Cistinuria: la importancia del sedimento / Cystinuria: the importance of sediment

La cistinuria es causada por el exceso de un aminoácido llamado cistina (dímero del aminoácido cisteína) en la orina. Fue descrita por primera vez a principios del siglo XIX. Es una enfermedad metabólica congénita con un patrón de herencia autosómico recesivo, se caracteriza por un defecto en el transporte que afecta a determinados aminoácidos dibásicos: cistina, ornitina, lisina y arginina (COLA) en su reabsorción en el túbulo renal y tracto gastrointestinal; como resultado solo la cistina, debido a su gran insolubilidad en orinas ácidas por aumento de la excreción y sobresaturación en la orina, favorece la formación de cristales o precipitados formando cálculos. Presentamos un caso de cistinuria en un adulto que fue diagnosticado por los cristales encontrados en el sedimento urinario, después de hacer diagnóstico diferencial con los cristales de colesterol anhidro, con los que pueden confundirse

Cystinuria is caused by the excess of an amino acid called cystine (amino acid dimer cysteine), in the urine. It was first described at the beginning of the 19th century. It is a congenital metabolic disease with an autosomal recessive inheritance pattern. It is characterised by a defect in transport, which affects certain dibasic amino acids, cystine, ornithine, lysine, and arginine in its reabsorption into the renal tubule and gastrointestinal tract. As a result, only cystine (due to its great insolubility in acid urine owing to increased excretion and supersaturation in urine), promotes the formation of crystals or precipitates that form stones. The case is presented of an adult with cystinuria, who was diagnosed by the crystals found in the urinary sediment, after making a differential diagnosis with the crystals of anhydrous cholesterol, with which they can be confused

Non-urate transporter 1, non-glucose transporter member 9-related renal hypouricemia and acute renal failure accompanied by hyperbilirubinemia after anaerobic exercise: a case report.

BACKGROUND: Renal hypouricemia (RHUC) is an inherited heterogenous disorder caused by faulty urate reabsorption transporters in the renal proximal tubular cells. Anaerobic exercise may induce acute kidney injury in individuals with RHUC that is not caused by exertional rhabdomyolysis; it is called acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE). RHUC is the most important risk factor for ALPE. However, the mechanism of onset of ALPE in patients with RHUC has not been elucidated. The currently known genes responsible for RHUC are SLC22A12 and SLC2A9. CASE PRESENTATION: A 37-year-old man presented with loin pain after exercising. Despite having a healthy constitution from birth, biochemical examination revealed hypouricemia, with a uric acid (UA) level of < 1 mg/dL consistently at every health check. We detected acute kidney injury, with a creatinine (Cr) level of 4.1 mg/dL, and elevated bilirubin; hence, the patient was hospitalized. Computed tomography revealed no renal calculi, but bilateral renal swelling was noted. Magnetic resonance imaging detected cuneiform lesions, indicating bilateral renal ischemia. Fractional excretion values of sodium and UA were 0.61 and 50.5%, respectively. Urinary microscopy showed lack of tubular injury. The patient's older sister had hypouricemia. The patient was diagnosed with ALPE. Treatment with bed rest, fluid replacement, and nutrition therapy improved renal function and bilirubin levels, and the patient was discharged on day 5. Approximately 1 month after onset of ALPE, his Cr, UA, and TB levels were 0.98, 0.8, and 0.9 mg/dL, respectively. We suspected familial RHUC due to the hypouricemia and family history and performed genetic testing but did not find the typical genes responsible for RHUC. A full genetic analysis was opposed by the family. CONCLUSIONS: To the best of our knowledge, this is the first report of ALPE with hyperbilirubinemia. Bilirubin levels may become elevated as a result of heme oxygenase-1 activation, occurring in exercise-induced acute kidney injury in patients with RHUC; this phenomenon suggests renal ischemia-reperfusion injury. A new causative gene coding for a urate transporter may exist, and its identification would be useful to clarify the urate transport mechanism.

High-speed video microscopy and numerical modeling of bubble dynamics near a surface of urinary stone.

