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.

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.

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.

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.

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.

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.

A novel homozygous GLUT9 mutation cause recurrent exercise-induced acute renal failure and posterior reversible encephalopathy syndrome.

Renal hypouricemia (RHU) is an autosomal recessive hereditary disease characterized by impaired renal urate reabsorption and subsequent profound hypouricemia. There are two types of RHU, type 1 and type 2, caused by the loss-of-function mutation of SLC22A12 and SLC2A9 genes, respectively. RHU predisposes affected people to exercise-induced acute renal failure (EIARF), posterior reversible encephalopathy syndrome (PRES) and nephrolithiasis. A Chinese patient had experienced three episodes of EIARF and one episode of PRES. The investigations showed profound hypouricemia and significantly increased renal excretion of UA. Cranial magnetic resonance imaging showed communicating hydrocephalus. Renal biopsy displayed interlobular artery intimal thickening with reduction of lumen and acute tubulointerstitial injury. The mutational analysis revealed a homozygous splice-site mutation in the SLC2A9 gene encoding glucose transporter 9. The patient was diagnosed as RHU type 2 caused by a loss-of-function mutation of the SLC2A9 gene. Consequently, he was strictly prohibited from strenuous exercise. During the 5-year follow-up, EIARF and PRES never recurred. Strenuous exercise may induce systemic (including renal and cerebrovascular) vasoconstriction eventually resulting in EIARF and PRES in patients with RHU. To our knowledge, this is the first report of a homozygous splice-site mutation in the SLC2A9 gene, renal arteriolar chronic lesion, concurrence of RHU and communicating hydrocephalus.

Diet: from food to stone.

Dietary factors have been shown to influence urine composition and modulate the risk of kidney stone disease. With the rising prevalence of stone disease in many industrialized nations, dietary modification as therapy to improve lithogenic risk factors and prevent stone recurrence has gained appeal, as it is both relatively inexpensive and safe. While some dietary measures, such as a high fluid intake, have been shown in long-term randomized clinical trials to have durable effectiveness, other dietary factors have been subjected to only short-term clinical or metabolic studies and their efficacy has been inferred. Herein, we review the current literature regarding the role of diet in stone formation, focusing on both the effect on urinary stone risk factors and the effect on stone recurrence.

Functional multiparametric magnetic resonance imaging of the kidneys using blood oxygen level dependent and diffusion-weighted sequences.

PURPOSE: Little data are available on noninvasive magnetic resonance imaging based assessment of renal function during upper urinary tract obstruction. We determined whether functional multiparametric kidney magnetic resonance imaging could monitor the treatment response in cases of acute unilateral upper urinary tract obstruction. MATERIAL AND METHODS: Between January 2008 and January 2010, 18 patients with acute unilateral upper urinary tract obstruction due to calculi were prospectively enrolled to undergo kidney magnetic resonance imaging with conventional, blood oxygen level dependent and diffusion-weighted sequences upon emergency hospital admission and after release of obstruction. We assessed functional imaging parameters of obstructed and contralateral unobstructed kidneys derived from blood oxygen level dependent (apparent spin relaxation rate) and diffusion-weighted (total apparent diffusion coefficient, pure diffusion coefficient and perfusion fraction) sequences during acute upper urinary tract obstruction and after its release. RESULTS: During acute obstruction the apparent spin relaxation rate and perfusion fraction were lower in the cortex (p=0.020 and 0.031) and medulla (p=0.012 and 0.190, respectively) of obstructed kidneys compared to contralateral unobstructed kidneys. After obstruction release the apparent spin relaxation rate and perfusion fraction increased in the cortex (p=0.016 and 0.004) and medulla (p=0.071 and 0.044, respectively) of formerly obstructed kidneys to values similar to those in contralateral kidneys. Total apparent diffusion coefficient and pure diffusion coefficient values did not significantly differ between obstructed and contralateral unobstructed kidneys during or after obstruction. CONCLUSIONS: In our patients with acute unilateral upper urinary tract obstruction due to calculi functional kidney magnetic resonance imaging using blood oxygen level dependent and diffusion-weighted sequences enabled us to monitor pathophysiological changes in obstructed kidneys during obstruction and after its release.