Risk Factors for Chronic Obstructive Pulmonary Disease Exacerbations among Individuals without a History of Recent Exacerbations: A COPDGene Analysis.

Rationale: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are detrimental events in the natural history of COPD, but the risk factors associated with future exacerbations in the absence of a history of recent exacerbations are not fully understood. Objectives: To identify risk factors for COPD exacerbations among participants in the Genetic Epidemiology of COPD Study (COPDGene) without a history of exacerbation in the previous year. Methods: We identified participants with a smoking history enrolled in COPDGene who had COPD (defined as forced expiratory volume in 1 second [FEV1]/forced vital capacity < 0.70), no exacerbation in the year before their second study site visit, and who completed at least one longitudinal follow-up questionnaire in the following 36 months. We used univariable and multivariable zero-inflated negative binomial regression models to identify risk factors associated with increased rates of exacerbation. Each risk factor's regression coefficient (ß) was rounded to the nearest 0.25 and incorporated into a graduated risk score. Results: Among the 1,528 participants with a smoking history and COPD enrolled in COPDGene without exacerbation in the year before their second study site visit, 508 participants (33.2%) had at least one moderate or severe exacerbation in the 36 months studied. Gastroesophageal reflux disease, chronic bronchitis, high symptom burden (as measured by Modified Medical Research Council Dyspnea Scale and COPD Assessment Test), and lower FEV1% predicted were associated with an increased risk of exacerbation. Each 1-point increase in our graduated risk score was associated with a 25-30% increase in exacerbation rate in the 36 months studied. Conclusions: In patients with COPD without a recent history of exacerbations, gastroesophageal reflux disease, chronic bronchitis, high symptom burden, and lower lung function are associated with increased risk of future exacerbation using a simple risk score that can be used in clinical practice.

Discriminative Accuracy of the CAPTURE Tool for Identifying Chronic Obstructive Pulmonary Disease in US Primary Care Settings.

Importance: Chronic obstructive pulmonary disease (COPD) is underdiagnosed in primary care. Objective: To evaluate the operating characteristics of the CAPTURE (COPD Assessment in Primary Care To Identify Undiagnosed Respiratory Disease and Exacerbation Risk) screening tool for identifying US primary care patients with undiagnosed, clinically significant COPD. Design, Setting, and Participants: In this cross-sectional study, 4679 primary care patients aged 45 years to 80 years without a prior COPD diagnosis were enrolled by 7 primary care practice-based research networks across the US between October 12, 2018, and April 1, 2022. The CAPTURE questionnaire responses, peak expiratory flow rate, COPD Assessment Test scores, history of acute respiratory illnesses, demographics, and spirometry results were collected. Exposure: Undiagnosed COPD. Main Outcomes and Measures: The primary outcome was the CAPTURE tool's sensitivity and specificity for identifying patients with undiagnosed, clinically significant COPD. The secondary outcomes included the analyses of varying thresholds for defining a positive screening result for clinically significant COPD. A positive screening result was defined as (1) a CAPTURE questionnaire score of 5 or 6 or (2) a questionnaire score of 2, 3, or 4 together with a peak expiratory flow rate of less than 250 L/min for females or less than 350 L/min for males. Clinically significant COPD was defined as spirometry-defined COPD (postbronchodilator ratio of forced expiratory volume in the first second of expiration [FEV1] to forced vital capacity [FEV1:FVC] <0.70 or prebronchodilator FEV1:FVC <0.65 if postbronchodilator spirometry was not completed) combined with either an FEV1 less than 60% of the predicted value or a self-reported history of an acute respiratory illness within the past 12 months. Results: Of the 4325 patients who had adequate data for analysis (63.0% were women; the mean age was 61.6 years [SD, 9.1 years]), 44.6% had ever smoked cigarettes, 18.3% reported a prior asthma diagnosis or use of inhaled respiratory medications, 13.2% currently smoked cigarettes, and 10.0% reported at least 1 cardiovascular comorbidity. Among the 110 patients (2.5% of 4325) with undiagnosed, clinically significant COPD, 53 had a positive screening result with a sensitivity of 48.2% (95% CI, 38.6%-57.9%) and a specificity of 88.6% (95% CI, 87.6%-89.6%). The area under the receiver operating curve for varying positive screening thresholds was 0.81 (95% CI, 0.77-0.85). Conclusions and Relevance: Within this US primary care population, the CAPTURE screening tool had a low sensitivity but a high specificity for identifying clinically significant COPD defined by presence of airflow obstruction that is of moderate severity or accompanied by a history of acute respiratory illness. Further research is needed to optimize performance of the screening tool and to understand whether its use affects clinical outcomes.

