Prostate volume on computed tomography correlates well with magnetic resonance imaging measurements and is reproducible across rater training levels.

BACKGROUND: Data are lacking for the accuracy of computed tomography (CT) in measuring prostate size, which can streamline care and prevent invasive procedures. We evaluate agreement and intra/inter-observer variability in prostate sizing between CT and magnetic resonance imaging (MRI) planimetry for a wide range of gland sizes. METHODS: We retrospectively reviewed 700 patients who underwent MRI fusion biopsy at a single institution and identified 89 patients that had a CT within 2 years of the MRI. Six reviewers from different training levels were categorized as student, resident, or attending and each measured prostate size on CT by the prolate ellipse method. Bland-Altman analysis determined the degree of agreement between CT and MRI. Inter- and intra-observer reliability was calculated for CT. RESULTS: Mean CT volume was higher than MRI volume in the < 60 g group (51.5 g vs. 44.5 g, p = 0.004), but not in the ≥ 60 g group (101 g vs. 100 g, p = 0.458). The bias for overestimation of prostate volume by CT was 4.1 g across prostate volumes, but the proportional agreement between modalities improved with size. The Pearson correlation coefficient between CT/MRI and inter/intra-rater reliability for CT increased in the ≥ 60 g vs. the < 60 g group for all training levels. CONCLUSIONS: Our data show that there is greater clinical utility for prostate size estimation by CT than previously established, particularly for larger glands where accurate size estimation may influence therapeutic decisions. In larger glands, prostate size estimation by CT is also reproducible across various training levels.

Factors associated with unplanned clinical encounters for ureteral stent-related symptoms.

BACKGROUND, INTRODUCTION AND AIM: Ureteral stent-related symptoms (USRS) often result in unplanned phone calls and ER visits. We hypothesize that patient factors can be identified to predict these unplanned encounters. METHODS AND MATERIALS: Retrospective analysis of indwelling ureteral stent placements from 2014 to 2019 at a single institution by CPT code was performed. Patient demographics, discharge medications, and clinical factors were evaluated using multiple logistic regression with respect to postoperative telephone and emergency room (ER) encounters for USRS. RESULTS: Of 374 patients, 75 (20.1%) had one or more encounters for USRS: 48 (12.8%) called the clinic and 39 (10.4%) returned to the ER. Chronic opioid use was predictive of calls to clinic and ER visits (OR 3.21 [CI 1.42-6.97], p < 0.01 and OR 3.64 [CI 1.45-8.98], p < 0.01). Survival analysis stratified by history of chronic opioid use and discharge opioid prescriptions demonstrated that opioid naïve patients receiving opioids at discharge had unplanned encounters sooner and more often [Calls p = 0.025, ER p = 0.041]), whereas patients with chronic opioid use returned to the ER sooner and more frequently when prescribed additional opioids (Calls p = 0.4, ER p = 0.002). CONCLUSION: Patients with a history of chronic opioid use may experience more intense USRS or have a lower threshold to seek medical care than opioid naïve patients and tend to bypass calling the clinic for the ER. Given that none of the studied medications reduced unplanned patient contact for USRS, urologists should consider upfront definitive management of urinary obstruction when appropriate.

Exploring ureteroscope design with computational fluid dynamics for improved intra-pelvic pressure.

High intra-pelvic pressure (IPP) during ureteroscopy can lead to complications including pyelovenous backflow, bleeding, and infection. Our primary goal was to identify the best cross-section and orientation of a ureteroscope within a Ureteral Access Sheath (UAS) to minimize IPP and maximize outflow. Our secondary goal was to validate our findings with a UAS prototype. To determine the optimal ureteroscope cross-section within a UAS, four ureteroscopes of equivalent cross-sectional area were simulated within a 10 Fr UAS using computational fluid dynamics software COMSOL. We then created a corresponding prototype by securing a 3-0 monofilament suture at the inferior aspect of the 12 Fr outer UAS, inducing an offset to the ureteroscope. Mean flow volumes through a 10/12 Fr UAS occupied by a 9.5-Fr single-use flexible ureteroscope were compared (17 iterations) to those through our prototype UAS. During the simulation, the lowest IPP and highest outflow were seen with an offset circular ureteroscope (41% resistance) compared to a ureteroscope centered in the UAS. The unmodified UAS had an average volume of 30.0 mL/min (SD ± 0.35) compared to 33.76 mL/min (SD ± 0.90) for the modified UAS (p < 0.05). We found that using a circular ureteroscope positioned along the sidewall maximizes outflow through a circular UAS. We made a prototype UAS to offset the ureteroscope and observed a 12.5% increase in outflow. This approach can potentially decrease IPP during ureteroscopy without impacting inflow or the working channel. Although modifying a ureteroscope is more difficult, it could create an offset without reducing UAS cross-section.

