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Key Points Idiopathic calcium stones are always accompanied by mineral deposits: interstitial deposits of apatite in patients with calcium oxalate (CaOx) stones or calcium phosphate (CaP) plugs in those with CaP stones Overgrowth of CaOx stones on plaque depends on the formation of an initial CaP phase; urine saturations of CaP and CaOx might, therefore, be equally important Microliths form on the open ends of tubule plugs but proof that these microliths can grow into clinically relevant stones is lacking Patients with tubule plugs who form CaP stones show varying degrees of cortical fibrosis and nephron loss Trial data support the use of high fluid intake, potassium citrate, thiazide diuretic agents and a reduced sodium diet for prevention of recurrent calcium renal stones As idiopathic hypercalciuria arises from reduced renal tubule calcium reabsorption and is associated with negative calcium balance and bone disease, management with a low calcium diet is contraindicated The most common predisposing factor for the formation of idiopathic calcium stones is hypercalciuria. Here, the authors discuss the mechanisms of idiopathic calcium stone formation and hypercalciuria as well as potential therapeutic strategies to reduce the risk of stone formation. The most common presentation of nephrolithiasis is idiopathic calcium stones in patients without systemic disease. Most stones are primarily composed of calcium oxalate and form on a base of interstitial apatite deposits, known as Randall's plaque. By contrast some stones are composed largely of calcium phosphate, as either hydroxyapatite or brushite (calcium monohydrogen phosphate), and are usually accompanied by deposits of calcium phosphate in the Bellini ducts. These deposits result in local tissue damage and might serve as a site of mineral overgrowth. Stone formation is driven by supersaturation of urine with calcium oxalate and brushite. The level of supersaturation is related to fluid intake as well as to the levels of urinary citrate and calcium. Risk of stone formation is increased when urine citrate excretion is <400 mg per day, and treatment with potassium citrate has been used to prevent stones. Urine calcium levels >200 mg per day also increase stone risk and often result in negative calcium balance. Reduced renal calcium reabsorption has a role in idiopathic hypercalciuria. Low sodium diets and thiazide-type diuretics lower urine calcium levels and potentially reduce the risk of stone recurrence and bone disease.

There is a need to develop early biomarkers of acute kidney injury following cardiac surgery, where morbidity and mortality are increased by its presence. Plasma cystatin C (CyC) and plasma and urine Neutrophil Gelatinase Associated Lipocalin (NGAL) have been shown to detect kidney injury earlier than changes in plasma creatinine in critically ill patients. In order to determine the utility of urinary CyC levels as a measure of kidney injury, we prospectively collected plasma and urine from 72 adults undergoing elective cardiac surgery for analysis. Acute kidney injury was defined as a 25% or greater increase in plasma creatinine or renal replacement therapy within the first 72 hours following surgery. Plasma CyC and NGAL were not useful predictors of acute kidney injury within the first 6 hours following surgery. In contrast, both urinary CyC and NGAL were elevated in the 34 patients who later developed acute kidney injury, compared to those with no injury. The urinary NGAL at the time of ICU arrival and the urinary CyC level 6 hours after ICU admission were most useful for predicting acute kidney injury. A composite time point consisting of the maximum urinary CyC achieved in the first 6 hours following surgery outperformed all individual time points. Our study suggests that urinary CyC and NGAL are superior to conventional and novel plasma markers in the early diagnosis of acute kidney injury following adult cardiac surgery.

No single theory of pathogenesis can properly account for human kidney stones, they are too various and their formation is too complex for simple understanding. Using human tissue biopsies, intraoperative imaging and such physiology data from ten different stone forming groups, we have identified at least three pathways that lead to stones. The first pathway is overgrowth on interstitial apatite plaque as seen in idiopathic calcium oxalate stone formers, as well as stone formers with primary hyperparathyroidism, ileostomy, and small bowel resection, and in brushite stone formers. In the second pathway, there are crystal deposits in renal tubules that were seen in all stone forming groups except the idiopathic calcium oxalate stone formers. The third pathway is free solution crystallization. Clear examples of this pathway are those patient groups with cystinuria or hyperoxaluria associated with bypass surgery for obesity. Although the final products may be very similar, the ways of creation are so different that in attempting to create animal and cell models of the processes one needs to be careful that the details of the human condition are included.

