Idiopathic Stone Research Articles

Multiomics Assessment of the Gut Microbiome in Rare Hyperoxaluric Conditions

IntroductionHyperoxaluria is a risk factor for kidney stone formation and chronic kidney disease progression. The microbiome is an important protective factor against oxalate accumulation through its oxalate-degrading enzyme activity. In this cross-sectional study, we leverage multi-omics to characterize the microbial community of participants with primary and enteric hyperoxaluria, as well as idiopathic calcium oxalate kidney stone (CKS) formers, focusing on the relationship between oxalate degrading functions of the microbiome. MethodsPatients diagnosed with Type I Primary Hyperoxaluria (PH), Enteric Hyperoxaluria (EH), and CKS were screened for inclusion in the study. Participants completed a food frequency questionnaire recording their dietary oxalate content while fecal oxalate levels were ascertained. DNA and RNA were extracted from stool samples and sequenced. Metagenomic and metatranscriptomic data were processed through our bioinformatics pipelines, and microbiome diversity, differential abundance, and networks were subject to statistical analysis in relationship with oxalate levels. Results38 subjects were recruited, including 13 healthy participants, 12 patients with recurrent CKS, 8 with PH, and 5 with EH. Urinary and fecal oxalate were significantly higher in the PH and the EH population compared to healthy controls. At the community level, alpha- and beta-diversity indices were similar across all populations. The respective contributions of single bacterial species to the total oxalate degradative potential were similar in healthy and PH subjects. Metatranscriptomic-based network analysis identified the most interactive bacterial network in PH patients. EH patients had a decreased abundance of multiple major oxalate degraders. ConclusionThe composition and inferred activity of oxalate-degrading microbiota were differentially associated with host clinical conditions. Identifying these changes improves our understanding of the relationships between dietary constituents, microbiota, and oxalate homeostasis, and suggests new therapeutic approaches protecting against hyperoxaluria.

Risk factors and predictors of urogenous sepsis after percutaneous nephrolithotomy for idiopathic calcium oxalate nephrolithiasis.

The aim of this study was to use bioinformatics approaches to screen and identify the key genes of idiopathic calcium oxalate nephrolithiasis, and explore its potential molecular mechanism. The GSE73680 kidney stone data set was downloaded from the Gene Expression Omnibus (GEO). R software (The R Foundation for Statistical Computing) was used to screen differentially expressed genes. GeneMANIA and Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) databases were used to analyze related genes interacting with crucial genes, and a protein-protein interaction (PPI) network was constructed. The differential genes were then subjected to the Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) database. The clinical data of 156 patients who received percutaneous nephrolithotomy (PCNL) therapy at our facility between January 2013 and December 2017 were retrospectively analyzed. The various parameters associated with postoperative urogenous sepsis were identified using multivariable logistic regression analysis. The study discovered one differentially expressed gene was nucleotide-binding oligomerization domain-containing protein 2 (NOD2). GO and KEGG analysis showed that NOD2 might affect the occurrence of idiopathic calcium oxalate kidney stones by affecting inflammation, receptor expression, immune environment, necrosis, apoptosis, and other pathways. The clinical parameter of patients who participated in the study, including preoperative urinary white blood cell (WBC) count, preoperative urinary nitrite, stone diameter, operation time, WBC count, and WBC D values, were statistically different between the systemic inflammatory response syndrome (SIRS) group and the urosepsis group. According to multivariate logistic regression analysis, the preoperative urine nitrite, calculus diameter, blood WBC, and NOD2 expression 3 hours after surgery were all independently associated with the urosepsis development. Preoperative urinary nitrite positive status, postoperative WBC count ≥2.98×109/L 3 hours after operation, stone diameter >6 cm, and low expression of NOD2 in renal papillary tissue are more likely to cause the urinary source of idiopathic calcium oxalate nephrolithiasis after PCNL urogenous sepsis. These parameters also offer a viable treatment paradigm for the perioperative management of PCNL in treating idiopathic calcium oxalate kidney stones.

Urinary Risk Profile, Impact of Diet, and Risk of Calcium Oxalate Urolithiasis in Idiopathic Uric Acid Stone Disease.