Laser enucleation of the prostate (LEP) vs. simple prostatectomy: an analysis of hospital charges and comparison of practice trends.

PURPOSE: Laser enucleation of the prostate (LEP) and simple prostatectomy (SP) are surgical treatment options for large gland Benign Prostatic Hyperplasia. While multiple studies compare clinical outcomes of these procedures, there are limited data available comparing hospital charges in the United States. Here, we present current practice trends and a hospital charge analysis on a national level using an annual insurance claims data repository. METHODS: The Healthcare Cost and Utilization Project National Inpatient Sample and Nationwide Ambulatory Surgery Sample databases for 2018 were queried. CPT and ICD-10PCS codes identified patients undergoing LEP or SP, who were then compared for practice setting, total hospital charges, and payor. Laser type for LEP and surgical approach for SP could not be differentiated. RESULTS: The median hospital charge of 5782 LEPs and 973 SPs is $26,689 and $51,250 (p < 0.001), respectively. LEP independently predicts a decreased hospital charge of $16,464 (p < 0.001) per case. Medicare is the primary payor for both procedures. More LEP procedures are completed in the outpatient setting (87.8%) vs. SPs (5.7%, p < 0.001). Median length of stay is longer for SP (LEP: 0, IQR: 0; SP: 3, IQR: 2-4; p < 0.001). In the Western region, LEP is least commonly performed (184, p < 0.001), most expensive ($43,960; p < 0.001), and has longer length of stay (2, p < 0.001). CONCLUSIONS: LEP should be considered a cost-effective alternative to SP. Regions of the U.S. that perform more LEPs have shorter length of stay and lower hospital charges associated with the procedure.

Effects of the environment on the evolution of the vertebrate urinary tract.

Evolution of the vertebrate urinary system occurs in response to numerous selective pressures, which have been incompletely characterized. Developing research into urinary evolution led to the occurrence of clinical applications and insights in paediatric urology, reproductive medicine, urolithiasis and other domains. Each nephron segment and urinary organ has functions that can be contextualized within an evolutionary framework. For example, the structure and function of the glomerulus and proximal tubule are highly conserved, enabling blood cells and proteins to be retained, and facilitating the elimination of oceanic Ca+ and Mg+. Urea emerged as an osmotic mediator during evolution, as cells of large organisms required increased precision in the internal regulation of salinity and solutes. As the first vertebrates moved from water to land, acid-base regulation was shifted from gills to skin and kidneys in amphibians. In reptiles and birds, solute regulation no longer occurred through the skin but through nasal salt glands and post-renally, within the cloaca and the rectum. In placental mammals, nasal salt glands are absent and the rectum and urinary tracts became separate, which limited post-renal urine concentration and led to the necessity of a kidney capable of high urine concentration. Considering the evolutionary and environmental selective pressures that have contributed to renal evolution can help to gain an increased understanding of renal physiology.

Identification of Clinically Insignificant Renal Calculi on Sonography.

