The impact of crystal phase transition on the hardness and structure of kidney stones.

Calcium oxalate kidney stones, the most prevalent type of kidney stones, undergo a multi-step process of crystal nucleation, growth, aggregation, and secondary transition. The secondary transition has been rather overlooked, and thus, the effects on the disease and the underlying mechanism remain unclear. Here, we show, by periodic micro-CT images of human kidney stones in an ex vivo incubation experiment, that the growth of porous aggregates of calcium oxalate dihydrate (COD) crystals triggers the hardening of the kidney stones that causes difficulty in lithotripsy of kidney stone disease in the secondary transition. This hardening was caused by the internal nucleation and growth of precise calcium oxalate monohydrate (COM) crystals from isolated urine in which the calcium oxalate concentrations decreased by the growth of COD in closed grain boundaries of COD aggregate kidney stones. Reducing the calcium oxalate concentrations in urine is regarded as a typical approach for avoiding the recurrence. However, our results revealed that the decrease of the concentrations in closed microenvironments conversely promotes the transition of the COD aggregates into hard COM aggregates. We anticipate that the suppression of the secondary transition has the potential to manage the deterioration of kidney stone disease.

Bisphosphonate Use May Reduce the Risk of Urolithiasis in Astronauts on Long-Term Spaceflights.

Long-duration spaceflight is associated with an increased risk of urolithiasis, and the pain caused by urinary calculi could result in loss of human performance and mission objectives. The present study investigated the risk of urolithiasis in astronauts during 6 months on the International Space Station, and evaluated whether the suppression of bone resorption by the bisphosphonate, alendronate (ALN), can reduce the risk. A total of 17 astronauts were included into the analysis: exercise using the advanced resistive exercise device (ARED) plus weekly oral 70 mg alendronate (ARED+ALN group, n = 7) was compared to resistive exercise alone (ARED group, n = 10). Urine volume decreased in both groups during spaceflight but recovered after return. The ARED group showed increased urinary calcium excretion from the 15th to 30th day of spaceflight, whereas urinary calcium was slightly decreased in the ARED+ALN group. Urinary N-terminal telopeptide (NTX) and helical peptide (HP) of type I collagen, as bone resorption markers, were elevated in the ARED group during and until 0 days after spaceflight, while there was no elevation in these parameters in the ARED+ALN group. Urinary oxalate and uric acid excretion tended to be higher in the ARED group than in the ARED+ALN group during spaceflight. These results demonstrate that astronauts on long-duration spaceflights may be at high risk for the formation of urinary calcium oxalate and calcium phosphate stones through increased urinary excretion of oxalate and uric acid, from degraded type I collagen, as well as of calcium from enhanced bone resorption. Our findings suggest that increased bone resorption during spaceflight, as a risk factor for urinary calculus formation, could be effectively prevented by an inhibitor of bone resorption. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Deregulated MTOR (mechanistic target of rapamycin kinase) is responsible for autophagy defects exacerbating kidney stone development.

Kidney stone disease is a lifestyle-related disease prevalent in developed countries; however, effective medical treatment for the disease is not yet well established. As cellular damage in renal tubular cells (RTCs) is responsible for the disease, here, we focused on the role of macroautophagy/autophagy in RTCs. We found that autophagic activity was significantly decreased in mouse RTCs exposed to calcium oxalate (CaOx) monohydrate crystals and in the kidneys of GFP-conjugated MAP1LC3B (microtubule- associated protein 1 light chain 3 beta) transgenic mice with CaOx nephrocalcinosis induced by glyoxylate. This caused accumulation of damaged intracellular organelles, such as mitochondria and lysosomes, the normal functioning of which is mediated by functional autophagy. An impairment of autophagy was also observed in the mucosa with plaques of CaOx kidney stone formers. We determined that the decrease in autophagy was caused by an upregulation of MTOR (mechanistic target of rapamycin kinase), which consequently resulted in the suppression of the upstream autophagy regulator TFEB (transcription factor EB). Furthermore, we showed that an MTOR inhibitor could recover a decrease in autophagy and alleviate crystal-cell interactions and the formation of crystals associated with increased inflammatory responses. Taken together, we conclude that autophagy compromised by MTOR deregulation is a fundamental feature in the pathology of kidney stone formation, and propose that chemical inhibition of MTOR could be a prospective strategy for disease suppression.Abbreviations: ACTB: actin, beta; CaOx: calcium oxalate; CKD: chronic kidney disease; COM: calcium oxalate monohydrate; LGALS3/galectin-3: lectin, galactose binding, soluble 3; GFP: green fluorescent protein; GOX: glyoxylate; HE: hematoxylin and eosin; MAPLC3B: microtubule- associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NAC: N-acetyl-L-cysteine; ROS: reactive oxygen species; RTC: renal tubular cell; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TEM: transmission electron microscopy; tfLC3: tandem fluorescent-tagged LC3; 3-MA: 3-methyladenine.

