Performance and Interpretation of Sonography in the Practice of Nephrology: Core Curriculum 2024.

Ultrasonography is increasingly being performed by clinicians at the point of care, and nephrologists are no exception. This Core Curriculum illustrates how ultrasonography can be incorporated into clinical decision making across the spectrum of kidney disease to optimize the care nephrologists provide to patients. Sonography is valuable in outpatient and inpatient settings for the diagnosis and management of acute and chronic kidney disease, evaluation of cystic disease, urinary obstruction, pain, hematuria, proteinuria, assessment of volume status, and in providing guidance for kidney biopsy. As kidney disease advances, ultrasound is useful in the placement and maintenance of temporary and permanent access for dialysis. After kidney transplantation, ultrasonography is critical for evaluation of allograft dysfunction and for biopsies. Sonography skills expedite patient care and enhance the practice of nephrology and are relatively easily acquired with training. It is our hope that this curriculum will encourage nephrologists to learn and apply this valuable skill.

Metabolic alkalosis in hemodialysis patients.

BACKGROUND: Hemodialysis solutions typically contain a high alkali concentration designed to counter interdialytic acidosis, but this could result in persistent alkalosis in some patients. The prevalence and significance of persistent alkalosis were therefore examined at four outpatient centers over a 10-year period. METHODS: Alkalosis was defined as a pre-dialysis serum [HCO3 ] ≥ 26 meq/L in >6 months of a 12-month period and was persistent if present in a majority of months thereafter. Control patients had a serum [HCO3 ] of 19-23 meq/L > 6 of every 12 months. Standard, citrate-containing dialysate was used in all patients without adjustment of bicarbonate concentration. RESULTS: 444 of 1271 patients had alkalosis that persisted in 73. Compared to control patients, persistently alkalotic patients were older, but gender, race, starting weight, comorbidities, and mortality did not differ. Dialysis dose was 7% greater, protein catabolic rate was 11% lower, and interdialytic weight gain was 29% lower, all p < 0.001. Persistently alkalotic patients had double the incidence of cardiac arrhythmias (p = 0.07) and a 20% greater intradialytic blood pressure decrease (p < 0.001). CONCLUSIONS: Alkalosis is common in hemodialysis patients and can be persistent, likely due to decreased protein catabolic rate and increased dialysis dose, and may have detrimental cardiovascular effects.

Point-of-Care Ultrasound Training during Nephrology Fellowship: A National Survey of Fellows and Program Directors.

BACKGROUND AND OBJECTIVES: Point-of-care ultrasound (POCUS)-performed by a clinician during a patient encounter and used in patient assessment and care planning-has many potential applications in nephrology. Yet, US nephrologists have been slow to adopt POCUS, which may affect the training of nephrology fellows. This study sought to identify the current state of POCUS training and implementation in nephrology fellowships. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Concise survey instruments measuring attitudes toward POCUS, its current use, fellow competence, and POCUS curricula were disseminated to (1) 912 US nephrology fellows taking the 2021 Nephrology In-Training Examination and (2) 229 nephrology training program directors and associate program directors. Fisher exact, chi-squared, and Wilcoxon rank sum tests were used to compare the frequencies of responses and the average responses between fellows and training program directors/associate program directors when possible. RESULTS: Fellow and training program directors/associate program directors response rates were 69% and 37%, respectively. Only 38% of fellows (240 respondents) reported receiving POCUS education during their fellowship, and just 33% of those who did receive POCUS training reported feeling competent to use POCUS independently. Similarly, just 23% of training program directors/associate program directors indicated that they had a POCUS curriculum in place, although 74% of training program directors and associate program directors indicated that a program was in development or that there was interest in creating a POCUS curriculum. Most fellow and faculty respondents rated commonly covered POCUS topics-including dialysis access imaging and kidney biopsy-as "important" or "very important," with the greatest interest in diagnostic kidney ultrasound. Guided scanning with an instructor was the highest-rated teaching strategy. The most frequently reported barrier to POCUS program development was the lack of available instructors. CONCLUSIONS: Despite high trainee and faculty interest in POCUS, the majority of current nephrology fellows are not receiving POCUS training. Hands-on training guided by an instructor is highly valued, yet availability of adequately trained instructors remains a barrier to program development. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_09_21_CJN01850222.mp3.

Impact of AJCC 8th edition staging system and definitive treatment choice on the prognosis of complete responders with p16+ and p16- oropharyngeal squamous cell carcinomas.

