24-Hour Urine Calcium Oxalate Supersaturation Risk Correlates with Computerized Tomography Volumetric Calcium Oxalate Stone Growth.

PURPOSE: In vitro experiments demonstrate calcium oxalate (CaOx) supersaturation (SS) drives CaOx nucleation and growth. We investigated the link between 24-hour urine SS CaOx and in vivo stone growth through a natural history, imaging study. MATERIALS AND METHODS: Using an institutional review board-approved database, we sought >80% CaOx stone formers who prior to stone intervention obtained 2 separate computerized tomography (CT) scans with at least one 24-hour urine collection between scans. Two blinded reviewers calculated bilateral 3-dimensional stone volume using the Visage 7® region of interest pen tool. CT volume difference was divided by time between scans, and SS CaOx was grouped into low (<5), medium (5-10) and high risk (>10). Statistical significance between groups was assessed by Kruskal-Wallis test. RESULTS: We identified 80 individuals with stone growth measured by 3-dimensional CT (mean ∼7 months between studies). Inter-reviewer reliability of CT volume measurement was well correlated (0.98, Gwet's AC2), and an arbitrator was only needed in 13/160 (8%) cases. Median stone volume growth/year was 15%, 71% and 177% for low, medium and high risk groups, respectively (p <0.001). Despite inter-individual variation, best fit of mean SS CaOx vs stone volume growth was moderately correlated (Spearman's rho=0.53, p <0.001). CONCLUSIONS: In a population of pure CaOx stone formers, increased 24-hour SS CaOx risk was associated with increased in vivo stone growth. Further investigations using CT volumetric stone growth may allow for the noninvasive study of stone growth modulators, improved stone risk prediction and development of a kidney stone simulator.

Obturator Nerve Blockade vs. Neuromuscular Blockade for the Prevention of Adductor Spasm in Patients Undergoing Transurethral Resection of Bladder Tumors: A Randomized Controlled Trial.

BACKGROUND: The obturator nerve runs along the posterolateral walls of the bladder and electrosurgical stimulation in this region can result in adductor spasm which can occur suddenly and unexpectedly with potentially catastrophic results. METHODS: Sixty patients were prospectively randomized to receive either a single-injection ultrasound-guided obturator nerve block (ONB) or intravenous rocuronium after induction of general anesthesia (i.e., neuromuscular block [NMB]). The primary objective was to compare the incidence of adductor spasm during posterolateral bladder tumor resection when ONB or NMB was used. Secondary objectives included assessment of fall risk and incidence of adverse events. RESULTS: Five patients in the ONB group and six in the NMB group had nonlateral wall lesions. One patient in the ONB group suffered a cardiac arrest after induction of general anesthesia. Of the remaining 48 patients, six (10.2%) experienced adductor spasm. Most of these patients were in the NMB group (5/24, 20.8%), with only one patient (1/24, 4.2%) experiencing obturator reflex in the ONB group; this difference was not statistically significant (P=0.19). Patients in the ONB group had a greater decrease in mean hip adductor strength. Our study population was found to be at high risk of falls before surgery. There were no statistically significant group differences in the Timed Up and Go test, with time to perform the test increasing in both groups. CONCLUSIONS: Both techniques are safe and efficacious for preventing adductor spasm. Our data and experience suggest that the ONB is relatively easy to perform and should be considered in patients with posterolateral bladder tumors.

Lessons from rodent gastric bypass model of enteric hyperoxaluria.

PURPOSE OF REVIEW: The aim of the article is to review studies on bone health and oxalate metabolism/therapeutics in the obese rodent model of Roux-en-Y gastric bypass (RYGB) and examine pathways to decrease procedural morbidity. RECENT FINDINGS: Compared with controls, RYGB rodents have up to 40-fold more fat in their stool (steatorrhea) which positively correlates to increased urinary oxalate. These unabsorbed intestinal fatty acids bind calcium and prevent gut calcium oxalate formation, increasing soluble luminal oxalate availability and absorption (enteric hyperoxaluria). When intraluminal fecal fat exceeded about 175 mg/24 h in our model, more paracellular and transcellular oxalate transport across the distal colon occurred. Increasing dietary calcium and colonization with Oxalobacter formigenes reduced hyperoxaluria, whereas vitamin B6 supplementation did not. RYGB animals, when severely calcium deficient, had bone mineral density loss that could not be rescued with vitamin D supplementation. SUMMARY: The findings of hyperoxaluria, steatorrhea, and decreased bone mineral density are seen in both human and rodent RYGB. Our model suggests that a low-fat, low-oxalate diet combined with calcium supplementation can decrease urinary oxalate and improve skeletal bone health. Our model is a useful tool to study renal and bone RYGB effects. Studies of longer duration are required to further evaluate mechanisms of disease and durability of therapeutics.

