Arterial stiffness and cardiovascular risk in patients with nephrolithiasis: a 10-year prospective study.

BACKGROUND: Nephrolithiasis is frequently associated with cardiovascular diseases. These conditions present common risk factors: systemic inflammation that promotes oxidative stress leading to arterial wall stiffening may also play a role in plaque formation predisposing to nephrolithiasis. OBJECTIVES: The aim of this study was to evaluate arterial stiffness indices at baseline and after a 10-year follow-up, in patients with nephrolithiasis compared with patients without. METHODS: A total of 82 patients (37 men; mean age 45 ±â€Š13 years) were enrolled at the Geriatrics and Nephrology Outpatient Clinic: 66 were diagnosed with nephrolithiasis, whereas the control group consisted of 16 individuals. At baseline and after 10 years, they underwent clinical evaluation and arterial stiffness measurement, such as carotid-femoral pulse wave velocity (CF-PWV), by arterial applanation tonometry. RESULTS: At baseline, when compared with the control group, patients with nephrolithiasis showed higher SBP and CF-PWV. After 10 years, patients with nephrolithiasis, but not those without, showed a significant raise in CF-PWV, even after adjustment for age and sex. In a stepwise regression model, with CF-PWV changes during the follow-up as the dependent variable, and age, sex, follow-up years, Δ mean arterial pressure, BMI, hypertension and nephrolithiasis as independent variables, nephrolithiasis was proved to be the only significant predictor of ΔCF-PWV, accounting for 6% of the variance. CONCLUSION: Our study shows higher baseline CF-PWV and greater increase in ΔCF-PWV within 10 years in individuals with nephrolithiasis than in those without, demonstrating an increased cardiovascular risk for nephrolithiasis patients.

Chronic Kidney Disease: Strategies to Retard Progression.

Chronic kidney disease (CKD), defined as the presence of irreversible structural or functional kidney damages, increases the risk of poor outcomes due to its association with multiple complications, including altered mineral metabolism, anemia, metabolic acidosis, and increased cardiovascular events. The mainstay of treatments for CKD lies in the prevention of the development and progression of CKD as well as its complications. Due to the heterogeneous origins and the uncertainty in the pathogenesis of CKD, efficacious therapies for CKD remain challenging. In this review, we focus on the following four themes: first, a summary of the known factors that contribute to CKD development and progression, with an emphasis on avoiding acute kidney injury (AKI); second, an etiology-based treatment strategy for retarding CKD, including the approaches for the common and under-recognized ones; and third, the recommended approaches for ameliorating CKD complications, and the final section discusses the novel agents for counteracting CKD progression.

Human kidney stones: a natural record of universal biomineralization.

GeoBioMed - a new transdisciplinary approach that integrates the fields of geology, biology and medicine - reveals that kidney stones composed of calcium-rich minerals precipitate from a continuum of repeated events of crystallization, dissolution and recrystallization that result from the same fundamental natural processes that have governed billions of years of biomineralization on Earth. This contextual change in our understanding of renal stone formation opens fundamentally new avenues of human kidney stone investigation that include analyses of crystalline structure and stratigraphy, diagenetic phase transitions, and paragenetic sequences across broad length scales from hundreds of nanometres to centimetres (five Powers of 10). This paradigm shift has also enabled the development of a new kidney stone classification scheme according to thermodynamic energetics and crystalline architecture. Evidence suggests that ≥50% of the total volume of individual stones have undergone repeated in vivo dissolution and recrystallization. Amorphous calcium phosphate and hydroxyapatite spherules coalesce to form planar concentric zoning and sector zones that indicate disequilibrium precipitation. In addition, calcium oxalate dihydrate and calcium oxalate monohydrate crystal aggregates exhibit high-frequency organic-matter-rich and mineral-rich nanolayering that is orders of magnitude higher than layering observed in analogous coral reef, Roman aqueduct, cave, deep subsurface and hot-spring deposits. This higher frequency nanolayering represents the unique microenvironment of the kidney in which potent crystallization promoters and inhibitors are working in opposition. These GeoBioMed insights identify previously unexplored strategies for development and testing of new clinical therapies for the prevention and treatment of kidney stones.

Novel Dent disease 1 cellular models reveal biological processes underlying ClC-5 loss-of-function.

