Uric Acid Renal Lithiasis: New Concepts.

BACKGROUND: Uric acid (UA) stones are responsible for 5-10% of the formation of all kidney stones. Recently, an association between UA stones and insulin resistance, diabetes mellitus, and obesity has been demonstrated and so the incidence has increased. The development of UA stones is dependent on several risk factors, including genetic predisposition, geographical location, dietary indiscretion, and various metabolic characteristics. SUMMARY: UA nephrolithiasis can arise from diverse etiologies, all with distinct underlying defects converging to one or more of 3 defects of hyperuricosuria, acidic urine pH, and low urinary volume. Low urinary pH is the commonest and by far the most important factor in UA nephrolithiasis, but the reason for this defect is unknown. Patients with UA nephrolithiasis have normal acid-base parameters assessed according to conventional clinical tests. Studies have revealed that there could be an insufficient production of urinary ammonium buffer. Many transport proteins are candidate participants in urate handling, with URAT1 and GLUT9 being the best characterized to date. Because low urine pH is the most important pathogenic factor of UA stone formation, urine alkalinization is an effective intervention to reduce UA crystallization and dissolve UA stones. Key Messages: Epidemiological and metabolic studies have indicated an association between UA nephrolithiasis and insulin resistance. Some potential mechanisms include impaired ammoniagenesis caused by resistance to insulin action in the renal proximal tubule or due to substrate competition by free fatty acids. The identification of novel complementary DNA has provided an interesting insight into the renal handling of UA, including one genetic cause of renal UA wasting.

MOnitored supplementation of VItamin D in preterm infants (MOSVID trial): study protocol for a randomised controlled trial.

BACKGROUND: The pivotal role of vitamin D (vit D) in skeletal health is well known. Neonatal vit D storage at birth is dependent on maternal levels, and newborns receive 50-70% of their mother's 25-hydroxyvitamin D [25(OH)D]. Deficiency of vit D can lead to prematurity bone disease, with an incidence of up to 55% in infants weighing < 1000 g. The aim of this study is to assess the effectiveness of monitored supplementation of vit D in a population of preterm infants. METHODS/DESIGN: Preterm infants born at 24-32 weeks of gestation will be recruited within the first 7 days of life. Depending on the type of feeding, and after reaching partial enteral feeding or at 7 days of life, vit D supplementation will consist of 500 IU and an additional 150-300 IU/kg included in human milk fortifiers (if fed exclusively with breast milk) or 190 IU/kg in milk formulas. Subjects will be randomised to either monitored (with an option of dose modification based on 25(OH)D levels as per protocol) or standard therapy up to 52 weeks of post-conceptional age (PCA). The primary outcome measure will be the number of neonates with deficiency or excess levels of 25(OH)D at 40 ±2 weeks of PCA. Additional 25(OH)D levels will be measured at birth, at 4 and 8 weeks of age, and/or at 35 and 52 ±2 weeks of PCA. Secondary objectives will include the incidence of osteopenia, nephrocalcinosis and nephrolithiasis. Serum parameters of calcium phosphorus metabolism will also be measured. DISCUSSION: Despite multiple years of research and numerous publications, there is still a lack of consensus in regard to how much vit D infants should receive and how long they should receive it. Because 80% of calcium and phosphorus placental transfer occurs between 24 and 40 weeks of gestation, preterm infants are especially prone to adverse effects of vit D insufficiency. However, both inadequate and excessive amounts of vit D may be unsafe and lead to serious health issues. The results of our study may shed new light on these concerns and contribute to optimising vit D supplementation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03087149 . Registered on 15 March 2017.

Adherence to the Mediterranean Dietary Pattern and Incidence of Nephrolithiasis in the Seguimiento Universidad de Navarra Follow-up (SUN) Cohort.