The role of diet in the pathogenesis of uric acid (UA) nephrolithiasis is incompletely understood. This study investigated the effect of dietary intervention on the risk of UA stone formation under standardized conditions. Twenty patients with idiopathic UA stone disease were included in the study. Dietary intake and 24 h urinary parameters were collected on the usual diet of the patients and a standardized balanced mixed diet. Although urinary UA excretion did not change, the relative supersaturation of UA decreased significantly by 47% under the balanced diet primarily due to the significant increase in urine volume and pH. Urinary pH was below 5.8 in 85% of patients under the usual diet, and in 60% of patients under the balanced diet. The supersaturation of calcium oxalate declined significantly under the balanced diet due to the significant decrease in urinary calcium and oxalate excretion and the increase in urine volume. Dietary intervention is a key component in the management of UA nephrolithiasis. Urinary calcium and oxalate excretion should also be monitored in patients with pure UA calculi to reduce the risk of mixed stone formation with calcium oxalate. Lower urinary pH in UA stone patients can only be partially explained by diet.

Inflammation and injury: what role do they play in the development of Randall’s plaques and formation of calcium oxalate kidney stones?

Urinary supersaturation is important for crystallization and likely cause of stone formation on ductal plugs. Formation of idiopathic stones that develop on Randall’s plaques in the presence of low supersaturation is, however, dependent upon immunological responses of the kidneys. Experimental data suggests osteogenic and inflammatory processes playing pivotal role in plaque formation and its exposure to the pelvic urine which is necessary for stone development. Inflammatory and crystallization modulating molecules are released into the urine, becoming incorporated within the crystals and stones as organic matrix. Many of these molecules play roles in both inflammation and crystallization.

Effect of a low-calorie diet on 24-hour urinary parameters of obese adults with idiopathic calcium oxalate kidney stones.

ABSTRACTPurpose:to evaluate the effect of low-calorie diet on 24-hour urinary metabolic parameters of obese adults with idiopathic calcium oxalate kidney stones.Materials and Methods:Adult idiopathic calcium oxalate stone formers, with body mass index (BMI) ≥30kg/m2 and a known lithogenic metabolic abnormality, were submitted to low-calorie diet for twelve weeks. After enrolment, anthropometric measures, serum exams, 24-hour urinary metabolic parameters and body impedance were collected one month prior to dietary intervention and at the end of twelve weeks. Correlations between weight loss, waist circumference loss, fat loss and variation in 24-hour urinary lithogenic parameters and calcium oxalate urinary supersaturation (CaOx SS) as per Tiselius equation were analysed.Results:From January 2017 to January 2018, 39 patients were enrolled to participate in this study. Median (range) prescribed diet was 1300 (1100-2100) Kcal/day. Mean age was 51.7±11.0 (29-68) years old and 69.2% were female. 30.8% of the participants shifted from obesity to BMI <30kg/m2 and none to BMI <25kg/m2. A significant correlation was found between baseline 24-hour urinary oxalate and weight (p=0.018) and BMI (p=0.026). No correlation was found between variation of weight, waist circumference, fat mass and 24-h urinary stone risk factors or CaOx SS.Conclusions:Short-term modest weight loss induced by twelve weeks of low-calorie diet is not associated with a decrease of 24-hour urinary lithogenic parameters in idiopathic calcium oxalate stone formers. Calcium oxalate urinary stone formation is probably multifactorial and driven by other factors than weight.

"Long-Term Health Related Survey Outcome of Pediatric Idiopathic Kidney Stone Formers"

In adults, the overall kidney stone prevalence has increased from 2.6% in the late 1960s to 8.8% in 2012 [1]. This trend was similarly seen in pediatric patients, as the incidence of kidney stone disease (hereafter, KSD) doubled from 6.9% between 1984- 1990 to 14.9% between 2003-2008

Prospective Randomized Evaluation of Idiopathic Hyperoxaluria Treatments.

