Joe Miller

New insights into the pathogenesis of renal calculi.

The pathophysiology of the various forms of urinary stone disease remains a complex topic. Epidemiologic research and the study of urine and serum chemistries have created an abundance of data to help drive the formulation of pathophysiologic theories. This article addresses the associations of urinary stone disease with hypertension, cardiovascular disease, atherosclerosis, obesity, dyslipidemia, diabetes, and other disease states. Findings regarding the impact of dietary calcium and the formation of Randalls plaques are also explored and their implications discussed. Finally, further avenues of research are explored, including genetic analyses and the use of animal models of urinary stone disease.

A Drosophila Model Identifies a Critical Role for Zinc in Mineralization for Kidney Stone Disease

Ectopic calcification is a driving force for a variety of diseases, including kidney stones and atherosclerosis, but initiating factors remain largely unknown. Given its importance in seemingly divergent disease processes, identifying fundamental principal actors for ectopic calcification may have broad translational significance. Here we establish a Drosophila melanogaster model for ectopic calcification by inhibiting xanthine dehydrogenase whose deficiency leads to kidney stones in humans and dogs. Micro X-ray absorption near edge spectroscopy (μXANES) synchrotron analyses revealed high enrichment of zinc in the Drosophila equivalent of kidney stones, which was also observed in human kidney stones and Randall’s plaques (early calcifications seen in human kidneys thought to be the precursor for renal stones). To further test the role of zinc in driving mineralization, we inhibited zinc transporter genes in the ZnT family and observed suppression of Drosophila stone formation. Taken together, genetic, dietary, and pharmacologic interventions to lower zinc confirm a critical role for zinc in driving the process of heterogeneous nucleation that eventually leads to stone formation. Our findings open a novel perspective on the etiology of urinary stones and related diseases, which may lead to the identification of new preventive and therapeutic approaches.

Activity, Energy Intake, Obesity, and the Risk of Incident Kidney Stones in Postmenopausal Women A Report from the Women’s Health Initiative

Obesity is a strong risk factor for nephrolithiasis, but the role of physical activity and caloric intake remains poorly understood. We evaluated this relationship in 84,225 women with no history of stones as part of the Womens Health Initiative Observational Study, a longitudinal, prospective cohort of postmenopausal women enrolled from 1993 to 1998 with 8 years median follow-up. The independent association of physical activity (metabolic equivalents [METs]/wk), calibrated dietary energy intake, and body mass index (BMI) with incident kidney stone development was evaluated after adjustment for nephrolithiasis risk factors. Activity intensity was evaluated in stratified analyses. Compared with the risk in inactive women, the risk of incident stones decreased by 16% in women with the lowest physical activity level (adjusted hazard ratio [aHR], 0.84; 95% confidence interval [95% CI], 0.74 to 0.97). As activity increased, the risk of incident stones continued to decline until plateauing at a decrease of approximately 31% for activity levels ≥10 METs/wk (aHR, 0.69; 95% CI, 0.60 to 0.79). Intensity of activity was not associated with stone formation. As dietary energy intake increased, the risk of incident stones increased by up to 42% (aHR, 1.42; 95% CI, 1.02 to 1.98). However, intake <1800 kcal/d did not protect against stone formation. Higher BMI category was associated with increased risk of incident stones. In summary, physical activity may reduce the risk of incident kidney stones in postmenopausal women independent of caloric intake and BMI, primarily because of the amount of activity rather than exercise intensity. Higher caloric intake further increases the risk of incident stones.

