Excretion of urine extracellular vesicles bearing markers of activated immune cells and calcium/phosphorus physiology differ between calcium kidney stone formers and non-stone formers.

BACKGROUNDS: Previous studies have demonstrated that excretion of urinary extracellular vesicles (EVs) from different nephron segments differs between kidney stone formers and non-stone formers (NSFs), and could reflect pathogenic mechanisms of urinary stone disease. In this study we quantified selected populations of specific urinary EVs carrying protein markers of immune cells and calcium/phosphorus physiology in calcium oxalate stone formers (CSFs) compared to non-stone formers (NSFs). METHODS: Biobanked urine samples from CSFs (n = 24) undergoing stone removal surgery and age- and sex- matched NSFs (n = 21) were studied. Urinary EVs carrying proteins related to renal calcium/phosphorus physiology (phosphorus transporters (PiT1 and PiT2), Klotho, and fibroblast growth factor 23 (FGF23); markers associated with EV generation (anoctamin-4 (ANO4) and Huntington interacting protein 1 (HIP1)), and markers shed from activated immune cells were quantified by standardized and published method of digital flow cytometry. RESULTS: Urine excretion of calcium, oxalate, phosphorus, and calcium oxalate supersaturation (SS) were significantly higher in CSFs compared to NSFs (P < 0.05). Urinary excretion of EVs with markers of total leukocytes (CD45), neutrophils (CD15), macrophages (CD68), Klotho, FGF23, PiT1, PiT2, and ANO4 were each markedly lower in CSFs than NSFs (P < 0.05) whereas excretion of those with markers of monocytes (CD14), T-Lymphocytes (CD3), B-Lymphocytes (CD19), plasma cells (CD138 plus CD319 positive) were not different between the groups. Urinary excretion of EVs expressing PiT1 and PiT2 negatively (P < 0.05) correlated with urinary phosphorus excretion, whereas excretion of EVs expressing FGF23 negatively (P < 0.05) correlated with both urinary calcium and phosphorus excretion. Urinary EVs with markers of HIP1 and ANO4 correlated negatively (P < 0.05) with clinical stone events and basement membrane calcifications on papillary tip biopsies. CONCLUSIONS: Urinary excretion of EVs derived from specific types of activated immune cells and EVs with proteins related to calcium/phosphorus regulation differed between CSFs and NSFs. Further validation of these and other populations of urinary EVs in larger cohort could identify biomarkers that elucidate novel pathogenic mechanisms of calcium stone formation in specific subsets of patients.

Elucidating measures of systemic racism to mitigate racial disparities in kidney transplantation.

PURPOSE OF REVIEW: Given recent national attention to the role of racism in perpetuating racial inequities in society and health, this review provides a timely and relevant summary of key measures of systemic racism in kidney transplantation. More specifically, the review identifies current and promising interventions, whereas highlighting the need for more sustainable and impactful interventions. RECENT FINDINGS: Racial disparities persist in kidney transplantation. Black and Hispanic individuals are less likely to receive a kidney transplant than non-Hispanic Whites despite disproportionately higher rates of kidney failure. Studies demonstrate that socioeconomic factors do not fully explain existing racial disparities in transplantation. Systemic racism at all levels, individual, interpersonal, institutional, and structural, is at the core of racial disparities, and current interventions are insufficient in mitigating their effects. Thus, targeted and sustainable interventions must be implemented to mitigate systemic racism in kidney transplantation. SUMMARY: Systemic racism in all its forms continues to influence disparities at all stages of kidney transplantation. This paper highlights recent findings that shed light on how racism contributes to racial disparities in kidney transplantation. Using these findings to identify targets and strategies for mitigation, relevant interventions and policies that show promise are detailed.

Kappa opioid agonists in the treatment of itch: just scratching the surface?

Chronic pruritus is a debilitating condition affecting 23-44 million Americans. Recently, kappa opioid agonists (KOAs) have emerged as a novel class of potent antipruritic agents. In 2021, the Food and Drug Administration approved difelikefalin (Korsuva) for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. Difelikefalin is a potent, peripherally restricted KOA that is intravenously available. Although promising, difelikefalin is currently available as an intravenous composition only, limiting the scope of use. Oral formulations of difelikefalin did not meet the primary endpoint criteria in recent phase 2 clinical trials; however, additional clinical studies are ongoing. The future for KOAs in the treatment of pruritus is encouraging. Orally active pathway-biased KOAs, such as triazole 1.1, may serve as viable alternatives with broader applications. Extended-release compositions, such as the TP-2021 ProNeura subdermal implant, may circumvent the pharmacokinetic issues associated with peptide-based KOAs. Lastly, dual-acting kappa opioid receptor agonist/mu opioid receptor antagonists are orally bioavailable and may be useful in the treatment of various forms of chronic itch. In this review, we summarize the results of KOAs in clinical and preclinical trials and discuss future directions of drug development.