Immunotherapy for stone disease.

PURPOSE OF REVIEW: In addition to traditional risk factors such as low urine volume or hypercalciuria, emerging data suggest that calcium oxalate (CaOx), one of the most common mineral complexes in the urine, elicits a strong immunologic response. This review highlights those studies and projects how future therapies may be directed for kidney stone prevention. RECENT FINDINGS: Over the last 2 years, several groups have studied the response of the immune system to CaOx crystals using cell culture and animal models. Dominguez et al. found that CaOx crystals were recognized by monocytes through an lipopolysaccharide-mediated mechanism, leading to M1 'inflammatory' macrophage phenotype. Patel et al. proposed excessive oxalate-mediated reactive oxygen species within macrophage mitochondria may impair their ability to properly clear stones. Two other groups developed mouse models (an androgen receptor knock-out and an overexpression of Sirtuin 3 protein) and demonstrated increased renal anti-inflammatory macrophage differentiation and decreased CaOx deposition in experimental compared with controls. Anders et al. fed hyperoxaluric mice 1,3-butanediol, which blocks an inflammatory form of cell death called NLRP3 inflammasome and found less intrarenal oxidative damage and higher anti-inflammatory renal infiltrates in experimentals. Finally, monocytes exposed to CaOx crystals followed by hydroxyapatite had reduced inflammatory cytokine and chemokine production compared with those without hydroxyapatite, suggesting that Randall's plaque may play a role in dampening M1-mediatiated CaOx inflammation. SUMMARY: By modulating the immune response, immunotherapy could provide the means to prevent stone recurrences in certain individuals. The promotion of M2 over M1 macrophages and inhibition of inflammation could prevent the cascade that leads to CaOx nucleation. Future therapies may target the ability of macrophages to degrade CaOx crystals to prevent stones.

Evaluating Region of Interest Measurement Strategies to Characterize Upper Urinary Tract Stones on Computerized Tomography.

PURPOSE: Computerized tomography imaging is regularly used to assess stone HU values as a surrogate for stone composition and fragility. Techniques for measuring HU values are unstandardized, leading to high variability. We investigated several region of interest measurement strategies to quantify this variability. MATERIALS AND METHODS: Patients from an institutional database who underwent preoperative computerized tomography, surgical stone extraction and stone composition analysis were identified. HU measurements were made of each patient stone using transverse/coronal slices in the abdominal/bone windows with 4 region of interest techniques, including 1) the maximum diameter region of interest, 2) the maximum diameter region of interest at all stone inclusive slices, 3) 2 equal-sized, nonoverlapping circular regions of interest and 4) 3 to 5 smaller nonoverlapping regions of interest randomly placed on the stone. Stones that were 80% or greater pure by composition were separately analyzed. RESULTS: A total of 172 patients were included in study. Mean ± SD stone size was 19.3 ± 15.6 mm. On subtype analysis 51 stones were calcium oxalate monohydrate, 9 were calcium oxalate dihydrate, 7 were calcium phosphate hydroxyapatite/brushite and 16 were uric acid. Mean HU values in the abdominal window for all stones identified by region of interest techniques 1 to 4 were 457 ± 253, 351 ± 210, 581 ± 363 and 587 ± 329, respectively. The distribution of means significantly differed across region of interest techniques, planes and windows when considering all stones together (p <0.0001), stones with greater than 80% calcium oxalate dihydrate (p = 0.0113) and greater than 80% calcium oxalate monohydrate (p <0.0001), and uric acid stones (p <0.0001). CONCLUSIONS: HU values obtained to assess stone density vary depending on window, plane and region of interest technique. We recommend that clinicians select a single region of interest measurement technique and use it consistently to minimize interinstitutional variability.

Calcium Oxalate Stone Fragment and Crystal Phagocytosis by Human Macrophages.