A Proteomic Network Approach across the Kidney Stone Disease Reveals Endoplasmic Reticulum Stress and Crystal-Cell Interaction in the Kidney.

Crystal-cell interactions are a vital step toward kidney stone formation. However, its mechanisms remained unclear. Here, a protein-protein interaction (PPI) network analysis of a kidney stone revealed that the proteins were enriched in a posttranslational protein modification process in the endoplasmic reticulum (ER). The in vitro study showed that the markers of ER stress, including Bip and CHOP, were upregulated, PERK and ATF6 were activated, and XBP-1 mRNA was spliced. An ER stress-specific protein, caspase-12, was activated in the apoptotic cells induced by calcium oxalate monohydrate (COM) crystals. The treatment with tunicamycin, an ER stress inducer, promoted the crystal-cell adhesion assayed by atomic absorption, reduced cell viability assayed by MTT, and downregulated the expression of proteins involved in the crystal formations. The treatment with salubrinal, an ER stress inhibitor, reversed the above effects for both tunicamycin and COM crystals. The aforementioned main observations were supported by in vivo study. These data demonstrated that ER stress was an essentially biological process of crystal-cell interactions. Our findings suggest that blocking ER stress may become a potential approach to preventing a kidney stone.

Active Phagocytosis and Diachronic Processing of Calcium Oxalate Monohydrate Crystals in an in vitro Macrophage Model.

BACKGROUND: We previously discovered that renal macrophages (Mφs) phagocytose renal calcium oxalate monohydrate (COM) crystals. This study investigated the processing of engulfed crystals using in vitro models. METHODS: J774.1 mouse Mφs were exposed to COM crystals and observed for 24 h using polarized light microscopy with/without cytochalasin B (CB), an inhibitor of phagocytosis, to confirm active crystal phagocytosis. LysoTracker and immunohistochemical staining using transmission electron microscopy for lysosomal-associated membrane protein 1 were used to confirm engulfed COM crystal uptake into lysosomes. Diachronic tracking of specific Mφs was performed to capture the entire course of engulfed COM crystal processing using polarized light microscopy. Follow-up studies of fluorescent COM (f-COM) crystals using imaging cytometry were performed in the presence and absence of nigericin to dissipate the pH gradient in acidic organelles. RESULTS: Phagocytosis rates increased with COM density and were significantly lower in cells treated with CB (p < 0.01). We observed that engulfed crystals colocalized within lysosomes of the Mφs; moreover, diachronic observation indicated that the engulfed COM crystals were subdivided during Mφ division and eliminated by the 7th day of culture. Additionally, imaging cytometry showed that the fluorescence level of f-COM crystals in the nigericin (-) group after 48 h was significantly lower than that in the nigericin (+) group. CONCLUSIONS: This study confirmed active phagocytosis and lysosomal processing of engulfed COM crystals by Mφs. This discovery is expected to contribute to the development of future drugs that enhance the COM crystal phagocytic ability of Mφs.

Novel Risk Loci Identified in a Genome-Wide Association Study of Urolithiasis in a Japanese Population.

BACKGROUND: A family history of urolithiasis is associated with a more than doubling of urolithiasis risk, and a twin study estimating 56% heritability of the condition suggests a pivotal role for host genetic factors. However, previous genome-wide association studies (GWAS) have identified only six risk-related loci. METHODS: To identify novel urolithiasis-related loci in the Japanese population, we performed a large-scale GWAS of 11,130 cases and 187,639 controls, followed by a replication analysis of 2289 cases and 3817 controls. Diagnosis of urolithiasis was confirmed either by a clinician or using medical records or self-report. We also assessed the association of urolithiasis loci with 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (such as body mass index, lipid storage, eGFR, serum uric acid, and serum calcium), using up to 160,000 samples from BioBank Japan. RESULTS: The analysis identified 14 significant loci, including nine novel loci. Ten regions showed a significant association with at least one quantitative trait, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic basis for urolithiasis and these quantitative traits. Four novel loci were related to metabolic traits, obesity, hypertriglyceridemia, or hyperuricemia. The remaining ten loci were associated with kidney- or electrolyte-related traits; these may affect crystallization. Weighted genetic risk score analysis indicated that the highest risk group (top 20%) showed an odds ratio of 1.71 (95% confidence interval, 1.42 to 2.06) - 2.13 (95% confidence interval, 2.00 to 2.27) compared with the reference group (bottom 20%). CONCLUSIONS: Our findings provide evidence that host genetic factors related to regulation of metabolic and crystallization pathways contribute to the development of urolithiasis.

