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BACKGROUND Eligibility for glucagon-like peptide 1 receptor agonists (GLP-1RA) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) has been expanded to patients with diabetes at lower cardiovascular risk, but whether treatment benefits differ by risk levels is not clear. PURPOSE To investigate whether patients with varying risks differ in cardiovascular and renal benefits from GLP-1RA and SGLT2i with use of meta-analysis and meta-regression. DATA SOURCES We performed a systematic review using PubMed through 7 November 2022. STUDY SELECTION We included reports of GLP-1RA and SGLT2i confirmatory randomized trials in adult patients with safety or efficacy end point data. DATA EXTRACTION Hazard ratio (HR) and event rate data were extracted for mortality, cardiovascular, and renal outcomes. DATA SYNTHESIS We analyzed 9 GLP-1RA and 13 SGLT2i trials comprising 154,649 patients. Summary HRs were significant for cardiovascular mortality (GLP-1RA 0.87 and SGLT2i 0.86), major adverse cardiovascular events (0.87 and 0.88), heart failure (0.89 and 0.70), and renal (0.84 and 0.65) outcomes. For stroke, efficacy was significant for GLP-1RA (0.84) but not for SGLT2i (0.92). Associations between control arm cardiovascular mortality rates and HRs were nonsignificant. Five-year absolute risk reductions (0.80–4.25%) increased to 11.6% for heart failure in SGLT2i trials in patients with high risk (Pslope < 0.001). For GLP1-RAs, associations were nonsignificant. LIMITATIONS Analyses were limited by lack of patient-level data, consistency in end point definitions, and variation in cardiovascular mortality rates for GLP-1RA trials. CONCLUSIONS Relative effects of novel diabetes drugs are preserved across baseline cardiovascular risk, whereas absolute benefits increase at higher risks, particularly regarding heart failure. Our findings suggest a need for baseline risk assessment tools to identify variation in absolute treatment benefits and improve decision-making.

Background: Prior research suggests cardiovascular (CV) benefits of glucose-lowering interventions may be mediated by changes in hemoglobin A1c (HbA1c), bodyweight, systolic blood pressure (SBP), hematocrit, and urine albumin-creatinine ratio (uACR). We evaluated the heterogeneity of CV benefits by these potential mediators for sodium-glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) using a meta-analytic approach. Methods: We performed a systematic review and meta-regression analyses of 12 SGLT2i and 9 GLP-1RA CV outcome trials using linear mixed models of treatment efficacy measured as log hazard ratios (HRs) vs changes in potential mediators. We extracted follow-up mediator data for treatment and control, preferably at 12 months post randomization. Outcomes included MI, stroke, and MACE (a composite of MI, stroke, or CV death). We investigated slope differences between drug classes using interaction terms and likelihood-ratio tests. Results: Treatment efficacy for MACE improved with more HbA1c reduction among GLP-1RA (slope .26; P slope .02) but not among SGLT2i trials (slope -.22; P slope .39; P interaction .06), see Figure . Treatment efficacy for MACE, MI, and stroke decreased with more weight loss for SGLT2i (slope –.17, –.29, –.39; P slope slope .30, .62, .32). Slopes differed significantly between drug classes: P interaction slope .07). We did not find any indication of mediation effects by SBP and uACR for SGLT2i or GLP-1RAs (slopes -.11 -.07; P slopes ≥ .05). Conclusion: We confirm previous findings of increased CV benefits with reductions in HbA1c for GLP1-RAs. Further research is needed to investigate the potential loss of SGLT2i efficacy with greater weight loss and increase in hematocrit.

Cardiovascular disease remains a leading cause of death and morbidity in kidney transplant recipients and a common reason for post-transplant hospitalization. Several traditional and nontraditional cardiovascular risk factors exist, and many of them present pretransplant and worsened, in part, due to the addition of immunosuppression post-transplant. We discuss optimal strategies for identification and treatment of these risk factors, including the emerging role of sodium-glucose cotransporter 2 inhibitors in post-transplant diabetes and cardiovascular disease. We present common types of cardiovascular disease observed after kidney transplant, including coronary artery disease, heart failure, pulmonary hypertension, arrhythmia, and valvular disease. We also discuss screening, treatment, and prevention of post-transplant cardiac disease. We highlight areas of future research, including the need for goals and best medications for risk factors, the role of biomarkers, and the role of screening and intervention.

