Role of Vitamin D Status in Diabetic Patients with Renal Disease.

Diabetes mellitus (DM) poses a major public health problem worldwide, with ever-increasing incidence and prevalence in recent years. The Institute for Alternative Futures (IAF) expects that the total number of people with type 1 and type 2 DM in the United States will increase by 54%, from 19,629,000 to 54,913,000 people, between 2015 and 2030. Diabetic Nephropathy (DN) affects about one-third of patients with DM and currently ranks as the first cause of end-stage kidney disease in the Western world. The complexity of interactions of Vitamin D is directly related with progressive long-term changes implicated in the worsening of renal function. These changes result in a dysregulation of the vitamin D-dependent pathways. Various studies demonstrated a pivotal role of Vitamin D supplementation in regression of albuminuria and glomerulosclerosis, contrasting the increase of glomerular basement membrane thickening and podocyte effacement, with better renal and cardiovascular outcomes. The homeostasis and regulation of the nephron's function are absolutely dependent from the cross-talk between endothelium and podocytes. Even if growing evidence proves that vitamin D may have antiproteinuric, anti-inflammatory and renoprotective effects in patients with DN, it is still worth investigating these aspects with both more in vitro studies and randomized controlled trials in larger patient series and with adequate follow-up to confirm the effects of long-term vitamin D analogue supplementation in DN and to evaluate the effectiveness of this therapy and the appropriate dosage.

Antioxidant agents for delaying diabetic kidney disease progression: A systematic review and meta-analysis.

BACKGROUND: Oxidative stress is a key player in the genesis and worsening of diabetic kidney disease (DKD). We aimed at collecting all available information on possible benefits of chronic antioxidant supplementations on DKD progression. STUDY DESIGN: Systematic review and meta-analysis. POPULATION: Adults with DKD (either secondary to type 1 or 2 diabetes mellitus). SEARCH STRATEGY AND SOURCES: Cochrane CENTRAL, Ovid-MEDLINE and PubMed were searched for randomized controlled trials (RCTs) or quasi-RCTs without language or follow-up restriction. INTERVENTION: Any antioxidant supplementation (including but not limited to vitamin A, vitamin C, vitamin E, selenium, zinc, methionine or ubiquinone) alone or in combination. OUTCOMES: Primary outcome was progression to end-stage kidney disease (ESKD). Secondary outcomes were change in albuminuria, proteinuria, serum creatinine and renal function. RESULTS: From 13519 potentially relevant citations retrieved, 15 articles referring to 14 full studies (4345 participants) met the inclusion criteria. Antioxidant treatment significantly decreased albuminuria as compared to control (8 studies, 327 participants; SMD: -0.47; 95% CI -0.78, -0.16) but had apparently no tangible effects on renal function (GFR) (3 studies, 85 participants; MD -0.12 ml/min/1.73m2; 95% CI -0.06, 0.01). Evidence of benefits on the other outcomes of interest was inconclusive or lacking. LIMITATIONS: Small sample size and limited number of studies. Scarce information available on hard endpoints (ESKD). High heterogeneity among studies with respect to DKD severity, type and duration of antioxidant therapy. CONCLUSIONS: In DKD patients, antioxidants may improve early renal damage. Future studies targeting hard endpoints and with longer follow-up and larger sample size are needed to confirm the usefulness of these agents for retarding DKD progression.

Role of Vitamin D in Vascular Complications and Vascular Access Outcome in Patients with Chronic Kidney Disease.