Applications of Mobile Health Technologies to Address Cardiometabolic Health Disparities in the United States: A Systematic Review.

Introduction: Black and Hispanic adults are disproportionately burdened by cardiometabolic disorders. The aim of this systematic review was to examine the effectiveness of mobile health technologies to promote disease prevention and self-management among US adults in diverse communities. Methods: Potential studies were identified using a comprehensive search of the PubMed and EMBASE databases for recent studies published from December 2018 through 2021. Keywords and search strategies were established to focus on health disparity populations and the application of mobile health technology for cardiovascular disease risk reduction. Titles and abstracts were assessed and, if a study was eligible, 2 independent reviewers completed a full-length review with extraction in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results: A total of 13 studies met our inclusion criteria. Study sample sizes ranged from 8 to 533 baseline participants. Studies were conducted in diverse communities (eg, North Carolina and California). Most studies used mobile applications (n=11) and a majority used accelerometers or similar technologies (eg, smartwatches) to assess changes in dietary behavior, blood pressure control, and physical activity. Overall, studies reported positive associations between mobile technology use and risk factor reduction actions and behaviors. Long-term adherence varied across studies. Those that prioritized culturally tailored approaches reported more significant impacts than those that did not. Conclusions: Evidence suggests that mobile technology may be useful in promoting disease self-management and risk reduction among populations at higher risk of cardiometabolic diseases. The use of mobile health technologies, particularly when tailored to target populations, may be a practical approach to advancing population health equity.

Inflammatory Cells in Nephrectomy Tissue from Patients without and with a History of Urinary Stone Disease.

BACKGROUND AND OBJECTIVES: Urinary stone disease has been associated with inflammation, but the specific cell interactions that mediate events remain poorly defined. This study compared calcification and inflammatory cell patterns in kidney tissue from radical nephrectomy specimens of patients without and with a history of urinary stone disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Nontumor parenchyma of biobanked radical nephrectomy specimens from age- and sex-matched stone formers (n=44) and nonstone formers (n=82) were compared. Calcification was detected by Yasue staining and inflammatory cell populations by immunohistochemistry for CD68 (proinflammatory M1 macrophages), CD163 and CD206 (anti-inflammatory M2 macrophages), CD3 (T lymphocytes), and tryptase (mast cells). Calcifications and inflammatory cells were quantified in cortex and medulla using Image-Pro analysis software. RESULTS: Calcification in the medulla of stone formers was higher than in nonstone formers (P<0.001). M1 macrophages in the cortex and medulla of stone formers were greater than in nonstone formers (P<0.001), and greater in stone former medulla than stone former cortex (P=0.02). There were no differences in age, sex, body mass index, tumor characteristics (size, stage, or thrombus), vascular disease status, or eGFR between the groups. M2 macrophages, T lymphocytes, and mast cells did not differ by stone former status. There was a correlation between M1 macrophages and calcification in the medulla of stone formers (rho=0.48; P=0.001) and between M2 macrophages and calcification in the medulla of nonstone formers (rho=0.35; P=0.001). T lymphocytes were correlated with calcification in the cortex of both nonstone formers (rho=0.27; P=0.01) and stone formers (rho=0.42; P=0.004), whereas mast cells and calcification were correlated only in the cortex of stone formers (rho=0.35; P=0.02). CONCLUSIONS: Higher medullary calcification stimulated accumulation of proinflammatory rather than anti-inflammatory macrophages in stone formers.

Human kidney stones: a natural record of universal biomineralization.