OBJECTIVE: To determine factors predicting if a radiologists... report of a .. stone... on ultrasound (US) was not actually a clinically significant stone, based on subsequent computed tomogram (CT). US often overestimates stone size and various pathologic entities are also hyperechoic;.ßthus, a subsequent CT without a clinically significant stone may represent unnecessary radiation exposure. A decision-tree and nomogram were developed to predict when stones are unlikely on subsequent CT. METHODS: Retrospective analysis of patients, of any age, receiving CT within 24.ßhours of a sonographic report documenting a single renal stone, during 2019...2020, in any phase of care, at one institution. Novel stone-likelihood-systems for US and CT (US-SLS, CT-SLS) were devised and validated to classify stones as clinically significant or insignificant, with CT as the gold standard. Binomial logistic regression predicting clinically significant stones was performed with sonographic and patient characteristics. RESULTS: Eight hundred twenty patients had US followed by CT, 228 (27.8%) reported documented stones, 140 (17.1%) reported a single stone. Clinically significant stones were associated with larger stone size (P: .002), location (P: .002), hydronephrosis (P: .04), shadowing-artifact (P: .02) depth.ßto.ßstone (P: .008), and Body mass Index (BMI) (P: .01). US-SLS had higher sensitivity (95.4%) and negative-predictive-value (81.8%) compared to a multivariate model of significant variables. CONCLUSION: US-SLS appears to exclude clinically irrelevant .. stones... better than established criteria including twinkle or shadow in this retrospective analysis. A diagnostic algorithm and nomogram are presented. US-SLS and the associated decision tree can assist providers in avoiding unnecessary radiation when clinically significant stones are unlikely.

Is There a Role for Prone Computed Tomography Before Percutaneous Nephrolithotomy?

Background: The majority of percutaneous nephrolithotomies (PCNLs) are performed prone, whereas most preoperative CT scans are done supine. The purpose of this pilot study is to determine if there is utility of prone CT scans in preoperative planning for prone PCNL by identifying patient populations at risk for organ injury and tract length-related complications. Materials and Methods: To represent typical preoperative planning using CT, two-dimensional (2D)-axial-prone/supine percutaneous tract measurements were performed by minimizing the distance from the target calix to the posterior-lateral skin in a single axial plane. The minimum distance and organ interception rates for the 2D-axial planning scans were recorded. Results: A total of 60 CT colonography and 13 CT urography patients were included in analysis. There were 42 women and 31 men with unspecified pathology reports ranging in age from 27 to 86 years and in body mass index (BMI) from 17.1 to 49. Multiple logistic regression identified female gender and low BMI as predictors of organ interception on the left. On multiple linear regression comparing the difference in axial prone/supine lengths; BMI, gender, and age were not significant independent predictors of changes in tract length in any pole when prone vs supine. However, shorter supine tracts tended to lengthen when prone, and longer supine tracts tended to shorten. Conclusions: This pilot study has demonstrated that patients with long and short estimates of tract length in the supine position may have shorter and longer tracts, respectively, with repositioning to prone. Thus, prone CT may have benefit when anticipating exceptionally long (>15 cm) tract lengths. Prone scans also revealed more potential organ interceptions, particularly for low BMI and women in the left upper pole. In patients for whom prone CT demonstrates an organ interception, the urologist should consider an alternate target calix or ultrasound-guided percutaneous access to identify the most appropriate needle trajectory.

Quantitative Characterization of the Prostatic Urethra Using MRI: Implications for Lower Urinary Tract Symptoms in Patients with Benign Prostatic Hyperplasia.

INTRODUCTION: The aim of this study was to perform a quantitative assessment of the prostate anatomy with a focus on the relation of prostatic urethral anatomic variation to urinary symptoms. METHODS: This retrospective study involved patients undergoing magnetic resonance imaging for prostate cancer who were also assessed for lower urinary tract symptoms. Volumetric segmentations were utilized to derive the in vivo prostatic urethral length and urethral trajectory in coronal and sagittal planes using a piece-wise cubic spline function to derive the angle of the urethra within the prostate. Association of anatomical factors with urinary symptoms was evaluated using ordinal univariable and multivariable logistic regression with IPSS score cutoffs of ≤7, 8-19, and >20 to define mild, moderate, and severe symptoms, respectively. RESULTS: A total of 423 patients were included. On univariable analysis, whole prostate volume, transition zone volume, prostatic urethral length, urethral angle, and retrourethral volume were all significantly associated with worse urinary symptoms. On multivariable analysis prostatic urethral length was associated with urinary symptoms with a normalized odds ratio of 1.5 (95% confidence interval 1.0-2.2, p = 0.04). In a subset analysis of patients on alpha blockers, maximal urethral angle, transition zone volume as well as urethral length were all associated with worse urinary symptoms. CONCLUSION: Multiple parameters were associated with worse urinary symptoms on univariable analysis, but only prostatic urethral length was associated with worse urinary symptoms on multivariable analysis. This study demonstrates the ability of quantitative assessment of prostatic urethral anatomy to predict lower urinary tract symptoms.

