Genetic Polymorphisms of MnSOD Modify the Impacts of Environmental Melamine on Oxidative Stress and Early Kidney Injury in Calcium Urolithiasis Patients.

Environmental melamine exposure increases the risks of oxidative stress and early kidney injury. Manganese superoxide dismutase (MnSOD), glutathione peroxidase, and catalase can protect the kidneys against oxidative stress and maintain normal function. We evaluated whether their single-nucleotide polymorphisms (SNPs) could modify melamine's effects. A total of 302 patients diagnosed with calcium urolithiasis were enrolled. All patients provided one-spot overnight urine samples to measure their melamine levels, urinary biomarkers of oxidative stress and renal tubular injury. Median values were used to dichotomize levels into high and low. Subjects carrying the T allele of rs4880 and high melamine levels had 3.60 times greater risk of high malondialdehyde levels than those carrying the C allele of rs4880 and low melamine levels after adjustment. Subjects carrying the G allele of rs5746136 and high melamine levels had 1.73 times greater risk of high N-Acetyl-ß-d-glucosaminidase levels than those carrying the A allele of rs5746136 and low melamine levels. In conclusion, the SNPs of MnSOD, rs4880 and rs5746136, influence the risk of oxidative stress and renal tubular injury, respectively, in calcium urolithiasis patients. In the context of high urinary melamine levels, their effects on oxidative stress and renal tubular injury were further increased.

Association of CASR, CALCR, and ORAI1 Genes Polymorphisms With the Calcium Urolithiasis Development in Russian Population.

Kidney stone disease is an urgent medical and social problem. Genetic factors play an important role in the disease development. This study aims to establish an association between polymorphisms in genes coding for proteins involved in calcium metabolism and the development of calcium urolithiasis in Russian population. In this case-control study, we investigated 50 patients with calcium urolithiasis (experimental group) and 50 persons lacking signs of kidney stone disease (control group). For molecular genetic analysis we used a previously developed gene panel consisting of 33 polymorphisms in 15 genes involved in calcium metabolism: VDR, CASR, CALCR, OPN, MGP, PLAU, AQP1, DGKH, SLC34A1, CLDN14, TRPV6, KLOTHO, ORAI1, ALPL, and RGS14. High-throughput target sequencing was utilized to study the loci of interest. Odds ratios and 95% confidence intervals were used to estimate the association between each SNP and risk of urolithiasis development. Multifactor dimensionality reduction analysis was also carried out to analyze the gene-gene interaction. We found statistically significant (unadjusted p-value < 0.05) associations between calcium urolithiasis and the polymorphisms in the following genes: CASR rs1042636 (OR = 3.18 for allele A), CALCR rs1801197 (OR = 6.84 for allele A), and ORAI1 rs6486795 (OR = 2.25 for allele C). The maximum OR was shown for AA genotypes in loci rs1042636 (CASR) and rs1801197 (CALCR) (OR = 4.71, OR = 11.8, respectively). After adjustment by Benjamini-Hochberg FDR we found only CALCR (rs1801197) was significantly associated with the risk of calcium urolithiasis development. There was no relationship between recurrent course of the disease and family history of urolithiasis in investigated patients. Thus we found a statistically significant association of polymorphism rs1801197 (gene CALCR) with calcium urolithiasis in Russian population.

Interrelationship of environmental melamine exposure, biomarkers of oxidative stress and early kidney injury.

Melamine contamination has remained pervasive in the environment even after the 2008 toxic milk scandal. Exposure to chronic low dosages of melamine is known to induce renal tubular damage, increasing the risk of stone formation and early kidney injury. This damage may come about via increased oxidative stress, but no studies of this possibility have been performed in humans. We conducted two human studies in 80 workers from melamine tableware factories (melamine workers) and 309 adult patients with calcium urolithiasis (stone patients) to evaluate the relationships between urinary melamine levels and two urinary biomarkers of oxidative stress, 8-oxo-2'-deoxyguanosine (8-OHdG) and malondialdehyde (MDA). Both human studies showed urinary melamine levels to be significantly and positively correlated with urinary 8-OHdG and MDA, indicating melamine exposure can increase oxidative stress. Additionally, we used structure equation modeling to evaluate relative contribution of type of melamine-induced oxidative stress on renal tubular injury and found that MDA mediated 36 %-53 % of the total effect of melamine on a biomarker of renal tubular injury, N-Acetyl-ß-d Glucosaminidase (NAG). In conclusion, our findings suggest exposure to low-dose melamine can increase oxidative stress and increase the risk of early damage to kidneys in humans.

[Urinary factors for calcium urolithiasis and their correction].