Artificial Intelligence-Enabled Electrocardiogram for Atrial Fibrillation Identifies Cognitive Decline Risk and Cerebral Infarcts.

OBJECTIVE: To investigate whether artificial intelligence-enabled electrocardiogram (AI-ECG) assessment of atrial fibrillation (AF) risk predicts cognitive decline and cerebral infarcts. PATIENTS AND METHODS: This population-based study included sinus-rhythm ECG participants seen from November 29, 2004 through July 13, 2020, and a subset with brain magnetic resonance imaging (MRI) (October 10, 2011, through November 2, 2017). The AI-ECG score of AF risk calculated for participants was 0-1. To determine the AI-ECG-AF relationship with baseline cognitive dysfunction, we compared linear mixed-effects models with global and domain-specific cognitive z-scores from longitudinal neuropsychological assessments. The AI-ECG-AF score was logit transformed and modeled with cubic splines. For the brain-MRI subset, logistic regression evaluated correlation of the AI-ECG-AF score and the high-threshold, dichotomized AI-ECG-AF score with infarcts. RESULTS: Participants (N=3729; median age, 74.1 years) underwent cognitive analysis. Adjusting for age, sex, education, and APOE ɛ4-carrier status, the AI-ECG-AF score correlated with lower baseline and faster decline in global-cognitive z-scores (P=.009 and P=.01, respectively, non-linear-based spline-models tests) and attention z-scores (P<.001 and P=.01, respectively). Sinus-rhythm-ECG participants (n=1373) underwent MRI. As a continuous measure, the AI-ECG-AF score correlated with infarcts but not after age and sex adjustment (P=.52). For dichotomized analysis, an AI-ECG-AF score greater than 0.5 correlated with infarcts (OR, 4.61; 95% CI, 2.45-8.55; P<.001); even after age and sex adjustment (OR, 2.09; 95% CI, 1.06-4.07; P=.03). CONCLUSION: The AI-ECG-AF score correlated with worse baseline cognition and gradual global cognition and attention decline. High AF probability by AI-ECG-AF score correlated with MRI cerebral infarcts. However, most infarcts observed in our cohort were subcortical, suggesting that AI-ECG not only predicts AF but also detects other non-AF cardiac disease markers and correlates with small vessel cerebrovascular disease and cognitive decline.

Incidence, Risk Factors, and Outcomes of Stroke Following Cardiac Transplantation.

Background and Purpose: Less is known about the risk factors and outcomes associated with stroke in the current era of increasing heart transplantation (HT) being performed in older patients. The impact of immunosuppression on risk of stroke has not yet been previously studied. We aimed to determine the incidence, risk factors and outcomes of stroke after HT. Methods: We retrospectively analyzed the incidence of ischemic and hemorrhagic strokes and associated outcomes in all consecutive HT recipients transplanted between 1994 and 2016 at a single institution. Results: Of 529 patients who underwent HT, 57 (10.7%) developed stroke, 8.1% had an ischemic events and (2.6%) had a hemorrhagic stroke. Age at HT (adjusted hazard ratio [HR] 1.33; P=0.03) and diabetes (HR, 2.60; P=0.02) were associated with increased risk of ischemic events. Patients with stroke (any type) were more likely to have worse kidney function (HR, 1.81; P=0.02) whereas patients with ischemic events were more likely to undergo combined organ transplantation (HR, 2.01; P=0.05). Cytomegalovirus infection was found to be associated with increased risk of any stroke (HR, 2.09; P=0.02).Conversion from calcineurin inhibitor to sirolimus-based immunosuppression was not found to be associated with a significant change in stroke risk (HR, 1.39; P=0. 45) compared with calcineurin inhibitor maintenance therapy. Stroke of any type and ischemic events were independently associated with increased risk of death (HR, 1.90; P=0.001 and HR, 2.14; P<0.001, respectively). Conclusions: Stroke after HT is associated with increased mortality. Older age at HT, diabetes, renal dysfunction, and CMV infection were associated with greater risk of stroke.