PURPOSE: In murine and human hyperoxaluric conditions macrophages can be seen surrounding renal calcium oxalate crystal deposits. We hypothesized that macrophages have a role in degrading and destroying these deposits. We investigated the inflammatory response and phagocytic mechanisms when macrophages were exposed to human kidney stones and inorganic crystals. MATERIALS AND METHODS: Human monocytes were differentiated into resting, fully differentiated macrophages by treatment with recombinant human macrophage colony-stimulating factor (M-CSF) or GM-CSF (granulocyte M-CSF) for 6 days. After confirming phenotype by flow cytometry the macrophages were exposed for 20 hours to fragments of sterile human calcium oxalate stones or calcium oxalate crystals. Crystal uptake was determined, and supernatant cytokine and chemokine profiles were analyzed using antibody arrays. Quantitative reverse transcriptase-polymerase chain reaction was done to validate mRNA profile expression. RESULTS: Under direct vision fluorescence microscopy activated human macrophages were noted to surround stone fragments and synthesized crystals, and destroy them in a step-by-step process that involved clathrin mediated endocytosis and phagocytosis. An inflammatory cascade was released by macrophages, including the chemokines chemokine ligand (CCL)2, CCL3, interleukin (IL)-1 receptor antagonist (IL-1ra), complement component C5/C5a and IL-8. Response patterns to stone and crystal material depended on macrophage phenotype and activation status. CONCLUSIONS: In our in vitro study macrophages differentiated with M-CSF showed greater ability to phagocytize crystal deposits than those treated with GM-CSF. Following clathrin mediated endocytosis macrophages released a number of cytokines that are crucial for the inflammatory immune response. This suggests that tissue macrophages have an important role in preventing kidney stone disease by removing and digesting interstitial renal crystal deposits.

Changing Default Fluoroscopy Equipment Settings Decreases Entrance Skin Dose in Patients.

PURPOSE: Proper fluoroscopic education and protocols may reduce the patient radiation dose but few prospective studies in urology have been performed. Using optically stimulated luminescent dosimeters we tested whether fluoroscopy time and/or entrance skin dose would decrease after educational and radiation reduction protocols. MATERIALS AND METHODS: At default manufacturer settings fluoroscopy time and entrance skin dose were prospectively measured using optically stimulated luminescent dosimeters in patients undergoing ureteroscopy, retrograde pyelogram/stent or percutaneous nephrolithotomy with access for stone disease. A validated radiation safety competency test was administered to urology faculty and residents before and after web based, hands-on fluoroscopy training. Default fluoroscopy settings were changed from continuous to intermittent pulse rate and from standard to half-dose output. Fluoroscopy time and entrance skin dose were then measured again. RESULTS: The cohorts of 44 pre-protocol and 50 post-protocol patients with stones were similarly matched. The change in mean fluoroscopy time and entrance skin dose from pre-protocol to post-protocol was -0.6 minutes and -11.6 mGy (33%) for percutaneous nephrolithotomy (p = 0.62 and <0.001), 0.5 minutes and -0.1 mGy (34%) for ureteroscopy (p = 0.42 and 0.31), and 0.1 minute and -0.1 mGy (29%) for retrograde pyelogram/stent (p = 0.85 and 0.49, respectively). Urologist post-training test scores increased 30% from pretraining scores (p = 0.1). CONCLUSIONS: Radiation safety training protocols improved clinical knowledge but did not significantly alter fluoroscopy time. Changing equipment default settings to intermittent pulse rate (12 frames per second) and half-dose lowered the entrance skin dose by 30% across all endourology patients but most significantly during percutaneous nephrolithotomy. To limit patient radiation exposure fluoroscopy default settings should be decreased before all endourology procedures and image equipment manufacturers should consider lowering standard default renal settings.

Calcium nephrolithiasis and bone demineralization: pathophysiology, diagnosis, and medical management.

