Metabolites Associated with Polygenic Risk of Breast Cancer.

While hundreds of germline genetic variants have been associated with breast cancer risk, the mechanisms underlying the impacts of most of these variants on breast cancer remain uncertain. Metabolomics may offer valuable insights into the mechanisms underlying genetic risks of breast cancer. Among 143 cancer-free female participants, we used linear regression analyses to explore associations between the genetic risk of breast cancer, as determined by a previously developed polygenic risk score (PRS) that included 266 single-nucleotide polymorphisms (SNPs), and 223 measures of metabolites obtained from blood samples using nuclear magnetic resonance (NMR). A false discovery rate of 10% was applied to account for multiple comparisons. PRS was statistically significantly associated with 45 metabolite measures. These were primarily measures of very low-density lipoproteins (VLDLs) and high-density lipoproteins (HDLs), including triglycerides, cholesterol, and phospholipids. For example, the strongest effect was observed with the percent ratio of medium VLDL triglycerides to total lipids (0.53 unit increase in mean-standardized ln-transformed percent ratio per unit increase in PRS; q = 0.1). While larger-scale studies are needed to confirm these results, this exploratory study presents biologically plausible findings that are consistent with previously reported associations between lipids and breast cancer risk. If confirmed, these lipids could be targeted for lifestyle and pharmaceutical interventions among women at increased genetic risk of breast cancer.

Disentangling the relationships of body mass index and circulating sex hormone concentrations in mammographic density using Mendelian randomization.

PURPOSE: Mammographic density phenotypes, adjusted for age and body mass index (BMI), are strong predictors of breast cancer risk. BMI is associated with mammographic density measures, but the role of circulating sex hormone concentrations is less clear. We investigated the relationship between BMI, circulating sex hormone concentrations, and mammographic density phenotypes using Mendelian randomization (MR). METHODS: We applied two-sample MR approaches to assess the association between genetically predicted circulating concentrations of sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG)], BMI, and mammographic density phenotypes (dense and non-dense area). We created instrumental variables from large European ancestry-based genome-wide association studies and applied estimates to mammographic density phenotypes in up to 14,000 women of European ancestry. We performed analyses overall and by menopausal status. RESULTS: Genetically predicted BMI was positively associated with non-dense area (IVW: ß = 1.79; 95% CI = 1.58, 2.00; p = 9.57 × 10-63) and inversely associated with dense area (IVW: ß = - 0.37; 95% CI = - 0.51,- 0.23; p = 4.7 × 10-7). We observed weak evidence for an association of circulating sex hormone concentrations with mammographic density phenotypes, specifically inverse associations between genetically predicted testosterone concentration and dense area (ß = - 0.22; 95% CI = - 0.38, - 0.053; p = 0.009) and between genetically predicted estradiol concentration and non-dense area (ß = - 3.32; 95% CI = - 5.83, - 0.82; p = 0.009), although results were not consistent across a range of MR approaches. CONCLUSION: Our findings support a positive causal association between BMI and mammographic non-dense area and an inverse association between BMI and dense area. Evidence was weaker and inconsistent for a causal effect of circulating sex hormone concentrations on mammographic density phenotypes. Based on our findings, associations between circulating sex hormone concentrations and mammographic density phenotypes are weak at best.

Novel renal injury markers in dogs with ehrlichiosis.

Canine monocytic ehrlichiosis (CME) has been observed to impact renal function. Currently, the recognition of acute kidney injury is through the nonspecific biomarker serum creatinine (sCr). Novel markers of renal injury such as urinary clusterin (uClust) and urinary cystatin B (uCysB) may increase our understanding of the relationship between ehrlichiosis and renal cellular injury. The aim of this study was to evaluate novel renal injury biomarkers in dogs with acute CME. Twenty healthy dogs were enrolled in the control group (CG), and 16 dogs naturally infected with Ehrlichia canis were included in the Ehrlichia Group (EG). All dogs were followed for 45 days. EG dogs were treated with doxycycline twice daily for the first 30 days. Urine and serum were collected at: 0, 0.5, 1, 15, 30, and 45 days after start of treatment. Urine concentrations of uClust and uCysB were determined using a research ELISA immunoassay. A linear mixed model was used to estimate population mean of renal injury markers with patient as the random effect, and day and treatment as fixed effects. EG was observed to have higher uClust values compared to CG (estimated population mean EG: 213 ng/dL vs. CG: 84 ng/dL, P < 0.001). EG was observed to have higher uCysB values compared to CG (estimated population mean EG: 248 ng/dL vs. CG: 38 ng/dL, P < 0.001). Increases in uCysB and uClust suggest the presence of renal injury and a possible mechanism for the observed predisposition to chronic kidney disease in dogs with ehrlichiosis.