Brown adipocytes and ß3-stimulant-induced brown-like adipocytes contribute to the prevention of renal crystal formation.

According to recent studies, kidney stones are associated with metabolic syndrome. We focused on brown adipocytes and ß3-stimulant-induced brown-like adipocytes to investigate how these adipocytes influence kidney stone disease. For the interscapular brown adipose tissue (iBAT) removal experiment, mice were subjected to either iBAT removal or sham operation (X-BAT group or sham group), and, after 3 wk, renal crystal deposition was induced by intra-abdominal injection of glyoxylate (GOX) for 6 days. For the ß3-stimulant experiment, mice were administered intra-abdominal injections of the ß3-stimulant (ß3-group) or saline (control group) for 6 days. Thereafter, renal crystal deposition was induced by intra-abdominal injection of GOX for 6 days. iBAT removal decreased the expression of Sod1 and increased that of chemokine (C-C motif) ligand 2 (Ccl2), EGF module-containing mucin-like receptor 1 (Emr1), and tumor necrosis factor (Tnf) in the kidneys. Renal crystal deposition was 2.06-fold higher in the X-BAT group than in the sham group. The ß3-stimulant caused differentiation of white adipocytes into brown-like adipocytes. In the kidneys of the ß3-group, the expression of Ccl2 and Emr1 decreased and that of Sod1 increased. Renal crystal deposition was 0.17-fold lower in the ß3-group than in the control group. In summary, iBAT removal promoted kidney inflammation and renal crystal formation. ß3-Stimulant-induced brown-like adipocytes reduced inflammation and improved antioxidant action in the kidneys, which suppressed renal crystal formation. This is the first report on the therapeutic role of brown and brown-like adipocytes for kidney stone formation.

Helper T-cell signaling and inflammatory pathway lead to formation of calcium phosphate but not calcium oxalate stones on Randall's plaques.

OBJECTIVES: To elucidate the difference in the lithogenesis of calcium oxalate and calcium phosphate stones. METHODS: Renal papillary tissues were obtained from 23 idiopathic calcium oxalate and seven calcium phosphate stone patients who had undergone endoscopic lithotripsy. Samples were individually collected from two different regions in each patient: the papillary mucosa containing Randall's plaque and mucosa not containing Randall's plaque. A microarray analysis was carried out on those tissues to compare their gene expression patterns. Furthermore, a causal pathway analysis comparing their differences was carried out. RESULTS: Cluster analysis showed that gene expression profiles of calcium phosphate stone patients markedly differed from those of calcium oxalate stone patients. Disease and function analysis showed that Randall's plaque-containing tissues of calcium phosphate stone-forming patients had significantly higher movement and migration of mononuclear leukocytes, and lower tendency toward infection and lymph node formation than Randall's plaque-containing tissues of calcium oxalate stone formers. Additional pathway analysis showed increased immune cell signaling in calcium phosphate formers, such as the helper T cell 1 and 2 pathways, which was confirmed by their messenger ribonucleic acid expression. CONCLUSIONS: The present results show the upregulation of helper T-cell signaling pathways in Randall's plaque-containing papillae in calcium phosphate, but not in calcium oxalate stone formers. Thus, helper T-cell immune responses and the related inflammatory processes seem to lead to the formation of calcium phosphate stones on Randall's plaques.

Identification of new urinary risk markers for urinary stones using a logistic model and multinomial logit model.