Ectopic biomineralization in kidney stone formers compared to non-stone formers.

BACKGROUND: Kidney stone formers (SFs) are at increased risk of stroke, myocardial infarction, and atherosclerosis of the carotid and coronary arteries. These cardiovascular and urologic pathologies can result from ectopic biomineral deposition. The objectives of this study are: (I) to evaluate risk factors for ectopic biomineralization, and (II) to characterize the overall burden of ectopic minerals in known SFs compared to non-stone formers (NSFs) matched for these risk factors. METHODS: Presence and quantity of biominerals at eight anatomic locations (abdominal aorta, common iliac arteries, pelvic veins, prostate or uterus, mesentery, pancreas, and spleen) were determined in a case control study by retrospective analysis of clinical non-contrast computed tomography scans obtained from 190 SFs and 190 gender- and age-matched NSFs (renal transplant donors). Predictors of biomineralization were determined using negative binomial regression. A subgroup of 140 SFs and 140 NSFs were matched for risk factors for systemic biomineralization, and mineralization was compared between these matched SFs and NSFs using ordinal logistic regression. RESULTS: Hypertension, hyperlipidemia, diabetes mellitus, and smoking were more common amongst SFs. Risk factors for increased systemic biomineralization included history of nephrolithiasis, male gender, older age, and history of hyperlipidemia. When controlling for these comorbidities, SFs had significantly increased biomineralization systemically and at the abdominal aorta, iliac arteries, prostate, mesentery, pancreas, and spleen compared to NSFs. CONCLUSIONS: The current study provides evidence that SFs are at increased risk of biomineralization systemically, independent of common risk factors of atherosclerosis.

Role of core body temperature in nephrolithiasis.

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

Stone formation in patients less than 20 years of age is associated with higher rates of stone recurrence: Results from the Registry for Stones of the Kidney and Ureter (ReSKU).

INTRODUCTION: Nephrolithiasis is a major source of morbidity in the United States. In recent decades, there has been a notable increase in stone incidence in the pediatric population. We investigate whether recurrent stone formers who had their initial stone episode earlier in life are at risk for more frequent stone recurrences, compared to those with initial episodes later in life. We also examine possible risk factors that might change our approach to treatment of these patients. METHODS: A review of prospectively collected data from the Registry for Stones of the Kidney and Ureter (ReSKU) from September 2015 to July 2018 was conducted to compare stone recurrence and other patient factors in patients who reported an initial stone episode prior to 20 years of age versus patients who reported an initial stone episode after age 20. Data on patient age, gender, BMI, family history, race, income, infectious symptoms, and number of prior stone episodes was analyzed. We excluded patients with a history of cystinuria stones. Univariate analysis was performed using Fisher's exact test and student's T test. Multivariate analysis was performed using logistic regression. RESULTS: Of the 1140 patients enrolled during this study period, 472 patients were recurrent stone formers, and of these, 66 had their first stone episode prior to the age of 20. On univariate analysis, early stone formers were more likely to be female, present at a younger age, and have more prior stone episodes on enrollment. Using multivariate modelling to control for age, gender, race, BMI, family history, and number of stone episodes, early stone formers were more likely to be female (CI 1.17 - 3.54) and have more than one prior stone episode (CI 1.13 - 3.78). Late stone formers were more likely to have BMI > 30 (CI 0.26 - 0.94). CONCLUSION: Recurrent stone formers who have their first episodes prior to age 20 are more likely to present to stone clinics with multiple prior recurrences and hence more aggressive stone disease. Female gender seems to be a risk factor. Earlier stone formers should be encouraged to have close follow up and surveillance due to the increased rate of recurrence. Adult stone databases focusing on early presentations can improve understanding of pediatric stone disease.

Ultrasound guidance can be used safely for renal tract dilatation during percutaneous nephrolithotomy.