Antihypertensive medications and risk of colorectal cancer in British Columbia.

Introduction: There is conflicting evidence for the association between antihypertensive medications and colorectal cancer risk, possibly reflecting methodological limitations of previously conducted studies. Here, we aimed to clarify associations between commonly prescribed antihypertensive medication classes and colorectal cancer risk in a large, retrospective, cohort study. Methods: Using linked administrative data between 1996 and 2017 from British Columbia, we identified a cohort of 1,693,297 men and women who were 50 years of age or older, initially cancer-free and nonusers of antihypertensive medications. Medication use was parameterized as ever use, cumulative duration, and cumulative dose. Cox proportional hazard models were used to estimate hazard ratios (HRs) and associated 95% confidence intervals (95% CIs) for associations of time-varying medication use [angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), beta-blockers (BBs), calcium channel blockers (CCBs), and diuretics] with colorectal cancer risk. Results: There were 28,460 incident cases of colorectal cancer identified over the follow-up period (mean = 12.9 years). When medication use was assessed as ever/never, diuretics were associated with increased risk of colorectal cancer (HR 1.08, 95% CI 1.04-1.12). However, no similar association was observed with cumulative duration or cumulative dose of diuretics. No significant associations between the other four classes of medications and colorectal cancer risk were observed. Conclusion: No compelling evidence of associations between antihypertensive medications and colorectal cancer were observed.

Provincial variation in colorectal cancer screening adherence in Canada; evidence from the Canadian Partnership for Tomorrow's Health.

Introduction: Although colorectal cancer (CRC) screening program is proven to reduce CRC incidence and mortality, understanding patterns and predictors of suboptimal adherence in screening program requires further investigation in Canada. Methods: We used self-reported data from five regional cohorts of the Canadian Partnership for Tomorrow's Health (CanPath), namely the BC Generations Project (BCGP), Alberta's Tomorrow Project (ATP), the Ontario Health Study (OHS), Quebec's CARTaGENE, and the Atlantic Partnership for Tomorrow's Health Study (Atlantic PATH). We stratified participants into the following four risk categories: 1) age 50-74 years, 2) family history in a first-degree relative, 3) personal history of chronic inflammatory bowel disease and/or polyps, and 4) co-existence of personal risk and family history. Multivariable logistic regression was used to identify predictors of adherence to the screening guidelines. Results: Adherence to CRC screening varied considerably between regions, ranging from 16.6% in CARTaGENE to 47.7% in OHS. Compared to the largest cohort OHS, the likelihood of non-adherence to CRC screening was significantly higher in BCGP (OR 1.15, 95% CI 1.11-1.19), the Atlantic PATH (OR 1.90, 95% CI 1.82-1.99) and CARTaGENE (OR 5.10, 95% CI 4.85-5.36). Low physical activity, current smoking, presence of personal risk, family history of CRC significantly reduced the likelihood of adherence to screening recommendations. Discussion/conclusion: Compared to the national target of ≥ 60% for participation in CRC screening, adherence to regular CRC screening was suboptimal in this cohort of Canadians and varied by region. Further efforts are needed to identify the specific barriers to screening adherence in different provinces and across risk categories.

Diabetes medications and cancer risk associations: a systematic review and meta-analysis of evidence over the past 10 years.