BACKGROUND: Risk assessment for urinary stones has been mainly based on urinary biochemistry. We attempted to identify the risk factors for urinary stones by statistically analyzing urinary biochemical and inflammation-related factors. METHODS: Male participants (age, 20-79 years) who visited Nagoya City University Hospital were divided into three groups: a control group (n = 48) with no history of stones and two stone groups with calcium oxalate stone experience (first-time group, n = 22; recurring group, n = 40). Using 25-µL spot urine samples, we determined the concentrations of 18 candidate urinary proteins, using multiplex analysis on a MagPix® system. RESULTS: In univariate logistic regression models classifying the control and first-time groups, interleukin (IL)-1a and IL-4 were independent factors, with significantly high areas under the receiver operating characteristic curve (1.00 and 0.87, respectively, P < 0.01 for both). The multivariate models with IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) showed higher areas under the receiver operating characteristic curve (0.93) compared to that for the univariate model with IL-4. In the classification of control, first-time, and recurrence groups, accuracy was the highest for the multinomial logit model with IL-4, GM-CSF, IL-1b, IL-10, and urinary magnesium (concordance rate 82.6%). CONCLUSIONS: IL-4, IL-1a, GM-CSF, IL-1b, and IL-10 were identified as urinary inflammation-related factors that could accurately distinguish control individuals from patients with urinary stones. Thus, the combined analysis of urinary biochemical data could provide an index that more clearly evaluates the risk of urinary stone formation.

Nationwide Increase in Cryptorchidism After the Fukushima Nuclear Accident.

OBJECTIVE: To estimate the change of discharge rate after cryptorchidism surgery between pre- and postdisaster in Japan. Cryptorchidism cannot be diagnosed before birth and is not a factor that would influence a woman's decision to seek an abortion. Therefore, this disease is considered suitable for assessing how the Great East Japan Earthquake and the subsequent Fukushima Daiichi nuclear accident (2011) influenced congenital diseases. MATERIALS AND METHODS: We obtained cryptorchidism discharge data collected over 6 years from hospitals that were included in an impact assessment survey of the Diagnosis Procedure Combination survey database in Japan and used these data to estimate the discharge rate after cryptorchidism surgery before and after the disaster. The 94 hospitals in Japan that participated in Diagnosis Procedure Combination system and had 10 or more discharges after cryptorchidism surgery within successive 6 years covering pre- and postdisaster period (FY2010-FY2015) were involved. The change in discharge rate between pre- and postdisaster was analyzed using a Bayesian generalized linear mixed model. RESULTS: Nationwide, a 13.4% (95% credible interval 4.7%-23.0%) increase in discharge rates was estimated. The results of all sensitivity analyses were similar to the reported main results. CONCLUSION: The discharge rate of cryptorchidism was increased nationwide. The rates of low-weight babies or preterm births, risk factors of cryptorchidism, were almost constant during the study period, and age distribution of the surgery was also not changed, which suggested that the other factors that associated with the disaster increased the incidence of cryptorchidism.

Kidney stone formers have more renal parenchymal crystals than non-stone formers, particularly in the papilla region.

BACKGROUND: We investigated the renoprotective ability of healthy people against kidney stone formation. To clarify intratubular crystal kinetics and processing in human kidneys, we performed a quantitative and morphological observation of nephrectomized renal parenchyma tissues. METHODS: Clinical data and pathological samples from 60 patients who underwent radical nephrectomy for renal cancer were collected from June 2004 to June 2010. The patients were retrospectively classified as stone formers (SFs; n = 30, kidney stones detected by preoperative computed tomography) and non-stone formers (NSFs; n = 30, no kidney stone history). The morphology of parenchymal intratubular crystals and kidney stone-related gene and protein expression levels were examined in noncancerous renal sections from both groups. RESULTS: SFs had a higher smoking rate (P = 0.0097); lower red blood cell, hemoglobin, and hematocrit values; and higher urinary red blood cell, white blood cell, and bacterial counts than NSFs. Scanning electron microscopy revealed calcium-containing crystal deposits and crystal attachment to the renal tubular lumen in both groups. Both groups demonstrated crystal transmigration from the tubular lumen to the interstitium. The crystal diffusion analysis indicated a significantly higher crystal existing ratio in the medulla and papilla of SFs and a significantly higher number of papillary crystal deposits in SFs than NSFs. The expression analysis indicated relatively high osteopontin and CD68, low superoxide dismutase, and significantly lower Tamm-Horsfall protein expression levels in SFs. Multivariate logistic regression analysis involving the above factors found the presence of renal papillary crystals as a significant independent factor related to SFs (odds ratio 5.55, 95% confidence interval 1.08-37.18, P = 0.0395). CONCLUSIONS: Regardless of stone formation, intratubular crystals in the renal parenchyma seem to transmigrate to the interstitium. SFs may have reduced ability to eliminate renal parenchymal crystals, particularly those in the papilla region, than NSFs with associated gene expression profiles.