PURPOSE OF REVIEW: To establish the relationship between calcium nephrolithiasis, bone densitometry scoring, and bone mineral density (BMD) loss according to bone turnover markers (BTMs) and urinary metabolites. RECENT FINDINGS: Patients with recurrent calcium nephrolithiasis and idiopathic fasting hypercalciuria (urinary calcium/creatinine ratio >0.11) are more likely to have BMD loss that may lead to osteopenia or osteoporosis. In these patients, BTMs may be used as a surrogate for both bone health and stone recurrence. Suspect higher lithogenic states when calcium stone formers have serum beta-crosslaps (resorptive marker) greater than 0.311 ng/ml, serum osteocalcin (formative marker) greater than 13.2 ng/ml, and beta-crosslaps/osteocalcin ratio greater than 0.024. SUMMARY: Patients with recurrent calcium nephrolithiasis and fasting hypercalciuria have a higher incidence of osteopenia and osteoporosis, measured by the dual-energy X-ray absorptiometry. These patients present not only with hypercalciuria and increased BTMs (mainly resorptive), but also up to 30% have hypocitraturia and increased urinary calcium/citrate ratio (>0.25). On the basis of these results, a diagnostic algorithm was created, classifying hypercalciurics according to their fasting calcium/creatinine and calcium/citrate ratio. Medical therapy for these patients is aimed at improving the dietary habits (normocalcemic, low salt, low animal protein diet), prescribing combinations of potassium citrate, thiazides, and bisphosphonates, and correcting bone and urinary abnormalities that may lower future skeletal and kidney stone risk.

Kidney stone risk following modern bariatric surgery.

Over the past 10 years, a variety of reports have linked bariatric surgery to metabolic changes that alter kidney stone risk. Most of these studies were retrospective, lacked appropriate controls, or involved bariatric patients with a variety of inclusion criteria. Despite these limitations, recent clinical and experimental research has contributed to our understanding of the pathophysiology of stone disease in this high-risk population. This review summarizes the urinary chemistry profiles that may be responsible for the increased kidney stone incidence seen in contemporary epidemiological bariatric studies, outlines the mechanisms of hyperoxaluria and potential therapies through a newly described experimental bariatric animal model, and provides a focused appraisal of recommendations for reducing stone risk in bariatric stone formers.

Renal papillary tip biopsy in stone formers: a review of clinical safety and insights.

Alexander Randall first published renal papillary tip findings from stone formers in 1937, paving the way for endoscopic assessment to study stone pathogenesis. We performed a literature search to evaluate the safety of papillary tip biopsy and clinical insights gained from modern renal papillary investigations. A search on the topic of renal papillary biopsy provided an overview of Randall's plaques (RP), classification systems for renal papillary grading, and a summary of procedure type, complications, and outcomes. Within 26 identified manuscripts, 660 individuals underwent papillary tip biopsy percutaneously (n = 562), endoscopically (n = 37), or unspecified (n = 23). Post-operative hemoglobin changes were similar to controls. One individual (0.2%) reported fever > 38°, and long-term mean serum creatinine post-biopsy (n = 32) was unchanged. Biopsies during ureteroscopy or PCNL added ~20-30 min of procedure time. Compared to controls, papillary plaque-containing tissue had upregulation in pro-inflammatory genes, immune cells, and cellular apoptosis. Urinary calcium and papillary plaque coverage were found to differ between RP and non-RP stone formers, suggesting differing underlying pathophysiology for these groups. Two renal papillary scoring systems have been externally validated and are used to classify stone formers. Overall, this review shows that renal papillary biopsies have a low complication profile with high potential for further research. Systematic adaption of a papillary grading scale, newer tissue analysis techniques, and the development of animal models of Randall's plaque may allow further exploration of plaque pathogenesis and identify targets for prevention therapies in patients with nephrolithiasis.

Steatorrhea and hyperoxaluria occur after gastric bypass surgery in obese rats regardless of dietary fat or oxalate.

PURPOSE: We determined the effect of dietary fat and oxalate on fecal fat excretion and urine parameters in a rat model of Roux-en-Y gastric bypass surgery. MATERIALS AND METHODS: Diet induced obese Sprague-Dawley® rats underwent sham surgery as controls (16), or Roux-en-Y gastric bypass surgery (19). After recovery, rats had free access to a normal calcium, high fat (40%) diet with or without 1.5% potassium oxalate for 5 weeks and then a normal (10%) fat diet for 2 weeks. Stool and urine were collected after each period. Fecal fat was determined by gas chromatography and urine metabolites were evaluated by assay spectrophotometry. RESULTS: Daily fecal fat excretion remained low in controls on either diet. However, Roux-en-Y gastric bypass rats ingested a food quantity similar to that of controls but had eightfold higher fecal fat excretion (p <0.001) and heavier stools (p = 0.02). Compared to controls, gastric bypass rats on the high fat diet with potassium oxalate had a fivefold increase in urine oxalate excretion (p <0.001), while gastric bypass rats without potassium oxalate had a twofold increase in urine calcium (p <0.01). Lowering dietary fat in gastric bypass rats with potassium oxalate led to a 50% decrease in oxalate excretion (p <0.01), a 30% decrease in urine calcium and a 0.3 U increase in urine pH (p <0.001). CONCLUSIONS: In this Roux-en-Y gastric bypass model high fat feeding resulted in steatorrhea, hyperoxaluria and low urine pH, which were partially reversible by lowering the dietary fat and oxalate content. Roux-en-Y gastric bypass rats on normal fat and no oxalate diets excreted twice as much oxalate as age matched, sham operated controls. Although Roux-en-Y gastric bypass hyperoxaluria appears primarily mediated by gut and diet, secondary causes of oxalogenesis from liver or other mechanisms deserve further exploration.