Background Diastolic dysfunction is an early marker of cardiac pathology in end-stage kidney disease (ESKD) patients. The ratio of transmitral filling velocity (E) to early diastolic strain rate (E/e'sr) is a novel non-invasive marker of early left ventricular (LV) filling pressure obtained using two-dimensional speckle tracking echocardiography (2DSTE). Methods In a prospective cohort of kidney transplant (KTX) recipients with echocardiograms performed pre-transplant we obtained repeat echocardiograms at 6 months following transplant. All echocardiograms were analyzed using 2DSTE where E/e'sr and global longitudinal strain were obtained. Paired tests were used to assess changes to cardiac structure and function following KTX. Results A total of 33 patients were included in the study (mean age was 46.6 ± 13.7 years and 42% were males). The primary causes of ESKD in the cohort were glomerular disease (33%), hypertension (30%), and polycystic kidney disease (12%). The median (IQR) time spent on dialysis was 5.4 years [2.9, 7.7 years]. A reverse remodeling of the LV was observed following KTX as LV mass decreased (189.2 ± 57.5 g vs 171.1 ± 56.8 g, P = 0.014). LV filling pressure decreased as assessed by E/e'sr (103.7 ± 51.1 cm vs 72.6 ± 35.5 cm, P = 0.009). E to early diastolic mitral annular tissue velocity (E/e') did not change following KTX (9.9 ± 4.5 vs 10.3 ± 4.1, P = 0.54). Additionally, both LV internal diastolic and systolic diameter decreased significantly. Conclusion Reverse cardiac remodeling following KTX was observed as improvements in LV mass and LV dimensions. LV filling pressure improved as assessed by E/e'sr decreased following KTX, whereas E/e' did not change.

Despite improved life expectancy from a heart transplant, transplant recipients remain at high risk for renal dysfunction and failure, including end-stage kidney disease (ESKD). The onset of ESKD is a poor prognostic marker and is associated with increased mortality in this setting, as in others. There is a need to identify risk factors for ESKD among heart transplant recipients in contemporary settings.We conducted an analysis of adult heart transplant recipients transplanted between 2008 and 2021 in the Organ Procurement and Transplantation Network database. 22,737 adult recipients of heart transplant alone were included in this analysis. We examined LVEF measured 1 year after transplant, and LVEF updated annually for association with ESKD using multivariate Cox regression models.LVEF at 1-year after transplant was associated with ESKD in multivariate models (Hazard Ratio 1.33 per 10-unit decrease, 95% CI 1.23-1.43, p0.001). In multivariate models using categorized LVEF, mildly reduced ejection fraction (EF 40-50%) was associated with ESKD (HR 1.76, 95% CI 1.45-2.14, p0.001), as was reduced ejection fraction (EF40%, HR 2.86, 95% CI 2.01-4.07, p0.001), relative to individuals with preserved ejection fraction (EF50%). These associations were consistent when using annually updated ejection fraction.Post-transplant left ventricular ejection fraction has value in predicting end stage kidney disease among adults who receive heart transplant alone. LVEF is routinely measured as part of contemporary post heart transplant care, and a diminished LVEF should signal to clinicians that a recipient is at increased risk of renal failure. This article is protected by copyright. All rights reserved.

Background: Prior research suggests cardiovascular (CV) benefits of glucose-lowering interventions are mediated by bodyweight changes, either through changes in fluid retention or body fat mass. For example, a meta-regression analysis of 30 randomized trials on glucose lowering interventions showed a 1 kg weight decrease was associated with a 5.9% (95% CI 3.9 - 8.0) relative reduction of heart failure risk (Ghosh et al., 2020) . We evaluated heterogeneity of CV benefits by weight change for two novel diabetes medications that lower weight: sodium glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) . Methods: We performed meta-regression analyses of published CV outcome trials (6 on SGLT2i, 8 on GLP-1RAs) using reported hazard ratios (HRs) and bodyweight difference across study arms. Dependent variables included log HRs for 1) all-cause mortality, 2) major adverse cardiovascular events (MACE) , and 3) hospitalization for heart failure. We ran linear mixed models with weights equal to the inverse of the variance of each study’s log HR. Results: The slopes from meta-regressions by pooling all trials and by drug type (Figure) were not significant and in some cases demonstrated an inverse relationship (SGLT2i for MACE, slope= -.102; p= .04) . Conclusion: We could not reproduce findings of increased CV benefits with more weight loss for SGLT2i and GLP-1RAs. Disclosure J.M.Rodriguez-valadez: None. W.Max: None. K.Fleischmann: None. B.Ferket: None. M.Hunink: None. U.Masharani: Advisory Panel; Ryse Health, Research Support; Clementia Pharmaceuticals. J.Yeboah: None. M.Park: Advisory Panel; Otsuka America Pharmaceutical, Inc., Reata Pharmaceuticals, Inc., Other Relationship; Merck & Co., Inc. L.Li: None. E.Weber: None. Y.Li: None. A.Berkalieva: None. Funding Research reported in this publication was supported by the National Heart, Lung, And Blood Institute of the National Institutes of Health under Award Number R01HL153456. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Background: Prior meta-analyses suggest that the relative cardiovascular (CV) risk reduction by sodium glucose transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) is larger in established CV disease. We investigated heterogeneity of treatment benefits along the continuum of CV risk. Methods: We performed meta-regression analyses of CV outcome trials (9 on SGLT2i, 8 on GLP-1RAs) using log hazard ratios and CV mortality rates in the control group as proxy for baseline risk and background treatment profile of trial populations. We evaluated effects for all-cause mortality, major adverse cardiovascular events (MACE) , and heart failure. We computed absolute risk difference (ARD) in 5-year CV mortality for each trial and studied its relationship with baseline risk. Results: We did not find statistically significant associations between baseline risk and log hazard ratios for any outcome (slope range -.to .21; p>.10) . The ARD for 5-year CV mortality increased significantly with higher baseline risk for SGLT2i, to a predicted 2.78% in high risk (Figure) . For GLP1-RA trials, this relationship was not significant likely due to less variation in baseline risk. Conclusion: Absolute, but not relative, CV benefits of novel diabetes drugs depend on baseline risk, which is important in guiding treatment decisions based on risk stratification. Disclosure J.M.Rodriguez-valadez: None. W.Max: None. K.Fleischmann: None. B.Ferket: None. M.Hunink: None. U.Masharani: Advisory Panel; Ryse Health, Research Support; Clementia Pharmaceuticals. J.Yeboah: None. M.Park: Advisory Panel; Otsuka America Pharmaceutical, Inc., Reata Pharmaceuticals, Inc., Other Relationship; Merck & Co., Inc. L.Li: None. E.Weber: None. Y.Li: None. A.Berkalieva: None. Funding Research reported in this abstract was supported by the National Heart, Lung, And Blood Institute (NHLBI) of the National Institutes of Health under award number: R01HL153456. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