Genetic differences in C57BL/6 mouse substrains affect kidney crystal deposition.

We previously established an experimental model of calcium oxalate crystal deposition in the mouse kidney using C57BL/6 mice. C57BL/6J (B6J) and C57BL/6N (B6N) are two core substrains of C57BL/6 mice. B6J and B6N substrains have approximately the same genomic sequence. However, in whole-genome analyses, substrains have slight genetic differences in some genes. In this study, we used these substrains as kidney crystal formation models and compared their genetic backgrounds to elucidate the pathogenic mechanisms of kidney stone formation. Eight-week-old male B6J and B6N mice (n = 15 in each group) were administered 80 mg/kg glyoxylate for 12 days, and the amount of kidney crystal depositions was compared. The expression levels of six genes (Snap29, Fgf14, Aplp2, Lims1, Naaladl2, and Nnt) were investigated by quantitative polymerase chain reaction, and the protein levels were evaluated by western blotting and immunohistochemistry. The amount of kidney crystal depositions was significantly higher in B6J mice than in B6N mice on days 6 and 12. The expression of nicotinamide nucleotide transhydrogenase (Nnt) gene was significantly lower in B6J mice than in B6N mice. The expression of Nnt protein was observed only in B6N mice, and preferential high expression was seen in renal tubular epithelial cells. The results of this study provide compelling evidence that differences in mouse substrains affect kidney crystal deposition and that the absence of Nnt protein could be involved in crystal formation in B6J mice.

A kit ligand, stem cell factor as a possible mediator inducing overactive bladder.

OBJECTIVE: To investigate whether c-kit ligand, stem cell factor (SCF) affects the biological behavior of overactive bladder (OAB) and discuss the role of SCF as a possible mediator inducing OAB. MATERIALS AND METHODS: First, we performed an immunohistochemical study to examine the localization of SCF in the guinea pig and human bladder. Next, urinary SCF levels were measured in patients with OAB and in control subjects to evaluate a potential biomarker for the diagnosis of OAB. Third, we examined the effect of SCF administration on the urinary bladder using guinea pigs to obtain additional information about SCF. The animals were administered with mouse SCF, and cystometry was performed. The following urodynamic parameters were analyzed: inter-contraction interval, maximum voiding pressure, pressure threshold, detrusor baseline pressure, and the number of non-voiding contractions. RESULTS: Immunohistochemical study showed that the expression of SCF was observed throughout the bladder wall, but especially in the urothelium of guinea pig and human bladder. Medians and IQRs of urinary SCF and SCF/creatinine levels in OAB patients (85.9 pg/mL [42.8, 199.0] and 1.30 [0.56, 2.71], respectively) were significantly higher than in control subjects (18.9 pg/mL [5.0, 43.6] and 0.26 [0.13, 0.43], respectively). SCF administration dose-dependently shortened the intercontraction interval and an increased number of non-voiding contractions (P < 0.05). CONCLUSIONS: Our present data suggest that SCF produced in the urinary bladder may act as a possible mediator by binding to c-kit, which is expressed in ICC-like cells in the suburothelial and muscle layers, to control bladder function.

Determinants of health-related quality of life for patients after urinary lithotripsy: ureteroscopic vs. shock wave lithotripsy.

PURPOSE: To compare the longitudinal health-related quality of life (HRQoL) after surgical intervention with ureteroscopic lithotripsy (URSL) and shock wave lithotripsy (SWL) and to evaluate the factors affecting HRQoL in urolithiasis patients. METHODS: A total of 262 patients who underwent lithotripsy (SWL, n = 61; URSL, n = 201) for upper urinary tract calculi treatment between June 2012 and January 2015 were evaluated. All patients were administered the Short-Form 36-item survey (SF-36) to assess HRQoL at four timepoints: before surgery, on the day of discharge, and 1 and 6 months after lithotripsy. Stone-free rates, complications, and analgesic requirements were evaluated to compare the effects of the two procedures on HRQoL. RESULTS: At the day of discharge, patients in the URSL group had significantly lower mean scores on five different subscales of the SF-36 questionnaire, namely, physical functioning, role-physical, social functioning, role-emotional, and mental health. The stone-free rate at 3 months after lithotripsy was significantly lower in the SWL group (72.1% vs. URSL, 93.0%; p < 0.001). The hospital stay was shorter in the SWL group (2.1 ± 0.07 vs. URSL, 4.1 ± 0.13 days; p < 0.001), and the analgesia requirements were also lower in the SWL group (0.3 ± 0.08 vs. URSL, 0.9 ± 0.20; p < 0.001). CONCLUSIONS: The post-lithotripsy HRQoL was superior for SWL compared to URSL on the discharge date despite the lower stone-free rate of the former. The longer hospital stay and higher postoperative pain appeared to be the determinants of the lower HRQoL in the URSL group.