Dent disease 1 (DD1) is a rare X-linked renal proximal tubulopathy characterized by low molecular weight proteinuria and variable degree of hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressing to chronic kidney disease. Although mutations in the electrogenic Cl-/H+ antiporter ClC-5, which impair endocytic uptake in proximal tubule cells, cause the disease, there is poor genotype-phenotype correlation and their contribution to proximal tubule dysfunction remains unclear. To further discover the mechanisms linking ClC-5 loss-of-function to proximal tubule dysfunction, we have generated novel DD1 cellular models depleted of ClC-5 and carrying ClC-5 mutants p.(Val523del), p.(Glu527Asp) and p.(Ile524Lys) using the human proximal tubule-derived RPTEC/TERT1 cell line. Our DD1 cellular models exhibit impaired albumin endocytosis, increased substrate adhesion and decreased collective migration, correlating with a less differentiated epithelial phenotype. Despite sharing functional features, these DD1 cell models exhibit different gene expression profiles, being p.(Val523del) ClC-5 the mutation showing the largest differences. Gene set enrichment analysis pointed to kidney development, anion homeostasis, organic acid transport, extracellular matrix organization and cell-migration biological processes as the most likely involved in DD1 pathophysiology. In conclusion, our results revealed the pathways linking ClC-5 mutations with tubular dysfunction and, importantly, provide new cellular models to further study DD1 pathophysiology.

Crosstalk between Renal and Vascular Calcium Signaling: The Link between Nephrolithiasis and Vascular Calcification.

Calcium (Ca2+) is an important mediator of multicellular homeostasis and is involved in several diseases. The interplay among the kidney, bone, intestine, and parathyroid gland in Ca2+ homeostasis is strictly modulated by numerous hormones and signaling pathways. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor, that is expressed in calcitropic tissues such as the parathyroid gland and the kidney, plays a pivotal role in Ca2+ regulation. CaSR is important for renal Ca2+, as a mutation in this receptor leads to hypercalciuria and calcium nephrolithiasis. In addition, CaSR is also widely expressed in the vascular system, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) and participates in the process of vascular calcification. Aberrant Ca2+ sensing by the kidney and VSMCs, owing to altered CaSR expression or function, is associated with the formation of nephrolithiasis and vascular calcification. Based on emerging epidemiological evidence, patients with nephrolithiasis have a higher risk of vascular calcification, but the exact mechanism linking the two conditions is unclear. However, a dysregulation in Ca2+ homeostasis and dysfunction in CaSR might be the connection between the two. This review summarizes renal calcium handling and calcium signaling in the vascular system, with a special focus on the link between nephrolithiasis and vascular calcification.

Idiopathic Osteoporosis and Nephrolithiasis: Two Sides of the Same Coin?

Idiopathic osteoporosis and nephrolithiasis are formidable health problems showing a progressive increase in their incidence and prevalence in the last decades. These temporal trends were observed in both pediatric and adult populations worldwide. Epidemiological and experimental studies indicate that both disorders show several common pathogenic environmental and genetic factors. In this review, we analyzed the clinical characteristics common to the two disorders and the state-of-the-art knowledge regarding the genetic predisposition and the environmental factors recognized as triggers in adult and pediatric ages. As a result of this work, we propose to consider idiopathic nephrolithiasis and osteoporosis as two possible expressions of a unique clinical syndrome. Accordingly, the clinical approach to both disorders should be modified in order to program an efficient primary and secondary prevention strategy.

Role of core body temperature in nephrolithiasis.

OBJECTIVES: To assess the role of core body temperature in urinary stone formation using a large clinical dataset. PATIENTS AND METHODS: We retrospectively collected 14 519 039 individual temperature measurements from 580 416 patients with medical history, laboratory values and medication history between 2013 and 2018 at a single institution. After exclusions and matching 2:1 (controls:cases) to account for confounding variables, 7104 patients with a history of urinary stones were identified. RESULTS: Patients with a history of urinary stones (cases) had an elevated mean (SD) oral temperature compared to matched controls, at 36.666 (0.17) vs 36.659 (0.20)°C (P = 0.012). Logistic regression of matched samples showed that higher core body temperature was predictive of a history of nephrolithiasis (odds ratio 1.21, 95% confidence interval 1.04-1.4; P = 0.015). CONCLUSION: Core body temperature was significantly higher in patients with a history of urinary stones compared to matched controls, contrary to the anticipated thermodynamic considerations leading to crystal aggregation. Given that the core body temperature is elevated, rather than decreased, thermodynamic process driving stone formation is unlikely.