BACKGROUND: Diet plays an important role in the pathogenesis of nephrolithiasis. Limited data are available to investigate the association between a Mediterranean dietary pattern and risk for nephrolithiasis. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 16,094 men and women without a history of nephrolithiasis who participated in the Seguimiento Universidad de Navarra Follow-up (SUN) Project. PREDICTORS: A validated 136-item food frequency questionnaire was used to assess baseline adherence to a Mediterranean dietary pattern that is high in fruits, vegetables, nuts, fish, and legumes, but moderate in alcohol and low in meats, saturated fats, and sugars. A Mediterranean dietary pattern score was calculated and categorized into 3 groups (0-3, 4-6, and 7-9 points). Additional factors included in statistical models were sex, age, body mass index, smoking, physical activity, time spent watching television, following a medical nutritional therapy, water and energy intake, calcium and vitamin D supplementation, and history of hypertension or diabetes. OUTCOMES: Incidence of nephrolithiasis. Participants were classified as having incident nephrolithiasis if they reported a physician-made diagnosis of nephrolithiasis during follow-up. RESULTS: After a mean follow-up of 9.6 years, 735 new cases of nephrolithiasis were identified. The multivariable HRs of nephrolithiasis for the 2 highest categories of adherence to the Mediterranean dietary pattern, using the lowest category as the reference, were 0.93 (95% CI, 0.79-1.09) and 0.64 (95% CI, 0.48-0.87); P for trend=0.01. The risk for nephrolithiasis was lower with greater consumption of dairy products and vegetables and greater with higher monounsaturated fatty acid to saturated fatty acid ratio. LIMITATIONS: No information for kidney stone composition. CONCLUSIONS: Greater adherence to a Mediterranean dietary pattern was associated with reduced risk for incident nephrolithiasis. Additional longitudinal studies are needed.

Do teas rich in antioxidants reduce the physicochemical and peroxidative risk factors for calcium oxalate nephrolithiasis in humans? Pilot studies with Rooibos herbal tea and Japanese green tea.

Several experimental and animal studies have demonstrated that substances rich in antioxidants can reduce the physicochemical and peroxidative risk factors for calcium oxalate (CaOx) renal stone formation in urine and blood. However, there are very few such investigations in humans. In the present pilot study, two varieties of tea, a green one from Japan (JGT) and a herbal one from South Africa (Rooibos) (RT), both rich in antioxidants, were administered to a group of CaOx stone formers (SF) (n = 8) for 30 days. Both teas were analysed for polyphenols by high-performance liquid chromatography and for minerals by plasma atomic and optical emission spectroscopy. 24 h urines (baseline and day 30) were analysed for lithogenic factors. CaOx metastable limits and crystal nucleation and growth kinetics were also determined in each urine sample. Deposited crystals were inspected by scanning electron microscopy. Blood samples were collected (baseline and day 30). Biomarkers of oxidative stress including plasma and urinary thiobarbituric acid reactive substances (TBARS) and urinary N-acetyl-ß-D-glucosaminidase (NAG) were also determined. Urinary physicochemical risk factors were also investigated after ingestion of RT for 30 days in two control groups (CG1 and CG2), the latter one of which consisted of habitual JGT drinkers. Statistical analyses were performed using Wilcoxon signed rank tests and Mann-Whitney tests for paired and independent measurements, respectively. Several flavonoids and catechins were quantified in RT and JGT, respectively, confirming that both teas are rich sources of antioxidants. Mineral content was found to be far below dietary reference intakes. There were no significant changes in any of the urinary physicochemical or peroxidative risk factors in the control groups or in SF, except for the supersaturation (SS) of brushite (Bru) which decreased in the latter group after ingestion of JGT. Crystal morphology showed a tendency to change from mixed CaOx mono- and di-hydrate to monohydrate after ingestion of each tea. Since the latter form has a stronger binding affinity for epithelial cells, this effect is not protective. Analysis of the physicochemical and peroxidative risk factors in CG1 and CG2 did not reveal any evidence of a synergistic effect between the two teas. Paradoxically, baseline risk factors in the habitual JGT control group were significantly raised relative to those in CG1. Our preliminary results suggest that ingestion of RT and JGT does not reduce the risk factors for CaOx stone formation in humans, but these findings need to be tested in further studies involving much larger sample sizes.

Calcium use in the management of osteoporosis: continuing questions and controversies.

Calcium is a vital element in the health and maintenance of growing and mature bone. The amount of calcium recommended for ingestion varies by age, and these requirements can be met by dietary sources or calcium supplementation. This article reviews the role of calcium in the body and the benefits and risks to calcium supplementation. The effects of calcium on fracture risk reduction, bone density, and bone turnover markers as well as the conflicting data on cardiovascular events and increased risk of nephrolithiasis associated with supplementation are discussed.

Biochemical determinants of severe lithogenic activity in patients with idiopathic calcium nephrolithiasis.

