Patients with glomerular disease are at high risk of cardiovascular disease but the contribution of immunosuppression to this risk is unclear. In this retrospective cohort study of 1912 patients (comprised of 759 with IgA nephropathy, 540 with focal segmental glomerulosclerosis, 387 with membranous nephropathy and 226 with minimal change disease) from British Columbia, Canada, we evaluated the association between exposure to specific immunosuppressive medications and a composite outcome including coronary artery, cerebrovascular and peripheral arterial events. Survival models were adjusted for baseline cardiovascular risk factors, type of glomerular disease, estimated glomerular filtration rate (eGFR) and proteinuria over time. During a median follow-up of 6.8 years, 212 patients (11.1%) experienced the primary outcome. Corticosteroid exposure was not significantly associated with the primary outcome after adjusting for cardiovascular risk factors. In fully adjusted models, cumulative calcineurin inhibitor exposure at modest (150-300 defined daily doses [DDD]) and higher (300 or more DDD) doses were associated with a 2-fold higher risk of cardiovascular events (hazard ratio 2.98, 95% confidence interval 1.27-6.95) and (2.78, 1.32-5.84), respectively. A peak daily dose of antimetabolite (azathioprine, mycophenolate mofetil and mycophenolate sodium) of 0.5 or more DDD was associated with higher risk of cardiovascular events after adjustment for baseline risk factors and type of glomerular disease, but not after adjusting for time-varying eGFR and proteinuria (1.70, 0.91-3.20). Each 10 grams of cumulative cyclophosphamide exposure was associated with a 1.5-fold higher risk of cardiovascular events in a fully adjusted model (1.46, 1.22-1.75) Thus, our findings suggest that immunosuppressive therapies used in the treatment of glomerular disease may have different cardiovascular risk profiles, which should be considered when deciding on immunosuppression for individual patients and as a safety endpoint in future clinical trials.

Purpose of review: Cardiovascular (CV) disease is a major cause of morbidity and mortality for patients with glomerular disease. Despite the fact that mechanisms underpinning CV disease risk in this population are likely distinct from other forms of kidney disease, treatment and preventive strategies tend to be extrapolated from studies of patients with undifferentiated chronic kidney disease (CKD). There is an unmet need to delineate the pathophysiology of CV disease in patients with glomerular disease, establish unique risk factors, and identify novel therapeutic targets for disease prevention. The aims of this narrative review are to summarize the existing knowledge regarding the epidemiology, molecular mechanisms, and management of CV disease in patients with common glomerular disease, highlight the patient perspective, and propose specific areas for future study. Sources of information: The literature for this narrative review was accessed using common research search engines, including PubMed, PubMed Central, Medline, and Google Scholar. Information for the patient perspective section was collected through iterative discussions with a patient partner. Methods: We reviewed the epidemiology, molecular mechanisms of disease, management approaches, and the patient perspective in relation to CV disease in patients with glomerulopathies. Throughout, we have highlighted the current knowledge and have discussed future research approaches, both clinical and translational, while integrating the patient perspective. Key findings: Patients with glomerular disease have significant CV disease risk driven by multifactorial, molecular mechanisms originating from their glomerular disease but complicated by existing comorbidities, kidney disease, and medication side effects. The current approach to risk stratification and treatment relies heavily on existing data from CKD patients, but this may not always be appropriate given the unique pathophysiology and mechanisms associated with CV disease risk in patients with glomerular disease. We highlight the need for ongoing glomerular disease-focused studies aimed to better delineate CV disease risk, while integrating the patient perspective. Limitations: This is a narrative review and does not represent a comprehensive and systematic review of the literature.