Comparison of clinical and genetic characteristics between Dent disease 1 and Dent disease 2.

BACKGROUND: Dent disease is associated with low molecular weight proteinuria and hypercalciuria and caused by pathogenic variants in either of two genes: CLCN5 (Dent disease 1) and OCRL (Dent disease 2). It is generally not accompanied by extrarenal manifestations and it is difficult to distinguish Dent disease 1 from Dent disease 2 without gene testing. We retrospectively compared the characteristics of these two diseases using one of the largest cohorts to date. METHODS: We performed gene testing for clinically suspected Dent disease, leading to the genetic diagnosis of 85 males: 72 with Dent disease 1 and 13 with Dent disease 2. A retrospective review of the clinical findings and laboratory data obtained from questionnaires submitted in association with the gene testing was conducted for these cases. RESULTS: The following variables had significantly higher levels in Dent disease 2 than in Dent disease 1: height standard deviation score (height SDS), serum creatinine-based estimated GFR (Cr-eGFR) (median: 84 vs. 127 mL/min/1.73 m2, p < 0.01), serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), serum lactate dehydrogenase (LDH), serum creatine phosphokinase (CK), serum potassium, serum inorganic phosphorus, serum uric acid, urine protein/creatinine ratio (median: 3.5 vs. 1.6 mg/mg, p < 0.01), and urine calcium/creatinine ratio. There were no significant differences in serum sodium, serum calcium, alkaline phosphatase (ALP), urine ß2-microglobulin, incidence of nephrocalcinosis, and prevalence of intellectual disability or autism spectrum disorder. CONCLUSIONS: The clinical and laboratory features of Dent disease 1 and Dent disease 2 were shown in this study. Notably, patients with Dent disease 2 showed kidney dysfunction at a younger age, which should provide a clue for the differential diagnosis of these diseases.

Case report: a Chinese girl with dent disease 1 and turner syndrome due to a hemizygous CLCN5 gene mutation and Isochromosome (Xq).

BACKGROUND: Female Dent disease 1 patients with low-molecular-weight proteinuria (LMWP) due to CLCN5 gene mutation were rarely reported, and these cases that the people were also with Turner syndrome (TS) were even hardly documented before. CASE PRESENTATION: Here we report a 3-year and 11-month old Chinese girl with short stature who had a karyotype of 46,X,i(X)(q10) and a de novo pathogenic variant in the CLCN5 gene on the short arm of X chromosome. Laboratory examinations showed that the patient had LMWP, hypercalciuria, hypophosphatemia, delayed bone age, and genital dysplasia. CONCLUSION: The combination of i(X)(q10) and CLCN5 mutation causes the deletion of the wild-type CLCN5 allele that results in Dent-1 and TS. To the best of our knowledge, this is the first case that a female CLCN5 mutation hemizygote is diagnosed with Dent-1 and Turner syndrome due to isochromosome X. Also, our case has indicated that the prevalence of the situation may be largely underestimated because of the mild signs of females with Dent-1.

[Nephrolithiasis: From mechanisms to preventive medical treatment]. / Lithiase rénale : des mécanismes au traitement médical préventif.

Renal lithiasis is a frequent pathology (prevalence ranging from 10 to 12% in France) and a recurrent condition. It is associated with chronic kidney disease and is responsible for 2 to 3% of cases of end-stage renal disease, especially if it is associated with nephrocalcinosis and/or is part of a monogenic disease (1.6% of lithiasis in adults, including 1% of cystinuria). In order to understand the pathophysiology of the nephrolithiasis, the analysis of stones (morphological and by infrared spectrophotometry) as well as a minimal biological evaluation including crystalluria must be carried out. Calcium nephrolithiasis is the most common form (more than 80%). Its preventive medical treatment relies on simple hygienic dietetics: non-alkaline hyperdiuresis greater than 2liters/day, normalization of calcium intakes (1g/day to be distributed over the three meals), restriction of sodium intakes (6g/day) and of protein intakes (0.8-1g/kg of theoretical weight/day), and avoidance of foods rich in oxalate. If there is a hypercalciuria (greater than 0.1mmol/kg of theoretical weight/day with normal calcium intakes), its mechanism should be explored with an oral calcium load test. In the absence of primary hyperparathyroidism, thiazide diuretics can be prescribed, taking care to prevent hypokalemia and iatrogenic hypocitraturia. The treatment of uric acid lithiasis includes alkaline hyperdiuresis (urinary pH 6.2 to 6.8). Allopurinol is only justified if the urinary excretion of uric acid exceeds 4mmol/day. With a well-managed medical treatment, more than 80% of recurrent lithiasis can be stopped, making nephrolithiasis one of the kidney diseases the more accessible to the preventive medical treatment.