Diabetes medications may modify the risk of certain cancers. We systematically searched MEDLINE, Embase, Web of Science, and Cochrane CENTRAL from 2011 to March 2021 for studies evaluating associations between diabetes medications and the risk of breast, lung, colorectal, prostate, liver, and pancreatic cancers. A total of 92 studies (3 randomized controlled trials, 64 cohort studies, and 25 case-control studies) were identified in the systematic review, involving 171 million participants. Inverse relationships with colorectal (n = 18; RR = 0.85; 95% CI = 0.78-0.92) and liver cancers (n = 10; RR = 0.55; 95% CI = 0.46-0.66) were observed in biguanide users. Thiazolidinediones were associated with lower risks of breast (n = 6; RR = 0.87; 95% CI = 0.80-0.95), lung (n = 6; RR = 0.77; 95% CI = 0.61-0.96) and liver (n = 8; RR = 0.83; 95% CI = 0.72-0.95) cancers. Insulins were negatively associated with breast (n = 15; RR = 0.90; 95% CI = 0.82-0.98) and prostate cancer risks (n = 7; RR = 0.74; 95% CI = 0.56-0.98). Positive associations were found between insulin secretagogues and pancreatic cancer (n = 5; RR = 1.26; 95% CI = 1.01-1.57), and between insulins and liver (n = 7; RR = 1.74; 95% CI = 1.08-2.80) and pancreatic cancers (n = 8; RR = 2.41; 95% CI = 1.08-5.36). Overall, biguanide and thiazolidinedione use carried no risk, or potentially lower risk of some cancers, while insulin secretagogue and insulin use were associated with increased pancreatic cancer risk.

Associations between perceptions of shared decision making and health among hysterectomy patients: A prospective observational study.

OBJECTIVE: To investigate patient and clinical factors that are associated with perceptions of shared decision making between hysterectomy patients and surgeons and to evaluate associations between shared decision making and postoperative health. METHODS: This study is based on a prospective cohort scheduled for hysterectomy for benign conditions in Vancouver, Canada. Validated patient-reported outcomes assessed shared decision making, pelvic health, depression, and pain. Regression analyses measured the association between perceptions of shared decision making with patient and clinical factors. Then, associations between shared decision making with postoperative pelvic health, pain and depression were evaluated using regression analysis and adjusted for patient and clinical factors. RESULTS: In this study, 308 participants completed preoperative measures, and a subset of 146 participants also completed the postoperative measures. More than 50% of participants reported less than optimal shared decision making scores. No significant associations were identified between patients' perceptions of shared decision making with patients' age, comorbidities, socioeconomic factors, indication for surgery, or preoperative depression and pain. Regression analyses found that higher/better self-reported shared decision making scores were associated with fewer postoperative pelvic organ symptoms (P = 0.01). CONCLUSION: Many patients' reporting lower than optimal scores on the shared decision making instrument highlight the opportunity to improve surgeon-patient communication in this surgical cohort. Strengthening shared decision making between surgeons and their patients may be associated with improved self-reported postoperative health.

Mental health, cancer risk, and the mediating role of lifestyle factors in the CARTaGENE cohort study.

BACKGROUND: Evidence on the association between mental health disorders and cancer risk is inconclusive, despite well-established associations between mental health disorders and lifestyle factors such as smoking. This study examines the relationships between depression, anxiety and cancer risk, and the potential mediating effects of lifestyle factors. METHODS: A study of 34,571 participants aged 40-69 years in the CARTaGENE cohort was conducted. Depression was defined by questionnaire (PHQ-9), antidepressant use, and a composite of questionnaire, antidepressant use, or lifetime self-reported physician diagnosis. Anxiety was defined by questionnaire (GAD-7). Co-morbid depression and anxiety was also assessed. Cox regression models were used to investigate associations between mental health and risk of prostate, lung, and all cancers combined. Mediating effects of lifestyle factors were assessed using Baron and Kenny mediation criteria. RESULTS: There were positive associations between mental health disorders, all cancers and lung cancer risk, however with the exception of anxiety and lung cancer in women (Hazard Ratio [HR] = 1.67, 95% CI: 1.01-2.76), associations were attenuated with adjustment for sociodemographics, health status and lifestyle factors. In the mediation analysis, smoking accounted for 27%, 18%, and 26%, of the total effect between depression (PHQ-9), anxiety, and co-morbidity and lung cancer, respectively in women. In men, smoking accounted for 17% of the total effect between depression (PHQ-9, antidepressant, or lifetime self-report of physician diagnosis) and all cancers. CONCLUSIONS: Positive associations were observed between mental health disorders, all cancer and lung cancer risk, however most relationships were attenuated with adjustment for lifestyle factors. Smoking status mediated a significant proportion of the relationships between mental health disorders and cancer risk.