GeoBioMed - a new transdisciplinary approach that integrates the fields of geology, biology and medicine - reveals that kidney stones composed of calcium-rich minerals precipitate from a continuum of repeated events of crystallization, dissolution and recrystallization that result from the same fundamental natural processes that have governed billions of years of biomineralization on Earth. This contextual change in our understanding of renal stone formation opens fundamentally new avenues of human kidney stone investigation that include analyses of crystalline structure and stratigraphy, diagenetic phase transitions, and paragenetic sequences across broad length scales from hundreds of nanometres to centimetres (five Powers of 10). This paradigm shift has also enabled the development of a new kidney stone classification scheme according to thermodynamic energetics and crystalline architecture. Evidence suggests that ≥50% of the total volume of individual stones have undergone repeated in vivo dissolution and recrystallization. Amorphous calcium phosphate and hydroxyapatite spherules coalesce to form planar concentric zoning and sector zones that indicate disequilibrium precipitation. In addition, calcium oxalate dihydrate and calcium oxalate monohydrate crystal aggregates exhibit high-frequency organic-matter-rich and mineral-rich nanolayering that is orders of magnitude higher than layering observed in analogous coral reef, Roman aqueduct, cave, deep subsurface and hot-spring deposits. This higher frequency nanolayering represents the unique microenvironment of the kidney in which potent crystallization promoters and inhibitors are working in opposition. These GeoBioMed insights identify previously unexplored strategies for development and testing of new clinical therapies for the prevention and treatment of kidney stones.

In Vivo Entombment of Bacteria and Fungi during Calcium Oxalate, Brushite, and Struvite Urolithiasis.

Background: Human kidney stones form via repeated events of mineral precipitation, partial dissolution, and reprecipitation, which are directly analogous to similar processes in other natural and manmade environments, where resident microbiomes strongly influence biomineralization. High-resolution microscopy and high-fidelity metagenomic (microscopy-to-omics) analyses, applicable to all forms of biomineralization, have been applied to assemble definitive evidence of in vivo microbiome entombment during urolithiasis. Methods: Stone fragments were collected from a randomly chosen cohort of 20 patients using standard percutaneous nephrolithotomy (PCNL). Fourier transform infrared (FTIR) spectroscopy indicated that 18 of these patients were calcium oxalate (CaOx) stone formers, whereas one patient formed each formed brushite and struvite stones. This apportionment is consistent with global stone mineralogy distributions. Stone fragments from seven of these 20 patients (five CaOx, one brushite, and one struvite) were thin sectioned and analyzed using brightfield (BF), polarization (POL), confocal, super-resolution autofluorescence (SRAF), and Raman techniques. DNA from remaining fragments, grouped according to each of the 20 patients, were analyzed with amplicon sequencing of 16S rRNA gene sequences (V1-V3, V3-V5) and internal transcribed spacer (ITS1, ITS2) regions. Results: Bulk-entombed DNA was sequenced from stone fragments in 11 of the 18 patients who formed CaOx stones, and the patients who formed brushite and struvite stones. These analyses confirmed the presence of an entombed low-diversity community of bacteria and fungi, including Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, and Aspergillus niger. Bacterial cells approximately 1 µm in diameter were also optically observed to be entombed and well preserved in amorphous hydroxyapatite spherules and fans of needle-like crystals of brushite and struvite. Conclusions: These results indicate a microbiome is entombed during in vivo CaOx stone formation. Similar processes are implied for brushite and struvite stones. This evidence lays the groundwork for future in vitro and in vivo experimentation to determine how the microbiome may actively and/or passively influence kidney stone biomineralization.

Comparison of two dimensional and three dimensional radiotherapy treatment planning in locally advanced non-small cell lung cancer treated with continuous hyperfractionated accelerated radiotherapy weekend less.

BACKGROUND AND PURPOSE: Patients with inoperable non-small cell lung cancer being treated with continuous hyperfractionated accelerated radiotherapy weekend less (CHARTWEL) were planned and treated with a three dimensional (3D) conformal protocol and comparison made with two dimensional (2D) planning, as used previously, to compare past practice and methods. PATIENTS AND METHODS: Twenty-four patients were planned initially using 3D and then replanned using a 2D system. The 2D plans were transferred onto the 3D system and recalculated. Dose volume histograms could then be constructed of planning target volumes for phases 1 and 2 (PTV 1 and 2, respectively), lung and spinal cord for the 2D plans and compared with the 3D plans. RESULTS: There was a significantly lower absolute dose to the isocentre with 2D compared to 3D planning with dose reductions of 3.9% for phase 1, 4.4% for phase 2 and 4.7% for those treated with a single phase. Maximum dose to spinal cord was greater in 17 of the 24 2D plans with a median dose reduction of 0.82 Gy for 3D (P=0.04). The percentage volume of whole lung receiving > or =20 Gy (V20) was greater in 16 of the 24 2D plans with a median reduction in V20 of 2.4% for 3D (P=0.03). CONCLUSIONS: A lower dose to tumour was obtained using 2D planning due to the method of dose calculation and spinal cord and lung doses were significantly higher.

Validation of active breathing control in patients with non-small-cell lung cancer to be treated with CHARTWEL.