Background and objective: Acute kidney injury (AKI) affects up to 20% of hospitalizations and is associated with chronic kidney disease, cardiovascular disease, increased mortality, and increased health care costs. Proper documentation of AKI in discharge summaries is critical for optimal monitoring and treatment of these patients once discharged. Currently, there is limited literature evaluating the quality of discharge communication after AKI. This study aimed to evaluate the accuracy and quality of documentation of episodes of AKI at a tertiary care center in British Columbia, Canada. Methods, design, setting, patients, and measurements: This was a retrospective chart review study of adult patients who experienced AKI during hospital admission between January 1, 2018, and December 31, 2018. Laboratory data were used to identify all admissions to the cardiac and general medicine ward complicated by AKI defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria. A random sample of 300 AKI admissions stratified by AKI severity (eg, stages 1, 2, and 3) were identified for chart review. Patients were excluded if they required ongoing renal replacement therapy after admission, had a history of kidney transplant, died during their admission, or did not have a discharge summary available. Discharge summaries were reviewed for documentation of the following: presence of AKI, severity of AKI, AKI status at discharge, practitioner and laboratory follow-up plans, and medication changes. Results: A total of 1076 patients with 1237 AKI admissions were identified. Of the 300 patients selected for discharge summary review, 38 met exclusion criteria. In addition, AKI was documented in 140 (53%) discharge summaries and was more likely to be documented in more severe AKI: stage 1, 38%; stage 2, 51%; and stage 3, 75%. Of those with their AKI documented, 94 (67%) documented AKI severity, and 116 (83%) mentioned the AKI status or trajectory at the time of discharge. A total of 239 (91%) of discharge summaries mentioned a follow-up plan with a practitioner, but only 23 (10%) had documented follow-up with nephrology. Patients with their AKI documented were more likely to have nephrology follow-up than those without AKI documented (17% vs 1%). Regarding laboratory investigations, 92 (35%) of the summaries had documented recommendations. In summaries that included medications typically held during AKI, only about half made specific reference to those medications being held, adjusted, or documented a post-discharge plan for that medication. For those with nonsteroidal anti-inflammatory drugs (NSAIDs) listing, 64% of discharge summaries mentioned holding, and 9% mentioned a discharge plan. For those with angiotensin converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) listing, 38% mentioned holding these medications, and 46% mentioned a discharge plan. In summaries with diuretics listed, 35% mentioned holding, and 51% included a discharge plan. Conclusions and limitations: We found suboptimal quality and completeness of discharge reporting in patients hospitalized with AKI. This may contribute to inadequate follow-up and post-hospitalization care for this patient population. Strategies are required for increasing the presence and quality of AKI reporting in discharge summaries. Limitations include our definition of AKI based on lab criteria, which may have missed some of the injuries that met the criteria based on urine output. Another limitation is that our definition of AKI based on the highest and lowest creatinine during admission may have led to some overclassification. In addition, without outpatient laboratories, it is possible that we have not captured the true baseline creatinine in some patients.

Nephrotic syndrome (NS) predisposes to venous thromboembolic events with membranous nephropathy carrying the highest risk.1 Clinicians caring for patients with NS must balance the benefits of anticoagulation against potential harms, primarily bleeding. The management of venous thromboembolic events risk is complicated by little quality data examining anticoagulation for thromboprophylaxis in NS. A well-conducted, randomized controlled trial could inform which patients might benefit most from anticoagulation and the optimal agents.

Rationale & Objective: Research in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has focused on reducing treatment toxicities, notably through reduction of exposure to glucocorticoids. Glucocorticoid-sparing therapies such as avacopan are not widely available in many countries, and patients are exposed to high glucocorticoid doses. There is little data concerning what clinicians should accept as the lowest glucocorticoid dosing that can be used in induction therapy for AAV. Study Design: International, online survey. Setting & Participants: Clinicians in various countries with experience in managing vasculitis. Exposure and Outcomes: Survey questions to gauge interest and preferences in studying an induction of remission regimen for severe AAV using only 2 or 4 weeks of glucocorticoids without avacopan. Data collected included general opinions about standard of care for induction agents, glucocorticoids, and avacopan. Respondents were presented with 3 candidate trial designs, 2 of which proposed a combination of cyclophosphamide and rituximab induction. Analytical Approach: Using a 10-point Likert scale, respondents ranked each candidate trial on its usefulness in demonstrating whether a minimal glucocorticoid regimen would be safe and effective and their willingness to randomize into the trial. Results: There were 210 respondents to the survey. The candidate trials were rated moderate-to- high for usefulness to demonstrate safety and efficacy i cacy (scores 6-7/10), and moderate (scores 56/10) for willingness to randomize. Four-week glucocorticoid duration was preferred to 2 weeks, and combination cyclophosphamide-rituximab with 4-week glucocorticoids was the most preferred design. Forty-two percent of respondents felt avacopan had to be incorporated into a minimal GC trial design to want to recruit patients. Limitations: Representativeness of survey sample and generalizability of fi ndings. Conclusions: Combination cyclophosphamiderituximab may be the ideal way of studying minimal glucocorticoid use in severe AAV. Given its increasing uptake, incorporating avacopan into a potential trial design is important.