Ultra-high-speed video microscopy and numerical modeling were used to assess the dynamics of microbubbles at the surface of urinary stones. Lipid-shell microbubbles designed to accumulate on stone surfaces were driven by bursts of ultrasound in the sub-MHz range with pressure amplitudes on the order of 1 MPa. Microbubbles were observed to undergo repeated cycles of expansion and violent collapse. At maximum expansion, the microbubbles' cross-section resembled an ellipse truncated by the stone. Approximating the bubble shape as an oblate spheroid, this study modeled the collapse by solving the multicomponent Euler equations with a two-dimensional-axisymmetric code with adaptive mesh refinement for fine resolution of the gas-liquid interface. Modeled bubble collapse and high-speed video microscopy showed a distinctive circumferential pinching during the collapse. In the numerical model, this pinching was associated with bidirectional microjetting normal to the rigid surface and toroidal collapse of the bubble. Modeled pressure spikes had amplitudes two-to-three orders of magnitude greater than that of the driving wave. Micro-computed tomography was used to study surface erosion and formation of microcracks from the action of microbubbles. This study suggests that engineered microbubbles enable stone-treatment modalities with driving pressures significantly lower than those required without the microbubbles.

Understanding the Link Between Gut Microbiome and Urinary Stone Disease.

PURPOSE OF REVIEW: With recent advances in sequencing technologies and increasing research into the gut microbiome (GMB), studies have revealed associations between the GMB and urinary stone disease (USD). We sought to determine whether the evidence pointed towards a few specific gut bacteria or the broader GMB network is seemingly responsible for this relationship. RECENT FINDINGS: Initially, Oxalobacter formigenes (OF) was pursued as the main link between GMB and USD given its ability to degrade oxalate in the gut. However, the latest studies consistently suggest that the entire GMB is much more likely to be involved in handling oxalate absorption and other risk factors for urinary stone formation, rather than just a few microbiota. The GMB has complex networks that are likely involved in the pathophysiology of USD, although the causal mechanisms remain unclear. With increasing interest and research, potential modalities that act on the GMB may help to prevent incidence of USD.

Distribution and Characteristics of Hypouricemia within the Japanese General Population: A Cross-Sectional Study.

Background and objectives: There is insufficient epidemiological knowledge of hypouricemia. In this study, we aimed to describe the distribution and characteristics of Japanese subjects with hypouricemia. Materials and Methods: Data from subjects who underwent routine health checkups from January 2001 to December 2015 were analyzed in this cross-sectional study. A total of 246,923 individuals, which included 111,117 men and 135,806 women, met the study criteria. The participants were divided into quartiles according to their serum uric acid (SUA) levels. We subdivided the subjects with hypouricemia, which was defined as SUA level ≤ 2.0 mg/dL, into two groups and compared their characteristics, including their cardiovascular risks. Results: The hypouricemia rates were 0.46% overall, 0.21% for the men and 0.66% for the women (P < 0.001). The number of the subjects with hypouricemia showed two distributions at SUA levels of 0.4⁻1.1 mg/dL (lower hypouricemia group), which included a peak at 0.7⁻0.8 mg/dL, and at SUA levels of 1.4⁻2.0 mg/dL (higher hypouricemia group). The men in the higher hypouricemia group had lower body mass indexes (BMI) and triglyceride (TG) levels and had higher fasting blood glucose levels than those in the lower hypouricemia group. The women in the higher hypouricemia group were younger; had lower BMI, total protein, TG, total cholesterol and low-density lipoprotein cholesterol levels; and had higher estimated glomerular filtration rates levels compared to those in the lower hypouricemia group. Conclusions: The characteristics of the individuals in the lower and higher hypouricemia groups differed significantly, indicating different pathophysiologies within each group.

Evaluation of the clinical significance of sonographic perinephric fluid in patients with renal colic.