Purpose: Calcium oxalate (CaOx) stone formation is influenced by urinary oxalate excretion. Stone formers with elevated urinary oxalate are commonly prescribed a low-oxalate diet or oral supplementation with vitamin B6 and magnesium to reduce urinary oxalate excretion. This study aims to compare the effects of dietary modification vs supplementation vs a combination of both on urinary oxalate. Materials and Methods: We enrolled patients with a documented history of CaOx stones and newly diagnosed idiopathic hyperoxaluria. Patients were randomized into three treatment groups: low oxalate diet (D), supplementation with 25 mg vitamin B6 and 400 mg magnesium oxide (S), or both low oxalate diet and B6/magnesium supplementation (DS). Baseline and 3-month postintervention 24-hour urine tests were obtained. The primary endpoint was change in 24-hour urinary oxalate (Ox24) at 12 weeks. Secondary endpoints included changes in other 24-hour urine parameters, compliance rates, and adverse effect rates. Results: In total, 164 patients were recruited and 62, 47, and 55 were enrolled into the D, S, and DS groups, respectively. Of these, 99 patients completed the study (56.5% of the D, 72.3% of the S, and 54.6% of the DS groups, respectively). Significant differences were noted in median percent reduction in Ox24 values (-31.1% vs -16.0% vs -23.9%, p = 0.007) in the D, S, and DS groups, respectively. Furthermore, the percentages of patients within each treatment arm who realized a decrease in Ox24 were also found to be significantly different: D = 91.4% vs. S = 67.6% vs DS = 86.7%, p = 0.027. No significant adverse events were observed in any of the study arms. Conclusion: Low oxalate diet is more effective than B6/magnesium supplementation at lowering urinary oxalate in idiopathic hyperoxaluric stone formers. Combination therapy did not produce greater reductions in urinary oxalate than either of the monotherapy arms suggesting it is of little clinical utility. Further study with long-term longitudinal follow-up is required to determine if these treatment strategies reduce recurrent stone events in this population.

Effect of age, BMI, and gender on urinary risk factors in pediatric idiopathic stone formers

The incidence of pediatric urolithiasis has been increasing over the years; however, the etiology of this increase is not well understood. Age, body mass index, and gender have been examined as possible risk factors for stone disease, but with inconsistent and variable associations. We aim to investigate the urine chemistry factors, as assessed by 24-h urinary parameters, in pediatric stone formers at a large volume tertiary referral center in the highest areas in the United States, the Southeast, based on age, body mass index, and gender. We retrospectively reviewed all pediatric stone formers who completed a 24-h study between 2005 and 2016. Patients were stratified by age (3-10 versus 11-18 years of age), overweight status (above versus below the 85th percentile for body mass index), and gender (male versus female) (Summary Figure). Statistical analysis included analysis of variance and logistic regression. 243 patients were included in our analysis. Patients in the first decade of life were found to have greater numbers of urinary risk factors than those in the second decade. Non-overweight patients were more likely to have hyperoxaluria and hyperuricosuria, while overweight patients were more likely to have hypocitraturia. Female patients were more likely to have higher hyperoxaluria, while male patients were more likely to have hypercalciuria. In contrast to prior publications, obesity is not linked to increased risk of urolithiasis with non-overweight individuals having a greater number of risk factors than the overweight cohort. Despite stone disease being more prevalent in adolescents, the greatest number of risk factors were present in the first decade of life. Lastly, female children had more urinary risk factors than males. Further understanding of the underlying causes of stone disease in various pediatric populations is warranted. While more urinary risk factors were identified in younger, non-overweight, and female patients, there remains no consensus on the urinary risk factors for pediatric urolithiasis. Further study is needed to elucidate the risk factors and pathophysiology of pediatric stone disease.

MO113CALCULATED URINARY CALCIUM-OXALATE SATURATION (ßCAOX) IS NOT SPECIFICALLY ELEVATED IN PATIENTS WITH PRIMARY HYPEROXALURIA

