsible for some of the systemic and renal effects evoked for the therapy with vitamin D. The administration of analogues of vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Moreover, vitamin D deficiency could contribute to an inappropriately activated or unsuppressed RAS, as a mechanism for progression of CKD and/or cardiovascular disease. Experimental data on the anti-RAS and anti-inflammatory effects treatment with active vitamin D analogues suggest a therapeutic option particularly in proteinuric CKD patients. This option should be considered for those subjects that are intolerant to anti-RAS agents or, as add-on therapy, in those already treated with anti-RAS but not reaching the safe threshold level of proteinuria.

Socio-Economic Factors, Food Habits and Phosphorus Levels in Patients on Hemodialysis.

BACKGROUND: Hyperphosphoremia is one of the most important risk factors for morbidity and mortality for chronic kidney disease (CKD) patients, and also, for the general population. Excessive dietary intake of phosphate (P) is one of the key factors. In particular, P in its inorganic form, which is contained in food additives, is more readily absorbed. Unfortunately, these food additives are mostly present in convenience so called "fast foods" (pre-cooked), soft drinks, which represent the typical food consumed by our hemodialysis (HD) population, composed by elderly people, mostly low-socio economic class, who often live alone. OBJECTIVES: We performed an observational retrospective multicenter study to find any association between social, cultural and economic situation, as well as food habits, and P levels in a cohort of patients on HD. Secondarily; we also examined the association between the fast food consumption and increased P levels, as well as patient compliance for P binding products. PATIENTS AND METHODS: To explore the association between socio-economic factors and serum P levels, we enrolled 100 patients on periodic HD treatment from three different units. Information on social, cultural, economic, diet habits, therapy for hyperphosphoremia and hematological and clinical parameters had been collected through specific questionnaires, administered by a physician. RESULTS: Results showed serum P level was reduced in patients who live alone compared to patients in family (P = 0.04), in self-sufficient (P = 0.05) and in patients belonging to middle-upper class, versus low-class (P = 0.003). Fast foods intake correlates with increase in P serum levels (P = 0.002), whilst the same correlation was not found for cheese intake. Our data show that socio-economic status and food habits are useful predictors of P serum levels. CONCLUSIONS: In conclusion, dietary counseling of patients on HD is mandatory. Interventions that consider the socio-economic situation allow delivering important messages on foods with the least amount of P and adequate protein content, and they may be a successful strategy in targeting patients at a higher risk of hyperphosphoremia.

Role of Paricalcitol in Modulating the Immune Response in Patients with Renal Disease.

Introduction. The aim was to highlight the existence of a relationship between vitamin D deficiency, chronic inflammation, and proteinuria, by measuring neutrophil gelatinase associated lipocalin (NGAL) and common inflammatory markers after administration of paricalcitol, a vitamin D analog, in vivo and in vitro. Methods. 40 patients with end-stage chronic kidney disease (CKD) and secondary hyperparathyroidism and 40 healthy subjects were enrolled. Serum calcium, phosphorus, 25(OH)-vitamin D, parathyroid hormone (PTH), erythrocyte sedimentation rate, high-sensitivity C-reactive protein, interleukin- (IL-) 17, IL-6, IL-1ß, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), plasmatic and urinary NGAL, and 24 h albuminuria and proteinuria were measured before and 24 h after an intravenous bolus of paricalcitol (5 mcg). Human peripheral blood mononuclear cells were isolated and stimulated with phytohaemagglutinin. NGAL, IL-1ß, IL-17, IL-6, TNF-α, and IFN-γ were measured in the culture medium and in the 24 h urine collection. Results. 25(OH)-vitamin D was lower in CKD than in controls (p < 0.0001), while inflammatory markers were higher in CKD group (p < 0.0001). In vivo and in vitro studies showed a downregulation of NGAL, IL-17, IL-6, IL-1ß, TNF-α, and IFN-γ after paricalcitol administration (p < 0.0001). Conclusions. 25(OH)-vitamin D regulates immune and inflammatory processes. Further studies are needed to confirm these data in order to improve the treatment of CKD patients.

[Lupus Nephritis and Enteritis, a dual simultaneous involvement with Arteriolar Thrombosis]. / Nefrite ed Enterite Lupica, un doppio coinvolgimento simultaneo con trombosi arteriolare.

Arteriolar thrombosis is a complication that may occur during systemic lupus erithematosus. The pathophysiology could be related to abnormal endothelial function secondary to immune dysregulation. In particular renal and intestinal vessels may be target of thrombosis. We report a simultaneous appearance of lupus nephritis and enteritis in a young female who presented with renal failure and proteinuria. The presence of renal arteriolar thrombosis together with intestinal ischemia lead us to speculate a possible common pathways.

Sevalamer Hydrochloride, Sevelamer Carbonate and Lanthanum Carbonate: In Vitro and In Vivo Effects on Gastric Environment.