ABSTRACT Over the past decade, several observational studies and case series have provided evidence suggesting a connection between glomerular diseases and the development of malignancies, with an estimated risk ranging from 5 to 11%. These malignancies include solid organ tumours as well as haematologic malignancies such as lymphoma and leukaemia. However, these risk estimates are subject to several sources of bias, including unmeasured confounding from inadequate exploration of risk factors, inclusion of glomerular disease cases that were potentially secondary to an underlying malignancy, misclassification of glomerular disease type and ascertainment bias arising from an increased likelihood of physician encounters compared with the general population. Consequently, population-based studies that accurately evaluate the cancer risk in glomerular disease populations are lacking. While it is speculated that long-term use of immunosuppressive medications and glomerular disease activity measured by proteinuria and estimated glomerular filtration rate may be associated with cancer risk in patients with glomerular disease, the independent role of these risk factors remains largely unknown. The presence of these knowledge gaps could lead to a lack of awareness of cancer as a potential chronic complication of glomerular disease, underutilization of routine screening practices in clinical care that allow early diagnosis and treatment of malignancies and underrecognition of modifiable risk factors to decrease the risk of de novo malignancies over time. This review summarizes the current evidence on the risk of cancer in patients with glomerular diseases, explores the limitations of prior studies and discusses methodological challenges and potential solutions for obtaining accurate estimates of cancer risk and identifying modifiable risk factors unique to GN populations.

Multiple myeloma frequently impacts the kidneys, with up to half of patients presenting with reduced kidney function at diagnosis.1Kyle R.A. Gertz M.A. Witzig T.E. et al.Review of 1027 patients with newly diagnosed multiple myeloma.Mayo Clin Proc. 2003; 78: 21-33https://doi.org/10.4065/78.1.21Abstract Full Text Full Text PDF PubMed Scopus (1759) Google Scholar, 2Finkel K.W. Cohen E.P. Shirali A. Abudayyeh A. American Society of Nephrology Onco-Nephrology ForumParaprotein-related kidney disease: evaluation and treatment of myeloma cast nephropathy.Clin J Am Soc Nephrol. 2016; 11: 2273-2279https://doi.org/10.2215/CJN.01640216Crossref PubMed Scopus (37) Google Scholar, 3Knudsen L.M. Hippe E. Hjorth M. Holmberg E. Westin J. Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group.Eur J Haematol. 1994; 53: 207-212https://doi.org/10.1111/j.1600-0609.1994.tb00190.xCrossref PubMed Scopus (223) Google Scholar, 4Dimopoulos M.A. Sonneveld P. Leung N. et al.International Myeloma Working Group recommendations for the diagnosis and management of myeloma-related renal impairment.J Clin Oncol. 2016; 34: 1544-1557https://doi.org/10.1200/JCO.2015.65.0044Crossref PubMed Scopus (269) Google Scholar The most common cause of kidney damage is light chain cast nephropathy,5Ecotiere L. Thierry A. Debiais-Delpech C. et al.Prognostic value of kidney biopsy in myeloma cast nephropathy: a retrospective study of 70 patients.Nephrol Dial Transplant. 2016; 31: 64-72https://doi.org/10.1093/ndt/gfv283Crossref PubMed Scopus (35) Google Scholar,6Bridoux F. Leung N. Belmouaz M. et al.Management of acute kidney injury in symptomatic multiple myeloma.Kidney Int. 2021; 99: 570-580https://doi.org/10.1016/j.kint.2020.11.010Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar and Bence Jones proteinuria is present in 64%-96% of cases at diagnosis.7Pascali E. Pezzoli A. The incidence of Bence-Jones proteinuria in multiple myeloma.Br J Haematol. 1986; 64: 847-850https://doi.org/10.1111/j.1365-2141.1986.tb02248.xCrossref PubMed Scopus (4) Google Scholar, 8Sinclair D. Dagg J.H. Smith J.G. Stott D.I. The incidence and possible relevance of Bence-Jones protein in the sera of patients with multiple myeloma.Br J Haematol. 