OBJECTIVES: To identify predictors of overall survival (OS) in oropharyngeal squamous cell carcinoma (OPSCC) patients who achieved complete response (CR). METHODS: We performed a retrospective study of OPSCC patients who achieved CR from a single academic medical center. Associations between OS, AJCC 8th edition staging system, definitive treatment choice, smoking history, and p16 status were assessed. RESULTS: p16+ status was associated with favorable prognosis for CR (p < 0.001) but not non-CR (p = 0.67) patients. For early stage, p16+ OPSCC patients who achieved CR, surgery + adjuvant radiation (RT) treatment was more durable compared to concurrent chemoradiation (CRT), particularly in smokers. CONCLUSIONS: Curative intent treatment choice and smoking history has an impact on the long-term OS of the CR p16+ OPSCC cohort. Prospective studies to define the optimal multi-modality treatment option to manage p16+ OPSCC patients is needed.

Repositioning Fenofibrate to Reactivate p53 and Reprogram the Tumor-Immune Microenvironment in HPV+ Head and Neck Squamous Cell Carcinoma.

Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV- HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.

Impact of p16 Status and Anatomical Site in Anti-PD-1 Immunotherapy-Treated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Patients.

In head and neck squamous cell carcinoma (HNSCC), anti-PD-1 inhibitors are approved for recurrent/metastatic (R/M) disease and anticipated to expand to other indications. The impact of p16 status and anatomical site on overall survival (OS) in immunotherapy-treated HNSCC patients remains unresolved. We performed a retrospective analysis of R/M HNSCC patients receiving anti-PD-1 immunotherapy at our academic medical center with an extensive community satellite network. Fifty-three R/M HNSCC patients were treated with anti-PD-1 immunotherapy and had a median OS of 6 months. Anatomical site was associated with distinct OS; oropharynx and larynx patients have superior OS compared to oral cavity patients. Analysis of the OPSCC subset showed p16+ status as a favorable, independent prognostic biomarker (HR 7.67 (1.23-47.8); p = 0.029). Further studies to assess the link between anatomical site, p16 status, and anti-PD-1 treatment outcomes in large cohorts of R/M HNSCC patients managed in real-world clinical practices and clinical trials should be prioritized.

SCU-Net: A deep learning method for segmentation and quantification of breast arterial calcifications on mammograms.

PURPOSE: Measurements of breast arterial calcifications (BAC) can offer a personalized, non-invasive approach to risk-stratify women for cardiovascular diseases such as heart attack and stroke. We aim to detect and segment breast arterial calcifications in mammograms accurately and suggest novel measurements to quantify detected BAC for future clinical applications. METHODS: To separate BAC in mammograms, we propose a lightweight fine vessel segmentation method Simple Context U-Net (SCU-Net). Due to the large image size of mammograms, we adopt a patch-based way to train SCU-Net and obtain the final whole-image-size results by stitching patchwise results together. To further quantify calcifications, we test five quantitative metrics to inspect the progression of BAC for subjects: sum of mask probability metric ( P M ), sum of mask area metric ( A M ), sum of mask intensity metric ( S I M ), sum of mask area with threshold intensity metric T A M X , and sum of mask intensity with threshold X metric T S I M X . Finally, we demonstrate the ability of the metrics to longitudinally measure calcifications in a group of 26 subjects and evaluate our quantification metrics compared with calcified voxels and calcium mass on breast CT for 10 subjects. RESULTS: Our segmentation results are compared with state-of-the-art network architectures based on recall, precision, accuracy, F1 score/Dice score, and Jaccard index evaluation metrics and achieve corresponding values of 0.789, 0.708, 0.997, 0.729, and 0.581 for whole-image-size results. The quantification results all show >95% correlation between quantification measures on predicted masks of SCU-Net as compared to the groundtruth and measurement of calcification on breast CT. For the calcification quantification measurement, our calcification volume (voxels) results yield R2 -correlation values of 0.834, 0.843, 0.832, 0.798, and 0.800 for the P M , A M , S I M , T A M 100 , T S I M 100 metrics, respectively; our calcium mass results yield comparable R2 -correlation values of 0.866, 0.873, 0.840, 0.774, and 0.798 for the same metrics. CONCLUSIONS: Simple Context U-Net is a simple method to accurately segment arterial calcification retrospectively on routine mammograms. Quantification of the calcifications based on this segmentation in the retrospective cohort study has sufficient sensitivity to detect the normal progression over time and should be useful for future research and clinical applications.

African Americans With p16+ and p16- Oropharyngeal Squamous Cell Carcinomas Have Distinctly Poor Treatment Outcomes Independent of Medical Care Access.