Abstract Background and Aims In the primary hyperoxalurias (PH; types 1-3) recurrent urolithiasis (UL) and/or progressive nephrocalcinosis (NC) are the clinical hallmarks. Three different enzyme defects lead to endogenous oxalate overproduction and to extremely elevated urinary oxalate excretion (UOx). Thus, it seems logical that urine is supersaturated for calcium-oxalate (CaOx). It was, hence, speculated that urinary CaOx saturation (ßCaOx), calculated by computed programs, is significantly higher as compared to that of patients with idiopathic CaOx stones. We now aimed to evaluate and calculate urinary ßCaOx in PH patients according to type, as well as in non-PH patients with UL or NC. Method The computed equilibrium program EQUIL2 was used for the calculation of ßCaOx. For this, 24 h urine specimen of 70 patients with non-PH NC (46 male, 24 female, median age 6.06 (range 0.3-31.4 years)), of 149 idiopathic CaOx UL (90/59 m/f, age 8.5 (0.1-68.6)), of 51 PH 1 patients (31/21, age 12.33 (0.8-63.8)), of 5 PH 2 patients (3/2, age 5.41 (4.3-12.9)) and of 14 PH 3 patients (8/6, age 8.5 (2.9-29.3)) were analyzed for all necessary components. All patients were in stable kidney function (eGFR &amp;gt; 45 ml/min). Results Uox was higher in the PH patients as compared to the non-PH UL or NC patients (p &amp;lt; 0.05). However, there was no statistical difference between the Uox in PH 1 vs PH 2 or PH 3 patients, although, a clear effect of B6 medication was visible in PH1 patients. Urinary calcium excretion was lower (not significant) in PH patients as compared to NC/UL. There was no difference in ßCaOx when PH were compared to non-PH patients and it mostly remained in the normal range. Conclusion Urine ßCaOx is similar in PH and non-PH stone formers. Therefore, calculation of ßCaOx using computed programs is not a reliable parameter to define the definitively extreme CaOx supersaturation of urine from PH patients. This miscalculation is related to a rather lowish urinary calcium excretion in PH as compared to other UL/NC patients. Therefore, we recommend not to use such programs to express the risk of recurrent stone disease or nephrocalcinosis in PH.

Etiology-Based Decision-Making Protocol for Pediatric Cholelithiasis

We reviewed hospital records of pediatric cholelithiasis to develop an etiology-based decision-making protocol. This retrospective study was conducted on consecutive pediatric cholelithiasis patients from July, 2014 to June, 2019 in a tertiary care center. Pediatric cholelithiasis was classified according to etiology, and the outcome of medical/surgical treatment was noted. Data of 354 pediatric patients were analyzed. Commonest (56.2%) etiology was idiopathic; followed by ceftriaxone pseudo-lithiasis (26.8%). Pigment stones were associated with the highest rate of complications. Non-hemolytic stones had a lower complication rate and a high rate of resolution with medical therapy. Hemolytic and symptomatic stones warrant an early cholecystectomy, whereas asymptomatic idiopathic stones, ceftriaxone stones, and TPN-induced stones are candidates for medical therapy under close observation.

Assessment of Vitamin D Level in Patients with Recurrent Renal Calcium Stones

Background: a higher concentration of the active vitamin D metabolite colic calciferol 1,25-dihydroxyvitamin D3 is associated with increased urinary calcium excretion, which could lead to increase the risk of stone formation. Objectives: To assess vitamin D level in patients with recurrent renal calcium (Ca) stones. Patients and methods: This study was conducted in Urology Department at Menoufia University Hospital during the period from March 2018 to December 2019. 96 patients were included in this study divided into two groups. The first group (group 1) consisted of 76 patients with renal Ca stone and the second group (group 2) consisted of 20 cases without renal stone. Patients who were included in this study seeking for treatment of recurrent renal stone that proved to be Ca stone by CT KUB or stone analysis. Results: there was no statistically significant difference between the two groups regarding vitamin D level, there was no statistically significant difference between different types of calcium stone in relation to vitamin D levels (P= 0.981). There was no statistically significant correlation between vitamin D levels with age (P=0.300), Hounsfield unites of stone (P=0.650) or serum creatinine (P=0.690). Conclusion: There was no statistically significant difference between studied groups regarding vitamin D level. Further studies are needed to determine whether there is any untoward consequence of a concomitant rise in intestinal absorption and urinary excretion of calcium associated with vit D supplementation in idiopathic stone formers.

Genetics of kidney stone disease.

Kidney stone disease (nephrolithiasis) is a common problem that can be associated with alterations in urinary solute composition including hypercalciuria. Studies suggest that the prevalence of monogenic kidney stone disorders, including renal tubular acidosis with deafness, Bartter syndrome, primary hyperoxaluria and cystinuria, in patients attending kidney stone clinics is ∼15%. However, for the majority of individuals, nephrolithiasis has a multifactorial aetiology involving genetic and environmental factors. Nonetheless, the genetic influence on stone formation in these idiopathic stone formers remains considerable and twin studies estimate a heritability of >45% for nephrolithiasis and >50% for hypercalciuria. The contribution of polygenic influences from multiple loci have been investigated by genome-wide association and candidate gene studies, which indicate that a number of genes and molecular pathways contribute to the risk of stone formation. Genetic approaches, studying both monogenic and polygenic factors in nephrolithiasis, have revealed that the following have important roles in the aetiology of kidney stones: transporters and channels; ions, protons and amino acids; the calcium-sensing receptor (a G protein-coupled receptor) signalling pathway; and the metabolic pathways for vitamin D, oxalate, cysteine, purines and uric acid. These advances, which have increased our understanding of the pathogenesis of nephrolithiasis, will hopefully facilitate the future development of targeted therapies for precision medicine approaches in patients with nephrolithiasis.