OBJECTIVES: To compare clinical outcomes in patients who underwent percutaneous nephrolithotomy (PCNL) with renal tract dilatation performed under fluoroscopic guidance vs renal tract dilatation with ultrasound guidance. PATIENTS AND METHODS: We conducted a prospective observational cohort study, enrolling successive patients undergoing PCNL between July 2015 and March 2018. Included in this retrospective analysis were cases where the renal puncture was successfully obtained with ultrasound guidance. Cases were then grouped according to whether fluoroscopy was used to guide renal tract dilatation or not. All statistical analyses were performed using Stata version 15.1 including univariate (Fisher's exact test, Welch's t-test) and multivariate analyses (binomial logistic regression, ordinal logistic regression, and linear regression). RESULTS: A total of 176 patients underwent PCNL with successful ultrasonography-guided renal puncture, of whom 38 and 138 underwent renal tract dilatation with fluoroscopic vs ultrasound guidance, respectively. There were no statistically significant differences in patient age, gender, body mass index (BMI), preoperative hydronephrosis, stone burden, procedure laterality, number of dilated tracts, and calyceal puncture location between the two groups. Among ultrasound tract dilatations, a higher proportion of patients were placed in the modified dorsal lithotomy position as opposed to prone, and a significantly shorter operating time was observed. Only modified dorsal lithotomy position remained statistically significant after multivariate regression. There were no statistically significant differences in postoperative stone clearance, complication rate, or intra-operative estimated blood loss. A 5-unit increase in a patient's BMI was associated with 30% greater odds of increasingly severe Clavien-Dindo complications. A 5-mm decrease in the preoperative stone burden was associated with 20% greater odds of stone-free status. No variables predicted estimated blood loss with statistical significance. CONCLUSIONS: Renal tract dilatation can be safely performed in the absence of fluoroscopic guidance. Compared to using fluoroscopy, the present study demonstrated that ultrasonography-guided dilatations can be safely performed without higher complication or bleeding rates. This can be done using a variety of surgical positions, and future studies centred on improving dilatation techniques could be of impactful clinical value.

Influence of Socioeconomic Factors on Stone Burden at Presentation to Tertiary Referral Center: Data From the Registry for Stones of the Kidney and Ureter.

OBJECTIVE: To determine social factors associated with advanced stone disease (defined as unilateral stone burden >2 cm) at time of presentation to a regional stone referral center. Little is known about social determinants of urolithiasis. We hypothesize that socioeconomic factors impact kidney stone severity at intake to referral centers. METHODS: A retrospective review of the prospectively collected data from the Registry for Stones of the Kidney and Ureter from 2015 to 2018 was conducted to evaluate patient characteristics predictive of having a large (>2 cm) unilateral kidney stone. Data on patient age, gender, body mass index, diabetes, race, language, education level, infection, distance, income, referring regional urologist density, American Society of Anesthesiologists score, and stone analysis were evaluated. RESULTS: Complete imaging and patient variable data was present in 650 of 1142 patients including 197 patients with unilateral stone burden >2 cm. On multivariate analysis, obesity, lower education level, increased distance from the referral center, and symptoms of infection predicted for unilateral stone burden greater than 2 cm. Among 191 patients with stone analysis data present, stone type, income, and urologist density predicted for unilateral stone burden greater than 2 cm. CONCLUSION: In addition to known biological risk factors, patients with lower education levels and from regions of lower mean income were found to be more likely to present to our tertiary care center with stone burden greater than 2 cm. More research is needed to elucidate the social and societal determinants of advanced stone disease and the impact this has on population costs for stone treatment.

The Impact of Stone Multiplicity on Surgical Decisions for Patients with Large Stone Burden: Results from ReSKU.