Drugs for preventing stone formation can be selected based on the average regional indicators, which have features depending on the region of the world. AIM: To investigate the features of urinary factors for lithogenesis (UFL) of calcium urolithiasis in Tashkent and evaluate the variants of their pharmacological correction. MATERIALS AND METHODS: The study analyzed data from 779 patients with calcium urolithiasis. Ninety-nine patients with uncomplicated calcium urolithiasis received non-selective preventive pharmacotherapy. Of them, patients of group 1 (n=21), 2 (n=56) and 3 (n=22) received alkaline citrate (AC) for 1 month, phytotherapy (PT) for 2 months, and combined therapy (AC + PT) for 1 month, respectively. Statistics of UFL in 779 patients with calcium urolithiasis were calculated, and the results of non-selective prophylaxis in 99 patients with uncomplicated calcium urolithiasis were analyzed. RESULTS: The most common UFLs were hypocitraturia (96.7%), decreased diuresis (96.3%), and hyperoxaluria (92.94%). In the patients of group 1, the treatment resulted in an increase in citrate by 54.14% and urine pH by 18.63%; diuresis did not change, and CaOx decreased by 50.63%. In group 2, there was an increase in citrate by 3.88% (on average for 2 months), urine pH by 10.82%, and diuresis by 32.17%; CaOx decreased by 32.59%. In group 3, citrate increased by 71.52%, urine pH by 18.07%, and diuresis by 34.71%; CaOx decreased by 69.15%. Correction of citraturia was effective in patients with initial hypocitraturia: in 80.95%, 78.6%, and 86.4% in groups 1-3, respectively. CONCLUSION: The findings confirm the potential of empirical therapy based on the average statistical indicators of the region. The combination of AC (Litren) and PT (Canephron N) proved to be most effective: CaOx decreased to a low level, it was possible to compensate for the undesirable effects of prolonged intake of the synthetic drug (AC). Nevertheless, we believe that long-term controlled studies are needed to confirm the validity of this approach, and the results of this study should be regarded as promising.

Urinary melamine excretion and increased markers of renal tubular injury in patients with calcium urolithiasis: A cross-sectional study.

Environmental low-dose melamine exposure has been associated with urolithiasis risk in adults, but it is unclear if this exposure can cause early renal damage. This cross-sectional study investigated the association of this exposure and early renal damage in patients with calcium urolithiasis. We recruited patients diagnosed with upper urinary tract calcium urolithiasis from three hospitals in southwestern Taiwan between November 2010 and January 2015. All patients completed a structured questionnaire and provided one-spot urine samples for the measurement of melamine level and markers of early renal injury, including N-acetyl b-d-glucosaminidase (NAG), ß2-microglobulin (ß2-MG), and microalbumin. We used urinary melamine levels as an indicator of environmental melamine exposure. A total of 309 patients (mean age of 54.7 ± 12.8 years) were studied. Median urinary melamine level (µg/mmol Cr) was 1.26 (interquartile range 0.48-3.29). A significant and positive correlation was found between urinary melamine concentration and urinary NAG levels (Spearman correlation coefficient, r = 0.157, p = 0.006, n = 309). With urinary melamine levels categorized into quartiles, multivariate regression results showed the same relationship, particularly in those with first stone episode. In this group, patients with the highest quartile of urinary melamine concentration had a 3.95-fold risk (95% confidence interval = 1.43-10.94) of high NAG levels (dichotomized by median), compared to the lowest quartile after adjustment. No association was found between urinary melamine concentration and urinary microalbumin levels. In conclusion, urinary melamine is significantly associated with urinary marker of early renal tubular injury, NAG, in urolithiasis patients, especially ones with first stone episode.

Correlation of Osteoporosis and Calcium Urolithiasis in Adult Population.

INTRODUCTION: Scientific studies indicate that there is a correlation between decreased bone mineral density and the age of the patient, especially in post menopausal women. GOAL: The aim of our study was to assess the connection between osteoporosis and the age of respondents, based on the DEXA findings in patients with calcium urolithiasis. MATERIAL AND METHODS: The study was prospectively and conducted in University Clinical Center Banja Luka, at the Urology Clinic and Clinic of Internal Medicine. In this study the respondents were divided into two groups: experimental group-subjects with calcium urolithiasis and control group without calcium urolithiasis. The study included 240 patients, in both groups of 120 patients who were divided into three age groups: 20-40 years, 40-60 years and more than 60 years. In both groups of respondents was conducted determination of bone mineral density in L2-L4 vertebra lumbar spine and hip by DEXA method. RESULTS: Observing the whole sample of the experimental group, according to age groups it can be noticed that DEXA results are at 72.5% normal, 27.5% below expected value, more in women within older subgroups, 20% show signs of osteopenia and osteoporosis in 7.5 %. Share of patients with osteoporosis is statistically different (p<0.05) only between sub-groups 20-40 years and over 60 years. Although appears absolute difference in the participation of patients with osteopenia by age groups, the differences are not statistically significant (p>0.05). The share of patients with normal DEXA values was significantly lower in the group over 60 years compared to the other two age groups (p<0.05). At age subgroups of the control group, the youngest group of respondents share with normal DEXA finding is 95% and among the oldest group (over 60 years) this share is much lower and is 60%, which represents a statistically significant difference, and confirms the relationship (p<0.01). Normal DEXA findings decreases with increasing years, the share of those who do not have normal findings is higher in the elderly population. CONCLUSION: Our study has just shown that in adult patients with calcium urolithiasis osteoporosis is more prevalent in older patients and more pronounced in patients with calcium urolithiasis in relation to the population without the same.