BACKGROUND: The optimal timing of dialysis access placement in individuals with stage 5 CKD is challenging to estimate. Preemptive living donor kidney transplant (LDKT) is the gold-standard treatment for ESKD due to superior graft survival and mortality, but dialysis initiation is often required. Among LDKT recipients, we sought to determine which clinical characteristics were associated with preemptive transplant. Among non–preemptive LDKT recipients, we sought to determine what dialysis access was used, and their duration of use before receipt of living donor transplant. METHODS: We retrospectively extracted data on 569 LDKT recipients, >18 years old, who were transplanted between January 2014 and July 2019 at UCSF, including dialysis access type (arteriovenous fistula [AVF], arteriovenous graft [AVG], peritoneal dialysis catheter [PD], and venous catheter), duration of dialysis, and clinical characteristics. RESULTS: Preemptive LDKT recipients constituted 30% of our cohort and were older, more likely to be White, more likely to have ESKD from polycystic kidney disease, and less likely to have ESKD from type 2 diabetes. Of the non–preemptive patients, 26% used AVF, 0.5% used AVG, 32% used peritoneal catheter, 11% used venous catheter, and 31% used more than one access type. Median (IQR) time on dialysis for AVF/AVG use was 1.86 (0.85–3.32) years; for PD catheters, 1.12 (0.55–1.92) years; for venous catheters, 0.66 (0.23–1.69) years; and for multimodal access, 2.15 (1.37–3.72) years. CONCLUSIONS: We characterized the dialysis access landscape in LDKT recipients. Venous catheter and PD were the most popular modality in the first quartile of dialysis, and patients using these modalities had shorter times on dialysis compared with those with an AVF. Venous catheter or PD can be considered a viable bridge therapy in patients with living donor availability given their shorter waitlist times. Earlier referral of patients with living donor prospects might further minimize dialysis need.

Introduction Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)–sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. Methods APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. Results The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. Conclusion This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation., Graphical abstract

The omission of outcomes that are of relevance to patients, clinicians, and regulators across trials in autosomal dominant polycystic kidney disease (ADPKD) limits shared decision making. The Standardized Outcomes in Nephrology-Polycystic Kidney Disease (SONG-PKD) Initiative convened an international consensus workshop on October 25, 2018, to discuss the identification and implementation of a potential core outcome set for all ADPKD trials. This article summarizes the discussion from the workshops and the SONG-PKD core outcome set. Key stakeholders including 11 patients/ caregivers and 47 health professionals (nephrologists, policy makers, industry, and researchers) attended the workshop. Four themes emerged: "Relevance of trajectory and impact of kidney function" included concerns about a patient's prognosis and uncertainty of when they may need to commence kidney replacement therapy and the lack of an early prognostic marker to inform long-term decisions; "Discerning and defining pain specific to ADPKD" highlighted the challenges in determining the origin of pain, adapting to the chronicity and repeated episodes of pain, the need to place emphasis on pain management, and to have a validated measure for pain; "Highlighting ADPKD consequences" encompassed cyst-related complications and reflected patient's knowledge because of family history and the hereditary nature of ADPKD; and "Risk for life-threatening but rare consequences" such as cerebral aneurysm meant considering both frequency and severity of the outcome. Kidney function, mortality, cardiovascular disease, and pain were established as the core outcomes for ADPKD.

Organ donors are systematically screened for infection, whereas screening for malignancy is less rigorous. The true incidence of donor-transmitted malignancies is unknown due to a lack of universal tumor testing in the posttransplant setting. Donor-transmitted malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. We describe the detection of a gastrointestinal adenocarcinoma transmitted from a young donor to 4 transplant recipients. Multidimensional histopathologic and genomic profiling showed aCDH1mutation andMETamplification, consistent with gastric origin. At the time of writing, one patient in this series remains alive and without evidence of cancer after prompt organ explant after cancer was reported in other recipients. Because identification of a donor-derived malignancy changes management, our recommendation is to routinely perform short tandem repeat testing (or a comparable assay) immediately upon diagnosis of cancer in any organ transplant recipient. Routine testing for a donor-origin cancer and centralized reporting of outcomes are necessary to establish a robust evidence base for the future development of clinical practice guidelines.