PURPOSE: Human papilloma virus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), diagnosed with p16 immunohistochemistry, is associated with favorable prognosis; however, this connection was established using European American (EA)-skewed populations. The impact of p16/human papillomavirus status on outcomes in African American (AA) OPSCC patients remains to be settled. In this study, we determine the association between cancer disparity and p16 status in an OPSCC cohort controlling for time to treatment initiation (TTI), a surrogate for medical care access. MATERIALS AND METHODS: We analyzed data from all patients diagnosed with OPSCC (N = 440) between 2010 and 2017, who received treatment at our academic medical center. Associations between age, disease stage, sex, p16 status, race, TTI, and overall survival (OS) were investigated. RESULTS: TTI was similar between AA and EA OPSCC patients in our p16+ (P = .291) or p16- (P = .715) cohorts. Among p16+ OPSCC patients, the median OS was > 8.65 years for EA patients compared with 5.038 years (95% CI, 2.019 to 5.30; P = .003, log-rank) for AA patients. For p16- patients, the median OS was 5.74 years (95% CI, 3.32 to 6.99) for EA patients and 1.85 years (95% CI, 0.978 to 4.50; P = .03, log-rank) for AA patients. Multivariate Cox regression analysis showed that race was an independent prognostic biomarker and the most impactful co-variate for OS (hazard ratio, 0.40; 95% CI, 0.00 to 0.69; P = .001). CONCLUSION: Our work showed that AAs with p16+ OPSCC have surprisingly poor clinical outcomes and are thus poor candidates for treatment de-escalation regimens. Caution should be exercised when extending clinical guidelines based on EA-majority studies to non-EA populations.

Plasma cell marker, immunoglobulin J polypeptide, predicts early disease-specific mortality in HPV+ HNSCC.

BACKGROUND: Patients with human papillomavirus (HPV+) head and neck squamous cell carcinoma (HNSCC) have superior prognoses compared with patients with HPV- HNSCC and strategies for treatment de-escalation are under investigation for the HPV+ setting. However, the survival advantage associated with HPV is not universal, and a subset of patients with HPV+ HNSCC fail definitive treatment and progress with metastatic/recurrent disease. Currently, no biomarker is available to distinguish aggressive from indolent HPV+ HNSCC. Immune dysfunction facilitates tumorigenesis and is associated with poor treatment response; therefore, we hypothesized that diminished intratumoral immune cell functionality may be attractive biomarkers to identify patients with HPV+ HNSCC at risk for early disease-specific mortality. METHODS: This is a retrospective analysis of The Cancer Genome Atlas (TCGA) HPV+ HNSCC cohort. RESULTS: Immunoglobulin J polypeptide (IGJ), uniquely expressed in plasma cells, showed a broad expression range in HPV+ HNSCC. Cox regression model, adjusting for clinical covariates, indicated that IGJ is an independent prognostic biomarker for disease-specific survival (DSS) and overall survival (OS). Patients with low IGJ had a 7.2-fold (p<0.001) increase in risk of disease-specific death with a median DSS of 13 months. Low IGJ showed an area under curve (AUC) of 0.89 with 91.0% sensitivity and 87.6% specificity to identify early disease-specific mortality (defined as DSS ≤12 months). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed a global dampening of immune pathways in low IGJ tumors. CONCLUSIONS: Our work showed that IGJ is a robust and independent prognostic biomarker for disease-specific mortality in HPV+ HNSCC. Patient with HPV+ HNSCC with limited adaptive immune functionality should not be candidates for treatment de-escalation modalities.

Vascular Calcification Slows But Does Not Regress After Kidney Transplantation.

INTRODUCTION: Medial arterial calcification is a common and progressive lesion in end-stage renal disease that is associated with poor cardiovascular outcomes. Whether this lesion can be arrested or reversed is unknown, and was examined retrospectively by measuring progression of breast arterial calcification before and after kidney transplantation. METHODS: Arterial calcification was measured on serial mammograms from patients with previous kidney transplantation and compared to measurements performed before transplantation or in patients on the active waitlist. Serum creatinine >2.0 mg/dl after transplantation or warfarin use were exclusions. RESULTS: Median (interquartile range) progression of arterial calcification was 12.9 mm/breast per year (5.9 to 32.6) in 34 patients before or awaiting transplantation compared to just 1.2 mm/breast per year (-0.54 to 5.1) in 34 patients after transplantation (P < 0.001). Slowing of progression was also seen in longitudinal analyses of patients with mammograms performed both before and after transplantation. Duration of end-stage renal disease before transplantation but not age, diabetes, baseline calcification, or serum chemistries correlated with progression after transplantation. Significant regression was not observed in any patient. CONCLUSION: In this first quantitative study of the effect of kidney transplantation, medial arterial calcification appeared to slow to rates seen in patients with normal renal function, indicating that the effect of renal failure may be completely abrogated. Overall, however, there was no significant regression, suggesting that calcification is irreversible and emphasizing the importance of prevention. Duration of pretransplant end-stage renal disease but not baseline calcification was a determinant of progression, consistent with cumulative, permanent changes to arteries that promote calcification.

Cerebral blood flow regulation in end-stage kidney disease.

Patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD) experience an increased risk of cerebrovascular disease and cognitive dysfunction. Hemodialysis (HD), a major modality of renal replacement therapy in ESKD, can cause rapid changes in blood pressure, osmolality, and acid-base balance that collectively present a unique stress to the cerebral vasculature. This review presents an update regarding cerebral blood flow (CBF) regulation in CKD and ESKD and how the maintenance of cerebral oxygenation may be compromised during HD. Patients with ESKD exhibit decreased cerebral oxygen delivery due to anemia, despite cerebral hyperperfusion at rest. Cerebral oxygenation further declines during HD due to reductions in CBF, and this may induce cerebral ischemia or "stunning." Intradialytic reductions in CBF are driven by decreases in cerebral perfusion pressure that may be partially opposed by bicarbonate shifts during dialysis. Intradialytic reductions in CBF have been related to several variables that are routinely measured in clinical practice including ultrafiltration rate and blood pressure. However, the role of compensatory cerebrovascular regulatory mechanisms during HD remains relatively unexplored. In particular, cerebral autoregulation can oppose reductions in CBF driven by reductions in systemic blood pressure, while cerebrovascular reactivity to CO2 may attenuate intradialytic reductions in CBF through promoting cerebral vasodilation. However, whether these mechanisms are effective in ESKD and during HD remain relatively unexplored. Important areas for future work include investigating potential alterations in cerebrovascular regulation in CKD and ESKD and how key regulatory mechanisms are engaged and integrated during HD to modulate intradialytic declines in CBF.

Warfarin Accelerates Medial Arterial Calcification in Humans.

OBJECTIVE: Warfarin is associated with medial arterial calcification in humans, but the magnitude and specificity of this effect and the role of other risk factors are unknown. Using serial mammograms, progression of arterial calcification was compared in women receiving no anticoagulants, warfarin, or other anticoagulants, and before, during, and after warfarin use. Approach and Results: Warfarin users with mammograms were identified by computerized searches of medical records that included renal function and diabetes mellitus. Lengths of calcified arterial segments were measured, with progression expressed as millimeters per breast per year and presented as medians and interquartile range (IQR). In women with normal renal function (estimated glomerular filtration rate >60 mL/minute per 1.73 m2), progression was 3.9-fold greater in warfarin users: 9.9 (3.8-16) versus 2.5 (0.7-6.7) in controls, P=0.0003, but not increased in users of other anticoagulants. In longitudinal analyses, progression increased from 2.1 (IQR, 0.3-3.9) to 13.8 (IQR, 7.8-38.7; P=0.011) after starting warfarin (n=11) and decreased from 8.8 (IQR, 1.1-10) to 1.9 (IQR, -10 to 6.7; P=0.024) after discontinuation of warfarin (n=13). Progression of calcification was similar in warfarin users with chronic kidney disease (7.3 [IQR, 3.6-17], n=29) but markedly accelerated in warfarin users with end-stage renal disease (47 [IQR, 31-183], n=11; P=0.0002). Progression was similar in diabetic and nondiabetic warfarin users (10.1 [IQR, 3.8-24] versus 7.8 [IQR, 3.6-15]) and did not correlate with age (r=0.09) or duration of warfarin therapy (r=0.12). CONCLUSIONS: Warfarin significantly accelerates medial arterial calcification in humans. This effect is markedly augmented in end-stage renal disease.

Progression of Medial Arterial Calcification in CKD.

INTRODUCTION: Medial arterial calcification is common in chronic kidney disease (CKD) and portends poor clinical outcomes, but its progression relative to the severity of CKD and the role of other risk factors is unknown because of the lack of reliable quantification. METHODS: Calcification of breast arteries detected by mammography, which is exclusively medial and correlates with medial calcification in peripheral arteries and with cardiovascular outcomes, was used to measure the progression of medial arterial calcification in women with CKD and end-stage renal disease (ESRD). Measurements showed intra- and interobserver correlations of 0.98, an interstudy variability of 8% to 11%, and a correlation with computed tomographic measurements of 0.92. RESULTS: Progression of calcification was measured in 60 control subjects (estimated glomerular filtration rate (eGFR) ≥ 90 ml/min per 1.73 m2) and 137 subjects with CKD (eGFR < 90 ml/min per 1.73 m2). Progression in control subjects was linear over time and independent of age. The rate of progression was increased in CKD but only at eGFR < 40 ml/min per 1.73 m2 (median, 8.1 vs. 3.9 mm/breast/yr in controls; P = 0.006). Progression accelerated markedly in subjects with ESRD (median, 20 mm/breast/yr; n = 36), but did not differ from controls after kidney transplantation (n = 25). Diabetes significantly augmented progression in subjects with CKD and ESRD but not in controls. CONCLUSION: Mammography is a convenient and reliable method to measure the progression of medial arterial calcification. Progression does not increase until advanced stages of CKD, accelerates markedly in ESRD, and returns to control rates after kidney transplantation. Diabetes significantly increases progression in CKD and ESRD.