Association of Aspirin Treatment With Cardiac Allograft Vasculopathy Progression and Adverse Outcomes After Heart Transplantation.

BACKGROUND: Enhanced platelet reactivity may play a role in cardiac allograft vasculopathy (CAV) progression. The use of antiplatelet agents after heart transplantation (HT) has been inconsistent and although aspirin (ASA) is often a part of the medication regimen after HT, limited evidence is available on its benefit. METHODS AND RESULTS: CAV progression was assessed by measuring the difference in plaque volume and plaque index between the last follow-up and the baseline coronary intravascular ultrasound examination. Overall, 529 HT recipients were retrospectively analyzed (337 had ≥2 intravascular ultrasound studies). The progression in plaque volume (P = .007) and plaque index (P = .002) was significantly attenuated among patients treated with early ASA (within the first year after HT). Over a 6.7-year follow-up, all-cause mortality was lower with early ASA compared with late or no ASA use (P < .001). No cardiac deaths were observed in the early ASA group, and the risk of CAV-related graft dysfunction was significantly lower in this group (P = .03). However, the composite of all CAV-related events (cardiac death, CAV-related graft dysfunction, or coronary angioplasty) was not significantly different between the groups (P = .16). CONCLUSIONS: Early ASA use after HT may delay CAV progression and decrease mortality and CAV-related graft dysfunction, but does not seem to affect overall CAV-associated events.

Genetic Predictors of Chemotherapy-Induced Peripheral Neuropathy from Paclitaxel, Carboplatin and Oxaliplatin: NCCTG/Alliance N08C1, N08CA and N08CB Study.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially permanent adverse effect of chemotherapeutic agents including taxanes such as paclitaxel and platinum-based compounds such as oxaliplatin and carboplatin. Previous studies have suggested that genetics may impact the risk of CIPN. We conducted genome-wide association studies (GWASs) for CIPN in two independent populations who had completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-CIPN20 assessments (a CIPN-specific 20-item questionnaire which includes three scales that evaluate sensory, autonomic, and motor symptoms). The study population N08Cx included 692 participants from three clinical trials (North Central Cancer Treatment Group (NCCTG) N08C1, N08CA, and N08CB) who had been treated with paclitaxel, paclitaxel plus carboplatin, or oxaliplatin. The primary endpoint for the GWAS was the change from pre-chemotherapy CIPN20 sensory score to the worse score over the following 18 weeks. Study population The Mayo Clinic Breast Disease Registry (MCBDR) consisted of 381 Mayo Clinic Breast Disease Registry enrollees who had been treated with taxane or platinum-based chemotherapy. The primary endpoint for the GWAS assessed was the earliest CIPN20 sensory score available after the completion of chemotherapy. In multivariate model analyses, chemotherapy regimen (p = 3.0 × 10-8) and genetic ancestry (p = 0.007) were significantly associated with CIPN in the N08Cx population. Only age (p = 0.0004) was significantly associated with CIPN in the MCBDR population. The SNP most associated with CIPN was rs56360211 near PDE6C (p =7.92 × 10-8) in N08Cx and rs113807868 near TMEM150C in the MCBDR (p = 1.27 × 10-8). Due to a lack of replication, we cannot conclude that we identified any genetic predictors of CIPN.

Hypomagnesemia at the time of autologous stem cell transplantation for patients with diffuse large B-cell lymphoma is associated with an increased risk of failure.

Magnesium is an essential element that is involved in critical metabolic pathways. A diet deficient in magnesium is associated with an increased risk of developing cancer. Few studies have reported whether a serum magnesium level below the reference range (RR) is associated with prognosis in patients with diffuse large B cell lymphoma (DLBCL). Using a retrospective approach in DLBCL patients undergoing autologous stem cell transplant (AHSCT), we evaluated the association of hypomagnesemia with survival. Totally, 581 patients eligible for AHSCT with a serum magnesium level during the immediate pre-transplant period were identified and 14.1% (82/581) had hypomagnesemia. Hypomagnesemia was associated with an inferior event-free (EFS) and overall survival (OS) compared to patients with a serum magnesium level within RR; median EFS: 3.9 years (95% CI: 1.63-8.98 years) versus 6.29 years (95% CI: 4.73-8.95 years) with HR 1.63 (95% CI: 1.09-2.43, p = 0.017) for EFS, and median OS: 7.3 years (95% CI: 2.91-upper limit not estimable) versus 9.7 years (95% CI: 6.92-12.3 years) with HR 1.90 (95% CI: 1.22-2.96, p = 0.005) for OS months 0-12, respectively. These findings suggest a potentially actionable prognostic factor for patients with DLBCL undergoing AHSCT.