1986; 62: 689-694https://doi.org/10.1111/j.1365-2141.1986.tb04092.xCrossref PubMed Scopus (18) Google Scholar, 9Smith D. Yong K. Multiple myeloma.BMJ. 2013; 346: f3863https://doi.org/10.1136/bmj.f3863Crossref PubMed Scopus (69) Google Scholar Nephrologists must be keenly aware of multiple myeloma as a potential diagnosis in cases of undifferentiated kidney dysfunction. Because of this, some employ a commonly taught “clinical pearl” assessing for discrepancy between the urinary protein-creatinine ratio (UPCR) and urinary albumin-creatinine ratio (UACR) as a surrogate screen for multiple myeloma. The theory behind this is that light chains in the urine will lead to discordance between the UPCR and the UACR, since overall protein levels will increase but albumin levels will not; however, other causes of non-albumin proteinuria are also known to occur (eg, tubular proteinuria). It remains unknown whether the absolute difference between UPCR and UACR, which we will refer to as the urine protein-to-albumin gap, is useful as a screen for multiple myeloma. We conducted a population-level retrospective cohort study of residents in Ontario, Canada, in 2009-2021 to examine the association between urine protein-to-albumin gap and subsequent diagnosis of multiple myeloma using linked databases held at ICES. ICES is an independent, not-for-profit research institute whose legal status under Ontario’s health information privacy law allows it to collect and analyze health care and demographic data, without consent, for health system evaluation and improvement. ICES captures data on all Ontario residents who undergo a health care encounter, including health care visits, laboratory tests, hospitalizations, and vital statistics. These datasets were linked using unique encoded identifiers and analyzed at ICES (Table S1). The use of data in this project is authorized under section 45 of Ontario’s Personal Health Information Protection Act and does not require review by a research ethics board. All Ontario residents aged 18-105 years with same-day quantifiable measurements of UPCR and UACR and without a prior history of multiple myeloma or monoclonal gammopathy from April 1, 2009, through March 31, 2021 were included (Fig S1). Individuals were categorized by quartile of urine protein-to-albumin gap and stratified at a UPCR threshold of 50 mg/mmol, the KDIGO definition of severely increased proteinuria.10Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1846) Google Scholar Multivariable time-to-event models measured the association between urine protein-to-albumin gap and subsequent diagnosis of multiple myeloma. Full methods are in Item S1. Baseline characteristics are given in Table S2. Mean age was 63 ± 18 (SD) years and 49% of individuals were female. Mean serum creatinine and estimated glomerular filtration rate (eGFR) were 1.28 ± 0.96 mg/dL and 71 ± 32 mL/min/1.73 m2, respectively. Median UPCR and UACR were 27 (IQR, 12-58) mg/mmol and 4 (IQR, 1-19) mg/mmol, respectively. Among 28,231 eligible individuals, 116 were diagnosed with multiple myeloma (0.4%) a median of 31 days from UACR and UPCR measurement. Among the overall population, with each successive quartile of urine protein-to-albumin gap, myeloma incidence rate (Table 1) and risk (Fig 1A) were progressively greater. We found evidence of effect modification of the 50 mg/mmol UPCR threshold on the association between urine protein-to-albumin gap quartiles and multiple myeloma (P = 0.04). Among individuals with UPCR >50 mg/mmol, the association between successive quartile of urine protein-to-albumin gap and subsequent myeloma diagnosis was strengthened (Fig 1B). In contrast, among those with UPCR ≤50 mg/mmol, there was no significant association (Fig 1C), though potentially this relates to the lower number of cases poststratification. As this population-based study was based on administrative health care data, limitations included an inability to determine the reason a provider ordered same-day UACR and UPCR measurements (which may impact the pretest probability for multiple myeloma), and a lack of standardization of albuminuria and proteinuria measurements across the many laboratories involved (which may have impacted performance metrics).Table 1Incidence Rates of Multiple Myeloma by Urine Protein-to-Albumin Gap Quartile in the Overall Population and Upon Stratification at a UPCR Threshold of 50 mg/mmolUrine Protein-to-Albumin GapNo. of