Autophagy-endoplasmic reticulum stress inhibition mechanism of superoxide dismutase in the formation of calcium oxalate kidney stones.

BACKGROUND: Nephrolithiasis is a common disease in urology, and its pathogenesis is associated with various factors. Recent studies have shown that reactive oxygen species (ROS) can promote autophagy in the formation of kidney stones and exacerbate kidney injury. Endoplasmic reticulum stress (ERS), a key factor in regulating intracellular environmental homeostasis, is also directly related to ROS production. Therefore, this study aimed to investigate the regulatory effect of superoxide dismutase (SOD) on autophagy-ERS response during the formation of calcium oxalate (CaOx) kidney stones in rats. METHODS: Thirty-two rats were randomly divided into four groups (n = 8): normal control group, stone model group, stone model with atorvastatin group, and stone model with diethyldithiocarbamic acid (DETC) group. Rat models of CaOx kidney stones were established by intragastric administration of 0.75 % ethylene glycol for 4 weeks. Kidney/body weight was used to assess renal enlargement. Renal function was assessed by measuring serum SOD, creatinine (CRE), and blood urea nitrogen (BUN) levels. The expression of autophagy-related proteins LC3B and BECN1 was detected through immunohistochemical staining. Meanwhile, the expression of autophagy-ERS response-related proteins LC3B, BECN1, p62, GRP78, and CHOP was detected using Western blot and RT-PCR. Renal tubular injury markers neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (Kim-1) were determined through enzyme-linked immunosorbent assay. The apoptosis of renal tubular cells and the expression of their signature proteins cleaved Caspase-3, Bax and Bcl-2 were detected using Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and Western blot assays, respectively. Crystal deposition and histological tissue injury were assessed through Von Kossa staining. RESULTS: Compared with the control group, the stone model group showed higher kidney/body weight ratio; evidently higher expression of autophagy-ERS response- and apoptosis-related proteins LC3B, BECN1, GRP78, CHOP, Bax and cleaved Caspase-3; and lower levels of p62, bcl-2 protein, and SOD. The stone model group also showed higher levels of apoptosis, serum CRE, BUN, NGAL, and Kim-1, as well as considerably greater crystal deposition and renal injury, than the control group. Atorvastatin reduced the levels of autophagy-ERS response, kidney injury, and crystal deposition, but they were increased by DETC. CONCLUSION: Enhanced SOD activity can protect the kidneys by reducing autophagy-ERS response and CaOx kidney stone formation. Atorvastatin may be a new option for the prevention and treatment of nephrolithiasis.

Antibiotic Use and Risk of Incident Kidney Stones in Female Nurses.

RATIONALE & OBJECTIVE: The intestinal microbiome may affect urinary stone disease by modulating the amount of oxalate absorbed from the intestine and subsequently excreted in urine. This study sought to explore the association between antibiotics, which alter the intestinal microbiota, and risk for urinary stone disease. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 5,010 women in the Nurses' Health Study (NHS) I and II who had collected 24-hour urine samples. EXPOSURES: Use of antibiotics during the age range of 40 to 49 (NHS II), 40 to 59 (NHS I), and 20 to 39 years (both cohorts). OUTCOMES: Incident symptomatic urinary stone disease; urine composition. ANALYTICAL APPROACH: Cause-specific hazards regression adjusted for age, body mass index, comorbid conditions, thiazide use, and dietary factors. Follow-up was censored at the time of asymptomatic kidney stones, cancer, or death. RESULTS: Cumulative use of antibiotics for a total of 2 or more months during the age range of 40 to 49 years (NHS II) and 40 to 59 years (NHS II) was associated with significantly higher risk for developing incident stones compared with no use (pooled HR, 1.48; 95% CI, 1.12-1.96). Similar results were found for the period of 20 to 39 years (pooled HR, 1.36; 95% CI, 1.00-1.84). Results were unchanged after excluding participants who reported urinary tract infection with their stone event or as the most common reason for antibiotic use. Urine composition was generally similar across antibiotic groups except for marginally lower urine pH and citrate values among those taking antibiotics for 2 or more months. LIMITATIONS: Observational design; lack of information for type of antibiotic used; relatively large span of time between antibiotic use and urine collection. CONCLUSIONS: Use of antibiotics for more than 2 months in early adulthood and middle age is associated with higher risk for urinary stone disease in later life.