Genetic Variations and Health-Related Quality of Life (HRQOL): A Genome-Wide Study Approach.

Health-related quality of life (HRQOL) is an important prognostic patient-reported outcome in oncology. Because prior studies suggest that HRQOL is, in part, heritable, we performed a GWAS to elucidate genetic factors associated with HRQOL in breast cancer survivors. Physical and mental HRQOL were measured via paper surveys that included the PROMIS-10 physical and mental health domain scales in 1442 breast cancer survivors participating in the Mayo Clinic Breast Disease Registry (MCBDR). In multivariable regression analyses, age and financial concerns were significantly associated with global physical health (age: p = 1.6 × 10-23; financial concerns: p = 4.8 × 10-40) and mental health (age: p = 3.5 × 10-7; financial concerns: p = 2.0 × 10-69). Chemotherapy was associated with worse global mental health (p = 0.01). In the GWAS, none of the SNPs reached the genome-wide association significance threshold of 5 × 10-8 for associations with either global physical or global mental health, however, a cluster of SNPs in SCN10A, particularly rs112718371, appeared to be linked to worse global physical health (p = 5.21 × 10-8). Additionally, SNPs in LMX1B, SGCD, PARP12 and SEMA5A were also moderately associated with worse physical and mental health (p < 10-6). These biologically plausible candidate SNPs warrant further study as possible predictors of HRQOL.

Comparison of the current renal staging, progression and response criteria to predict renal survival in AL amyloidosis using a Mayo cohort.

Three sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5-5.3, p = .001] and 2.5 [CI: 1.4-4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17-0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post-treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post-treatment. These differences are important when choosing endpoints for clinical trials.

Kidney Microstructural Features at the Time of Donation Predict Long-term Risk of Chronic Kidney Disease in Living Kidney Donors.

OBJECTIVE: To determine whether microstructural features on a kidney biopsy specimen obtained during kidney transplant surgery predict long-term risk of chronic kidney disease in the donor. PATIENTS AND METHODS: We studied kidney donors from May 1, 1999, through December 31, 2018, with a follow-up survey for the results of recent blood pressure and kidney function tests (estimated glomerular filtration rate [eGFR] and proteinuria). If not recently available, blood pressure and eGFRs were requested from a local clinic. Microstructural features on kidney biopsy at the time of donation were assessed as predictors of hypertension and kidney function after adjusting for years of follow-up, baseline age, sex, and clinical predictors. RESULTS: There were 807 donors surveyed a mean 10.5 years after donation. An eGFR less than 45 mL/min/1.73 m2 in 6.4% (43/673) of donors was predicted by larger glomerular volume per standard deviation (odds ratio [OR], 1.48; 95% CI, 1.08 to 2.04) and nephron number below the age-specific 5th percentile (OR, 3.38; 95% CI, 1.31 to 8.72). An eGFR less than 60 mL/min/1.73 m2 in 42.5% (286/673) of donors was not predicted by any microstructural feature. Residual eGFR (postdonation/predonation eGFR) was predicted by nephron number below the age-specific 5th percentile (difference, -6.07%; 95% CI, -10.24% to -1.89%). Self-reported proteinuria in 5.1% (40/786) of donors was predicted by larger glomerular volume (OR, 1.42; 95% CI, 1.08 to 1.86). Incident hypertension in 18.8% (119/633) of donors was not predicted by any microstructural features. CONCLUSION: Low nephron number for age and larger glomeruli are important microstructural predictors for long-term risk of chronic kidney disease after living kidney donation.

Artificial Intelligence-Electrocardiography to Predict Incident Atrial Fibrillation: A Population-Based Study.

