Arsenic-mediated nephrotoxicity.

Chronic kidney disease (CKD) is an important global health problem that affects 8-15% of the population according to epidemiological studies done in different countries. Essential to prevention is the knowledge of the environmental factors associated with this disease, and heavy metals such as lead and cadmium are clearly associated with kidney injury and CKD progression. Arsenic is one of the most abundant contaminants in water and soil, and many epidemiological studies have found an association between arsenic and type 2 diabetes mellitus, hypertension and cancer; however, there is a scarcity of epidemiological studies about its association with kidney disease, and the evidence linking urinary arsenic excretion with CKD, higher urinary excretion of low molecular proteins, albuminuria or other markers of renal in injury is still limited, and more studies are necessary to characterize the role of arsenic on renal injury and CKD progression. Global efforts to reduce arsenic exposure remain important and research is also needed to determine whether specific therapies are beneficial in susceptible populations.

Tubular dysfunction and non-albuminuric renal disease in subjects with type 2 diabetes mellitus.

INTRODUCTION: Micro-albuminuria is considered an early marker of glomerular injury in patients with diabetes but it has yet to be determined whether testing for markers of tubular injury can also identify people who are at risk of progressive renal disease. OBJECTIVE: To evaluate markers of tubular injury and renal characteristics in a sample of community treated type 2 diabetic subjects. MATERIAL AND METHODS: We carry-out an assessment of a group of community diabetic patients, anthropometric measures, creatinine clearance, HbA1c, lipid profile, the mean fast serum glucose levels, albuminuria and α1-microglobulin (α1M) urine excretion were evaluated. RESULTS: From 95 included patients, 45.2% had α1M urinary excretion ≥ 10 µg/gCr, 23.1% micro-albuminuria, 9.6% macroalbuminuria and 27.2% had a GFR < 60 mL/min. The most important risk factor associated with a1M excretion was fasting glucose level (OR 4.3, 95IC 1.7-11.1 p = 0.001); HbA1c ≥ 8% and age were the most important risk factors associated with GFR ≤ 60 mL/min. Most of patients had uncontrolled glucose levels and 45.1% patients with albuminuria were not receiving any drug with anti-proteinuric effects. CONCLUSIONS: Fasting glucose levels was the most important risk factor associated with tubular dysfunction; non-albuminuric presentation of CKD defined as GFR < 60 mL/min was frequent in our population, so is necessary to implement different strategies for surveillance in patients with type 2 diabetes aiming to delay progression to CKD.

Appendicular Muscle Mass Index as the Most Important Determinant of Bone Mineral Content and Density in Small for Gestational Age Children.

Preterm small for gestational age (SGA) children are at increased risk for low bone mineral content later in life; however, data on SGA children born at term are scarce. We included 44 SGA and 57 adequate for gestational age (AGA) children aged 6 to 11 years to compare bone mineral density (BMD) and bone mineral content (BMC) and to identify which anthropometric and biochemical values influence bone mineralization in these children. Fat mass, appendicular skeletal muscle mass index (ASMMI), BMC, and BMD were significantly lower in SGA children than in AGA (P ≤ .005). Appendicular muscle mass index correlated with BMC(TBLH,FN,L1-L4) and BMD(TBLH,FN,L1-L4) in both groups (r2 = 0.7, P < .05). In multivariate analysis, ASMMI was strongly associated with BMC and BMD in both groups. There were no differences in clinical biomarkers, calcium intake, and physical activity between the groups. Achieving adequate muscle mass contributes to adequate bone mineralization and a lower risk for low BMC and BMD in SGA children.

Levosulpiride for the treatment of diabetic macular oedema: a phase 2 randomized clinical trial.