Discrepancy Between Stone and Tissue Mineral Type in Patients with Idiopathic Uric Acid Stones.

Objectives: To describe the papillary pathology found in uric acid (UA) stone formers, and to investigate the mineral form of tissue deposits. Materials and Methods: We studied eight UA stone formers treated with percutaneous nephrolithotomy. Papillae were imaged intraoperatively using digital endoscopy, and cortical and papillary biopsies were taken. Biopsies were analyzed by light microscopy, micro-CT, and microinfrared spectroscopy. Results: As expected, urine pH was generally low. UA supersaturation exceeded one in all but one case, compatible with the stone material. By intraoperative imaging, the renal papillae displayed a heterogeneous mixture of plaque and plugging, ranging from normal to severe. All patients had mineral in ducts of Bellini and inner medullary collecting ducts, mainly apatite with lesser amounts of urate and/or calcium oxalate in some specimens. Papillary and cortical interstitial tissue injury was modest despite the tubule plugging. No instance was found of a stone growing attached to either plaque or plugs. Conclusions: UA stone formers resemble those with ileostomy in having rather low urine pH while forming tubule plugs that contain crystals that can only form at pH values above those of their bulk urine. This discrepancy between tissue mineral deposits and stone type suggests that local tubular pH exceeds that of the bulk urine, perhaps because of localized tubule injury. The manner in which UA stones form and the discordance between tubule crystals and stone type remain open research questions.

Nanoscale Analysis of Randall’s Plaques by Electron Energy Loss Spectromicroscopy: Insight in Early Biomineral Formation in Human Kidney

Idiopathic kidney stones originate mainly from calcium phosphate deposits at the tip of renal papillae, known as Randall's plaques (RPs), also detected in most human kidneys without stones. However, little is known about the mechanisms involved in RP formation. The localization and characterization of such nanosized objects in the kidney remain a real challenge, making their study arduous. This study provides a nanoscale analysis of the chemical composition and morphology of incipient RPs, characterizing in particular the interface between the mineral and the surrounding organic compounds. Relying on data gathered from a calculi collection, the morphology and chemical composition of incipient calcifications in renal tissue were determined using spatially resolved electron energy-loss spectroscopy. We detected microcalcifications and individual nanocalcifications found at some distance from the larger ones. Strikingly, concerning the smaller ones, we show that two types of nanocalcifications coexist: calcified organic vesicles and nanometric mineral granules mainly composed of calcium phosphate with carbonate in their core. Interestingly, some of these nanocalcifications present similarities with those reported in physiological bone or pathological cardiovascular biominerals, suggesting possible common formation mechanisms. However, the high diversity of these nanocalcifications suggests that several mechanisms may be involved (nucleation on a carbonate core or on organic compounds). In addition, incipient RPs also appear to present specific features at larger scales, revealing secondary calcified structures embedded in a fibrillar organic material. Our study proves that analogies exist between physiological and pathological biominerals and provides information to understand the physicochemical processes involved in pathological calcification formation.

Number of Metabolic Syndrome Components Is the Central Predictor of the Impact of Metabolic Syndrome on Outcome of Percutaneous Nephrolithotomy in Staghorn Nephrolithiasis.