BACKGROUND: An artificial intelligence (AI) algorithm applied to electrocardiography during sinus rhythm has recently been shown to detect concurrent episodic atrial fibrillation (AF). We sought to characterize the value of AI-enabled electrocardiography (AI-ECG) as a predictor of future AF and assess its performance compared with the CHARGE-AF score (Cohorts for Aging and Research in Genomic Epidemiology-AF) in a population-based sample. METHODS: We calculated the probability of AF using AI-ECG, among participants in the population-based Mayo Clinic Study of Aging who had no history of AF at the time of the baseline study visit. Cox proportional hazards models were fit to assess the independent prognostic value and interaction between AI-ECG AF model output and CHARGE-AF score. C statistics were calculated for AI-ECG AF model output, CHARGE-AF score, and combined AI-ECG and CHARGE-AF score. RESULTS: A total of 1936 participants with median age 75.8 (interquartile range, 70.4-81.8) years and median CHARGE-AF score 14.0 (IQR, 13.2-14.7) were included in the analysis. Participants with AI-ECG AF model output of >0.5 at the baseline visit had cumulative incidence of AF 21.5% at 2 years and 52.2% at 10 years. When included in the same model, both AI-ECG AF model output (hazard ratio, 1.76 per SD after logit transformation [95% CI, 1.51-2.04]) and CHARGE-AF score (hazard ratio, 1.90 per SD [95% CI, 1.58-2.28]) independently predicted future AF without significant interaction (P=0.54). C statistics were 0.69 (95% CI, 0.66-0.72) for AI-ECG AF model output, 0.69 (95% CI, 0.66-0.71) for CHARGE-AF, and 0.72 (95% CI, 0.69-0.75) for combined AI-ECG and CHARGE-AF score. CONCLUSIONS: In the present study, both the AI-ECG AF model output and CHARGE-AF score independently predicted incident AF. The AI-ECG may offer a means to assess risk with a single test and without requiring manual or automated clinical data abstraction.

Weight loss over time and survival: a landmark analysis of 1000+ prospectively treated and monitored lung cancer patients.

BACKGROUND: Eligibility criteria and endpoints for cancer cachexia trials-and whether weight loss should be included-remain controversial. Although most cachexia trials enrol patients after initial cancer diagnosis, few studies have addressed whether weight loss well after a cancer diagnosis is prognostic. METHODS: We pooled data from non-small cell lung cancer patients from prospectively conducted trials within the Alliance for Clinical Trials in Oncology (1998-2008), a nationally funded infrastructure. We examined (i) weight data availability and weight changes and (ii) survival. RESULTS: A total of 822 patients were examined. Of these, 659 (80%) were on treatment at the beginning of Cycle 2 of chemotherapy; weight was available for 656 (80%). By Cycles 3 and 4, weight was available for 448 (55%) and 384 (47%), respectively. From baseline to immediately prior to Cycle 2, 208 (32%) gained weight; 225 (34%) lost <2% of baseline weight; and 223 (34% of 656) lost 2% or more. Median survival from the beginning of Cycle 2 was 13.0, 10.9, and 6.9 months for patients with weight gain, weight loss of <2%, and weight loss of 2% or more, respectively. In multivariate analyses, adjusted for age, sex, performance score, type of treatment, and body mass index, weight loss of 2% or more was associated with poor overall survival compared with weight gain [hazard ratio (HR) = 1.66; 95% confidence interval (CI): 1.33-2.07; P < 0.001] and compared with weight loss of <2% (HR = 1.57; 95% CI: 1.27-1.95; P < 0.001). Although weight loss of <2% was not associated with poorer overall survival compared with weight gain, it was associated with poorer progression-free survival (HR = 1.24; 95% CI: 1.01-1.51; P = 0.036). Similar findings were observed in a separate 255-patient validation cohort. CONCLUSIONS: Weight should be integrated into cancer cachexia trials because of its ease of frequent measurement and sustained prognostic association.

Patient factors associated with discrepancies between patient-reported and clinician-documented peripheral neuropathy in women with breast cancer receiving paclitaxel: A pilot study.