Litiasis renal y riesgo cardiovascular / Nephrolithiasis and cardiovascular risk

La litiasis renal es una enfermedad frecuente cuya prevalencia ha aumentado en los últimos años. En la actualidad se la considera como una patología sistémica; no limitada al riñón y a las vías urinarias, sino relacionada en gran medida a diabetes mellitus, obesidad, hipertensión arterial, hiperuricemia, hipercolesterolemia y enfermedad renal crónica, todos factores de riesgo cardiovascular que suelen vincularse a eventos severos como accidentes cerebrovasculares, enfermedad coronaria o infarto agudo de miocardio. Numerosos estudios transversales y meta-análisis han demostrado la asociación entre estas dos entidades. En esta revisión intentaremos demostrar los mecanismos involucrados en la fisiopatología de la litiasis renal y su relación con enfermedad cardiovascular. Como mecanismos involucrados, se mencionan tres asociaciones. La primera se refiere al estrés oxidativo y la inflamación. La segunda asociación se refiere a la presencia de mecanismos litogénicos que contribuyen a la calcificación vascular. Como última teoría se realiza la asociación ya conocida, de obesidad, síndrome metabólico, diabetes e hipertensión arterial, todos factores de riesgo para el desarrollo de litiasis renal así como de enfermedad cardiovascular, recordando que la litiasis renal es causa, en un 8%, del desarrollo de enfermedad renal crónica, otro factor de riesgo para enfermedad y muerte cardiovascular. Como conclusión se confirma la teoría de que la litiasis renal no es una enfermedad limitada al riñón y la vía urinaria, si no que se trata de una enfermedad sistémica, con riesgo de eventos cardiovasculares tan severos que pueden llevar a la muerte.

Renal lithiasis is a frequent disease whose prevalence has increased in recent years. Nowadays it is considered as a systemic pathology, not limited to the kidney and the urinary tract, but largely related to diabetes mellitus, obesity, hypertension, hyperuricemia, hypercholesterolemia and chronic kidney disease; all cardiovascular risk factors that are usually linked to severe events such as stroke, coronary heart disease or acute myocardial infarction. Numerous cross-sectional studies and meta-analyzes have proved the association between renal lithiasis and cardiovascular disease. In this review we will try to demonstrate the mechanisms involved in the pathophysiology of these two entities. Three associations are mentioned. The first one refers to oxidative stress and inflammation. The second association refers to the presence of lithogenetic mechanisms contributing to vascular calcification. The last theory is the already known correlation with obesity, metabolic syndrome, diabetes and hypertension; all risk factors for the development of renal lithiasis as well as cardiovascular disease. Let us remember that renal lithiasis is the cause, in 8% of cases, of the development of chronic kidney disease, another risk factor for cardiovascular disease and death. In conclusion, the theory that renal lithiasis is not a disease limited to the kidney and the urinary tract is confirmed; it is rather a systemic disease, with a risk of cardiovascular events so severe that they can lead to death.

Curcumin ameliorates glyoxylate-induced calcium oxalate deposition and renal injuries in mice.