A New Navigation System of Renal Puncture for Endoscopic Combined Intrarenal Surgery: Real-time Virtual Sonography-guided Renal Access.

OBJECTIVE: To evaluate the clinical utility of a new navigation technique for percutaneous renal puncture using real-time virtual sonography (RVS) during endoscopic combined intrarenal surgery. MATERIALS AND METHODS: Thirty consecutive patients who underwent endoscopic combined intrarenal surgery for renal calculi, between April 2014 and July 2015, were divided into the RVS-guided puncture (RVS; n = 15) group and the ultrasonography-guided puncture (US; n = 15) group. In the RVS group, renal puncture was repeated until precise piercing of a papilla was achieved under direct endoscopic vision, using the RVS system to synchronize the real-time US image with the preoperative computed tomography image. In the US group, renal puncture was performed under US guidance only. In both groups, 2 urologists worked simultaneously to fragment the renal calculi after inserting the miniature percutaneous tract. The mean sizes of the renal calculi in the RVS and the US group were 33.5 and 30.5 mm, respectively. RESULTS: A lower mean number of puncture attempts until renal access through the calyx was needed for the RVS compared with the US group (1.6 vs 3.4 times, respectively; P = .001). The RVS group had a lower mean postoperative hemoglobin decrease (0.93 vs 1.39 g/dL, respectively; P = .04), but with no between-group differences with regard to operative time, tubeless rate, and stone-free rate. None of the patients in the RVS group experienced postoperative complications of a Clavien score ≥2, with 3 patients experiencing such complications in the US group. CONCLUSION: RVS-guided renal puncture was effective, with a lower incidence of bleeding-related complications compared with US-guided puncture.

Robot-assisted laparoscopic pyeloplasty for ureteropelvic junction obstruction: comparison between pediatric and adult patients-Japanese series.

Robotic-assisted procedures are gaining traction as a viable form of minimally invasive surgery in the field of reconstructive surgery. In this article, the aim is to present our initial experience and clinical outcomes of robot-assisted laparoscopic pyeloplasty (RAL-P). We performed RAL-P in 22 patients for the management of ureteropelvic junction obstruction between December 2012 and August 2015. The da Vinci® S surgical system was utilized for all cases. All procedures were performed via a transperitoneal approach. We assessed perioperative outcomes, and furthermore, compared between pediatric and adult patients undergoing this procedure. Dismembered procedures were performed in 19 patients. Three patients underwent Y-V plasty, and two patients who experienced failure during the primary pyeloplasty had to undergo reoperation. Although the console time for pediatric patients was significantly shorter than that of adults (123.1 ± 18.3, 162.4 ± 23.9 min, respectively, p < 0.001), success rate was not significantly different between pediatric and adults (100 vs 90 %, p = 0.512). According to a comparison of surgical outcomes by age, the console time was significantly shorter in pediatric than in adult patients. This finding may be attributable to the differences in intraabdominal fatty tissues. Besides, RAL-P with Y-V plasty was applicable even for cases of failed pyeloplasty. In conclusion, the surgical outcomes of RAL-P were favorable and safe for both pediatric and adult patients, and comparable to findings of previous reports. To our knowledge, this is the first report of a case series of RAL-P in Japan.

Genome-Wide Gene Expression Profiling of Randall's Plaques in Calcium Oxalate Stone Formers.