OBJECTIVE: To evaluate the significance of sonographic perinephric fluid collection on the emergent management of patients with acute urinary stone obstruction. METHODS: We conducted a prospective study with retrospective analysis. Since January 2016 through July 2017, patients admitted to our tertiary hospital's emergency department (ED) with suspected symptomatic urinary stones underwent ultrasound evaluation. Images were prospectively interpreted by experienced radiologist who analyzed each case for the following imaging features: hydronephrosis, perinephric fluid and urethral stone identification. The presence and measurements of perinephric fluid were re-evaluated by second radiologist who was blinded for the first reader's measurements. Retrospective analysis was conducted to evaluate for an association between perinephric fluid collection and the following outcome variables: need for analgesics, the number of doses of analgesics and the amount of morphine (mg) in the ED, elevation of creatinine levels, hospitalization and need for urological interventions. RESULTS: The need for analgesics, the number of doses of analgesics and the amount of morphine were significantly associated with the presence of perinephric fluid (p < 0.05). The odds ratio for the need for analgesics was 3.8 in the presence of any perinephric fluid, and 8.9 in the presence of moderate/severe perinephric fluid. No other patient outcome variables were found to be significantly associated with the presence of perinephric fluid (p > 0.05). CONCLUSIONS: This study shows a correlation between sonographic evidence of perinephric fluid and more severe pain. Therefore, an emergency physician can consider the evidence of perinephric fluid, in acute urethral stone obstruction, a predictor for more severe pain.

The influence of serum uric acid on renal function in patients with calcium or uric acid stone: A population-based analysis.

OBJECTIVES: To determine the influence of serum uric acid (UA) levels on renal impairment in patients with UA stone. MATERIALS AND METHODS: We retrospectively analyzed 463 patients with calcium oxalate and/or calcium phosphate stones (CaOx/CaP), and 139 patients with UA stones. The subjects were divided into the serum UA-high (UA ≥ 7.0 mg/dL) or the UA-low group (UA < 7.0 mg/dL). The control group comprised 3082 community-dwelling individuals that were pair-matched according to age, sex, body mass index, comorbidities, hemoglobin, serum albumin, and serum UA using propensity score matching. We compared renal function between controls and patients with UA stone (analysis 1), and between patients with CaOx/CaP and with UA stone (analysis 2). Logistic regression analysis was used to evaluate the impact of the hyperuricemia on the development of stage 3 and 3B chronic kidney disease (CKD) (analysis 3). RESULTS: The renal function was significantly associated with serum UA levels in the controls and patients with CaOx/CaP and UA stones. In pair-matched subgroups, patients with UA stone had significantly lower renal function than the control subjects (analysis 1) and patients with CaOx/CaP stones (analysis 2) regardless of hyperuricemia. Multivariate logistic regression analysis revealed that patients with UA stone, CaOx/CaP, hyperuricemia, presence of cardiovascular disease, higher body mass index, older age and lower hemoglobin had significantly higher risk of stage 3 and 3B CKD (analysis 3). CONCLUSION: Patients with UA stones had significantly worse renal function than controls and CaOx/CaP patients regardless of hyperuricemia. Urolithiasis (CaOx/CaP and UA stone) and hyperuricemia had an association with impaired renal function. Our findings encourage clinicians to initiate intensive treatment and education approaches in patients with urolithiasis and/or hyperuricemia in order to prevent the progression of renal impairment.

Presentation of a method at the Exploration Stage according to IDEAL: Percutaneous nephrolithotomy (PCNL) under local infiltrative anesthesia is a feasible and effective method - retrospective analysis of 439 patients.

INTRODUCTION: This study addresses minimally invasive anesthesiologic and analgetic approaches for stone surgery in the upper urinary tract. Aim of this retrospective analysis is to compare feasibility, safety and complication rates of percutaneous nephrolithotomy (PCNL) under local infiltration anesthesia alone (Group I) and additive intravenous analgetics and/or sedative medications (Group II). MATERIAL AND METHODS: This is a single center study. A total of 439 patients have been included from November 2003 until March 2012. A total of 226 patients were assigned to Group I receiving local infiltration anesthesia alone, whereas 213 patients were assigned to Group II receiving additive intravenous analgetics and/or sedative medications. Demographic characteristics and stone characteristics have been evaluated to determine feasibility, complication rates for safety, and stone-free rates for effectiveness. The study and the reported technique have then been retrospectively analysed according to the IDEAL stages of surgical innovation. RESULTS: All included patients who accepted local infiltration anesthesia underwent PCNL successfully. The mean American Society of Anesthesiologists score (ASA) of the included patients was 2.15 ±0.37 (range, 1-4). PCNL was indicated in 138 patients due to pelvic calculi, in 171 patients due to renal calculi, in 66 patients due to partial staghorn, in 48 patients due to complete staghorn and in 16 patients due to upper ureteral stones. The total stone free rate in our patients was 78.4% over all stone localizations. Compared to the possibility of using additive intravenous analgetics and/or sedative medications we could show differences in the median age (p=0.005) suggesting that older patients did better tolerate the infiltration anesthesia than patients at younger ages. We did also remark not statistically significant differences in Group I and Group II as for number of tracts, operation duration, hemoglobin drop, fever, transfusion rate, and stone free rate, but not for severe complications such as perirenal hematoma, colon perforation, pleura perforation, AV fistula, skin fistula, and mortality rate. CONCLUSION: PCNL performed under local infiltration anesthesia is a feasible method. It provides satisfactory positive clinical outcomes. Younger age seems to predispose to conversion to extended anesthesiologic procedures. When retrospectively applying the IDEAL criteria, the method can be assigned to the E level or stage 2b.