PURPOSE: Discrepancies between clinicians' assessment of chemotherapy-induced peripheral neuropathy (CIPN) and patient-reported outcomes (PRO) have been described, though the underlying reasons are unknown. Our objective was to identify potential patient-specific factors associated with under-describing of CIPN to clinicians in women with non-metastatic breast cancer treated with paclitaxel. METHODS: Patients enrolled in an observational study (n = 60) completed weekly CIPN PRO using the EORTC CIPN20. Clinician-documented CIPN using the NCI CTCAE were abstracted from the electronic medical record and paired with CIPN20 data at weeks 7 and 10. Patients were classified as under-describers if their CIPN20 was above the 80th percentile of the CIPN20 distribution for that CTCAE grade from an independent clinical trial (N08CA). Demographics, Assessment of Survivor Concerns (ASC), Trust in Oncologist Scale (TiOS), and health literacy assessment were collected post-treatment via survey. Repeated measures cumulative logistic regression models were used to identify factors associated with under-describing CIPN. RESULTS: Forty-two women completed the survey (response rate 70%). Three and 9 patients were categorized as under-describers at weeks 7 and 10, respectively. Women who were not working (OR = 9.00, 95%CI 1.06-76.15), had lower income (OR = 7.04, 95%CI 1.5-32.99), and displayed higher trust in their oncologist's competence (OR = 1.29, 95%CI 1.03-1.62 for a 0.1-unit increase in score) were more likely to under-describe CIPN symptoms. CONCLUSIONS: This preliminary study identified non-working status, low income and trust in oncologist's competence as potential factors influencing under-description of CIPN to the clinical team. Further work is needed to clarify these relationships and test additional factors.

Neurological safety of oxaliplatin in patients with uncommon variants in Charcot-Marie-tooth disease genes.

Oxaliplatin therapy can be complicated by chemotherapy-induced peripheral neuropathy (CIPN). Other neurotoxic chemotherapies have been linked to single nucleotide variants (SNV) in Charcot-Marie-Tooth disease (CMT) genes. Whether oxaliplatin carries increased risks of CIPN due to SNV in CMT-associated genes is unknown. 353 patients receiving oxaliplatin in NCCTG N08CB were serially evaluated for CIPN using a validated patient-reported outcome (PRO) instrument, the CIPN20 questionnaire (sensory scale). 49 canonical CMT-associated genes were analyzed for rare and common SNV by nextgen sequencing. The 157 patients with the highest and lowest susceptibility to CIPN (cases and controls) harbored 270 non-synonymous SNV in CMT-associated genes (coding regions). 143 of these were rare, occurring only once ("singletons"). CIPN cases had 0.84 singletons per patient compared with 0.98 in controls. An imbalance in favor of cases was noted only in few genes including PRX, which was previously highlighted as a candidate CIPN gene in patients receiving paclitaxel. However, the imbalance was only modest (5 singleton SNV in cases and 2 in controls). Therefore, while singleton SNV were common, they did overall not portend an increased risk of CIPN. Furthermore, testing CMT-associated genes using recurrent non-synonymous SNV did not reveal any significant association with CIPN. Genetic analysis of patients from N08CB provides clinical guidance that oxaliplatin chemotherapy decisions should not be altered by the majority of SNV that may be encountered in CMT-associated genes when common genetic tests are performed, such as exome or genome sequencing. Oxaliplatin's CIPN risk appears unrelated to CMT-associated genes.

Kidney Structural Features from Living Donors Predict Graft Failure in the Recipient.

BACKGROUND: Nephrosclerosis, nephron size, and nephron number vary among kidneys transplanted from living donors. However, whether these structural features predict kidney transplant recipient outcomes is unclear. METHODS: Our study used computed tomography (CT) and implantation biopsy to investigate donated kidney features as predictors of death-censored graft failure at three transplant centers participating in the Aging Kidney Anatomy study. We used global glomerulosclerosis, interstitial fibrosis/tubular atrophy, artery luminal stenosis, and arteriolar hyalinosis to measure nephrosclerosis; mean glomerular volume, cortex volume per glomerulus, and mean cross-sectional tubular area to measure nephron size; and calculations from CT cortical volume and glomerular density on biopsy to assess nephron number. We also determined the death-censored risk of graft failure with each structural feature after adjusting for the predictive clinical characteristics of donor and recipient. RESULTS: The analysis involved 2293 donor-recipient pairs. Mean recipient follow-up was 6.3 years, during which 287 death-censored graft failures and 424 deaths occurred. Factors that predicted death-censored graft failure independent of both donor and recipient clinical characteristics included interstitial fibrosis/tubular atrophy, larger cortical nephron size (but not nephron number), and smaller medullary volume. In a subset with 12 biopsy section slides, arteriolar hyalinosis also predicted death-censored graft failure. CONCLUSIONS: Subclinical nephrosclerosis, larger cortical nephron size, and smaller medullary volume in healthy donors modestly predict death-censored graft failure in the recipient, independent of donor or recipient clinical characteristics. These findings provide insights into a graft's "intrinsic quality" at the time of donation, and further support the use of intraoperative biopsies to identify kidney grafts that are at higher risk for failure.