A comparison of patient-reported outcomes among Canadian women having hysterectomies.

PURPOSE: Many indications for hysterectomy can negatively affect patients' quality of life. This study uses patient-reported outcomes to measure changes in self-reported health among hysterectomy patients. METHOD: A prospective cohort of 294 hysterectomy patients completed patient-reported outcomes preoperatively and six months postoperatively in Vancouver, Canada. Patient-reported outcomes measured pelvic health, sexual function, pain, and depression. Changes in health were compared with paired t-tests, and multi-variable regression analysis measured associations between patient and clinical factors with postoperative outcomes RESULTS: Many patients reported improvements in health. Unadjusted analysis found that 65% of participants reported less pelvic distress, 55% reported less pain, and 47% reported less depression symptoms postoperatively. Multivariable regression analysis found that poorer preoperative health was associated with poorer postoperative outcomes in all domains of health measured (p-value < 0.01). Postoperative pain scores were lower (less pain) by 0.78 among residents of the most affluent neighborhoods (p-value = 0.02) compared to those in less affluent neighborhoods. Postoperative depression scores were 1.58 points worse among participants with endometriosis (p-value = 0.03) and 1.02 points worse among participants having abdominal surgery (p-value = 0.02). CONCLUSION: Many participants reported improvements in pelvic symptoms, pain, and depression after hysterectomy. Lower socioeconomic status patients may be at risk for reporting higher pain after surgery, and endometriosis patients may report higher depression. Further investigation is needed to determine effective interventions for the higher postoperative pain observed in this study for residents of less affluent neighborhoods.

Dietary Intake and the Neighbourhood Environment in the BC Generations Project.

Poor diet is a major risk factor for many chronic diseases including cancer. Understanding broader contextual factors that influence dietary intake is important for making tangible progress towards improving diet at the population level. This study investigated neighbourhood social and built environment factors and fruit and vegetable intake among ~28,000 adults aged 35−69 years within the BC Generations Project. Daily fruit and vegetable intake was categorized according to guidelines (≥5 servings/day vs. <5 servings/day). Geospatial characteristics included walkability, greenness, marginalization, and material and social deprivation, reflecting access to goods and amenities and social relationships. Generalized, linear mixed-effect models adjusted for sociodemographic factors and lifestyle variables were used to estimate the odds ratios (ORs). Participants living in neighbourhoods with greater material deprivation (e.g., OR = 0.77; 95% CI: 0.70−0.86 for very high material deprivation) and very high social deprivation (OR = 0.90; 95% CI: 0.82−0.99) were less likely to meet recommendations for fruit and vegetable consumption relative to those living in areas with very low material deprivation and very low social deprivation, respectively. Relative to participants living in areas with very low greenness, participants living in neighbourhoods with high (OR = 1.10, 95% CI 1.01−1.20) to very high (OR = 1.11, 95% CI 1.01−1.21) greenness were more likely to meet recommendations for fruits and vegetables. These findings highlight the complexity of dietary intake which may be shaped by multiple neighbourhood characteristics.

Colorectal Cancer and Onset of Anxiety and Depression: A Systematic Review and Meta-Analysis.