BACKGROUND/OBJECTIVE: The prokinetic levosulpiride elevates vasoinhibin levels in the vitreous of patients with proliferative diabetic retinopathy (PDR) suggesting clinical benefits due to the anti-vasopermeability and anti-angiogenic properties of vasoinhibin. We investigated the biological activity of levosulpiride in centre-involving diabetic macular oedema (DME). PATIENTS/METHODS: Prospective, randomized, double-blinded, dual-centre, phase 2 trial in patients with centre-involving DME orally treated with placebo (n = 17) or levosulpiride (n = 17) for 8 weeks or in patients with PDR undergoing elective pars plana vitrectomy and receiving placebo (n = 18) or levosulpiride (n = 18) orally for the 1 week before vitrectomy. RESULTS: Levosulpiride improved changes from baseline in best-corrected visual acuity (p ≤ 0.037), central foveal thickness (CFT, p ≤ 0.013), and mean macular volume (MMV, p ≤ 0.002) at weeks 4, 6, and 8 compared to placebo. At 8 weeks, the proportion of eyes gaining ≥5 ETDRS letters at 4 m (41% vs. 28%), losing ≥21 µm in CFT (55% vs. 28%), and dropping ≥0.06 mm3 in MMV (65% vs. 29%) was higher after levosulpiride than placebo. The overall grading of visual and structural parameters improved with levosulpiride (p = 0.029). Levosulpiride reduced VEGF (p = 0.025) and PlGF (p = 0.008) levels in the vitreous of PDR patients. No significant adverse side-effects were detected. CONCLUSIONS: Oral levosulpiride for 8 weeks improved visual and structural outcomes in patients with centre-involving DME by mechanisms that may include intraocular upregulation of vasoinhibin and downregulation of VEGF and PlGF. Larger clinical trials evaluating long-term efficacy and safety are warranted.

Tight junction disruption and the pathogenesis of the chronic complications of diabetes mellitus: A narrative review.

The chronic complications of diabetes mellitus constitute a major public health problem. For example, diabetic eye diseases are the most important cause of blindness, and diabetic nephropathy is the most frequent cause of chronic kidney disease worldwide. The cellular and molecular mechanisms of these chronic complications are still poorly understood, preventing the development of effective treatment strategies. Tight junctions (TJs) are epithelial intercellular junctions located at the most apical region of cell-cell contacts, and their main function is to restrict the passage of molecules through the paracellular space. The TJs consist of over 40 proteins, and the most important are occludin, claudins and the zonula occludens. Accumulating evidence suggests that TJ disruption in different organs, such as the brain, nerves, retina and kidneys, plays a fundamental pathophysiological role in the development of chronic complications. Increased permeability of the blood-brain barrier and the blood-retinal barrier has been demonstrated in diabetic neuropathy, brain injury and diabetic retinopathy. The consequences of TJ disruption on kidney function or progression of kidney disease are currently unknown. In the present review, we highlighted the molecular events that lead to barrier dysfunction in diabetes. Further investigation of the mechanisms underlying TJ disruption is expected to provide new insights into therapeutic approaches to ameliorate the chronic complications of diabetes mellitus.

Liposoluble vitamins A and E in kidney disease.

Kidney disease (KD) is characterized by the presence of elevated oxidative stress, and this is postulated as contributing to the high cardiovascular morbidity and mortality in these individuals. Chronic KD (CKD) is related to high grade inflammatory condition and pro-oxidative state that aggravates the progression of the disease by damaging primary podocytes. Liposoluble vitamins (vitamin A and E) are potent dietary antioxidants that have also anti-inflammatory and antiapoptotic functions. Vitamin deficits in CKD patients are a common issue, and multiple causes are related to them: Anorexia, dietary restrictions, food cooking methods, dialysis losses, gastrointestinal malabsorption, etc. The potential benefit of retinoic acid (RA) and α-tocopherol have been described in animal models and in some human clinical trials. This review provides an overview of RA and α tocopherol in KD.

Sulpiride-induced hyperprolactinaemia increases retinal vasoinhibin and protects against diabetic retinopathy in rats.