BACKGROUND: Nephrolithiasis is one of the most common and frequent urologic diseases worldwide. Several pathophysiological mechanisms are involved in stone formation, including oxidative stress, inflammation, apoptosis, fibrosis and autophagy. Curcumin, the predominant active component of turmeric, has been shown to have pleiotropic biological and pharmacological properties, such as antioxidant, anti-inflammatory and antifibrotic effects. PURPOSE: The current study proposed to systematically investigate the protective effects and the underlying mechanisms of curcumin in a calcium oxalate (CaOx) nephrolithiasis mouse model. METHODS: The animal model was established in male C57BL/6 mice by successive intraperitoneal injection of glyoxylate (100 mg/kg) for 1 week. Curcumin was orally given to mice 7 days before the injection of glyoxylate and for a total of 14 days at 50 mg/kg or 100 mg/kg. Bilateral renal tissue was harvested and processed for oxidative stress index detection, histopathological examinations and other analyses. RESULTS: Coadministration of curcumin could significantly reduce glyoxylate-induced CaOx deposition and simultaneous tissue injury in mouse kidneys. Meanwhile, curcumin alleviated the oxidative stress response via reducing MDA content and increasing SOD, CAT, GPx, GR and GSH levels in this animal model. Moreover, treatment with curcumin significantly inhibited apoptosis and autophagy induced by hyperoxaluria. Curcumin also attenuated the high expression of IL-6, MCP-1, OPN, CD44, α-SMA, Collagen I and collagen fibril deposition, which were elevated by hyperoxaluria. Furthermore, the results revealed that both the total expression and nuclear accumulation of Nrf2, as well as its main downstream products such as HO-1, NQO1 and UGT, were decreased in the kidneys of mice in the crystal group, while treatment with curcumin could rescue this deterioration. CONCLUSION: Curcumin could significantly alleviate CaOx crystal deposition in the mouse kidney and the concurrent renal tissue injury. The underlying mechanism involved the combination of antioxidant, anti-apoptotic, inhibiting autophagy, anti-inflammatory, and antifibrotic activity and the ability to decrease expression of OPN and CD44 through the Nrf2 signaling pathway. The pleiotropic antilithic properties, combined with the minimal side effects, make curcumin a good potential choice to prevent and treat new or recurrent nephrolithiasis.

Net Acid Excretion and Urinary Organic Anions in Idiopathic Uric Acid Nephrolithiasis.

BACKGROUND AND OBJECTIVES: Idiopathic uric acid nephrolithiasis, which is closely associated with obesity and the metabolic syndrome, is increasing in prevalence. Unduly acidic urine pH, the quintessential pathophysiologic feature of this disease, is in part explained by inadequate excretion of the principal urinary buffer ammonium. The role of net acid excretion in the pathogenesis of uric acid nephrolithiasis is incompletely understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We compared acid-base parameters of patients with idiopathic uric acid nephrolithiasis with matched control subjects under controlled diets in an inpatient metabolic unit. Measurements included fasting blood and 24-hour urine chemistries and 24-hour urine metabolomic analysis. Comparisons between groups included analysis of covariance models controlling for urine pH or body mass index. RESULTS: Subjects with idiopathic uric acid nephrolithiasis had lower urine pH (5.5 versus 5.9; P<0.001) and higher net acid excretion (60 versus 43 mEq/24 h; P<0.001), with the excess H+ carried by nonammonium buffers. In all subjects, there was a positive relationship of net acid excretion with higher body mass index in spite of strictly controlled equivalent dietary acid intake. This relationship was most evident among control subjects (r=0.36; P=0.03). It was attenuated in patients with idiopathic uric acid nephrolithiasis whose net acid excretion remained fixedly high and ammonium excretion remained low relative to net acid excretion, resulting in low urine pH over a wide body mass index range. Urinary metabolomics was performed to attempt to identify excess organic acids presented to the kidney in idiopathic uric acid nephrolithiasis. Among the tricarboxylic acid cycle intermediates and amino acid and lipid metabolites analyzed, 26 organic anions with acid dissociation constants values in the range of urine pH showed greater protonation. However, protons carried by the identified organic acids did not entirely account for the higher titratable acidity seen in idiopathic uric acid nephrolithiasis. CONCLUSIONS: Higher acid load to the kidney, resulting in higher urinary net acid excretion, is an important factor in the pathogenesis of idiopathic uric acid nephrolithiasis.

The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases.

The Ca2+-sensing receptor (CaSR) is a dimeric family C G protein-coupled receptor that is expressed in calcitropic tissues such as the parathyroid glands and the kidneys and signals via G proteins and ß-arrestin. The CaSR has a pivotal role in bone and mineral metabolism, as it regulates parathyroid hormone secretion, urinary Ca2+ excretion, skeletal development and lactation. The importance of the CaSR for these calcitropic processes is highlighted by loss-of-function and gain-of-function CaSR mutations that cause familial hypocalciuric hypercalcaemia and autosomal dominant hypocalcaemia, respectively, and also by the fact that alterations in parathyroid CaSR expression contribute to the pathogenesis of primary and secondary hyperparathyroidism. Moreover, the CaSR is an established therapeutic target for hyperparathyroid disorders. The CaSR is also expressed in organs not involved in Ca2+ homeostasis: it has noncalcitropic roles in lung and neuronal development, vascular tone, gastrointestinal nutrient sensing, wound healing and secretion of insulin and enteroendocrine hormones. Furthermore, the abnormal expression or function of the CaSR is implicated in cardiovascular and neurological diseases, as well as in asthma, and the CaSR is reported to protect against colorectal cancer and neuroblastoma but increase the malignant potential of prostate and breast cancers.