Vitamin D has been known for a long time as a major factor involved in the calcium- phosphate balance and homeostasis, along with parathyroid hormone (PTH). While vitamin D effects on calcium and phosphate are fully known, recent studies attempted to link vitamin D status and cardiovascular diseases. The involvement of vitamin D on vascular remodeling is mediated by several mechanisms such as activation of renin-angiotensin-aldosterone system (RAAS), cell proliferation and anti-apoptotic cell pathways. This correlation is highlighted by the fact that the activated form of vitamin D (1,25 (OH)2 D3) can be synthesized by the same endothelial cells, due to the constitutive presence of endothelial 1α-hydroxylase. Vitamin D reduces the expression of angiotensin 2 receptor (AT2R) on the endothelial cell surface (AT2R), leading to a cascade of events that result in the synthesis of vasodilators, such as nitric oxide. The activation of vitamin D receptors (VDRs) on endothelial cells induces changes in the metabolic activity of the endothelium and is responsible for cell survival, proliferation and neoangiogenesis. Moreover, altered signaling of VDR due to gene polymorphisms has been demonstrated in patients with cardiac disorders and chronic kidney disease (CKD). Recently, vascular access outcome has been associated with vitamin D status. Future studies will help to better define the need of vitamin D supplementation for a better cardiovascular as well as vascular access outcome in patients with CKD.

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.

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.

Can neutrophil gelatinase-associated lipocalin help depict early contrast material-induced nephropathy?

PURPOSE: To evaluate the utility of serum and urinary neutrophil gelatinase-associated lipocalin (NGAL) in depicting an event of contrast material-induced nephropathy (CIN) in patients who received iodinated contrast media, gadoterate meglumine, or radiopharmaceutical technetium-99m ((99m)Tc) and to evaluate the protective effect exerted by isotonic saline infusion, sodium bicarbonate administration, or N-acetylcysteine administration. MATERIALS AND METHODS: Institutional ethics committee approval was given, and informed consent was obtained. One hundred twenty patients were enrolled in a prospective study and divided into three groups: iomeprol group, magnetic resonance (MR) imaging group (gadoterate meglumine), and renal scintigraphy group ((99m)Tc). They randomly received N-acetylcysteine, physiologic saline, or sodium bicarbonate. Receiver operating characteristic (ROC) analysis, Kaplan-Meier curves, and Cox proportional hazard regression analysis were used. RESULTS: In the MR imaging and renal scintigraphy groups, there were significant changes in serum creatinine and NGAL levels, and there were no cases of CIN. In the iomeprol group, an early rise in NGAL was found, while serum creatinine level changes occurred 24 hours after contrast material administration. At ROC analysis, NGAL showed high sensitivity and specificity (serum NGAL: area under the curve, 0.995; 95% confidence interval [CI]: 0.868, 0.992; urinary NGAL: area under the curve, 0.992; 95% CI: 0.925, 1.000) in identifying CIN 8 hours after iomeprol administration. Regression analysis showed that NGAL independently predicted CIN. Administration of N-acetylcysteine, sodium bicarbonate, or physiologic saline did not influence NGAL level. CONCLUSION: NGAL depicted CIN in patients who received iodinated contrast material within 8 hours of contrast material administration. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120578/-/DC1.

From chronic kidney disease to transplantation: the roles of obestatin.

BACKGROUND: Kidney transplantation is the therapy of choice in most cases of end stage renal disease. The purpose of the present study was to evaluate serum obestatin levels in kidney transplant recipients (Tx), compare levels in patients with renal failure (CKD) with those in healthy subjects (HS), and to assess the role of this hormone in energetic metabolism. PATIENTS AND METHODS: A total of 95 subjects were studied: 40 were Tx; 35 had CKD and 20 were HS. Inclusion criteria were age>18years and good allograft function. Patients with an inflammatory disease or a diagnosis of cancer were excluded from the study. RESULTS: Obestatin levels in Tx patients were significantly lower than in HS (3.5 [3-4.8] versus 11 [8.56-28.60] ng/mL; p<0.0001) and patients with CKD (3.5 [3-4.8] versus 4.7 [3, 5-6, 1] ng/mL; p=0.008). At univariate analysis, a direct correlation was found between obestatin and calcemia (p: 0.0001; r: 0.51), phosphoremia (p: 0.0005; r: 0, 46), calcium-phosphate product (p<0.0001; r:0.53), and parathormone (p: 0.01; r: 0.32), whereas significant inverse correlations were evidenced for BMI (p<0.0001; r: -0.52). At multivariate analysis, significance was maintained for the correlation between obestatin and phosphoremia (ß=0.47; p=0.008), for the calcium-phosphate product (ß=0.55; p=0.0005) and for BMI (ß=-0.53; p=0.01). CONCLUSION: Obestatin, present in lower levels in Tx patients than in CKD patients and HS, plays a role in energy metabolism, affecting BMI and the metabolism of calcium-phosphorus.