Glomerular Volume and Glomerulosclerosis at Different Depths within the Human Kidney.

BACKGROUND: Age, CKD risk factors, and kidney function are associated with larger glomerular volume and a higher percentage of globally sclerotic glomeruli. Knowledge of how these associations may differ by cortical depth is limited. METHODS: To investigate glomerular volume and glomerulosclerosis across different depths of cortex, we studied wedge sections of the renal parenchyma from 812 patients who underwent a radical nephrectomy (for a tumor), separately characterizing glomeruli in the superficial (subcapsular), middle, and deep (juxtamedullary) regions. We compared the association of mean nonsclerotic glomerular volume and of glomerulosclerosis (measured as the percentage of globally sclerotic glomeruli) with age, obesity, diabetes, smoking, kidney function, and structural pathology in the superficial, middle, and deep regions. RESULTS: The superficial, middle, and deep regions showed significant differences in glomerular volume (0.0025, 0.0031, and 0.0028 µm3, respectively) and in glomerulosclerosis (18%, 7%, and 11%, respectively). There was a marked increase in glomerulosclerosis with age in the superficial region, but larger glomerular volume was not associated with age at any cortical depth. Glomerulosclerosis associated more strongly with arteriosclerosis and ischemic-appearing glomeruli in the superficial region. Hypertension, lower eGFR, and interstitial fibrosis associated with glomerulosclerosis and glomerular volume to a similar extent at any depth. Diabetes and proteinuria more strongly associated with glomerulosclerosis in the deep and middle regions, respectively, but neither associated with glomerular volume differently by depth. Obesity associated more strongly with glomerular volume in the superficial cortex. CONCLUSIONS: Most clinical characteristic show similar associations with glomerulosclerosis and glomerulomegaly at different cortical depths. Exceptions include age-related glomerulosclerosis, which appears to be an ischemic process and is more predominant in the superficial region.

Global Glomerulosclerosis in Kidney Biopsies With Differing Amounts of Cortex: A Clinical-Pathologic Correlation Study.

RATIONALE & OBJECTIVE: The number of glomeruli is often used to determine the adequacy of a kidney biopsy (eg, at least 10 glomeruli). It is often assumed that biopsy specimens with limited amounts of cortex are too imprecise for detection of focal pathology. STUDY DESIGN: Clinical-pathologic correlation (cross-sectional). SETTING & PARTICIPANTS: Living kidney donors who underwent a needle core biopsy of their kidney at the time of donation. EXPOSURE: The amount of cortex biopsied as determined by either the number of glomeruli or area of cortex on histology. OUTCOME: The percentage of globally sclerotic glomeruli, density of interstitial fibrosis foci, and severity of arteriosclerosis were determined. ANALYTICAL APPROACH: A beta-binomial model assessed how the mean percentage of globally sclerotic glomeruli and patient variability in percentage of globally sclerotic glomeruli differed with the number of glomeruli on the biopsy specimen. Additional models assessed the association of interstitial fibrosis and arteriosclerosis with number of glomeruli. RESULTS: There were 2,915 kidney donors studied. Fewer glomeruli on the biopsy specimen associated with higher mean percentage of globally sclerotic glomeruli and higher patient variability in percentage of globally sclerotic glomeruli. Smaller cortical volume on imaging correlated with both less cortex on biopsy and higher percentage of globally sclerotic glomeruli. Based on a statistical simulation, the probability of patient percentage of globally sclerotic glomeruli ≥ 10% if the biopsy percentage of globally sclerotic glomeruli is ≥10% (positive predictive value) was 45% with 1 to 9 glomeruli versus 31% with 10 or more glomeruli; the negative predictive value was 91% versus 98%. Fewer glomeruli also associated with more interstitial fibrosis and arteriosclerosis. LIMITATIONS: The study was limited to living kidney donors. Patient variability in percentage of globally sclerotic glomeruli was based on a statistical model because multiple biopsy specimens per patient were not available. CONCLUSIONS: The amount of cortex on a needle core biopsy is not completely random. Chronic changes from loss of cortex contribute to low amounts of cortex on a kidney biopsy specimen.