Prenatal metal levels and congenital anomalies of the kidney and urinary tract: The Japan Environment and Children's Study.

BACKGROUND: Prenatal exposure to metal elements has been reported as a potential risk factor for congenital malformation. However, studies on the relationship with congenital anomalies of the kidney and urinary tract (CAKUT) are very scarce. METHODS: Participants of a prospective cohort from the Japan Environment and Children's Study, conducted at 15 research centers, were recruited between January 2011 and March 2014. The exposure factors were concentrations of lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se), and manganese (Mn) measured from maternal whole blood in the second or third trimester. The primary outcome was CAKUT diagnosed during the first three years of life, which was classified into isolated cases and complicated cases accompanied by extrarenal congenital defects. To conduct a nested case-control design within the cohort, we selected 351 isolated cases with 1404 matched controls, and 79 complicated cases with 316 matched controls. RESULTS: A logistic regression model was used to examine the associations between individual metal concentrations and each subtype of CAKUT. A higher level of Se was associated with an increased risk of isolated CAKUT (adjusted odds ratio [95 % confidence interval]: 3.22 [1.33-7.77]). Meanwhile, higher levels of Pb and Mn were associated with a reduced risk of the complicated subtype (0.46 [0.24-0.90] and 0.33 [0.15-0.73], respectively). A Bayesian kernel machine regression model accounting for mixed effects of multiple metals further demonstrated that a higher level of Mn alone was significantly associated with a reduced occurrence of the complicated subtype. CONCLUSIONS: Using a stringent statistical approach, the present study demonstrated that a higher Mn concentration in the maternal blood was associated with a lower risk of complicated CAKUT in offspring. Further cohort and experimental studies are needed to verify the clinical impact of this finding.

An Elevation of Serum Ferritin Level Might Increase Clinical Risk for the Persistence of Patent Ductus Arteriosus, Sepsis and Bronchopulmonary Dysplasia in Erythropoietin-Treated Very-Low-Birth-Weight Infants.

BACKGROUND: The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants. OBJECTIVE: The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs). METHODS: This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml. RESULTS: Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia. CONCLUSIONS: Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection.

Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability.

BACKGROUND: Chronic supplementation with L-citrulline plus L-arginine has been shown to exhibit anti-atherosclerotic effects. However, the short-term action of this combination on the nitric oxide (NO)-cGMP pathway remains to be elucidated. The objective of the present study was to investigate the acute effects of a combination of oral L-citrulline and L-arginine on plasma L-arginine and NO levels, as well as on blood circulation. METHODS: Rats or New Zealand white rabbits were treated orally with L-citrulline, or L-arginine, or a combination of each at half dosage. Following supplementation, plasma levels of L-arginine, NOx, cGMP and changes in blood circulation were determined sequentially. RESULTS: L-Citrulline plus L-arginine supplementation caused a more rapid increase in plasma L-arginine levels and marked enhancement of NO bioavailability, including plasma cGMP concentrations, than with dosage with the single amino acids. Blood flow in the central ear artery in rabbits was also significantly increased by L-citrulline plus L-arginine administration as compared with the control. CONCLUSION: Our data show for the first time that a combination of oral L-citrulline and L-arginine effectively and rapidly augments NO-dependent responses at the acute stage. This approach may have clinical utility for the regulation of cardiovascular function in humans.

Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men.

BACKGROUND: Nitric oxide (NO) plays a key role in the maintenance of vascular tone, contributing to the functional regulation of arterial stiffness. Although oral L-citrulline could become the effective precursor of L-arginine (substrate for endothelial NO synthase) via the L-citrulline/ L-arginine pathway, little is known about the efficacy of L-citrulline application on arterial stiffness. OBJECTIVE: We examined the short-term effects of L-citrulline supplementation on arterial stiffness in humans. METHODS: In a double-blind, randomized, placebo-controlled parallel-group trial, 15 healthy male subjects (age: 58.3 ± 4.4 years) with brachial-ankle pulse wave velocity (baPWV; index of arterial stiffness >1400 cm/sec) were given 5.6g/day of L-citrulline (n=8) or placebo (n=7) for 7 days. baPWV and various clinical parameters were measured before (baseline) and after oral supplementation of L-citrulline or placebo. RESULTS: Compared with the placebo group, baPWV was significantly reduced in the L-citrulline group (p<0.01). No significant differences in blood pressure (BP) were found between the two groups, and no correlation was observed between BP and baPWV. The serum nitrogen oxide (NOx, the sum of nitrite plus nitrate) and NO metabolic products were significantly increased only in the L-citrulline group (p<0.05). Plasma citrulline, arginine and the ratio of arginine/asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase (arginine/ADMA ratio) were significantly increased in the L-citrulline group compared with the placebo group (p<0.05, p<0.01, p<0.05, respectively). Moreover, there was a correlation between the increase of plasma arginine and the reduction of baPWV (r=-0.553, p<0.05). CONCLUSION: These findings suggest that short-term L-citrulline supplementation may functionally improve arterial stiffness, independent of blood pressure, in humans.