OBJECTIVE: To analyze the biochemical alterations in plasma and the urine determinants of severe lithogenic activity in patients with idiopathic calcium nephrolithiasis. METHODS: We performed a cross-sectional study of 120 patients divided into 2 groups: group 1, 60 patients without nephrolithiasis; and group 2, 60 patients with severe and/or recurrent calcium nephrolithiasis. In all patients, a study of renal function, calcium metabolism, and bone remodeling markers, and a study of the lithogenic factors were performed in urine after fasting and in 24-hour urine samples. RESULTS: We observed greater values for phosphorus in group 1 than in group 2 (P=.03). Also, we found greater values for intact parathyroid hormone (P=.01), osteocalcin (P=.000), and ß-crosslaps (P=.000) in group 2 than in group 1. In the 24-hour urine samples, significant differences were found between groups 1 and 2 in calciuria (11.7 vs 17.4 mg/dL; P=.000), citraturia (50.6 vs 33.5 mg/dL; P=.002), calcium/creatinine quotient (0.14 vs 0.20; P=.001), calcium/citrate quotient (0.05 vs 0.13; P=.04), and calcium/creatinine quotient after fasting (0.09 vs 0.16; P=.000). CONCLUSION: We consider the determinants of severe and/or recurrent calcium lithiasis to be hypercalciuria and hypocitraturia and a calcium/citrate quotient>0.06. As risk markers we can consider phosphatemia<2.9 mg/dL, phosphate/chlorine quotient>35, alkaline phosphatase>80 U/L, intact parathyroid hormone>60 pg/mL, osteocalcin>16 ng/mL, ß-crosslaps>0.400 ng/mL, and ß-crosslaps/osteocalcin quotient>0.028.

Demographic, dietary, and urinary factors and 24-h urinary calcium excretion.

BACKGROUND AND OBJECTIVES: Higher urinary calcium is a risk factor for nephrolithiasis. This study delineated associations between demographic, dietary, and urinary factors and 24-h urinary calcium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cross-sectional studies were conducted of 2201 stone formers (SF) and 1167 nonstone formers (NSF) in the Health Professionals Follow-up Study (men) and Nurses' Health Studies I and II (older and younger women). RESULTS: Median urinary calcium was 182 mg/d in men, 182 mg/d in older women, and 192 mg/d in younger women. Compared with NSF, urinary calcium as a fraction of calcium intake was 33 to 38% higher in SF (P values < or =0.01). In regression analyses, participants were combined because associations with urinary calcium were similar in each cohort and in SF and NSF. After multivariate adjustment, participants in the highest quartile of calcium intake excreted 18 mg/d more urinary calcium than those in the lowest (P trend =0.01). Caffeine and family history of nephrolithiasis were positively associated, whereas urinary potassium, thiazides, gout, and age were inversely associated, with urinary calcium. After multivariate adjustment, participants in the highest quartiles of urinary magnesium, sodium, sulfate, citrate, phosphorus, and volume excreted 71 mg/d, 37 mg/d, 44 mg/d, 61 mg/d, 37 mg/d, and 24 mg/d more urinary calcium, respectively, than participants in the lowest (P values trend < or =0.01). CONCLUSIONS: Intestinal calcium absorption and/or negative calcium balance is greater in SF than NSF. Higher calcium intakes at levels typically observed in free-living individuals are associated with only small increases in urinary calcium.

Calcium supplementation and incident kidney stone risk: a systematic review.

BACKGROUND: A report of a small increase in kidney stone risk in the calcium treatment arm of the Women's Health Initiative (WHI) led to a reduction in U.S. calcium supplement sales. OBJECTIVE: To reassess kidney stone risk in postmenopausal women using data accumulated in calcium supplement trials, bone active agent registration trials, and in unpublished WHI data available online; and to compare these estimates with formal published epidemiological studies of stone risk. METHODS: Literature review of published studies relating calcium intake to stone risk; adverse event report data from pharmaceutical industrial trials designed to evaluate bone active agents. RESULTS: Stone risk in postmenopausal women has increased substantially in the past 40 years, but absolute population incidence estimates vary widely from a low of about 70 incidents/100,000/yr for Olmsted County, MN, today, to a concurrent high of approximately 190/100,000/yr for the Nurses' Health Study II. Reported WHI incidence rates are higher still, with values around 300/100,000/yr for various WHI subgroupings. The reasons for these discordances are unclear. Despite this uncertainty about background rate, most of the studies show no increase in stone risk with high calcium intake (from either diet or supplements). Contrariwise there is a substantial body of evidence, both from controlled trials and from observational studies, indicating that there is an inverse relationship between calcium intake and stone risk.