A 43-year-old man presents for evaluation of recurrent kidney stones. He passed his first stone 9 years earlier and has had two additional symptomatic stones. Analysis of two stones showed that they contained 80% calcium oxalate and 20% calcium phosphate. The urinary volume was 1.54 liters per day, and the urine pH was 5.6. The patient had been treated with 20 to 40 mmol of potassium citrate daily since he passed his first stone. How should he be further evaluated and treated? Foreword This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations. Stage A 43-year-old man presents for evaluation of recurrent kidney stones. He passed his first stone 9 years earlier and has had two additional symptomatic stones. Analysis of the first and the last stones showed that they contained 80% calcium oxalate and 20% calcium phosphate. Analysis of a 24-hour urine collection while the patient was not receiving medications revealed a calcium level of 408 mg (10.2 mmol), an oxalate level of 33 mg (367 μmol), and a volume of 1.54 liters; the urine pH was 5.6. The patient had been treated with 20 to 40 mmol of potassium citrate daily . . .

Background Animal models have demonstrated an interactive relationship between the epithelial anion exchanger SLC26A6 and transporter NaDC‐1 that regulates citrate and oxalate homeostasis. This relationship is a potential mechanism to protect against kidney stones as higher urine oxalate is accompanied by higher urine citrate but it has not been explored in humans. Methods We examined 24‐h urine data on 13,155 kidney stone forming patients (SF) from separate datasets at the University of Chicago and Litholink, a national laboratory, and 143 non‐kidney stone forming participants (NSF) to examine this relationship in humans. We used multivariate linear regression models to examine the association between oxalate and citrate in all study participants and separately in SF and NSF. Results Higher urinary oxalate was associated with higher urinary citrate in both SF and NSF. In NSF, the multivariate adjusted urine citrate excretion was 3.0 (1.5–4.6) (mmol)/creatinine (mmol) per oxalate (mmol)/creatinine (mmol). In SF, the multivariate adjusted urine citrate excretion was 0.3 (0.2–0.4) (mmol)/creatinine (mmol) per oxalate (mmol)/creatinine (mmol). Conclusions Higher urinary oxalate excretion was associated with higher urinary citrate excretion and this effect was larger in non‐kidney stone forming participants compared with those who form kidney stones. Adult male offspring of a rat model of polycystic ovary syndrome is born small compared to controls, and as adults have lower body weights, with higher cholesterol and proteinuria. Although the male PCOS offspring have similar blood pressure as controls, they have an exaggerated pressor response to angiotensin II. These data suggest that male offspring of PCOS women may develop cardiometabolic disease as adults or with aging.

We have biopsied the papillae of patients who have cystine stones asking if this stone type is associated with specific tissue changes. We studied seven cystine stone formers (SF) treated with percutaneous nephrolithotomy using digital video imaging of renal papillae for mapping and obtained papillary biopsies. Biopsies were analyzed by routine light and electron microscopy, infrared spectroscopy, electron diffraction, and micro-CT. Many ducts of Bellini (BD) had an enlarged ostium, and all such were plugged with cystine crystals, and had injured or absent lining cells with a surrounding interstitium that was inflamed to fibrotic. Crystal plugs often projected into the urinary space. Many inner medullary collecting ducts (IMCD) were dilated with or without crystal plugging. Apatite crystals were identified in the lumens of loops of Henle and IMCD. Abundance of interstitial Randall's plaque was equivalent in amount to that of non-SF. In the cortex, glomerular obsolescence and interstitial fibrosis exceeded normal. Cystine crystallizes in BD with the probable result of cell injury, interstitial reaction, nephron obstruction, and with the potential of inducing cortical change and loss of IMCD tubular fluid pH regulation, resulting in apatite formation. The pattern of IMCD dilation, and loss of medullary structures is most compatible with such obstruction, either from BD lumen plugs or urinary tract obstruction from stones themselves.