Symptoms and risk factors associated with first urinary tract infection in college age women: a prospective cohort study.

PURPOSE: We identified epidemiological risk factors for the initial urinary tract infection in females of college age compared to age matched controls. MATERIALS AND METHODS: We performed a prospective cohort study from July 2001 to January 2006 at the student health care facility at our institution. A total of 180 women experiencing a first urinary tract infection were compared to 80 asymptomatic women with no urinary tract infection history who served as controls. Urinalysis and urine culture were done at study enrollment. Questionnaires were used to obtain information on clinical symptoms and behaviors, including sexual and dietary practices, and alcohol consumption. Logistic regression was performed to identify potential risk factors in women who presented with an initial urinary tract infection compared with controls. Principal component analysis was then done to identify key sexual activity variables for multiple regression models. RESULTS: Urinary frequency and urgency were the most common urinary tract infection symptoms. Recent sexual activity was a significant risk factor for urinary tract infection with vaginal intercourse (p = 0.002) and the number of sexual partners in the last 2 weeks (p <0.001) as the 2 primary variables. Alcohol consumption was associated with 2 of the 3 main principal components of sexual activity. Caffeinated beverage consumption also increased the risk of urinary tract infection (p <0.04). Escherichia coli was the predominant pathogen isolated, followed by urease positive microbes. CONCLUSIONS: Recent sexual activity, the frequency of that activity and the number of sexual partners pose an increased risk of urinary tract infection. Alcohol consumption frequency and amount correlated with these behaviors.

Proposal for pathogenesis-based treatment options to reduce calcium oxalate stone recurrence.

Objective: Prevalence of kidney stone disease continues to increase globally with recurrence rates between 30% and 50% despite technological and scientific advances. Reduction in recurrence would improve patient outcomes and reduce cost and stone morbidities. Our objective was to review results of experimental studies performed to determine the efficacy of readily available compounds that can be used to prevent recurrence. Methods: All relevant literature up to October 2020, listed in PubMed is reviewed. Results: Clinical guidelines endorse the use of evidence-based medications, such as alkaline agents and thiazides, to reduce urinary mineral supersaturation and recurrence. However, there may be additional steps during stone pathogenesis where medications could moderate stone risk. Idiopathic calcium oxalate stones grow attached to Randall's plaques or plugs. Results of clinical and experimental studies suggest involvement of reactive oxygen species and oxidative stress in the formation of both the plaques and plugs. The renin-angiotensin-aldosterone system (RAAS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, mitochondria, and NOD-like receptor pyrin domain containing-3 (NLRP3) inflammasome have all been implicated at specific steps during stone pathogenesis in animal models. Conclusion: In addition to supersaturation-reducing therapies, the use of anti-oxidants, free radical scavengers, and inhibitors of NADPH oxidase, NLRP3 inflammasome, and RAAS may prove beneficial for stone prevention. Compounds such as statins and angiotensin converting enzyme inhibitors are already in use as therapeutics for hypertension and cardio-vascular disease and have previously shown to reduce calcium oxalate nephrolithiasis in rats. Although clinical evidence for their use in stone prevention in humans is limited, experimental data support they be considered along with standard evidence-based medications and clinical expertise when patients are being counselled for stone prevention.

Caution! AI Bot Has Entered the Patient Chat: ChatGPT Has Limitations in Providing Accurate Urologic Healthcare Advice.