How do stones form? Is unification of theories on stone Formation possible? / ¿Cómo se forman las piedras? ¿Es posible la unificación de las teorías sobre la formación de las piedras?

There are two basic pathways for formation of calcium based kidney stones. Most idiopathic calcium oxalate (CaOx) stones are formed in association with sub-epithelial plaques of calcium phosphate (CaP), known as Randall’s plaques, on renal papillary surfaces. Crystal formation and retention within the terminal collecting ducts, the ducts of Bellini, leading to the formation of Randall’s plugs, is the other pathway. Both pathways require supersaturation leading to crystallization, regulated by various crystallization modulators produced in response to changing urinary conditions. High supersaturation, as a result of a variety of genetic and environmental factors, leads to crystallization in the terminal collecting ducts, eventually plugging their openings into the renal pelvis. Stasis behind the plugs may lead to the formation of attached or unattached stones in the tubular lumen. Deposition of crystals on the plug surface facing the pelvic or tubular urine may result in stone formation on the Randall’s plugs. Kidneys of idiopathic stone formers may be subjected to oxidative stress as a result of increased urinary excretion of calcium/oxalate/phosphate and/or decrease in the production of functional crystallization inhibitors or in relation to co-morbidities such as hypertension, atherosclerosis, or acute kidney injury. We have proposed that production of reactive oxygen species (ROS) causes dedifferentiation of epithelial/endothelial cells into osteoblast type cells and deposition of CaP in the basement membrane of renal tubules or vessels. Growth, aggregation and melding of CaP crystals leads to the formation of plaque which grows by further calcification of interstitial collagen and membranous vesicles. Plaque becomes exposed to pelvic urine once the covering papillary epithelium is breached. Surface layers of CaP are replaced by CaOx through direct transformation or demineralization of CaP and mineralization of CaOx. Alternatively, or in addition, CaOx crystals nucleate directly on the plaque surface. Stone growth may also depend upon supersaturation in the pelvic urine, triggering further nucleation, growth and aggregation

Existen dos vías básicas para la formación de las litiasis renales. La mayoría de las litiasis idiopáticas de oxalato cálcico (OxCa) se forman adheridas a placas subepiteliales de fosfato cálcico (FCa) en las superficies papilares renales, las placas de Randall. La otra vía es la formación y retención de cristales dentro de los tubos colectores terminales, los tubos de Bellini, que conducen a la formación de los tapones de Randall. Ambas vías requieren supersaturación que lleve a la cristalización regulada por varios moduladores de la cristalización producidos en respuesta a las condiciones cambiantes de la orina. Una alta supersaturación como resultado de una variedad de factores genéticos y ambientales lleva a cristalización en los tubos colectores distales taponando eventualmente su apertura a la pelvis renal. La estasis urinaria por encima de los tapones llevaría a la formación de piedras, ancladas o no, en la luz tubular. El depósito de cristales en la superficie del tapón que mira a la orina piélica o tubular daría como resultado la formación de piedras en los tapones de Randall. Los riñones de formadores idiopáticos de piedras pueden sufrir estrés oxidativo como resultado del aumento de la excreción urinaria de calcio/oxalato/fosfato y/o disminuciones de la producción de inhibidores funcionales de la cristalización o de comorbilidades cómo hipertensión, arteriosclerosis o lesión renal aguda. Nosotros hemos propuesto que la producción de especies reactivas de oxígeno causa desdiferenciación de las células epiteliales/endoteliales hacia células tipo osteoblasto y deposición de FCa en la membrana basal de las células de los túbulos o de los vasos renales. El crecimiento, la agregación y la fusión de los cristales de FCa lleva a la formación de una placa que crece mediante la calcificación adicional del colágeno intersticial y las vesículas membranosas. La placa termina expuesta a la orina piélica una vez que el epitelio papilar se rompe. Las capas superficiales de FCa son substituidas por OxCa mediante transformación directa o desmineralización del FCa o mineralización del OxCa. Alternativamente, o adicionalmente, los cristales de OxCa forman núcleos directamente en la superficie de la placa. El crecimiento de las piedras depende de la supersaturación de la orina piélica que desencadena más nucleación, crecimiento y agregación