Research suggests that colorectal cancer (CRC) is associated with mental health disorders, primarily anxiety and depression. To synthesize this evidence, we conducted a systematic review and meta-analysis of studies evaluating the onset of anxiety and depression among patients with CRC. We searched EMBASE and Medline from inception to June 2022. We included original, peer-reviewed studies that: used an epidemiologic design; included patients with CRC and a comparator group of individuals without cancer; and evaluated anxiety and depression as outcomes. We used random effects models to obtain pooled measures of associations. Quality assessment was completed using the Newcastle-Ottawa scale. Of 7326 articles identified, 8 were eligible; of which 6 assessed anxiety and depression and 2 assessed depression only. Meta-analyses showed a non-significant association between CRC and anxiety (pooled HR 1.67; 95% CI 0.88 to 3.17) and a significant association between CRC and depression (pooled HR 1.78; 95% CI 1.23 to 2.57). Predictors of anxiety and depression among patients with CRC included clinical characteristics (e.g., comorbidities, cancer stage, cancer site), cancer treatment (e.g., radiotherapy, chemotherapy, colostomy), and sociodemographic characteristics (e.g., age, sex). The impacts of anxiety and depression in patients with CRC included increased mortality and decreased quality of life. Altogether, our systematic review and meta-analysis quantified the risks and impacts of CRC on anxiety and depression, particularly an increased risk of depression after CRC diagnosis. Findings provide support for oncologic care that encompasses mental health supports for patients with CRC.

Healthcare Workers' Low Knowledge of Female Genital Schistosomiasis and Proposed Interventions to Prevent, Control, and Manage the Disease in Zanzibar.

Objectives: This study was conducted to explore healthcare workers' knowledge of female genital schistosomiasis (FGS) and describe proposed interventions to raise awareness about FGS and strengthen healthcare facilities' capacity to manage FGS cases. Methods: We conducted four cross-sectional focus group discussions and 16 key informant interviews with purposively selected healthcare workers in Zanzibar. Discussions and interviews were digitally recorded, transcribed, and analyzed using NVivo software. Results: Most participants had limited or no knowledge of FGS and lacked skills for managing it. They confused FGS with urogenital schistosomiasis and thought it was sexually transmitted. A few participants knew about FGS and associated it with Human Immunodeficiency Virus (HIV), ectopic pregnancy, cervical cancer, and infertility. To prevent and control FGS, participants proposed interventions targeting communities (including community-based health education) and the healthcare system (including training healthcare workers on FGS). Conclusion: Healthcare workers lacked knowledge of and skills for managing FGS. Besides, healthcare facilities had no diagnostic capacity to manage FGS. Along with on-going interventions to break S. haematobium transmission and eventually eliminate urogenital schistosomiasis in Zanzibar, we recommend training healthcare workers on FGS and equip healthcare facilities with medical equipment and supplies for managing FGS.

A genome-wide gene-based gene-environment interaction study of breast cancer in more than 90,000 women.

Background: Genome-wide association studies (GWAS) have identified more than 200 susceptibility loci for breast cancer, but these variants explain less than a fifth of the disease risk. Although gene-environment interactions have been proposed to account for some of the remaining heritability, few studies have empirically assessed this. Methods: We obtained genotype and risk factor data from 46,060 cases and 47,929 controls of European ancestry from population-based studies within the Breast Cancer Association Consortium (BCAC). We built gene expression prediction models for 4,864 genes with a significant (P<0.01) heritable component using the transcriptome and genotype data from the Genotype-Tissue Expression (GTEx) project. We leveraged predicted gene expression information to investigate the interactions between gene-centric genetic variation and 14 established risk factors in association with breast cancer risk, using a mixed-effects score test. Results: After adjusting for number of tests using Bonferroni correction, no interaction remained statistically significant. The strongest interaction observed was between the predicted expression of the C13orf45 gene and age at first full-term pregnancy (PGXE=4.44×10-6). Conclusion: In this transcriptome-informed genome-wide gene-environment interaction study of breast cancer, we found no strong support for the role of gene expression in modifying the associations between established risk factors and breast cancer risk. Impact: Our study suggests a limited role of gene-environment interactions in breast cancer risk.

Projected Impact of Weight Gain During the COVID-19 Pandemic on the Future Burden of Cancer in Canada.

The COVID-19 pandemic and resulting public health measures have had significant impacts on daily life, including shifts in health behaviours which contribute to weight gain and may increase subsequent risk of chronic diseases such as cancer. Using OncoSim, a web-based microsimulation tool, we estimated the future burden of cancer in Canada by incorporating data on unintentional weight gain among adults during the first year of the COVID-19 pandemic. Population impact measures were estimated until 2042, assuming a 12-year latency period. We estimated 14,194 excess cancer cases and 5,324 excess cancer deaths by 2042 due to COVID-19 related weight gain. Particularly large impacts were estimated for endometrial and breast cancer among women, with 2,983 and 2,151 excess cases by 2042. For men, 1,700 excess colorectal cases and 1,188 excess kidney cancer cases were projected by 2042. Changes in health behavior during the COVID-19 pandemic are likely to have significant and long-lasting impacts on cancer burden. These projections highlight the immediate need for investment into the development and implementation of effective cancer prevention strategies.

Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies.

BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. CONCLUSIONS: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Relevance of the MHC region for breast cancer susceptibility in Asians.

BACKGROUND: Human leukocyte antigen (HLA) genes play critical roles in immune surveillance, an important defence against tumors. Imputing HLA genotypes from existing single-nucleotide polymorphism datasets is low-cost and efficient. We investigate the relevance of the major histocompatibility complex region in breast cancer susceptibility, using imputed class I and II HLA alleles, in 25,484 women of Asian ancestry. METHODS: A total of 12,901 breast cancer cases and 12,583 controls from 12 case-control studies were included in our pooled analysis. HLA imputation was performed using SNP2HLA on 10,886 quality-controlled variants within the 15-55 Mb region on chromosome 6. HLA alleles (n = 175) with info scores greater than 0.8 and frequencies greater than 0.01 were included (resolution at two-digit level: 71; four-digit level: 104). We studied the associations between HLA alleles and breast cancer risk using logistic regression, adjusting for population structure and age. Associations between HLA alleles and the risk of subtypes of breast cancer (ER-positive, ER-negative, HER2-positive, HER2-negative, early-stage, and late-stage) were examined. RESULTS: We did not observe associations between any HLA allele and breast cancer risk at P < 5e-8; the smallest p value was observed for HLA-C*12:03 (OR = 1.29, P = 1.08e-3). Ninety-five percent of the effect sizes (OR) observed were between 0.90 and 1.23. Similar results were observed when different subtypes of breast cancer were studied (95% of ORs were between 0.85 and 1.18). CONCLUSIONS: No imputed HLA allele was associated with breast cancer risk in our large Asian study. Direct measurement of HLA gene expressions may be required to further explore the associations between HLA genes and breast cancer risk.

Evaluation of renal injury and function biomarkers, including symmetric dimethylarginine (SDMA), in the rat passive Heymann nephritis (PHN) model.

Symmetric dimethylarginine (SDMA) is a serum biomarker of excretory renal function which consistently correlates with glomerular filtration rate (GFR) across multiple species including rats, dogs, and humans. In human and veterinary clinical settings SDMA demonstrates enhanced sensitivity for detection of declining renal function as compared to other serum biomarkers, but application in preclinical study designs thus far has been limited. The purpose of this study was to determine the performance of serum SDMA in a rat passive Heyman nephritis model of glomerulopathy. In addition to SDMA other biomarkers of excretory renal function were measured including serum creatinine (sCr), blood urea nitrogen (BUN), and cystatin C along with creatinine clearance. Urinary renal biomarkers including microalbumin (µALB), clusterin (CLU), cystatin C, kidney injury marker-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were also measured. PHN was induced using commercial sheep anti-Fx1A serum. Tissue, serum, and urine were collected from groups of control and anti-Fx1A-treated animals for biomarker evaluation, hematology, urinalysis, serum biochemistry, and histologic examination of kidney. Over the course of a 28-day study, concentrations of the urinary biomarkers µALB, CLU, cystatin C, NGAL, KIM-1 and the serum biomarker cystatin C increased significantly in anti-Fx1A-treated rats as compared to controls but no significant increase in serum SDMA, sCr, BUN, or creatinine clearance were noted in anti-Fx1A-treated rats. Given lack of direct GFR measurement or significant change in the renal function biomarkers sCr, BUN, and creatinine clearance, it is unclear if GFR differed significantly between control and anti-Fx1A-treated rats in this study, though urinary biomarkers and histopathologic findings supported renal injury in anti-Fx1A-treated rats over the time course investigated. This study is among the first to investigate serum SDMA in a rat model relevant to preclinical safety assessment and serves to inform future experimental designs and biomarker selection when evaluation of glomerular injury is of priority.