OBJECTIVE: To conduct the first study examining the accuracy of ChatGPT, an artificial intelligence (AI) chatbot, derived patient counseling responses based on clinical care guidelines in urology using a validated questionnaire. METHODS: We asked ChatGPT a set of 13 urological guideline-based questions three times. Answers were evaluated for appropriateness and using Brief DISCERN (BD), a validated healthcare information assessment questionnaire. Data analysis included descriptive statistics and Student's t test (SAS Studio). RESULTS: 60% (115/195) of ChatGPT responses were deemed appropriate. Variability existed between responses to the same prompt, with 25% of the 13 question sets having discordant appropriateness designations. The average BD score was 16.8 ± 3.59. Only 7 (54%) of 13 topics and 21 (54%) of 39 responses met the BD cut-off score of ≥16 to denote good-quality content. Appropriateness was associated with higher overall and Relevance domain scores (both P < .01). The lowest BD domain scores were for Source categories, since ChatGPT does not provide references by default. With prompting, 92.3% had ≥1 incorrect, misinterpreted, or nonfunctional citations. CONCLUSION: While ChatGPT provides appropriate responses to urological questions more than half of the time, it misinterprets clinical care guidelines, dismisses important contextual information, conceals its sources, and provides inappropriate references. Chatbot models hold great promise, but users should be cautious when interpreting healthcare-related advice from existing AI models. Additional training and modifications are needed before these AI models will be ready for reliable use by patients and providers.

Expression and secretion of glycosylated barley oxalate oxidase in Pichia pastoris.

Oxalate oxidase is an enzyme that degrades oxalate and is used in commercial urinary assays to measure oxalate levels. The objective of this study was to establish an enhanced expression system for secretion and purification of oxalate oxidase using Pichia pastoris. A codon optimized synthetic oxalate oxidase gene derived from Hordeum vulgare (barley) was generated and cloned into the pPICZα expression vector downstream of the N-terminal alpha factor secretion signal peptide sequence and used for expression in P. pastoris X-33 strain. A novel chimeric signal peptide consisting of the pre-OST1 sequence fused to pro-αpp8 containing several amino acid substitutions was also generated to enhance secretion. Active enzyme was purified to greater than 90% purity using Q-Sepharose anion exchange chromatography. The purified oxalate oxidase enzyme had an estimated Km value of 256µM, and activity was determined to be 10U/mg. We have developed an enhanced oxalate oxidase expression system and method for purification.

Initial experience: ex-vivo perfused pig kidney to study urinary oxalate excretion.

Existing animal models of renal oxalate excretion utilize either gut or peritoneal cavity for oxalate absorption. Ex vivo renal perfusion is an established tool for graft preservation. We sought to repurpose this concept to study the early pathogenesis of urinary lithiasis. Juvenile female Yorkshire porcine kidneys were removed laparoscopically and placed on an ex vivo cardiopulmonary bypass circuit utilizing whole-blood based perfusate. Pre-defined goals were identified for each attempt (n = 5) with plans to increase physiologic model complexity. Tissue perfusion and oxygenation were monitored by serial perfusate iSTAT testing. Once steady urine production was achieved, aqueous oxalate was injected into the perfusate. Renal outcomes were assessed by histology and blood/urinary assays. After demonstrating proof-of-concept in early trials, normothermic (37 °C) ex vivo whole-blood perfusion with Steen Solution™ was performed exceeding three hours at physiologic mean arterial pressures. Circuit parameters remained in the physiologic range for electrolytes, temperature, mean arterial pressure, lactate, and pH. Urine was produced in three experiments. Urinary filtrate demonstrated consistently higher urine creatinine compared to perfusate, and arterial perfusate oxalate boluses lead to urinary oxalate spikes followed by continuous oxalate clearance. Histopathologic analysis with H&E and Pizzolato's method staining demonstrated formation of calcium oxalate crystals. In light of these promising metabolite clearances, ex vivo porcine renal perfusion appears to be a feasible alternative to study oxalate excretion. Longer validation studies are necessary to establish this technique as a model for kidney stone pathogenesis.

Ultrastructural investigation of crystal deposits in Npt2a knockout mice: are they similar to human Randall's plaques?