To better portray the clinical phenotype of kidney stone patients with high calcium phosphate (CaP) stone abundance, we present here clinical and laboratory findings of large numbers of stone formers (SF) with stone CaP ranging from 0% to 100%. Our purpose was to inform clinicians and highlight areas that seem to deserve further research. We calculated average percent CaP (CaP%) in all stones of 1201 patients, and classified them into CaOx (N= 1011) or CaP (N= 190). Sex differences, stone formation rates, urine stone risk factors, extracorporeal shock wave lithotripsy (ESWL) treatments, and relapse during treatment were quantified in relation to stone CaP content. CaP% has risen for three decades, especially among women. ESWL rates adjusted for numbers of stones and duration of stone disease were higher in CaP SF (0.6 vs. 1.86 and 0.73 vs. 1.82, CaOx vs. CaP, men and women, respectively, P < 0.001), and especially when stones contained brushite (2.90 vs. 1.02 and 3.11 vs. 1.35, brushite vs. not, males and females, respectively, P < 0.001). Urine pH and CaP supersaturation rose in proportion to CaP% in a dose response manner. Relapse rates of CaP and CaOx SF did not differ, and both did well with medical prevention. Stone CaP% has risen for three decades. CaP SF, particularly with brushite stones, receive more ESWL treatments than CaOx SF, not explained by stone number or duration of stone disease. Urine supersaturations explain the high CaP%. High CaP% does not hamper medical stone prevention.

Exposure to global health increases health care students’ cultural humility, improves interprofessional communication, and deepens empathy. However, graduate nursing programs rarely provide students with international clinical rotations for electives, much less mandate it in the curriculum. This article seeks to provide nursing faculty with guidance on the design and implementation of a global health course for advanced practice registered nurse students based on the development and implementation of a clinical rotation at an outpatient clinic in Belize. The design of the course proposal, the application process, student recruitment, implementation, and evaluation of 2 student cohorts are included, with lessons learned. •Global health increases cultural competency and interprofessional communication.•Global health has bidirectional benefit for visiting students and native communities.•Students participating in global health gain interest in future global opportunities.

Issue Title: Special Issue: The Role of Randall's Plaques in Urolithiasis The precise mechanisms of kidney stone formation and growth are not completely known, even though human stone disease appears to be one of the oldest diseases known to medicine. With the advent of the new digital endoscope and detailed renal physiological studies performed on well phenotyped stone formers, substantial advances have been made in our knowledge of the pathogenesis of the most common type of stone former, the idiopathic calcium oxalate stone former as well as nine other stone forming groups. The observations from our group on human stone formers and those of others on model systems have suggested four entirely different pathways for kidney stone formation. Calcium oxalate stone growth over sites of Randall's plaque appear to be the primary mode of stone formation for those patients with hypercalciuria. Overgrowths off the ends of Bellini duct plugs have been noted in most stone phenotypes, do they result in a clinical stone? Micro-lith formation does occur within the lumens of dilated inner medullary collecting ducts of cystinuric stone formers and appear to be confined to this space. Lastly, cystinuric stone formers also have numerous small, oval, smooth yellow appearing calyceal stones suggestive of formation in free solution. The scientific basis for each of these four modes of stone formation are reviewed and used to explore novel research opportunities.[PUBLICATION ABSTRACT]

Apatite plaque particles in inner medulla of kidneys of calcium oxalate stone formers: Osteopontin localization. We have previously shown that interstitial plaque particles appear first in the basement membranes of thin loops of Henle and then in the interstitial space. However, it is not known if the plaque in the basement membrane of thin loops of Henle is of the same or different form than the interstitial plaque. Thus our purpose here is to detail the structure of the interstitial and membrane-bound plaque and explore the relationship of plaque apatite to osteopontin, a well-known crystal-associated urine protein. Deep papillary biopsy tissue was studied from all 15 calcium oxalate stone formers and four nonforming subjects that we previously reported on [Evan et al, J Clin Ivest, 2003]. Routine light and transmission electron microscopy (TEM) as well as light microscopy and TEM immunohistochemical localization of osteopontin antibody were performed on all 19 subjects. In the basement membrane, plaque particles are individual and appear laminated with alternating light regions of crystal and electron-dense organic layers. In the interstitium, individual particles are not abundant but are instead aggregated to form regions of attached particles and in some regions what appears to be a fusion or syncytium in which crystal islands float in an organic sea. By light microscopy immunohistochemistry, osteopontin was localized to cells of the loops of Henle and collecting ducts as well as on sites of plaque. By immunoelectron microscopy, osteopontin immunogold label was found mainly on the surfaces of apatite crystal phase, at the junction of the crystal/organic layers. A similar immunogold labeling pattern was seen in the particles forming the syncytial islands of interstitial plaque. If indeed we accept the hypothesis that apatite plaque may be an anchored site on which calcium oxalate stones form and grow, the present work makes clear that it is unlikely that the surface of plaque presented to the final urine will be apatite crystal per se. However, our findings clearly show osteopontin is one of the crystal-associated urine proteins involved in the formation of the organic layers of the plaque particles.