Randall plaques (RPs) can contribute to the formation of idiopathic calcium oxalate (CaOx) kidney stones; however, genes related to RP formation have not been identified. We previously reported the potential therapeutic role of osteopontin (OPN) and macrophages in CaOx kidney stone formation, discovered using genome-recombined mice and genome-wide analyses. Here, to characterize the genetic pathogenesis of RPs, we used microarrays and immunohistology to compare gene expression among renal papillary RP and non-RP tissues of 23 CaOx stone formers (SFs) (age- and sex-matched) and normal papillary tissue of seven controls. Transmission electron microscopy showed OPN and collagen expression inside and around RPs, respectively. Cluster analysis revealed that the papillary gene expression of CaOx SFs differed significantly from that of controls. Disease and function analysis of gene expression revealed activation of cellular hyperpolarization, reproductive development, and molecular transport in papillary tissue from RPs and non-RP regions of CaOx SFs. Compared with non-RP tissue, RP tissue showed upregulation (˃2-fold) of LCN2, IL11, PTGS1, GPX3, and MMD and downregulation (0.5-fold) of SLC12A1 and NALCN (P<0.01). In network and toxicity analyses, these genes associated with activated mitogen-activated protein kinase, the Akt/phosphatidylinositol 3-kinase pathway, and proinflammatory cytokines that cause renal injury and oxidative stress. Additionally, expression of proinflammatory cytokines, numbers of immune cells, and cellular apoptosis increased in RP tissue. This study establishes an association between genes related to renal dysfunction, proinflammation, oxidative stress, and ion transport and RP development in CaOx SFs.

Potassium-sodium citrate prevents the development of renal microcalculi into symptomatic stones in calcium stone-forming patients.

OBJECTIVES: To evaluate the effect of potassium-sodium citrate on the development of computed tomography-detected renal microcalculi into symptomatic stones in calcium stone-forming patients. METHODS: Patients (aged 20-80 years) with history of calcium component stones who visited Nagoya City Hospital, Nagoya, Aichi, Japan, between April 2009 and June 2014 were included. They were retrospectively divided into those who did not receive potassium-sodium citrate (non-citrate group, n = 157) and those who did (citrate group, n = 60). For patients in both groups, we evaluated blood and urine biochemistry and sediment, number of computed tomography-detected microcalculi, number of asymptomatic microcalculi disappearances, and pain events. Observations were made at study initiation and 12 months later. RESULTS: The citrate group showed a significantly increased urine pH (P < 0.001) and daily citrate excretion (P < 0.001) over the study period. The non-citrate group showed increased numbers of microcalculi at study completion (P = 0.002); over the same period, the number of microcalculi in the citrate group decreased significantly (P = 0.03). Additionally, multivariable analysis showed more asymptomatic microcalculi disappearances (odds ratio 2.84, 95% confidence interval 1.49-5.39) and fewer pain events (odds ratio 0.37, 95% confidence interval 0.16-0.72) in the citrate group than in the non-citrate group. A sex-adjusted analysis showed more asymptomatic microcalculi disappearances (odds ratio 3.96, 95% confidence interval 1.57-10.02) and fewer pain events (odds ratio 0.22, 95% confidence interval 0.07-0.70) in women than in men after citrate treatment. CONCLUSIONS: Potassium-sodium citrate prevents the development of renal microcalculi into symptomatic stones in calcium stone-forming individuals.

Pathophysiology-based treatment of urolithiasis.

Urolithiasis, a complex multifactorial disease, results from interactions between environmental and genetic factors. Epidemiological studies have shown the association of urolithiasis with a number of lifestyle-related diseases, including cardiovascular diseases, hypertension, chronic kidney disease, diabetes and metabolic syndrome. Elucidation of the mechanisms underlying urinary stone formation will enable development of new preventive treatments. The present article reviews the epidemiology, pathophysiology and potential treatment of urolithiasis. Recent literature has shown that oxidative stress and reactive oxygen species could be one such mechanistic pathway. Calcium oxalate crystals adhering to renal tubular cells are incorporated into the cells through the involvement of osteopontin. Stimulation of crystal-cell adhesion impairs acceleration of the mitochondrial permeability transition pore in tubular cells, resulting in mitochondrial collapse, oxidative stress and activation of the apoptotic pathway in the initial steps of renal calcium crystallization. With regard to genetic factors, studies show that single nucleotide polymorphisms in genes encoding calcium-sensing receptor, vitamin D receptor and osteopontin are correlated with urolithiasis. Genome-wide association studies have shown that CLDN14 and NPT2 are associated with urolithiasis in Caucasian and Japanese populations, respectively. Thus, single nucleotide polymorphism analysis would aid in the prediction of urolithiasis risk and recurrence. New diagnostic methods and preventive approaches, along with complete removal of stones, will improve the management of urolithiasis.