Silvia Lucisano

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.

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.

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, Crohns 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.

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-1β, 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-1β, 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-1β, 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.

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.

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.

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 (CO2) 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 CO2 production. Sevelamer HCl was the most tolerated chelator because it did not produce CO2, while lanthanum carbonate was the least soluble.

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.

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.

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.