Introduction: How to quantify the impact of metabolic syndrome (MetS) on percutaneous nephrolithotomy (PCNL) is unclear. We aimed to evaluate the quantified effect of the number of MetS components on the outcome of PCNL.Materials and Methods: In this retrospective cohort study, consecutive 606 patients with idiopathic staghorn renal stones undergoing PCNL were included. The participants were divided into two groups: MetS(+) and MetS(−). The number of MetS components were calculated as 0 to 5. Primary outcomes were stone-free rate (SFR) and overall complication rate.Results: MetS, obesity, hypertension, increased triglycerides (TG), decreased high-density lipoprotein cholesterol (HDL), and diabetes mellitus were found in 24.1%, 38.1%, 70.0%, 29.9%, 34.5%, and 26.4% of the patients, respectively. SFR values were comparable between groups. MetS resulted in a higher rate of overall complication (p < 0.001, odds ratio [OR] = 2.4, 95% confidence interval [CI] 1.67–3.69), blood transfusion, urosepsis, larger hemoglobin deficiency, and length of hospital stay. Multivariable analysis confirmed that fasting plasma glucose (FPG) (p = 0.033, OR = 1.164, 95% CI 10.22–1.348) and number of MetS components (p = 0.001, OR = 1.496, 95% CI 1.184–1.890) were independent risk factors, whereas HDL (p = 0.014, OR = 0.428, 95% CI 0.217–0.837) played an independent protective role. Compared with 0, having 3, 4, and 5 MetS components was associated with stepwise increase in complication rate (19.5% vs 34.2%, 41.5%, 62.5%, p = 0.027, 0.006, <0.001; OR = 2.1, 2.9, 6.9). Subgroup analysis showed that MetS(+) patients without complications were associated with lower systolic blood pressure, TG, and FPG (p = 0.010, 0.031, 0.002, respectively).Conclusions: The number of MetS components is the central predictor in assessing both inner severity of MetS and outer risk for PCNL. The number of MetS components is recommended to be calculated on a scale of 0 to 5. Three, four, and five MetS components increase risk for PCNL in a stepwise manner regardless of the presence or absence of obesity. MetS components should be controlled preoperatively.

Idiopathic calcium nephrolithiasis with pure calcium oxalate composition: clinical correlates of the calcium oxalate dihydrate/monohydrate (COD/COM) stone ratio.

Pure calcium oxalate is the most frequent type of idiopathic kidney stone composition. Fourier transform infrared spectroscopy (FT-IR) allows to detect the ratio of calcium oxalate dihydrate (COD) and monohydrate (COM) crystals in stones, but the clinical significance of this parameter remains uncertain. The objective of this observational study was to verify the association of clinical and laboratory parameters of kidney stone disease with COD/COM ratio in a group of 465 (322M, age 46 ± 14) patients suffering from idiopathic calcium nephrolithiasis with pure calcium oxalate stones (≥ 97%). Each participant underwent a complete clinical examination, serum chemistry, 24-h urine collection for the determination of the profile of lithogenic risk, and had stones analyzed by FT-IR. Most (62%) of the stones had a COD/COM ratio ≤ 0.25, and the urine chemistry of the corresponding patients showed a low prevalence of urinary metabolic abnormalities. With increasing COD/COM ratio intervals (0-0.25, 0.26-0.50, 0.51-0.75, 0.76-1), a significant association was observed for the number of urological procedures, serum calcium, 24-h urinary calcium excretion, prevalence of hypercalciuria and relative calcium oxalate supersaturation, and a negative trend was detected for the age of the first stone episode (all p values < 0.05). A linear regression model showed that the only parameters significantly associated with COD/COM ratio were 24-h urinary calcium excretion (standardized β = 0.464, p < 0.001) and urine pH (standardized β = 0.103, p = 0.013). In pure calcium oxalate idiopathic stones, COD/COM ratio may reflect the presence of urinary metabolic risk factors, and represent a guide for the prescription of urinary analyses.

CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype.

Loss of function mutations in the CYP24A1 gene, involved in vitamin D catabolism and in calcium homeostasis, are known to be the genetic drivers of both idiopathic infantile hypercalcemia (IIH) and adult renal stone disease. Recently, also defects in the SLC34A1 gene, encoding for the renal sodium-phosphate transporter NaPi-IIa, were associated with the disease. IIH typically affects infants and pediatric patients with a syndrome characterized by severe hypercalcemia, hypercalciuria, suppressed parathyroid hormone level and nephrolithiasis. In SLC34A1 mutated carriers, hypophosphatemia is also a typical biochemical tract. IIH may also persist undiagnosed into adulthood, causing an increased risk of nephrocalcinosis and renal complication. To note, a clinical heterogeneity characterizes IIH manifestation, principally due to the controversial gene-dose effect and, to the strong influence of environmental factors. The present review is aimed to provide an overview of the current molecular findings on the IIH disorder, giving a comprehensive description of the association between genotype and biochemical and clinical phenotype of the affected patients. We also underline that patients may benefit from genetic testing into a targeted diagnostic and therapeutic workflow.