Introduction: American Urological Association (AUA) guidelines recommend percutaneous nephrolithotomy (PCNL) for total stone burden greater than 20 mm, yet it is unclear if the number of stones affects adherence to this guideline. We aim to assess the impact of stone multiplicity on the choice of ureteroscopy (URS) vs PCNL as a first-line therapy for patients with high burden (>20 mm), and examine whether the AUA guideline-discordant care impacts patient outcomes. Materials and Methods: Data were collected from the Registry for Stones of the Kidney and Ureter (ReSKU) database, a prospectively collected registry of patients with stone disease. Multivariate logistic regression (MLR) was used to estimate the association between stone multiplicity and the decision to perform URS for high stone burden (>20 mm) patients. MLR was further used to estimate the association between performing URS and the following outcomes: stone-free rate, need for a second operation, and complications. Postoperative hospital stay was compared between patients receiving URS vs PCNL using Student's t-test. Results: One hundred twenty-five patients were included in this analysis. For patients with total stone burden exceeding 20 mm, those with more than three stones had roughly nine times the likelihood of undergoing URS over PCNL compared with patients with a single stone (adjusted odds ratio 9.21, confidence interval [95% CI] 2.55-40.58, p = 0.001). Stone-free rates, Clavien-Dindo scores, and frequency of second-look operations did not differ significantly between URS and PCNL patients. URS patients were discharged an average of 1.26 days earlier than patients who received PCNL (95% CI 0.72-1.81, p < 0.001). Discussion: Stone multiplicity strongly predicts which patients with stone burden >20 mm will undergo URS and who will undergo PCNL. These deviations from AUA guidelines do not appear to worsen patient outcomes. These results suggest that careful consideration of each patient may warrant deviation from guidelines.

Factors Associated with Regional Adoption of Ureteroscopy in California from 2005 to 2016.

PURPOSE: To explore regional adoption of ureteroscopy (URS) over extracorporeal shockwave lithotripsy (SWL) in the state of California (CA) and to identify factors associated with this adoption over time. MATERIALS AND METHODS: We used the California Office of Statewide Health Planning and Development (OSHPD) public data to identify URS and SWL procedures performed for renal and ureteral stones from 2005 to 2016. The level of analysis was the region wherein each procedure was performed, defined by the 19 CA labor market regions. OSHPD data were supplemented with the Area Health Resource File to provide information on regional characteristics. Generalized linear regression was used to determine procedural rates adjusted for age, gender and race. Choropleth time series maps were used to illustrate adoption of URS by region over time. RESULTS: A total of 328,795 URS and SWL procedures were identified from 2005 to 2016. The number of URS procedures surpassed the number of SWL procedures in 2011. Fourteen regions became URS predominant by 2016 and were characterized as having a higher per capita income, higher percentages with a college education and lower percentage of female heads-of-household (all p-values <0.05). A higher percentage of patients in these regions were male and had private or Medicare insurance (p = 0.03 for both). CONCLUSIONS: From 2005 to 2016, most CA regions adopted URS as the primary renal and ureteral stone management strategy. These regions demonstrated characteristics of higher socioeconomic status compared to regions that remained SWL predominant. A better understanding of such differences in practice patterns will allow urologists to better negotiate for the capital expenditures required to conform to evolving standards of care and allow patients the ability to make more informed decisions on where they receive care.

Architecture-Guided Fluid Flow Directs Renal Biomineralization.

Nephrocalcinosis often begins on a calcium phosphate deposit, at the tip of the medullo-papillary complex (MPC) known as Randall's plaque (RP). Contextualizing proximally observed biominerals within the MPC has led us to postulate a mechanobiological switch that can trigger interstitial biomineralization at the MPC tip, remote from the intratubular biominerals. Micro X-ray computed tomography scans of human MPCs correlated with transmission and scanning electron micrographs, and X-ray energy dispersive spectrometry demonstrated novel findings about anatomically-specific biominerals. An abundance of proximal intratubular biominerals were associated with emergence of distal interstitial RP. The fundamental architecture of the MPC and mineral densities at the proximal and distal locations of the MPC differed markedly. A predominance of plate-like minerals or radially oriented plate-like crystallites within spheroidal minerals in the proximal intratubular locations, and core-shell type crystallites within spheroidal minerals in distal interstitial locations were observed. Based on the MPC anatomic location of structure-specific biominerals, a biological switch within the mineral-free zone occurring between the proximal and distal locations is postulated. The "on" and "off" switch is dependent on changes in the pressure differential resulting from changes in tubule diameters; the "Venturi effect" changes the "circumferential strain" and culminates in interstitial crystal deposits in the distal tubule wall in response to proximal tubular obstruction. These distal interstitial mineralizations can emerge into the collecting system of the kidney linking nephrocalcinosis with nephrolithiasis.

Novel insights into renal mineralization and stone formation through advanced imaging modalities.