Claudins and nephrolithiasis.

PURPOSE OF REVIEW: The greatest risk factor for kidney stone formation is increased urinary calcium excretion. Most filtered calcium is reabsorbed from the proximal tubule and the thick ascending limb (TAL) of Henle's loop via a paracellular pathway. Claudins are tight junction proteins that confer the permeability properties of an epithelium. We review the contribution of renal claudins to nephron calcium permeability and how perturbations in these pathways cause alterations in tubular calcium transport, hypercalciuria, nephrocalcinosis, or nephrolithiasis. RECENT FINDINGS: Claudin-16 and Claudin-19 form a complex with claudin-3 enabling divalent cation permeability in the TAL. Claudin-14 interacts with claudin-16 to attenuate calcium permeability through this pore. Intronic mutations in claudin-14 increase expression causing hypercalciuria and kidney stones. A different type of TAL tight junction pore is composed of claudin-10b, which does not preferentially permeate calcium. Deletion of claudin-10b results in increased expression of the claudin-16/claudin-19 complex expressed in the medullary TAL and nephrocalcinosis. SUMMARY: Alterations to claudins expressed in the TAL tight junction greatly affects calcium homeostasis as highlighted by point mutations in claudin-16 or claudin-19 causing FHHNC or gain of function mutations in claudin-14 causing kidney stones.

Nephrolithiasis and risk of hypertension: a meta-analysis of observational studies.

BACKGROUND: Observational studies have demonstrated an association between nephrolithiasis and hypertension. The aim of this meta-analysis was to summarize all available evidence. METHODS: PubMed, EMBASE, the Cochrane Central Register of Controlled Trials databases, and the reference lists of relevant articles were searched to identify observational studies that reported study-specific risk estimates comparing the risk of hypertension in patients with nephrolithiasis. We used a random-effect model to pool the study-specific risk estimates. We also assessed the potential heterogeneity by subgroup analyses, meta-regression analyses, and sensitivity analyses. RESULTS: A total of 7 articles including 9 studies (n = 313,222 participants) were eventually identified in this meta-analysis. In comparison with the patients who did not have nephrolithiasis, nephrolithiasis significantly increased the risk of hypertension (OR, 1.43; 95% CI, 1.30-1.56), with significant heterogeneity between these studies (I 2 = 83.5%, P <0.001). The heterogeneity reduced in subgroups of cohort studies, USA, large sample size trials, men, and adjustment for confounding factors ≥ 5. Sensitivity analysis further demonstrated the results to be robust. CONCLUSIONS: Nephrolithiasis is associated with increased risk of hypertension. Future randomized, high-quality clinical trials are encouraged to definitively clarify the relationship between nephrolithiasis and hypertension, which may influence clinical management and primary prevention of hypertension in nephrolithiasis patients.

Urinary metals in a spontaneous canine model of calcium oxalate urolithiasis.

Calcium oxalate urolithiasis is a common and painful condition in people. The pathogenesis of this disease is complex and poorly understood. Laboratory animal and in vitro studies have demonstrated an effect of multiple trace metals in the crystallization process, and studies in humans have reported relationships between urinary metal concentrations and stone risk. Dogs are a spontaneous model of calcium oxalate urolithiasis, and the metal content of canine calcium oxalate stones mirrors that of human stones. The aim of this study was to test for a relationship between urinary metals and calcium oxalate urolithiasis in dogs. We hypothesized that urinary metals would differ between dogs with and without calcium oxalate urolithiasis. Urine from 122 dogs (71 cases and 51 stone-free controls) was analyzed for calcium and 12 other metals. The cases had higher urinary calcium, copper, iron, and vanadium and lower urinary cobalt. Higher urinary vanadium in the cases was associated with being fed a therapeutic stone-prevention diet. Urinary calcium had a strong positive correlation with strontium and moderate positive correlations with chromium, nickel, and zinc. The results of this study complement the findings of similar human studies and suggest a potential role of trace metals in calcium oxalate urolithiasis. Further investigation into how trace metals may affect stone formation is warranted.