Neuroprotective effect of erythropoietin and darbepoetin alfa after experimental intracerebral hemorrhage.

OBJECTIVE: Intracerebral hemorrhage (ICH) is a devastating clinical syndrome for which no truly efficacious therapy has yet been identified. In preclinical studies, erythropoietin (EPO) and its long-lasting analog, darbepoetin alfa, have been demonstrated to be neuroprotective in several models of neuronal insult. The objectives of this study were to analyze whether the systemic administration of recombinant human EPO (rHuEPO) and its long-lasting derivative darbepoetin alfa expedited functional recovery and brain damage in a rat model of ICH. METHODS: Experimental ICH was induced in rats by injecting autologous blood into the right striatum under stereotactic guidance. Subsequently, animals underwent placebo treatment, daily injections of rHuEPO, or weekly injections of darbepoetin alfa. Animals were killed 14 days after injury. RESULTS: Both rHuEPO and darbepoetin alfa were effective in reducing neurological impairment after injury, as assessed by the neurological tasks performed. rHuEPO- and darbepoetin alfa-treated animals exhibited a restricted brain injury with nearly normal parenchymal architecture. In contrast, the saline-treated group exhibited extensive cerebral cytoarchitectural disruption and edema. The number of surviving NeuN-positive neurons was significantly higher in the rats treated with rHuEPO and darbepoetin alfa compared with those that received saline (P < 0.05). CONCLUSION: These results demonstrate that weekly administered darbepoetin alfa confers behavioral and histological neuroprotection after ICH in rats similar to that of daily EPO administration. Administration of EPO and its long-lasting recombinant forms affords significant neuroprotection in an ICH model and may hold promise for future clinical applications.

Malnutrition in the elderly patient on dialysis.

Approximately one-third of all dialysis patients have mild to moderate malnutrition, while 6-8% have severe malnutrition, which is associated with increased morbidity and mortality rates and numerous pre-existing factors directly correlated with, or existing prior to, replacement hemodialysis. However, moderate to severe malnutrition (present in 10-30% of dialysis patients) is a prevalent cause of death among the elderly. Many of these patients have a particularly unstable cardiovascular and metabolic status that, independent of any underlying uremia and/or dialysis, impacts negatively on both their quality of life and clinical status. Moreover, their condition is often further exacerbated by dialysis itself, with its acute (e.g., hypotension and sensorial alterations) and chronic complications, including an exacerbation of malnutrition and systemic vascular disease. Malnutrition can occur secondary not only to erroneous dietary choices or uremia, but it may also depend on the patient's level of tolerance to dialysis and on the dialysis modality. Despite the improvements made to dialysis techniques, the nutritional condition of elderly patients on dialysis for chronic renal failure remains a cause for concern. In this patient category, it is therefore mandatory to ensure the daily supervision of nutritional status and early control when the first signs of malnutrition appear.

Effects of phytoestrogen genistein on cytogenetic biomarkers in postmenopausal women: 1 year randomized, placebo-controlled study.