Excessive vasopermeability and angiogenesis compromise vision in diabetic macular oedema (DME) and diabetic retinopathy (DR). Vasoinhibin is a fragment of the hormone prolactin (PRL) that inhibits diabetes-induced retinal hypervasopermeability and ischaemia-induced retinal angiogenesis in rodents. Hyperprolactinaemia generated by the dopamine D2 receptor antagonist, levosulpiride, is associated with higher levels of vasoinhibin in the vitreous of patients with DR, implying a beneficial outcome due to vasoinhibin-mediated inhibition of retinal vascular alterations. Here, we tested whether hyperprolactinaemia induced by racemic sulpiride increases intraocular vasoinhibin levels and inhibits retinal hypervasopermeability in diabetic rats. Diabetes was generated with streptozotocin and, 4 weeks later, rats were treated for 2 weeks with sulpiride or osmotic minipumps delivering PRL. ELISA, Western blot, and Evans blue assay were used to evaluate serum PRL, retinal vasoinhibin, and retinal vasopermeability, respectively. Hyperprolactinaemia in response to sulpiride or exogenous PRL was associated with increased levels of vasoinhibin in the retina and reduced retinal hypervasopermeability. Furthermore, sulpiride decreased retinal haemorrhages in response to the intravitreal administration of vascular endothelial growth factor (VEGF). Neither sulpiride nor exogenous PRL modified blood glucose levels or bodyweight. We conclude that sulpiride-induced hyperprolactinaemia inhibits the diabetes- and VEGF-mediated increase in retinal vasopermeability by promoting the intraocular conversion of endogenous PRL to vasoinhibin. These findings support the therapeutic potential of sulpiride and its levorotatory enantiomer, levosulpiride, against DME and DR.

Vitamin D status, proinflammatory cytokines and bone mineral density in Mexican people with multiple sclerosis.

BACKGROUND: Vitamin D (VD) has been classically associated with calcium homeostasis and bone mineral density since it has a key role on mineralization and resorption. Immunomodulatory effects have been attributable to VD; low concentrations of VD have been associated with elevation of inflammatory markers. Inflammatory autoimmune diseases, such as multiple sclerosis (MS), a chronic neurodegenerative suffering, whose etiology is still unknown, is directly related to an increase in pro-inflammatory cytokines such as interleukin 17 and interleukin 1ß who play an important role in this physiopathology. Nowadays, even though additional studies have linked MS's clinical signs with low VD concentration, there is scarce information of this association in people from regions with sufficient sun exposure. The aim of this study was to evaluate serum VD and cytokine concentrations, and bone density, in Mexican people with MS. METHODS: Vitamin D (25OHD), interleukin 1ß, interleukin 6 and interleukin 17 concentrations of twenty-five volunteers with MS were determined by enzyme-linked immunosorbent assay. Bone mineral density and body composition assessment was performed by dual energy X-Ray absorptiometry. RESULTS: A mean concentration of 17.3 ± 4.6 ng/ml of 25OHD was obtained, in a range of 5.15 to 25.71 ng/ml; when international advisory bodies thresholds were applied 76% of the participants exhibited some degree of VD inadequacy. Pro-inflammatory markers were detectable among the participants: interleukin 1ß in 100%, interleukin 6 in 64%, whereas interleukin 17 was found in 24% of the volunteers. Bone mineral density below the expected for the age was found in 8% of the participants, with lumbar spine as the most affected anatomic region. Non-significant correlations were found between VD and bone mineral density (Z-score) or pro-inflammatory markers. CONCLUSION: Although non-significant correlations were found between VD and bone mineral density or cytokines, it is important to highlight that an important percentage of our participants exhibited some degree of VD inadequacy, an unknown fact for them, since these are not included in routine clinical evaluations. The low concentrations of VD among this sample regardless of annual UVB sun exposure may suggest the involvement of endogenous and not environmental factors. Further works are needed in order to deepen the physiological causes and effects of VD deficiency in people with MS.

Levosulpiride Increases the Levels of Prolactin and Antiangiogenic Vasoinhibin in the Vitreous of Patients with Proliferative Diabetic Retinopathy.