A 10-plex urine-based bladder cancer (BCa) diagnostic signature has the potential to non-invasively predict the presence of BCa in at-risk patients, as reported in various case-control studies. The present meta-analysis was performed to re-evaluate and demonstrate the robustness and consistency of the diagnostic utility of the 10-plex urine-based diagnostic assay. We re-analyzed primary data collected in five previously published case-control studies on the 10-plex diagnostic assay. Studies reported the sensitivity and specificity of ten urinary protein biomarkers for the detection of BCa, including interleukin 8, matrix metalloproteinases 9 and 10, angiogenin, apolipoprotein E, syndecan 1, alpha-1 antitrypsin, plasminogen activator inhibitor-1, carbonic anhydrase 9, and vascular endothelial growth factor A. Data were extracted and reviewed independently by two investigators. Log odds ratios (ORs) were calculated to determine how strongly the 10-plex biomarker panel and individual biomarkers are associated with the presence of BCa. Data pooled from 1,173 patients were analyzed. The log OR for each biomarker was improved by 1.5 or greater with smaller 95% CI in our meta-analysis of the overall cohort compared with each analysis of an individual cohort. The combination of the ten biomarkers showed a higher log OR (log OR: 3.46, 95% CI: 2.60-4.31) than did any single biomarker irrespective of histological grade or disease stage of tumors. We concluded that the 10-plex BCa-associated diagnostic signature demonstrated a higher potential to identify BCa when compared to any single biomarker. Our results justify further advancement of the 10-plex protein-based diagnostic signature toward clinical application.

Background and aimsTumor necrosis factor receptor type 1 (TNFR1) is associated with kidney disease and mortality risk in various populations. Whether or not kidney function mediates mortality risk is unknown. We evaluated associations of TNFR1 levels with measures of kidney function, cardiovascular events, and mortality in a population of veterans with stable ischemic heart disease.MethodsTNFR1 was measured from baseline serum samples in the Heart and Soul Study; elevated levels were defined by the highest quartile (Q4, >3.4ng/ml). We evaluated associations of high TNFR1 with baseline estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (ACR) and with longitudinal changes in eGFR (rapid loss), as well as with incident myocardial infarction (MI), heart failure hospitalizations (HF), and mortality over a median follow-up time of 8.9 years. Covariates included demographics and comorbid conditions.ResultsAmong 985 participants who had TNFR1 measurements, median TNFR1 was 2.33ng/ml (IQR 1.8-3.1). Relative to Q1, Q4 had higher risk of eGFR

Background and objectives CKD is an important risk factor for cardiovascular disease (CVD) and death. We investigated whether select urine kidney injury biomarkers were associated with higher risk of heart failure (HF), CVD, and death in persons with CKD enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. Design, setting, participants, & measurements Urine kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin, liver fatty acid-binding protein, and N -acetyl -β- d-glucosaminidase were measured in urine of a subset of CRIC participants ( n =2466). We used Cox proportional hazards regression to examine associations between these biomarkers indexed to urinary creatinine (Cr) and ( 1 ) HF, ( 2 ) a composite of atherosclerotic CVD events (myocardial infarction, ischemic stroke, or peripheral artery disease), and ( 3 ) all-cause death. Results At baseline, mean age of study participants was 59.5±10.8 years, 46% were women, and 34% had a self-reported history of any CVD. Median follow-up was 6.5 (interquartile range, 5.6–6.8) years. A total of 333 HF events, 282 atherosclerotic CVD events, and 440 deaths were observed during a median follow-up of 6.5 (interquartile range, 5.6–6.8) years. Those in the highest two quintiles of KIM-1/Cr levels had a higher risk of HF relative to the lowest quintile (quintile 5 versus quintile 1 adjusted hazard ratio [aHR] of 1.73 [95% confidence interval, 1.05 to 2.85]). N -acetyl -β- d-glucosaminidase/Cr was associated with HF in continuous analyses (aHR per log SD higher 1.18 [95% confidence interval, 1.01 to 1.38]). Only KIM-1/Cr was independently associated with atherosclerotic CVD events (aHR per log SD higher 1.21 [95% confidence interval, 1.02 to 1.41]), whereas both KIM-1/Cr (quintile 5 versus quintile 1 aHR of 1.56 [95% confidence interval, 1.06 to 2.31]) and neutrophil gelatinase-associated lipocalin/Cr (quintile 5 versus quintile 1 aHR of 1.82 [95% confidence interval, 1.19 to 2.8]) were associated with all-cause death. Conclusions Selected urine kidney injury biomarkers were independently associated with higher risk of HF, CVD events, and death in CRIC. Among the biomarkers examined, only KIM-1/Cr was associated with each outcome. Further work is needed to determine the utility of these biomarkers to improve risk prediction for these adverse outcomes.