La litiasis urinaria como enfermedad sistémica / Urinary lithiasis as a systemic disease

La litiasis urinaria es una patología prevalente de origen desconocido, que acarrea problemas al paciente tanto por el potencial daño a la vía urinaria, parénquima renal y organismo en su conjunto como por la tendencia frecuente de esta enfermedad a la recidiva. Historicamente se ha estudiado y tratado como una alteración aislada pero hoy en día cada vez conocemos mas sus conexiones con un conjunto de entidades patológicas con las que frecuentemente concurre. En un pequeño porcentaje de pacientes, enfermedades como el hiperparatiroidismo primario y la acidosis tubular renal tienen una clara correlación etiológica con la litiasis así como enfermedades inflamatorias digestivas y cirugía bariatrica. Sin embargo la conexión entre enfermedades frecuentes en la población, como la osteoporosis, el síndrome metabólico y la nefrolitiasis está en estudio, por si su prevención puede contribuir a frenar la tendencia al aumento de la incidencia y prevalencia de estas patologías en la sociedad occidental en las últimas décadas

Urinary lithiasis is a prevalent disorder of uncertain origin which provokes health problems through potential harm to the urinary system, renal parenchyma or the body as a whole, with a frequent trend to relapse. Historically urinary calculi have been studied and treated as an isolated disease but nowadays we know more about their connection with other pathological entities. In a small percentage of patients, diseases like primary hyperparathyroidism, tubular renal acidosis, inflammatory bowel disease or bariatric surgery have a fairly well studied physiopathological link with kidney stones. However, papers have been published recently describing connections between prevalent diseases such as bone disease or metabolic syndrome and nephrolithiasis. Attempts to prevent or treat these affections can possibly influence the other´s prevalence since their trend to increase is clear in western countries

Factores etiopatogénicos de los diferentes tipos de urolitiasis / Etiopathogenic factors of the different types of urinary litiasis

En este artículo de revisión se analizan los principios etiopatogénicos de la formación de la litiasis urinaria. A nivel renal, como consecuencia de procesos que lesionan el urotelio se producen calcificaciones a nivel de la papila y de los conductos de Bellini que pueden ser causantes de la formación del cálculo renal. Con la mejora de las pruebas de imagen, fundamentalmente micro-TAC es posible detectarlas y podemos ser capaces de anticiparnos a la formación de la litiasis. Como bien conocemos, existen diferentes factores que influyen en la formación del cálculo y que dependerán de la composición de la misma. En la litiasis cálcica es fundamental reseñar la modificación de los tipos de hipercalciuria, actualmente distinguimos dos tipos en lugar de tres, gracias al cociente calcio/creatinina de ayunas, diferenciándose hipercalciuria absortiva e hipercalciuria de ayunas. En la hipercalciuria de ayunas es importante destacar la relación que existe entre este factor y la pérdida de densidad mineral ósea en pacientes con litiasis renal cálcica recidivante, siendo por tanto preceptivo el estudio del metabolismo óseo mediante marcadores de remodelado óseo y densitometría ósea en este tipo de pacientes. Respecto a los otros factores que intervienen en la formación de la litiasis cálcica debemos hacer especial hincapié en la hipercalciuria y su creciente aumento por su relación con la obesidad y el síndrome metabólico, así como la hipocitraturia, presente en un porcentaje importante de pacientes y relacionada en algunos casos con acidosis metabólica y también osteopenia-osteoporosis. Con respecto a la litiasis de ácido úrico hay que destacar que el pH urinario es el factor más determinante y que por tanto el control y las modificaciones del mismo serán fundamentales en la prevención de este tipo de litiasis. En la litiasis infectiva es obligatorio la presencia de gérmenes que desdoblen la urea, generándose iones de amonio, capaces de lesionar el urotelio y de formar litiasis de fosfato amónico magnésico fundamentalmente. En cuanto a la litiasis de cistina, poco frecuente, clásicamente dividida en 3 tipos, ha pasado a dividirse en tipo A y B en función del gen mutado y resulta más útil su medición directa en orina de 24 horas que realizar test de screening que tienen baja sensibilidad. En líneas generales, hemos tratado de dar una visión de conjunto de los diferentes tipos de litiasis haciendo hincapié en aquellos puntos más interesantes desde el punto de vista clínico para el urólogo