To evaluate in a twelve-month, randomized placebo-controlled study whether pure administration of phytoestrogen genistein (54 mg/day) might reduce cytogenetic biomarkers in peripheral lymphocytes of postmenopausal women. A total of 57 postmenopausal women met the criteria and were randomly assigned to receive phytoestrogen genistein (n = 30) or placebo (n = 27). There was no significant difference in age, length of time since menopause or body mass index between the two groups. After one year, plasma genistein level was 0.14 +/- 0.01 micromol/L in the control group and 0.72 +/- 0.08 micromol/L in the genistein group (P < 0.0001). At baseline, sister chromatid exchange rate was 4.97 +/- 2.17 in the control group and 4.96 +/- 1.83 in the genistein group (P = 0.89). After one year, sister chromatid exchange rate was 4.96 +/- 2.16 in the control group and 3.98 +/- 1.14 in the genistein group (P < 0.05). High frequency cells count was 3% in the genistein group and 5% in the control group (P < 0.05) at the end of the study. Chromosomal aberration frequency was 5.55% in the control group at time 0 and 5.75% in the genistein group; after one year, the figures were 5.86% in the control group and 4.5% in the genistein group (P < 0.05). After one year, there was a negative relationship between sister chromatid exchange rate and plasma levels (r = - 0.43; P < 0.05) in the genistein group. Phytoestrogen genistein has been shown in postmenopausal women to be effective in the reduction of cytogenetic biomarkers. The protective effect on genomic damage appears to be a particularly promising tool in reducing the risk of cancer.

Hypophosphatemia as unusual cause of ARDS in Cushing's syndrome secondary to ectopic CRH production. A case report.

Hypophosphatemia is an unusual cause of acute respiratory distress syndrome (ARDS). We describe a hypophosphatemia-related ARDS case report of a 50-year-old woman with ACTH dependent Cushing's syndrome secondary to ectopic CRH production. The patient clinically showed hypotension tachypnea and increasing dyspnea. Laboratory data showed carbohydrate intolerance, severe hypokalemia, and hypophosphatemia. Arterial blood gases measurement revealed hypocapnia and elevation in bicarbonate values. Chest X-ray showed diffuse bilateral alveolar infiltrates similar to acute pulmonary edema and Kerley's striae. Chest CT scan evidenced diffuse ground glass opacification, bilateral patchy consolidation, and fibrosis, compatible with the recovery phase of ARDS. Clinical symptoms and laboratory examinations supported the diagnosis of ARDS. The patient was managed with supplemental potassium, octreotide, and oxygen therapy. Hypophosphatemia was managed by treating the underlying disorder. Successive surgical removal of the adrenal gland led to complete resolution of Cushing's syndrome. In conclusion, although rare and associated with specific risk factors, hypophosphatemia should be suspected in patients who develop unexplained ARDS.

Effects of the phytoestrogen genistein on cardiovascular risk factors in postmenopausal women.

OBJECTIVE: The phytoestrogen genistein has been shown to be the most efficacious in clinical and experimental studies. We studied whether genistein treatment affects some cardiovascular risk markers in postmenopausal women. DESIGN: Sixty healthy postmenopausal women, who were 52 to 60 years of age, were enrolled in a 6-month double-blind, placebo-controlled, randomized study. After a 4-week stabilization on a standard fat-reduced diet, participants were randomly assigned to receive either genistein (n = 30; 54 mg/d) or placebo (n = 30). At baseline and after a 6-month treatment, we measured fasting glucose, insulin, insulin resistance (HOMA-IR), osteoprotegerin (OPG), fibrinogen, and sex hormone-binding globulin (SHBG). RESULTS: By comparison with placebo, genistein treatment decreased significantly fasting glucose (genistein = -8.7 +/- 2.3%; placebo = 3.2 +/- 2.3%; P < 0.001), fasting insulin (genistein = -12 +/- 3.33%; placebo = 36 +/- 3.29%; P < 0.001), and HOMA-IR (genistein = -14 +/- 5.8%; placebo = 42 +/- 0.6%; P < 0.001). After genistein-treatment, fibrinogen decreased (genistein = 3.18 +/- 0.12 g/L; placebo = 3.83 +/- 0.04 g/L; P < 0.001) with respect to placebo. In the genistein group, serum OPG was lower (-2 +/- 0.3%) than in placebo (9 +/- 1.5%; P < 0.001), and serum SHBG was higher (63 +/- 3.8 nmol/L) compared with placebo (53 +/- 2.9 nmol/L; P < 0.05). CONCLUSION: Our study suggests that genistein may have a favorable effect on some cardiovascular markers.