BACKGROUND AND OBJECTIVES: Poor identification of individuals with CKD is a major barrier to research and appropriate clinical management of the disease. We aimed to develop and validate a pragmatic electronic (e-) phenotype to identify patients likely to have CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The e-phenotype was developed by an expert working group and implemented among adults receiving in- or outpatient care at five healthcare organizations. To determine urine albumin (UA) dipstick cutoffs for CKD to enable use in the e-phenotype when lacking urine albumin-to-creatinine ratio (UACR), we compared same day UACR and UA results at four sites. A sample of patients, spanning no CKD to ESKD, was randomly selected at four sites for validation via blinded chart review. RESULTS: The CKD e-phenotype was defined as most recent eGFR 90 days prior and/or a UACR of ≥30 mg/g in the most recent test with at least one positive value >90 days prior. Dialysis and transplant were identified using diagnosis codes. In absence of UACR, a sensitive CKD definition would consider negative UA results as normal to mildly increased (KDIGO A1), trace to 1+ as moderately increased (KDIGO A2), and ≥2+ as severely increased (KDIGO A3). Sensitivity, specificity, and diagnostic accuracy of the CKD e-phenotype were 99%, 99%, and 98%, respectively. For dialysis sensitivity was 94% and specificity was 89%. For transplant, sensitivity was 97% and specificity was 91%. CONCLUSIONS: The CKD e-phenotype provides a pragmatic and accurate method for EHR-based identification of patients likely to have CKD.

Author(s): Lentine, Krista L; Holscher, Courtenay M; Naik, Abhijit S; Lam, Ngan N; Segev, Dorry L; Garg, Amit X; Axelrod, David; Xiao, Huiling; Henderson, Macey L; Massie, Allan B; Kasiske, Bertram L; Hess, Gregory P; Hsu, Chi-Yuan; Park, Meyeon; Schnitzler, Mark A | Abstract: BackgroundLimited data are available regarding clinical implications of lower renal function after living kidney donation. We examined a novel integrated database to study associations between postdonation estimated glomerular filtration rate (eGFR) and use of antihypertensive medication (AHM) treatment after living kidney donation.MethodsStudy data were assembled by linking national U.S. transplant registry identifiers, serum creatinine (SCr) values from electronic medical records, and pharmacy fill records for 3222 living donors (1989-2016) without predonation hypertension. Estimated GFR (mL/min per 1.73 m2) was computed from SCr values by the CKD-EPI equation. Repeated measures multivariable mixed effects modeling examined the associations (adjusted odds ratio, 95%LCLaOR95% UCL) between AHM use and postdonation eGFR levels (random effect) with fixed effects for baseline donor factors.ResultsThe linked database identified an average of 3 postdonation SCr values per donor (range: 1-38). Lower postdonation eGFR (vs ≥75) bore graded associations with higher odds of AHM use (eGFR 30-44: aOR 0.951.472.26; l30: aOR 1.082.525.90). Other independent correlates of postdonation AHM use included older age at donation (aOR per decade: 1.081.231.40), black race (aOR 1.031.512.21), body mass index g 30 kg/m2 (aOR 1.011.452.09), first-degree donor-recipient relationship (aOR 1.071.381.79), "prehypertension" at donation (systolic blood pressure 120-139: aOR 1.101.461.94; diastolic blood pressure 80-89: aOR 1.061.451.99).ConclusionsThis novel linkage illustrates the ability to identify postdonation kidney function and associate it with clinically meaningful outcomes; lower eGFR after living kidney donation is a correlate of AHM treatment requirements. Further work should define relationships of postdonation renal function, hypertension, and other morbidity measures.

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.

Table S1A. Associations with GLS, Linear Regression (those who were on Beta blocker were excluded from analysis). Table S1B. Associations with E/SRe, Linear Regression (those who were on Beta blocker were excluded from analysis). Table S2A. Associations with GLS: Logistic regression (those who were on Beta blocker were excluded from analysis). Table S2B. Associations with E/SRe: Logistic regression (those who were on Beta blocker were excluded from analysis). (DOCX 18 kb)

414 Background: Donor-derived malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. Early recognition of donor-derived malignancy has treatment implications. We describe the molecular characterization of a gastric cancer transmitted from an organ donor to heart, liver (LR), left kidney (LKR), and right kidney-pancreas (KPR) recipients. Methods: IRB approval for chart review was obtained; LR, LKR, and KPR also provided research consent for molecular profiling. Short Tandem Repeat (STR) genotyping was performed by polymerase chain reaction and gel electrophoresis. Tumor and germline DNA from patients and the organ donor were subjected to next generation sequencing (NGS) of 479 genes. Fluorescence in situ hybridization (FISH) was used to confirm MET amplification. Results: Donor origin was established by STR analysis, with the tumors showing high levels of donor alleles. Pathology revealed a poorly differentiated adenocarcinoma with signet ring features. Immunohistochemical staining and CA-19-9 elevation were most consistent with gastric or pancreas origin. Tumor sequencing was notable for somatic mutation of CDH1, MET amplification and wild-type KRAS genes. Tumors from LR and KPR were nearly identical based on pathogenic variants, allele frequency, and copy number variation. Insufficient tumor cellularity in all LKR specimens precluded NGS profiling, but clinical testing found that the cancer was mismatch repair proficient; ERBB2 equivocal; and PDL-1 positive. A circulating tumor DNA test did not uncover any genomic alterations; however, MET amplification was confirmed in this tumor using FISH probes. Conclusions: STR analysis and reporting should be standard immediately following diagnosis of cancer in an organ transplant recipient to ascertain donor derivation. Further molecular characterization, including NGS, may aid in defining primary tumor origin. Here, diagnosis with PDL1-positive gastric cancer enabled use of pembrolizumab. One patient remains alive and without evidence of cancer following prompt organ explant after cancer was reported in other recipients.

Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disease. It carries high lifetime morbidity not only due to chronic kidney disease, but also due to a higher risk of cardiovascular death. Multiple metabolic abnormalities associated with ADPKD including insulin resistance and hyperlipidemia as well as subclinical cardiovascular abnormalities, such as left ventricular hypertrophy (LVH), contribute to this cardiovascular risk. These conditions may manifest before evidence of worsening estimated glomerular filtration rate (eGFR). Renal oxidative stress also occurs early in the disease and is a driver of ADPKD progression. Animal models have shown that calorie restriction may mitigate these inflammatory processes. Further research is required to show whether attenuation of metabolic abnormalities associated with ADPKD may improve renal and cardiovascular morbidity. .

Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys.

Recipients of kidney transplants (KTR) are at increased risk for cardiovascular events, graft failure, and death. It is unknown whether urine kidney injury biomarkers are associated with poor outcomes among KTRs. We conducted a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial using a case-cohort study design, selecting participants with adjudicated cardiovascular events, graft failure, or death. Urine neutrophil gelatinase–associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver–type fatty acid binding protein (L-FABP) were measured in spot urine samples and standardized to urine creatinine concentration. We adjusted for demographics, cardiovascular risk factors, eGFR, and urine albumin-to-creatinine ratio. Patients had 291 cardiovascular events, 257 graft failure events, and 359 deaths. Each log increase in urine NGAL/creatinine independently associated with a 24% greater risk of cardiovascular events (adjusted hazard ratio [aHR], 1.24; 95% confidence interval [95% CI], 1.06 to 1.45), a 40% greater risk of graft failure (aHR, 1.40; 95% CI, 1.16 to 1.68), and a 44% greater risk of death (aHR, 1.44; 95% CI, 1.26 to 1.65). Urine KIM-1/creatinine and IL-18/creatinine independently associated with greater risk of death (aHR, 1.29; 95% CI, 1.03 to 1.61 and aHR, 1.25; 95% CI, 1.04 to 1.49 per log increase, respectively) but not with risk of cardiovascular events or graft failure. Urine L-FABP did not associate with any study outcomes. In conclusion, among prevalent KTRs, higher urine NGAL, KIM-1, and IL-18 levels independently and differentially associated with greater risk of adverse outcomes.

Author(s): Shlipak, Michael; Hsu, Chi-Yuan; Park, M; Shlipak, MG; Vittinghoff, E; Katz, R; Siscovick, D; Sarnak, M; Lima, JA; Hsu, CY; Peralta, CA

Background and objectives Elevations in N-terminal pro–B-type natriuretic peptide and high-sensitivity troponin T are associated with poor cardiovascular outcomes. Whether elevations in these cardiac biomarkers are associated with decline in kidney function was evaluated. Design, setting, participants, & measurements N-terminal pro–B-type natriuretic peptide and troponin T were measured at baseline in 3752 participants free of heart failure in the Cardiovascular Health Study. eGFR was determined from the Chronic Kidney Disease Epidemiology Collaboration equation using serum cystatin C. Rapid decline in kidney function was defined as decline in serum cystatin C eGFR≥30%, and incident CKD was defined as the onset of serum cystatin C eGFR n =2786). Cox regression models were used to examine the associations of each biomarker with kidney function decline adjusting for demographics, baseline serum cystatin C eGFR, diabetes, and other CKD risk factors. Results In total, 503 participants had rapid decline in serum cystatin C eGFR over a mean follow-up time of 6.41 (1.81) years, and 685 participants developed incident CKD over a mean follow-up time of 6.41 (1.74) years. Participants in the highest quartile of N-terminal pro–B-type natriuretic peptide (>237 pg/ml) had an 67% higher risk of rapid decline and 38% higher adjusted risk of incident CKD compared with participants in the lowest quartile (adjusted hazard ratio for serum cystatin C eGFR rapid decline, 1.67; 95% confidence interval, 1.25 to 2.23; hazard ratio for incident CKD, 1.38; 95% confidence interval, 1.08 to 1.76). Participants in the highest category of troponin T (>10.58 pg/ml) had 80% greater risk of rapid decline compared with participants in the lowest category (adjusted hazard ratio, 1.80; 95% confidence interval, 1.35 to 2.40). The association of troponin T with incident CKD was not statistically significant (hazard ratio, 1.17; 95% confidence interval, 0.92 to 1.50). Conclusions Elevated N-terminal pro–B-type natriuretic peptide and troponin T are associated with rapid decline of kidney function and incident CKD. Additional studies are needed to evaluate the mechanisms that may explain this association.