In this review, we analyze the etiopathogenic principles of urinary lithiasis formation. In the kidney, calcifications that may cause renal lithiasis are produced as a consequence of processes that injury the urothelium at the papilla and Bellini´s ducts. With the improvement of imaging techniques, mainly micro CT scan, it is possible to detect them and we may be able to anticipate to the formation of lithiasis. As we well know, there are different factors that influence the formation of the calculi depending on their composition. In calcium lithiasis it is key to review the modification of the categories of hypercalciuria, we currently distinguish two types instead of three, thanks to the fasting calcium/ creatinine ratio, differentiating absorptive hypercalciuria and fasting hypercalciuria. In the fasting hypercalciuria, it is important to emphasize the relationship between this factor and the loss of bone mineral density in patients with recurrent renal calcic lithiasis, so that in this kind of patients it is compulsory the study of bone metabolism by bone remodelling markers and bone densitometry. Regarding the other factors that participate in the formation of calcium lithiasis we should specially emphasize on hypercalciuria and its growing increase because of its relationship with obesity and metabolic syndrome, as well as hipocitraturia, present in an important percentage of patients and related in some cases with metabolic acidosis and osteopenia-osteoporosis too. In relation to uric acid lithiasis it should be highlighted that urinary pH is the most determinant factor and, therefore, its control and modifications would be paramount for prevention of this type of lithiasis. In the infectious lithiasis, the presence of germs that split urea is mandatory. They generate ammonia ions with the ability to injure the urothelium and to form magnesium ammonium phosphate lithiasis mainly. Regarding cystine lithiasis, rare, it was classically divided in three types and now passed to be classified in type A and B depending on the muted gene, and it is more useful to perform direct 24-hour urine measurement than screening tests which have low sensitivity. In general, we tried to give a comprehensive view of the various types of lithiasis emphasizing the most interesting clinical points for the urologist

Cystine Stone Formers Have Impaired Health-Related Quality of Life Compared with Noncystine Stone Formers: A Case-Referent Study Piloting the Wisconsin Stone Quality of Life Questionnaire Among Patients with Cystine Stones.

INTRODUCTION: Cystinuria is a rare cause of urolithiasis. Affected patients have an earlier onset and more aggressive disease than patients with other stone etiologies. We assessed the health-related quality of life (HRQOL) of cystine stone-forming patients using the disease-specific Wisconsin Stone Quality of Life questionnaire (WISQOL). METHODS: Cystine patients treated in our stone clinics (n = 12) completed the WISQOL; information about medical and stone histories was gathered. Patients were matched with noncystine stone formers (n = 12) for gender, age, and comorbidities. In addition, a second control group (n = 90), also from our institution and consisting of mixed calcium stone formers, was included. WISQOL responses were compared between groups. RESULTS: Cystine patients had significantly lower total WISQOL scores than noncystine patients. Compared with noncystine stone formers, cystine stone formers also had lower HRQOL scores for subscales (domains) related to social impact, emotional impact, disease impact, and vitality (p ≤ 0.04 for all). On specific items, cystine patients reported significantly more sleep problems (p = 0.02), more bother with nocturia (p = 0.03), and feeling tired or fatigued (p = 0.02). Among those with current stones, cystine patients scored lower than noncystine patients for total score and in two of four domains. CONCLUSIONS: Using a stone-specific questionnaire, patients with cystine stones have lower HRQOL compared with noncystine stone formers. Identifying and addressing specific areas of decrement in patients with cystine stones may improve disease management and patients' HRQOL.