Correlation of serum and ionized calcium in patients with calcium nephrolithiasis.

INTRODUCTION: Pathogenesis of kidney stones includes many factors, whereas uroliths, as a generic term for kidney stones, are of a different composition. In pathogenesis of calcium urolithiasis hypercalcemia/hypercalciuria takes a significant place. Hypercalcemia exists when the serum calcium is of increased values, along with measurement and calculation of physiologically active calcium, when there are differences in the Ph of the blood or albumin. GOAL: the goal of this research is to determine the correlation of values of the serum (CaS) and ionized calcium (Ca++) in patients with the calcium nephrolithiasis, whom have been established not to have hyperparathyroidism and malign diseases. MATERIAL AND METHODS: the research was prospective and implemented at the Clinical Center in Banja Luka, at the Urology Clinic, in the period between 1(st) April 2012 - 1(st) January 2013 and it included 120 patients with the calcium lithiasis of the upper part of the urinary tract, divided into three age categories. Diagnosis of the calcium lithiasis of the upper part of the urinary tract was established on the basis of the ultrasonography of the urinary tract as well as native urinary tract/intravenous urography and chemical analysis of the stone in patients with spontaneous stone emission or after some of the methods for active removal of the stone. Chemical laboratory analysis of the serum and ionized calcium was done for all the patients, with 3ml of blood being taken for establishing the aforementioned parameters (1-2 ml of the serum) in vacuumed test tubes or glass tubes of capillary blood. Increased parathormone values (PHT) and history of malignity were excluding factors. RESULTS: out of the 120 patients observed, Cs(S) had the value in the reference interval with most of them, that is, in 110 patients (91.7%). Those, whose value was out of the interval, are of an older age (all above 40). Average value of this parameter amounted to 2.3017, with an average difference (the standard deviation) of 0.11391. Observing the value of Ca++, the value within the reference interval was found in 106 patients (88.3%). Out of the remaining 14 patients, only two simultaneously had the value of Ca(S) out of the permitted interval. The majority of this group consisted of older patients (a half of those whose values were outside the interval was over 60). Average value of Ca++ amounted to 1.22 mmol/L with an average difference of 0.06454. In the 2 aforementioned patients, who simultaneously had increased values of CaS and Ca++, the blood Ph was within the referential value limits, which suggests that, in line with the hyporcalcemia definition, only 2 patients with nephrolithiasis, in the total sample of 120 patients of our research sample, could have had a true hypercalcemia. CONCLUSION: the biggest number of patients with the calcium urolithiasis, who do not have hyperparathyroidism and history of malign diseases, do not have a real hypercalcemia.

Biochemical Effect of Dietary Natural Fruit Juice in the Patients with Hypocitraturic Calcium Urolithiasis / 대한비뇨기과학회지

PURPOSE: Citrate is a well recognized inhibitor of the formation of urinary calcium stones, and hypocitraturia plays an important role in the recurrent calcium urolithiasis. We evaluated the biochemical effects of dietary natural fruit juice in calcium stone formers with hypocitraturia in an attempt to decrease or eliminate the need for pharmacological therapy. MATERIALS AND METHODS: This prospective study included 26 women and 34 men (mean age 42.5 years) with documented calcium urolithiasis. Among 60 patients, hypocitraturia(0.05). But, levels of urinary citrate were significantly increased in 29(97%) patients in orange juice group(n=30) and were normalized in 19(95%) patients with hypocitraturia. In grape juice group(n=30), levels of urinary citrate were significantly increased in 28(93%) patients and were normalized in 18(90%) patients with hypocitraturia. But, in hypocitraturic patients taking orange juice, urinary oxalate increased in 12(60%) patients. The natural juice therapy was well tolerated. Some G-I trouble occured(11%) but did not require cessation of therapy. Cirtate supplementation with natural fruit juice increased urinary citrate more than 1.5-2 times, but increased urinary oxalate value in orange juice group with hypocitraturia. CONCLUSIONS: Natural fruit juices, orange and grape, are well tolerated dietary source of citrate, and may be useful as adjunctive treatment for patients with hypocitraturic calcium urolithiasis.