PURPOSE: Active breathing control (ABC) was validated using patients with non-small-cell lung cancer (NSCLC) to be treated with continuous hyperfractionated accelerated radiotherapy weekend-less (CHARTWEL). Effects of breath hold (BH) on accuracy and normal tissue doses were evaluated. METHODS AND MATERIALS: Eleven patients were studied. Immediately after a free breathing (FB) planning scan, two ABC scans (ABC 1 and 2) were performed to assess intrafraction variation. A third ABC scan (ABC 3) was performed some weeks later to assess interfraction variation. Assisted BH was set at 75% of vital capacity and reproducibility assessed using computed tomography (CT) lung volumes. Planning target volumes (PTVs), doses to lung and spinal cord for FB and ABC 1 scans were compared. RESULTS: Results were available for 10 patients. Disease and elective nodal regions were easier to define on ABC scans making PTVs smaller. ABC lung volumes showed no significant variation over several weeks, percentage volume of whole lung receiving > or =20 Gy (V(20)) was reduced in all (median 6.4%, p = 0.005), and spinal cord dose in 80% (median 1.03 Gy, p = 0.02), of the plans. CONCLUSION: ABC allowed reproducible BH, and enabled better delineation of tumor and normal structures, as well as reduction in PTV, V(20), and spinal cord dose.

Referral guidelines for colorectal cancer--do they work?

AIMS AND METHODS: Urgent referral guidelines for patients with suspected colorectal cancer were introduced in 2000. In a district general hospital, we prospectively assessed the effect of these guidelines on the number of urgent referrals received and the number found to have cancer. RESULTS: Over the first year, 180 urgent referrals were received of whom 95 (55%) fitted the guidelines. Of these 95 patients, 24 (25%) had colorectal cancer. Conversely, only 2 of the 85 patients (2%) who did not fit the guidelines had colorectal cancer. During the same time period, a total of 145 new cancers were identified within the district of which 119 (82%) were in patients who had not been urgently referred to out-patients as suspected colorectal cancer. DISCUSSION: The guidelines are effective in that patients who fit them have a significant chance of having colorectal cancer. However, the majority of cancers are identified outside the new system. Efforts to reduce delays in diagnosis need to recognise that many patients do not have features which fit published referral criteria. Improved support for general practitioners and better access to specialist services are required to reduce delays in diagnosis.

Toxicity and outcome of a phase II trial of taxane-based neoadjuvant chemotherapy and 3-dimensional, conformal, accelerated radiotherapy in locally advanced nonsmall cell lung cancer.

BACKGROUND: The objective of this study was to evaluate prospectively the acute and late adverse effects of taxane/carboplatin neoadjuvant chemotherapy and 3-dimensional, conformal radiotherapy in patients with locally advanced nonsmall cell lung cancer (NSCLC). METHODS: Forty-two patients were entered into a nonrandomized Phase II study of continuous, hyperfractionated, accelerated radiotherapy (CHART) week-end less (CHARTWEL) to a dose of 60 grays (Gy). Three cycles of chemotherapy were given over 9 weeks before radiotherapy. Dose escalation with paclitaxel was from 150 mg/m2 to 225 mg/m2. Systemic toxicity to chemotherapy was monitored throughout. Radiation-induced, early, adverse effects were assessed during the first 9 weeks from the start of radiotherapy, and late effects were assessed from 3 months onward. Overall survival, disease-free survival, and locoregional tumor control also were monitored. RESULTS: Twenty percent of patients failed to receive chemotherapy as planned, primarily because of neutropenia. The incidence of Dische Dictionary Grade >or=2 and Grade >or=3 dysphagia was 57.5% and 10%, respectively, with an average duration of 1.2 weeks and 1.5 days, respectively. By 9 weeks, <3% of patients were symptomatic; and, eventually, all acute reactions were healed, and there has been no evidence of consequential damage. At 6 months, the actuarial incidence of moderate-to-severe pneumonitis was 10%. During this time, all patients were free of severe pulmonary complications. Actuarial estimates of Grade >or=2 late lung dysfunction were 3% at 1 year, 10% at 2 years, and remained at this level thereafter. The actuarial 3-year locoregional control and overall survival rates were 54% and 45%, respectively. CONCLUSIONS: Neoadjuvant chemotherapy followed by 3-dimensional, conformal CHARTWEL 60-Gy radiotherapy in patients with advanced NSCLC was feasible and was tolerated well. Historic comparisons indicated that locoregional tumor control is not compromised by the use of conformal techniques.