Systemic endothelial function measured by flow-mediated dilation is impaired in patients with urolithiasis.

Some in vitro and animal studies have shown endothelial dysfunction in hyperoxaluria models indicating its role in pathogenesis of urolithiasis and relation to CVD. The aim of this study was to investigate endothelial function in patients with urolithiasis in relation to urinary stone risk factors and metabolic parameters. A total of 120 subjects without any known CVD (60 with urolithiasis and 60 healthy subjects) were included into study. Fasting blood and 24-h urine samples were collected to study metabolic parameters (glucose and lipids) and urine stone risk factors (oxalate, citrate, uric acid, and calcium, pH). Endothelial function was assessed as flow-mediated dilation (FMD) at the brachial artery. Age, sex, and body mass index were similar in patients and controls. Of urine stone risk factors, oxalate and citrate were higher in patients than controls. Fasting blood glucose, total LDL cholesterol, and triglyceride were higher, and HDL cholesterol was lower in patients than controls. Although within normal limits systolic blood pressure was higher in patient group, patients with urolithiasis had a lower %FMD than controls. Percent FMD was negatively correlated with urinary oxalate/creatinine ratio (p = 0.019, r = -0.315), calcium/creatinine ratio (p = 0.0001, r = -0.505) age (p < 0.001, r = -0.694), BMI (p < 0.001, r = -0.838), total cholesterol (p < 0.001, r = -0.559), and triglyceride (p < 0.001, r = -0.529). Urine oxalate/creatinine ratio was positively correlated with age (p = 0.01, r = 0.327) and calcium/creatinine ratio with BMI (p = 0.001, r = 0.410). This is the first study demonstrating endothelial dysfunction in human subjects with urolithiasis. This indicates a possible predictive role of urolithiasis in future development of cardiovascular diseases.

Urinary Tract Stones and Osteoporosis: Findings From the Women's Health Initiative.

Kidney and bladder stones (urinary tract stones) and osteoporosis are prevalent, serious conditions for postmenopausal women. Men with kidney stones are at increased risk of osteoporosis; however, the relationship of urinary tract stones to osteoporosis in postmenopausal women has not been established. The purpose of this study was to determine whether urinary tract stones are an independent risk factor for changes in bone mineral density (BMD) and incident fractures in women in the Women's Health Initiative (WHI). Data were obtained from 150,689 women in the Observational Study and Clinical Trials of the WHI with information on urinary tract stones status: 9856 of these women reported urinary tract stones at baseline and/or incident urinary tract stones during follow-up. Cox regression models were used to determine the association of urinary tract stones with incident fractures and linear mixed models were used to investigate the relationship of urinary tract stones with changes in BMD that occurred during WHI. Follow-up was over an average of 8 years. Models were adjusted for demographic and clinical factors, medication use, and dietary histories. In unadjusted models there was a significant association of urinary tract stones with incident total fractures (HR 1.10; 95% CI, 1.04 to 1.17). However, in covariate adjusted analyses, urinary tract stones were not significantly related to changes in BMD at any skeletal site or to incident fractures. In conclusion, urinary tract stones in postmenopausal women are not an independent risk factor for osteoporosis.

Which anthropometric measurements including visceral fat, subcutaneous fat, body mass index, and waist circumference could predict the urinary stone composition most?