Acute kidney injury (AKI) is a critical determinant of outcomes in hospitalized patients with cirrhosis, but little is known of the impact of AKI in the outpatient setting. We analyzed 385 adult outpatients with cirrhosis listed for liver transplant at a single center; excluded were those with severe hepatic encephalopathy, with hepatocellular carcinoma, or on hemodialysis. Baseline serum creatinine (bCr) was defined as the lowest value recorded, peak Cr as the highest value, ΔCr as peak Cr minus bCr, AKI as a rise in serum Cr (sCr) by ≥0.3 mg/dL from bCr, persistent kidney injury as elevation of sCR by ≥0.3 mg/dL from bCr on each subsequent clinical assessment. Among 385 outpatients with cirrhosis, bCr was ≤0.70, 0.70-0.97, and ≥0.97 mg/dL in 28%, 38%, and 34%, respectively. At a median follow-up of 16 (range 8-28) months, 143 (37%) had one or more AKI episode, which increased significantly by bCr group (24% versus 37% versus 48%, P = 0.001). Of these 143 with AKI, 13% developed persistent kidney injury. A multivariable Cox regression analysis highlighted that bCr (hazard ratio [HR], 2.96) and ΔCr (HR, 2.05) were the only factors independently associated with the development of persistent kidney injury (P

Tumor necrosis factor receptor type 1 (TNFR1) is associated with kidney disease and mortality risk in various populations [1], [2]. We evaluated associations of TNFR1 with mortality and mediators of this relationship in doi: 10.1016/j.atherosclerosis.2017.05.021. Whether or not these associations are influenced by age, gender, or baseline kidney function are not known. We evaluated associations of TNFR1 levels with measures of kidney function stratifying by these variables. Our outcomes included estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2, albumin to creatinine ratio (ACR) >30mg/g, and rapid kidney function loss, defined as a change in eGFR of greater than 3% per year.

Background Autosomal dominant polycystic kidney disease (PKD) is the most common genetic renal disease and the fourth leading cause of end-stage renal disease in the United States. Although there is no cure for PKD, several treatments are considered to be beneficial, including blood pressure control, exercise, low-salt diet, and high volume water intake. However, levels of understanding of the importance of these treatments and adherence to these recommendations vary among patients. This study explores illness perception models of patients with PKD to reveal barriers in adherence to prescribed therapies; satisfaction with medical care; and sources of medical information. Methods We designed a phenomenological interview study to evaluate illness perception models of individuals with PKD. Patients were identified from the national PKD Foundation e-mail distribution list (N = 190) and responded voluntarily to an introductory survey (N = 50). Seventeen PKD patients in the Bay Area were scheduled for one-on-one in-depth interviews with one trained interviewer (W-CT). Open-ended questions administered with an interview guide were used to evaluate patients’ beliefs. Results Mean age was 56.6 +/− 12 years (range 29–78); 65% were female. Many of the PKD patients in this study were highly motivated and willing to incorporate blood pressure, exercise, low-salt diet, and high volume water intake into their daily routines. Barriers to adherence to these therapies include personal beliefs and confusion due to unclear recommendations. Conclusions These findings suggest there is variability between what patients understand about their disease and treatments and what they believe their doctors have told them. Not all physicians focus on lifestyle-based treatments, but the majority of PKD patients in our study are motivated and willing to incorporate blood pressure control, exercise, low-salt diet, and high volume water intake into their daily routines and would like specific recommendations on how to implement these. These findings support a role for further exploring patient beliefs about the disease and its necessary treatments in order to design strategies to improve communication and meet the needs of these patients. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0641-3) contains supplementary material, which is available to authorized users.

Interview Guide: List of questions used to guide patient interviews (DOCX 18 kb)

Background The study of novel urinary biomarkers of acute kidney injury has expanded exponentially. Effective interpretation of data and meaningful comparisons between studies require awareness of factors that can adversely affect measurement. We examined how variations in short-term storage and processing might affect the measurement of urine biomarkers. Study Design Cross-sectional prospective. Setting & Participants Hospitalized patients from 2 sites: Yale New Haven Hospital (n=50) and University of California, San Francisco Medical Center (n=36). Predictors We tested the impact of 3 urine processing conditions on these biomarkers: (1) centrifugation and storage at 4°C for 48 hours before freezing at −80°C, (2) centrifugation and storage at 25°C for 48 hours before freezing at −80°C, and (3) uncentrifuged samples immediately frozen at −80°C. Outcomes Urine concentrations of 5 biomarkers: neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), liver-type fatty acid–binding protein (L-FABP), and cystatin C. Measurements We measured urine biomarkers by established enzyme-linked immunosorbent assay methods. Biomarker values were log-transformed, and agreement with a reference standard of immediate centrifugation and storage at −80°C was compared using concordance correlation coefficients (CCCs). Results Neither storing samples at 4°C for 48 hours nor centrifugation had a significant effect on measured levels, with CCCs higher than 0.9 for all biomarkers tested. For samples stored at 25°C for 48 hours, excellent CCC values (>0.9) also were noted between the test sample and the reference standard for NGAL, cystatin C, L-FABP and KIM-1. However, the CCC for IL-18 between samples stored at 25°C for 48 hours and the reference standard was 0.81 (95% CI, 0.66-0.96). Limitations No comparisons to fresh, unfrozen samples; no evaluation of the effect of protease inhibitors. Conclusions All candidate markers tested using the specified assays showed high stability with both short-term storage at 4°C and without centrifugation prior to freezing. For optimal fidelity, urine for IL-18 measurement should not be stored at 25°C before long-term storage or analysis.