Drosophila Melanogaster as an Emerging Translational Model of Human Nephrolithiasis

PURPOSEnThe limitations imposed by human clinical studies and mammalian models of nephrolithiasis have hampered the development of effective medical treatments and preventive measures for decades. The simple but elegant Drosophila melanogaster is emerging as a powerful translational model of human disease, including nephrolithiasis. It may provide important information essential to our understanding of stone formation. We present the current state of research using D. melanogaster as a model of human nephrolithiasis.nnnMATERIALS AND METHODSnWe comprehensively reviewed the English language literature using PubMed®. When necessary, authoritative texts on relevant subtopics were consulted.nnnRESULTSnThe genetic composition, anatomical structure and physiological function of Drosophila malpighian tubules are remarkably similar to those of the human nephron. The direct effects of dietary manipulation, environmental alteration and genetic variation on stone formation can be observed and quantified in a matter of days. Several Drosophila models of human nephrolithiasis have been developed, including genetically linked and environmentally induced stones. A model of calcium oxalate stone formation is among the most recent fly models of human nephrolithiasis.nnnCONCLUSIONSnThe ability to readily manipulate and quantify stone formation inxa0D. melanogaster models of human nephrolithiasis presents the urological community with a unique opportunity to increase our understanding of this enigmatic disease.

Microcomposition of human urinary calculi using advanced imaging techniques

PURPOSEnCommon methods of commercial urolithiasis analysis, such as light microscopy and Fourier transform infrared spectroscopy, provide limited or no information on the molecular composition of stones, which is vital when studying early stone pathogenesis. We used synchrotron radiation based microfocused x-ray fluorescence, x-ray absorption and x-ray diffraction advanced imaging techniques to identify and map the elemental composition, including trace elements, of urinary calculi on a μm (0.0001 cm) scale.nnnMATERIALS AND METHODSnHuman stone samples were obtained during serial percutaneous nephrolithotomy and ureteroscopy procedures. A portion of each sample was sent for commercial stone analysis and a portion was retained for synchrotron radiation based advanced imaging analysis.nnnRESULTSnSynchrotron radiation based methods of stone analysis correctly identified stone composition and provided additional molecular detail on elemental components and spatial distribution in uroliths. Resolution was on the order of a few μm.nnnCONCLUSIONSnKnowledge of all elements present in lithogenesis at this detail allows for better understanding of early stone formation events, which may provide additional insight to prevent and treat stone formation.

Strontium substitution for calcium in lithogenesis

PURPOSEnStrontium has chemical similarity to calcium, which enables the replacement of calcium by strontium in biomineralization processes. Incorporating strontium into human bone and teeth has been studied extensively but little research has been performed of the incorporation of strontium into urinary calculi. We used synchrotron based x-ray fluorescence and x-ray absorption techniques to examine the presence of strontium in different types of human kidney stones.nnnMATERIALS AND METHODSnMultiple unique human stone samples were obtained via consecutive percutaneous nephrolithotomies/ureteroscopies. A portion of each stone was sent for standard laboratory analysis and a portion was retained for x-ray fluorescence and x-ray absorption measurements. X-ray fluorescence and x-ray absorption measurements determined the presence, spatial distribution and speciation of strontium in each stone sample.nnnRESULTSnTraditional kidney stone analyses identified calcium oxalate, calcium phosphate, uric acid and cystine stones. X-ray fluorescence measurements identified strontium in all stone types except pure cystine. X-ray fluorescence elemental mapping of the samples revealed co-localization of calcium and strontium. X-ray absorption measurements of the calcium phosphate stone showed strontium predominately present as strontium apatite.nnnCONCLUSIONSnAdvanced x-ray fluorescence imaging identified strontium in all calcium based stones, present as strontium apatite. This finding may be critical since apatite is thought to be the initial nidus for calcium stone formation. Strontium is not identified by standard laboratory stone analyses. Its substitution for calcium can be reliably identified in stones from multiple calcium based stone formers, which may offer opportunities to gain insight into early events in lithogenesis.