PURPOSE: Idiopathic Ca oxalate stones may develop with attachment to renal interstitial Ca phosphate deposits (Randall's plaques). Sodium phosphate cotransporter (Npt2a) null mice have hypercalciuria and hyperphosphaturia, and produce tubular and interstitial Ca phosphate deposits. To determine whether this mouse is suitable for Randall's plaque investigations we chronologically studied Ca phosphate deposit sites, structure and composition. MATERIALS AND METHODS: The kidneys of Npt2a null mice 2 days to 1 year old were examined by light, scanning and transmission electron microscopy. Electron diffraction and energy dispersive x-ray microanalyses were done to determine mineral composition. RESULTS: Poorly crystalline, biological apatite deposits were seen in collecting duct lumina. Deposits consisted of aggregates approximately 5 µm in diameter appearing as microspheres of concentrically organized needle or plate-like, matrix rich crystals. Epithelium/crystal interfaces were filled with membrane bound vesicles. Some tubules were completely occluded by crystals and occasionally lost the epithelium while crystals moved into the interstitium. CONCLUSIONS: Ca phosphate crystals formed in the tubular lumina and were organized as microspheres. The aggregation of Ca phosphate crystals produced nuclei, which grew by adding crystals at the periphery. They eventually became large enough to occlude the tubular lumina and obliterate the tubular epithelium, leading to the relocation of microliths into the interstitium. The pathogenesis of interstitial deposits in Npt2a null mice appears different from that proposed for Randall's plaques. Since Npt2a null mice purge the renal crystal deposits, these mice may serve as a model in which to investigate the elimination of crystal deposits in children and adults with nephrocalcinosis.

Office Cystoscopy Urinary Tract Infection Rate and Cost before and after Implementing New Handling and Storage Practices.

INTRODUCTION: Based on 2010 American Urological Association recommendations our practice transitioned from sterile to high level disinfection flexible cystoscope reprocessing and from sterile to clean handling practices. We examined symptomatic urinary tract infection rate and cost before and after policy implementation. METHODS: We retrospectively reviewed 30-day outcomes following 1,888 simple cystoscopy encounters that occurred from 2007 to 2010 (sterile, 905) and 2012 to 2015 (high level disinfection, 983) at the Malcom Randall Veterans Affairs Medical Center. We excluded veterans who had recent instrumentation, active or recent urinary tract infection, performed intermittent catheterization, or had complicated cystoscopy (dilation, biopsy etc). Patient/procedural factors and cost were collected and compared between groups. RESULTS: Both cohorts had similar age (mean 68 years), race (Caucasian, 82%), comorbidities (cancer history, 62%; diabetes mellitus, 36%; tobacco use, 24.5%), and cystoscopy procedural indications (cancer surveillance, 50%; hematuria, 34%). Urological complication rate was low between groups (1.43%) with no significant difference in symptomatic urinary tract infection events (0.99% sterile vs 0.51% high level disinfection, p=0.29) or unplanned clinic/emergency department visits (0.66% sterile vs 0.71% high level disinfection, p=0.91). Roughly 95% of the cohorts were given prophylactic antibiotics, most commonly fluoroquinolones (91%). High level disinfection was $82 cheaper per procedure than sterile with most cost disparity stemming from reprocessing. Total savings for our facility by switching to high level disinfection was more than $100,000 annually. CONCLUSIONS: In an older, morbid veteran population receiving centralized care and prophylactic antibiotics we found no difference in symptomatic urinary tract infection or unplanned visits between sterile or high level disinfection techniques. However, high level disinfection was associated with a sizable cost savings, improved clinic workflow, and reduced use of personal protective equipment.

Randall's plaque and calcium oxalate stone formation: role for immunity and inflammation.

Idiopathic calcium oxalate (CaOx) stones often develop attached to Randall's plaque present on kidney papillary surfaces. Similar to the plaques formed during vascular calcification, Randall's plaques consist of calcium phosphate crystals mixed with an organic matrix that is rich in proteins, such as inter-α-trypsin inhibitor, as well as lipids, and includes membrane-bound vesicles or exosomes, collagen fibres and other components of the extracellular matrix. Kidney tissue surrounding Randall's plaques is associated with the presence of classically activated, pro-inflammatory macrophages (also termed M1) and downregulation of alternatively activated, anti-inflammatory macrophages (also termed M2). In animal models, crystal deposition in the kidneys has been associated with the production of reactive oxygen species, inflammasome activation and increased expression of molecules implicated in the inflammatory cascade, including osteopontin, matrix Gla protein and fetuin A (also known as α2-HS-glycoprotein). Many of these molecules, including osteopontin and matrix Gla protein, are well known inhibitors of vascular calcification. We propose that conditions of urine supersaturation promote kidney damage by inducing the production of reactive oxygen species and oxidative stress, and that the ensuing inflammatory immune response promotes Randall's plaque initiation and calcium stone formation.