Purpose/Aim: The most common kidney stone composed of calcium oxalate forms on interstitial calcium phosphate mineral known as a Randall's plaque (RP). Due to limited information about events leading to the initial deposition of nanometer size interstitial calcium phosphate pre-clusters, there continues to be a debate on the initial site of calcium phosphate deposition and factors leading to stone formation. MATERIALS AND METHODS: High-resolution X-ray micro-computed tomography (CT), and light and electron microscopy techniques were used to characterize human renal pyramids and five representative kidney stones with identifiable stems. Mineral densities of mineralized aggregates within these specimens were correlated with micro- and ultra-structures as seen using light and electron microscopy techniques. RESULTS: The earliest detectable biominerals in the human renal papilla were proximal intratubular plate-like calcium phosphate deposits. Unoccluded tubules in stems connected to calcium phosphate stones were observed by electron microscope and X-ray micro-CT. These tubules were similar in diameter (30-100 µm) and shape to those observed in the distal regions of the renal papilla. CONCLUSIONS: Observations were patterned through a novel and unified theory of stepwise-architecture guided biomineralization (a combination of smaller structures leading to a larger but similar structural framework). A plausible stepwise progression in renal biomineralization is proposed; proximal intratubular calcium phosphate deposits can lead to interstitial yet calcium phosphate rich RP and mature into a stem on which a calcium oxalate stone grows within the collecting system of a kidney.

Beginnings of nephrolithiasis: insights into the past, present and future of Randall's plaque formation research.

PURPOSE OF REVIEW: Kidney stones form as a result of heterogeneous nucleation on a calcium phosphate lesion in the renal papilla known as Randall's plaque. Stone disease has plagued humans for millennia with relatively little progress made in the realm of prevention. An understanding of the historical aspects of research into Randall's plaque is necessary to interpret novel correlative imaging discoveries. Focus for the past several decades has been on the distal papillary tip, and the overlooked Anderson-Carr-Randall progression is revitalized with novel supporting evidence. RECENT FINDINGS: Novel correlative techniques of three-dimensional micro-XCT imaging combined with electron and light microscopy techniques have revealed that the earliest mineralization event in the papilla is a distinct event that occurs proximal to the region where Randall's plaque has traditionally been identified. SUMMARY: The history of Randall's plaque research and the Anderson-Carr-Randall progression is reviewed. Proximal intratubular mineral deposits in normal and Randall's plaque affected papillae may be a target for future therapeutic interventions for nephrolithiasis. Further collaboration between nephrologists and urologists is necessary to cure this debilitating disease.

A continuum of mineralization from human renal pyramid to stones on stems.

The development of new modalities for kidney stone prevention rests upon understanding the progression of mineralization within the renal pyramid. The progression from small foci of mineralized volumes within the renal pyramid to larger interstitial plaques that ultimately lead into clinically detectable calcium-based stones on calcium phosphate stems will be presented through correlative microscopy approach. High resolution X-ray computed tomography (micro-XCT), electron microscopy, and energy dispersive X-ray (EDX) compositional analyses of interstitial plaques, stems, and attached stones were performed. Increase in mineral density progressed with mineralization severity, with the highest mineral densities detected within mature Randall's plaque and stems to which kidney stones were attached. EDX analyses revealed variable elemental composition within interstitial plaque, stems, and stones. Micro-XCT reconstructions of stones with stems enabled visualization of unoccluded tubules within stems, with average tubule diameters corresponding to thin limbs of Henle, blood vessels, and collecting ducts. Correlative microscopy confirmed that the progression of mineralization leading to calcium-based nephrolithiasis occurs through a continuum involving four anatomically and structurally distinct biomineralization regions: 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall's plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones. STATEMENT OF SIGNIFICANCE: Nephrolithiasis is a common condition affecting nearly 1 in 11 Americans. The most common type of stone, calcium oxalate is known to form on a calcium phosphate deposit on the renal papilla known as Randall's plaque. Novel imaging techniques have identified distinct regions of biomineralization not just at the tip, but throughout the renal papilla. The classic understanding of Randall's plaque formation is reformulated using correlative imaging techniques. This study establishes a stepwise progression of anatomically-specific biomineralization events including, 1) proximal intratubular mineralization within the renal pyramid; 2) interstitial Randall's plaque near the tip of the papilla; 3) emerging plaque (stems); and, 4) the body of heterogeneous stones, and provides insights into the need for plausible site-specific therapeutic intervention.