Renal calyceal anatomy characterization with 3-dimensional in vivo computerized tomography imaging

PURPOSEnCalyceal selection for percutaneous renal access is critical for safe, effective performance of percutaneous nephrolithotomy. Available anatomical evidence is contradictory and incomplete. We present detailed renal calyceal anatomy obtained from in vivo 3-dimentional computerized tomography renderings.nnnMATERIALS AND METHODSnA total of 60 computerized tomography urograms were randomly selected. The renal collecting system was isolated and 3-dimensional renderings were constructed. The primary plane of each calyceal group of 100 kidneys was determined. A coronal maximum intensity projection was used for simulated percutaneous access. The most inferior calyx was designated calyx 1. Moving superiorly, the subsequent calyces were designated calyx 2 and, when present, calyx 3. The surface rendering was rotated to assess the primary plane of the calyceal group and the orientation of the select calyx.nnnRESULTSnThe primary plane of the upper pole calyceal group was mediolateral in 95% of kidneys and the primary plane of the lower pole calyceal group was anteroposterior in 95%. Calyx 2 was chosen in 90 of 97 simulations and it was appropriate in 92%. Calyx 3 was chosen in 7 simulations but it was appropriate in only 57%. Calyx 1 was not selected in any simulation and it was anteriorly oriented in 75% of kidneys.nnnCONCLUSIONSnAppropriate lower pole calyceal access can be reliably accomplished with an understanding of the anatomical relationship between individual calyceal orientation and the primary plane of the calyceal group. Calyx 2 is most often appropriate for accessing the anteroposterior primary plane of the lower pole. Calyx 1 is most commonly oriented anterior.

Complications associated with percutaneous nephrolithotomy.

The increasing global prevalence of nephrolithiasis continues to burden the healthcare delivery systems of industrialized nations and exact a disproportionate humanitarian toll on populations of the developing world (1). In the United States alone, the prevalence of nephrolithiasis is nearly twice the rate reported in the 1960s (2-5). The subsequent rise in surgical interventions for nephrolithiasis has resulted in the development of new minimally invasive technologies and techniques, but it has also led to the resurgence of established methods such as percutaneous nephrolithotomy (PNL).

Randall plaque versus renal stone

A 43-year-old patient has just left the office. Her primary care physician had dutifully evaluated her recent complaint of vague abdominal pain with an abdominal ultrasound. The multiple, small, punctate hyperechoic lesions in the kidney were deemed concerning for renal calculi and an abdominal computed tomography (CT) scan was ordered to better delineate these renal stones. The CT report revealed multiple bilateral punctate calcifications consistent with possible nephrolithiasis versus nephrocalcinosis , and the patient was referred to urology clinic for further evaluation. In our clinic the patient was interviewed and examined and the scan was carefully reviewed. The patient denied symptoms of renal colic and physical examination demonstrated no costovertebral angle tenderness. No hydronephrosis or evidence of urinary obstruction could be seen on the scan, and we provided a diagnosis of Randall plaques and nephrocalcinosis. The patient was reassured that there were no stones to treat and there was no need for surgery. General lifestyle and dietary modification counseling for stone prevention were provided, and the patient was discharged from our clinic, happy with her benign diagnosis.

Intracorporeal Lithotripsy: Electrohydraulic, Pneumatic, and Ultrasonic

The evolution of ureteroscopy using electrohydraulic lithotripsy (EHL), pneumatic lithotripsy (PL), and ultrasonic lithotripsy (USL) for the treatment of ureteral stones offered a much less invasive alternative to contemporary open ureterolithotomy, and a was major advancement for the fledgling field of endourology. As new energy sources became widely available, studies examining the safety, efficacy, and cost sought to determine the one best modality to treat ureteral stones. EHL, while efficient and safe for treatment of bladder stones proved to be too powerful to use for the treatment of most stones within the ureter. USL and PL were safer and often times more efficient than EHL, but the breadth of their applicability was somewhat limited by the rigid nature of their probes. The advent of shock wave lithotripsy and laser lithotripsy, and their subsequent widespread affordability and availability, eclipsed other energy sources as the first-line treatment for ureteral stones. Contemporaneous and modern clinical studies however prove that the traditional lithotrites, including EHL, PL, and USL, still have utility and can be especially effective when cost constraints dictate equipment choice.