The CACNA1H gene encodes the pore-forming α1 subunit of the T-type voltage-dependent calcium channel CaV3.2, expressed abundantly in the adrenal cortex. Mutations in CACNA1H are associated with various forms of primary aldosteronism (PA), including familial hyperaldosteronism type 4 (FH4). We describe a patient with refractory hypokalaemia and elevated aldosterone secretion independent of renin activity. Despite the absence of overt hypertension in this patient, the laboratory evaluation was consistent with a diagnosis of PA. Whole-exome sequencing revealed a de novo missense variant, R890H, in the voltage sensing domain of CACNA1H. Expression of the variant channel in cells resulted in decreased whole-cell current, consistent with a loss-of-function. We hypothesise this variant is the genetic cause of pathological aldosterone secretion in this patient, and thereby expand the current understanding of the genetic basis of FH4.

Cardiovascular risk remains high in kidney transplant recipients (KTRs) despite improved kidney function after transplant. Urinary markers of kidney fibrosis and injury may help to reveal mechanisms of this risk. In a case-cohort study among stable KTRs who participated in the FAVORIT trial, we measured four urinary proteins known to correlate with kidney tubulointerstitial fibrosis on biopsy (urine alpha 1 microglobulin [α1m], monocyte chemoattractant protein-1 [MCP-1], procollagen type I [PINP] and type III [PIIINP] N-terminal amino peptide) and evaluated associations with cardiovascular disease (CVD) events (n = 300) and death (n = 371). In adjusted models, higher urine α1m (hazard ratio [HR] per doubling of biomarker 1.40 [95% confidence interval [CI] 1.21, 1.62]), MCP-1 (HR 1.18 [1.03, 1.36]), and PINP (HR 1.13 [95% CI 1.03, 1.23]) were associated with CVD events. These three markers were also associated with death (HR per doubling α1m 1.51 [95% CI 1.32, 1.72]; MCP-1 1.31 [95% CI 1.13, 1.51]; PINP 1.11 [95% CI 1.03, 1.20]). Higher concentrations of urine α1m, MCP-1, and PINP may identify KTRs at higher risk for CVD events and death. These markers may identify a systemic process of fibrosis involving both the kidney and cardiovascular system, and give new insights into mechanisms linking the kidney with CVD.

Background Acute kidney injury is a risk factor for death in cardiac surgical patients. Plasma cystatin C and creatinine have different temporal profiles in the postoperative setting, but the associations of simultaneous changes in both filtration markers compared with change in only one marker with prognosis after hospital discharge are not well described. Methods This is a longitudinal study of 1,199 high-risk adult cardiac surgical patients in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium who survived hospitalization. We examined in-hospital peak changes of cystatin C and creatinine in the 3 days after cardiac operations. We evaluated associations of these filtration markers with death, adjusting for demographics, operative characteristics, medical comorbidities, preoperative estimated glomerular filtration rate, preoperative urinary albumin-to-creatinine ratio, and site. Results During the first 3 days of hospitalization, nearly twice as many patients had a 25% or higher rise in creatinine (30%) compared with a 25% or higher peak rise in cystatin C (15%). The risk of death was higher in those with elevations in cystatin C (adjusted hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.4 to 2.37) or creatinine (adjusted HR, 1.90; 95% CI, 1.32 to 2.72) compared with patients who experienced a postoperative decrease in either filtration marker. Patients who had simultaneous elevations of 25% or higher in cystatin C and creatinine were at similar adjusted risk for 3-year mortality (HR, 1.79; 95% CI, 1.03 to 3.1) as those with a 25% or higher increase in cystatin C alone (HR, 2.2; 95% CI, 1.09 to 4.47). Conclusions Elevations in creatinine postoperatively are more common than elevations in cystatin C. However, elevations in cystatin C appeared to be associated with a higher risk of death after hospital discharge.

Summary Background and objectives Clinical heart failure (HF) is associated with CKD and faster rates of kidney function decline. Whether subclinical abnormalities of cardiac structure are associated with faster kidney function decline is not known. The association between cardiac concentricity and kidney function decline was evaluated. Design, setting, participants, & measurements This is a longitudinal study of 3866 individuals from the Multi-Ethnic Study of Atherosclerosis (2000–2007) who were free of clinical cardiovascular disease, with an estimated GFR (eGFR) ≥60 ml/min per 1.73 m2 at baseline and 5 years of follow-up. Concentricity, a measurement of abnormal cardiac size, was assessed by magnetic resonance imaging and evaluated as a continuous measurement and in quartiles. GFR was estimated by creatinine (eGFRcr) and cystatin C (eGFRcys). The association of concentricity with annual eGFR decline, incident CKD, and rapid kidney function decline (>5% per year) was investigated using linear mixed models as well as Poisson and logistic regression, respectively. Analyses adjusted for demographics, BP, diabetes, and inflammatory markers. Results Median decline was −0.8 (interquartile range, −3.1, −0.5) by eGFRcr. Compared with the lowest quartile of concentricity, persons in the highest quartile had an additional 21% (9%–32%) decline in mean eGFRcr in fully adjusted models. Concentricity was also associated with incident CKD and with rapid kidney function decline after adjustment. Conclusions Subclinical abnormalities in cardiac structure are associated with longitudinal kidney function decline independent of diabetes and hypertension. Future studies should examine mechanisms to explain these associations.