BACKGROUND: Although there is growing evidence of relationship between obesity and some specific stone compositions, results were inconsistent. Due to a greater relationship between metabolic syndrome and some specific stone type, obesity measured by body mass index (BMI) has limitation in determining relationship between obesity and stone compositions. The aim of this study was to determine the relationship among BMI, visceral fat, and stone compositions. METHODS: We retrospectively reviewed data of patients with urinary stone removed over a 5 year period (2011-2014). Data on patient age, gender, BMI, urinary pH, stone composition, fat volumes (including visceral fat, subcutaneous fat, total fat, waist circumference), and ratio for visceral to total fat using computed tomography based delineation were collected. To figure out the predicting factor while adjusting other confounding factors, discriminant analysis was used. RESULTS: Among 262 cases, average age was 52.21 years. Average BMI and visceral fat were 25.03 cm(2) and 124.75 cm(2), respectively. By chi square test, there was significant (p < 0.001) difference in stone types according to sex. By ANOVA test, BMI, visceral fat, visceral to subcutaneous fat ratio, the percentage of visceral fat and total fat showed significant association with stone types. By discriminant analysis, visceral fat was proved to be a powerful factor to predict stone composition (structure matrix of visceral fat = -0.735) with 42.0% of predictive value. CONCLUSION: Visceral fat adiposity strongly related with uric acid stone and has better predictive value than BMI or urinary pH to classify the types of stone.

Association between hypouricemia and reduced kidney function: a cross-sectional population-based study in Japan.

BACKGROUND: Hypouricemia, conventionally defined as a serum uric acid level of ≤2 mg/dl, is considered a biochemical disorder with no clinical significance. However, individuals with renal hypouricemia have a high risk of urolithiasis and exercise-induced acute kidney injury, both of which are risk factors for reduced kidney function. METHODS: To test the hypothesis that individuals with hypouricemia would be at a higher risk of reduced kidney function, we conducted a population-based cross-sectional study using data from the Specific Health Checkups and Guidance System in Japan. Logistic analysis was used to examine the relationship between hypouricemia and reduced kidney function, defined as estimated glomerular filtration rate <60 ml/min/1.73 m(2). RESULTS: Among 90,710 men (mean age, 63.8 years) and 136,935 women (63.7 years), 193 (0.2%) and 540 (0.4%) were identified as having hypouricemia, respectively. The prevalence of hypouricemia decreased with age in women (p for trend <0.001), but not in men (p for trend = 0.24). Hypouricemia was associated with reduced kidney function in men (odds ratio, 1.83; 95% confidence interval, 1.23-2.74), but not in women (0.61; 0.43-0.86), relative to the reference category (i.e., serum uric acid levels of 4.1-5.0 mg/dl) after adjusting for age, drinking, smoking, diabetes, hypertension, hypercholesterolemia, obesity, and history of renal failure. Sensitivity analyses stratified by diabetic status yielded similar results. CONCLUSIONS: This study is the first to provide evidence that hypouricemia is associated with reduced kidney function in men. Further research will be needed to determine the long-term prognosis of individuals with hypouricemia.

Depletion of Uric Acid Due to SLC22A12 (URAT1) Loss-of-Function Mutation Causes Endothelial Dysfunction in Hypouricemia.

BACKGROUND: Uric acid (UA) serves as an antioxidant in vascular endothelial cells. UA transporter 1 (URAT1) encoded by SLC22A12 is expressed in the kidney and vessels and its loss of function causes hypouricemia. The purpose of this study was to examine whether there is any endothelial dysfunction in patients with hypouricemia. METHODS AND RESULTS: Twenty-six patients with hypouricemia (<2.5 mg/dl) and 13 healthy control subjects were enrolled. Endothelial function was evaluated using flow-mediated dilation (FMD). mRNA of UA transporters expressed in cultured human umbilical endothelial cells (HUVEC) was detected on RT-PCR. There was a positive correlation between FMD and serum UA in the hypouricemia group. URAT1 loss-of-function mutations were found in the genome of 21 of 26 patients with hypouricemia, and not in the other 5. In the hypouricemia groups, serum UA in homozygous and compound heterozygous patients was significantly lower than in other groups, suggesting that severity of URAT1 dysfunction may influence the severity of hypouricemia. Thirteen of 16 hypouricemia subjects with homozygous and compound heterozygote mutations had SUA <0.8 mg/dl and their FMD was lower than in other groups. HUVEC do not express mRNA of URAT1, suggesting the null role of URAT1 in endothelial function. CONCLUSIONS: Depletion of UA due to SLC22A12/URAT1 loss-of-function mutations causes endothelial dysfunction in hypouricemia patients.