Effects of physical properties of nano-sized hydroxyapatite crystals on cellular toxicity in renal epithelial cells

Hydroxyapatite (HAP) is not only a common component of most idiopathic CaOx stones, but also the core of Randall's plaque. HAP is a nest that can induce the formation of Randall's plaques and even kidney stones. We studied the toxic effects and mechanisms of four different types of nano-HAP crystals (H-Sphere, 72.5 nm × 72.5 nm; H-Needle, 37.2 nm × 162.7 nm; H-Rod, 42.3 nm × 115.3 nm; and H-Plate, 145.5 nm × 272.9 nm) on human renal proximal tubular epithelial cells (HK-2). HAP crystals could cause oxidative stress that triggered a series of cell dysfunction problems, resulting in decreased cell viability, loss of cell membrane integrity, cell swelling, and cell necrosis. The toxic effect of HAP was mainly attributed to its entry into cell by endocytosis and its accumulation in the lysosomes, causing the level of intracellular reactive oxygen species (ROS) to rise, the mitochondrial membrane potential (Δψm) to decrease, the lysosomal integrity to be destroyed, and the cell cycle blocked during the G0/G1 phase. The cytotoxicity of the four kinds of HAP crystals was ranked as follows: H-Sphere > H-Needle > H-Rod > H-Plate. The cytotoxicity of each crystal was positively correlated with low absolute zeta potential, conduciveness to internalized morphology, large specific surface area and aspect ratio, and small particle size. These results indicated that nano-HAP could damage HK-2 cells, and the physical properties of HAP crystals play a vital effect in their cytotoxicity.

Prevention of Calcium Nephrolithiasis: The Influence of Diuresis on Calcium Oxalate Crystallization in Urine.

A high fluid intake is still the most evidence-based measure for the prevention of idiopathic stone disease. The recommendation of current guidelines on urolithiasis to increase diuresis to 2–2.5 L/day is mainly based on a single clinical study. The present paper shows the influence of diuresis on calcium oxalate (CaOx) crystallization and especially aggregation (AGN) which can explain the initial development of Ca stones on papillary calcifications as well as stone growth in the renal pelvic system. Diuresis determines the urinary transit time (UT) through the kidney and together with the afflux of Ca and Ox the state of urinary saturation with respect to CaOx being the most frequent stone mineral. High supersaturation inducing crystallization during UT and a high urinary ion concentration interfering with the inhibition of crystal AGN by urinary macromolecules seem to be critical parameters for stone formation. Using data from the literature the influence of diuresis on these parameters is evaluated for short-term recurrent stone formers (RSF), idiopathic stone patients, and healthy controls, the latter two collectives with and without excessive oxalate ingestion. This investigation suggests that a diuresis of 2 L/day may protect from stone formation even after dietary Ox excesses and in RSF. However, in RSF with a continuously high Ca and Ox afflux into urine a permanent high diuresis is required which is difficult to sustain over 24 hours.

Activation of liver X receptor suppresses osteopontin expression and ameliorates nephrolithiasis.

Nephrolithiasis is a common disease of the urinary system, of which idiopathic calcium oxalate (CaOx) kidney stones, in particular, are one of the special types. In the initial stages of CaOx kidney stone formation, Randall's plaques (RPs) develop. Liver X receptors (LXRs) inhibit oxidative stress and inflammatory in other diseases; nevertheless, the role of LXRs in nephrolithiasis has yet to be elucidated. In this study, the role of LXRs in the progression of RP formation was investigated. Microarray analysis revealed that LXR/RXR levels were significantly greater in low-plaque tissues (<5%) than in high-plaque tissues (>5%), confirming the link between LXR activation and RP formation. Correspondingly, expression levels of two LXR target genes, LXRα and LXRβ, were lower in high-plaque tissues than in low-plaque tissues. In vitro, LXR agonist alleviated calcium oxalate monohydrate-induced cellular calcium deposits and apoptosis. LXR activation decreased reactive oxygen species production and gene expression of inflammatory mediators, including osteopontin that has recently been demonstrated to correlate with the development of RPs. Moreover, p38 MAPK and JNK signaling may mediate LXR-regulated expression in HK-2 cells. In an animal model, the deposition was reduced by activating LXR, and osteopontin expression was also inhibited. Our findings suggest a role for LXRs in the progression of idiopathic CaOx kidney stones; LXR agonists may have therapeutic potential for the treatment of nephrolithiasis.