Purpose: High circulating levels of the hormone prolactin (PRL) protect against experimental diabetic retinopathy (DR) due to the retinal accumulation of vasoinhibin, a PRL fragment that inhibits blood vessel permeability and growth. A phase 2 clinical trial is investigating a new therapy for DR based on elevating serum PRL levels with levosulpiride, a prokinetic dopamine D2 receptor blocker. Here, we tested whether levosulpiride-induced hyperprolactinemia elevates PRL and vasoinhibin in the vitreous of volunteer patients with proliferative DR (PDR) undergoing elective pars plana vitrectomy. Methods: Patients were randomized to receive placebo (lactose pill, orally TID; n = 19) or levosulpiride (25 mg orally TID; n = 18) for the 7 days before vitrectomy. Vitreous samples from untreated non-diabetic (n = 10) and PDR (n = 17) patients were also studied. Results: Levosulpiride elevated the systemic (101 ± 13 [SEM] vs. 9.2 ± 1.3 ng/mL, P < 0.0001) and vitreous (3.2 ± 0.4 vs. 1.5 ± 0.2 ng/mL, P < 0.0001) levels of PRL, and both levels were directly correlated (r = 0.58, P < 0.0002). The vitreous from non-diabetic patients or from PDR patients treated with levosulpiride, but not from placebo-treated PDR patients, inhibited the basic fibroblast growth factor (bFGF)- and vascular endothelial growth factor (VEGF)-induced proliferation of endothelial cells in culture. Vasoinhibin-neutralizing antibodies reduced the vitreous antiangiogenic effect. Matrix metalloproteases (MMPs) in the vitreous cleaved PRL to vasoinhibin, and their activity was higher in non-diabetic than in PDR patients. Conclusions: Levosulpiride increases the levels of PRL in the vitreous of PDR patients and promotes its MMP-mediated conversion to vasoinhibin, which can inhibit angiogenesis in DR. Translational Relevance: These findings support the potential therapeutic benefit of levosulpiride against vision loss in diabetes.

Basis and Design of a Randomized Clinical Trial to Evaluate the Effect of Levosulpiride on Retinal Alterations in Patients With Diabetic Retinopathy and Diabetic Macular Edema.

BACKGROUND: Diabetic retinopathy (DR) and diabetic macular edema (DME) are potentially blinding, microvascular retinal diseases in people with diabetes mellitus. Preclinical studies support a protective role of the hormone prolactin (PRL) due to its ocular incorporation and conversion to vasoinhibins, a family of PRL fragments that inhibit ischemia-induced retinal angiogenesis and diabetes-derived retinal vasopermeability. Here, we describe the protocol of an ongoing clinical trial investigating a new therapy for DR and DME based on elevating the circulating levels of PRL with the prokinetic, dopamine D2 receptor blocker, levosulpiride. METHODS: It is a prospective, randomized, double-blind, placebo-controlled trial enrolling male and female patients with type 2 diabetes having DME, non-proliferative DR (NPDR), proliferative DR (PDR) requiring vitrectomy, and DME plus standard intravitreal therapy with the antiangiogenic agent, ranibizumab. Patients are randomized to receive placebo (lactose pill, orally TID) or levosulpiride (75 mg/day orally TID) for 8 weeks (DME and NPDR), 1 week (the period before vitrectomy in PDR), or 12 weeks (DME plus ranibizumab). In all cases the study medication is taken on top of standard therapy for diabetes, blood pressure control, or other medical conditions. Primary endpoints in groups 1 and 2 (DME: placebo and levosulpiride), groups 3 and 4 (NPDR: placebo and levosulpiride), and groups 7 and 8 (DME plus ranibizumab: placebo and levosulpiride) are changes from baseline in visual acuity, retinal thickness assessed by optical coherence tomography, and retinal microvascular abnormalities evaluated by fundus biomicroscopy and fluorescein angiography. Changes in serum PRL levels and of PRL and vasoinhibins levels in the vitreous between groups 5 and 6 (PDR undergoing vitrectomy: placebo and levosulpiride) serve as proof of principle that PRL enters the eye to counteract disease progression. Secondary endpoints are changes during the follow-up of health and metabolic parameters (blood pressure, glycated hemoglobin, and serum levels of glucose and creatinine). A total of 120 patients are being recruited. DISCUSSION: This trial will provide important knowledge on the potential benefits and safety of elevating circulating and intraocular PRL levels with levosulpiride in patients with DR and DME. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Ethics Committees of the National University of Mexico (UNAM) and the Instituto Mexicano de Oftalmología, I.A.P. Dissemination will include submission to peer-reviewed scientific journals and presentation at congresses. CLINICAL TRIAL REGISTRATION: Registered at www.ClinicalTrials.gov, ID: NCT03161652 on May 18, 2017.

Recent advances in diagnosis and treatment of acute kidney injury in patients with cancer.

Acute Kidney Injury (AKI) is a common complication in patients with cancer and even though there are many causes of renal failure in this population the classical classification of prerenal, renal, and postrenal is useful as a diagnostic guide. Important risk factors for AKI are dehydration, use of nephrotoxic drugs, preexisting renal impairment and large tumor burden. The development of AKI is associated with poor prognosis but early recognition and treatment initiation are associated with better outcomes in this population.