Hyperphosphatemia is common in patients with chronic renal failure. Phosphate binders are associated with gastric intolerance, representing the main reason of drug discontinuation. The aim of this study was to compare the effects in vitro and in vivo of sevelamer hydrochloride (SH), sevelamer carbonate (SC) and lanthanum carbonate (LC) on gastric microenvironment. We have also evaluated the efficacy and tolerability of these drugs in hemodialysis (HD) patients. In vitro analysis: Dissolution time, ability to uptake phosphorus, changes in pH starting from gastric milieu and the amount of carbon dioxide (CO(2)) produced were the variables analyzed. In vivo analysis: 24-h esophago-gastric pH measurement was evaluated in 24 HD patients treated with phosphate binders and proton pump inhibitor (PPI). In vitro: LC dissolved over a longer time compared with SC (58 ± 2.4 vs. 12 ± 0.6 min; P < 0.001) and SH (58 ± 2.4 vs. 10.3 ± 0.8 min; P < 0.001), determining the most alkaline pH. SC had the highest chelation power, binding 4.00 × 10(-9) mol/L of phosphoric acid. CO2 volume released was increased in LC solution (53.2 ± 7.8) compared to SC (33.9 ± 6.2; P < 0.001) and SH (2.3 ± 1.8; P < 0.001). In vivo: gastric pH increased after administration of phosphate binder. The most alkaline pH was recorded in patients treated with SC. The alkalinization of the gastric environment was not prevented by PPI therapy. 424 episodes of esophageal reflux were registered, 74% of them were alkaline. The LC group was characterized by the highest number of episodes. Sevelamer carbonate had a greater capacity and rapidity to chelate phosphorus, with a mild tolerability, due to its low CO(2) production. Sevelamer HCl was the most tolerated chelator because it did not produce CO(2), while lanthanum carbonate was the least soluble.

The future of phosphate binders: a perspective on novel therapeutics.

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a common complication of CKD. The therapeutic strategies for the treatment of CKD-MBD include phosphate binders, active vitamin D analogs and calcimimetics. The first class of drugs provided nephrologists with a range of phosphate binders that are able to decrease circulating phosphate and parathyroid hormone but involve some tolerability and safety issues. In the past 2 years, new phosphate binders have been launched and others are still under development. Serum phosphate increases only in the late stages of CKD but clinical abnormalities begin to occur earlier when multiple mechanisms try to compensate for the progressive reduced ability of the kidney to eliminate phosphorus with urine. Accordingly, starting phosphate binders when phosphatemia reaches values higher than normal may represent a late therapeutic approach. Serum phosphorus is not the ideal biomarker for the diagnosis and treatment of phosphate imbalance. This role could be better played by fibroblast growth factor 23, whose serum concentrations rise earlier in CKD. A more detailed knowledge of the mechanisms underlying CKD-MBD development will provide new therapeutic targets and then new perspectives for the treatment of phosphate imbalance in the future.

New therapeutic strategies under development to halt the progression of renal failure.

INTRODUCTION: Chronic kidney disease (CKD) is a pathological condition associated with high morbidity and mortality. Accordingly, prevention of CKD onset and progression is mandatory. As pharmacological agents already used in clinical practice are not yet able to halt the progression of renal damage, new therapeutic strategies are being explored. AREAS COVERED: The authors carried out a systematic review on completed and ongoing Phase I and II clinical trials with an aim to evaluate the safety and efficacy of novel therapeutic approaches to CKD. The data in this manuscript was retrieved from the currently available scientific literature as well as from the ClinicalTrials.gov website. EXPERT OPINION: Several drugs are currently under investigation due to their supposed antiproteinuric action, such as selective endothelin-A receptor antagonists and vitamin D analogues. Other drugs could be used in CKD because of their antifibrotic, anti-inflammatory and antioxidative properties or due to the hypothetical ability to repair damaged podocytes. A fascinating therapeutic approach involves the use of progenitor/stem cells. There is still some way to go in the use of stem cells in clinical practice but remarkable progress has been made. This is especially true in terms of the understanding of their biology and behaviour, as well as in the procedures required to mobilize and activate endogenous stem cells in damaged kidneys or simply introducing them.

Neutrophil gelatinase-associated lipocalin (NGAL) and endothelial progenitor cells (EPCs) evaluation in aortic aneurysm repair.

BACKGROUND: Acute kidney injury (AKI) develops in 10% of patients after surgical abdominal aortic aneurysm (AAA) repair. Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of AKI and Endothelial Progenitor Cells (EPCs) represent a potential repair mechanism for vascular lesions. We evaluated the diagnostic power of serum (s) and urine (u) NGAL in detecting a possible event of AKI in patients undergoing surgical treatment for AAA repair. We also investigated the influence of vascular injury on EPCs. METHODS: We examined 50 patients who underwent open AAA repair. Blood and urine was collected preoperatively and every hour after surgery until 8 h to quantify sNGAL, uNGAL and circulating EPCs. AKI, was defined as a ≥25% decrease in eGFR compared with baseline values. RESULTS: There was an inverse correlation between eGFR, sNGAL and uNGAL, while a direct correlation between sNGAL APACHE II Score and EPCs was found. At receiver operating characteristic (ROC) analysis, sNGAL and uNGAL showed a very good diagnostic profile. Kaplan Meier curves showed that NGAL is a highly sensitive predictor of incidence of AKI. Univariate followed by multivariate Cox proportional hazard regression analysis showed that uNGAL and sNGAL predicted AKI independently of other potential confounders, including eGFR and APACHE II Score. Patients had at baseline and after surgical stress a significantly higher number of EPCs than control group. CONCLUSIONS: NGAL represents an independent renal predictor of incidence of AKI. EPCs reflect the degree of vascular damage and could be considered as an indicator of disease with a reparative-regenerative vascular-endothelial function.

NGAL is a precocious marker of therapeutic response.

NGAL (Neutrophil Gelatinase-Associated Lipocalin) is a small 25-kD peptide belonging to the lipocalin superfamily. Several studies highlight its role as an organ injury and disease activity biomarker. In the present review, instead, we wanted to study NGAL as a precocious marker of therapeutic response in renal and non-renal diseases (glomerulonephritis, vasculitis, LES, Crohn's disease and other chronic inflammatory pathologies). The obtained outcomes support the hypothesis that NGAL could be employed as a biomarker of response to different therapeutic schemes, because its levels sensibly and precociously change compared to other haematologic and biochemical parameters.