PatientsIncidence Rate of Multiple Myeloma (95% CI)P for TrendOverallMyeloma CasesOverall population<0.001 Quartile 1: ≤9.3 mg/mmol7,174145.63 (3.34-9.51) Quartile 2: 9.4-18.0 mg/mmol6,955167.06 (4.32-11.52) Quartile 3: 18.1-43.4 mg/mmol7,0502712.39 (8.50-18.07) Quartile 4: >43.4 mg/mmol7,0525928.54 (22.11-36.84)UPCR >50 mg/mmol<0.001 Quartile 1: ≤34.2 mg/mmol1,908≤5aIn accordance with ICES privacy policies, cell sizes ≤5 cannot be reported.6.14 (2.31-16.37) Quartile 2: 34.3-57.5 mg/mmol1,8926-1015.30 (7.65-30.59) Quartile 3: 57.6-111.8 mg/mmol1,8991534.66 (20.90-57.50) Quartile 4: >111.8 mg/mmol1,9003479.91 (57.10-111.84)UPCR ≤50 mg/mmol0.2 Quartile 1: ≤7.9 mg/mmol5,252137.03 (4.08-12.11) Quartile 2: 8.0-12.6 mg/mmol5,121116.53 (3.62-11.79) Quartile 3: 12.7-23.7 mg/mmol5,117106.23 (3.35-11.58) Quartile 4: >23.7 mg/mmol5,1422111.50 (7.50-17.63)Incidence rate is given per 10,000 person-years; P for trend is across quartiles.a In accordance with ICES privacy policies, cell sizes ≤5 cannot be reported. Open table in a new tab Incidence rate is given per 10,000 person-years; P for trend is across quartiles. In summary, these results show that among individuals with UPCR >50 mg/mmol, the risk for myeloma was significantly higher for urine protein-to-albumin gap greater than ˜50 mg/mmol (˜4-fold higher risk), particularly when this gap exceeded ˜100 mg/mmol (˜11-fold higher risk). However, when these thresholds are used as screening cutoffs for multiple myeloma, their performance is modest. For UPCR >50 mg/mmol with urine protein-to-albumin gap >50 mg/mmol, sensitivity was 85%; specificity, 43%; positive likelihood ratio, 1.49; and negative likelihood ratio, 0.35. For UPCR >50 mg/mmol and urine protein-to-albumin gap >100 mg/mmol, sensitivity was 61%; specificity, 72%; positive likelihood ratio, 2.16; and negative likelihood ratio, 0.55. These results may help guide clinicians who use UPCR-UACR discrepancy as a screen for potential multiple myeloma in cases of undifferentiated kidney dysfunction. In turn, this may provide information to guide when further testing to evaluate for multiple myeloma is imperative. Study concept and design: GLH, HI, MMS, AA; data acquisition/analysis: GLH, HI, MMS, AA; data interpretation: GLH, HI, AV, AM, GK, MB, MC, DM, PT, CM, MMS, AA. MMS and AA contributed equally to this work. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. Dr Hundemer is supported by the Lorna Jocelyn Wood Chair for Kidney Research. Dr Sood is supported by the Jindal Research Chair for the Prevention of Kidney Disease. This study was supported by ICES. The funders had no role in study design; collection, analysis, and interpretation of the data; writing the report; or the decision to submit the report for publication. Dr Sood has received speaker fees from AstraZeneca. Dr Akbari has received speaker fees from AstraZeneca and holds research grants from Otsuka. The other authors declare that they have no relevant financial interests. ICES is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). This document used data adapted from the Statistics Canada Postal CodeOM Conversion File, which is based on data licensed from Canada Post Corporation, and/or data adapted from the Ontario Ministry of Health Postal Code Conversion File, whic contains data copied under license from Canada Post Corporation and Statistics Canada. We would like to thank IQVIA Solutions Canada Inc for use of their Drug Information File. Parts of this material are based on data and/or information compiled and provided by the Canadian Institute for Health Information, the Ontario MOH, and Ontario Health. The research was conducted by members of the ICES Kidney, Dialysis and Transplantation team, at the ICES Ottawa facility. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. Received July 28, 2022. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form November 6, 2022. Download .pdf (.32 MB) Help with pdf files Supplementary File (PDF) Figure S1; Item S1; Tables S1-S2.

Intermittent hemodialysis remains a cornerstone of extracorporeal KRT in the intensive care unit, either as a first- line therapy for AKI or a second-line therapy when patients transition from a continuous or prolonged intermittent therapy. Intermittent hemodialysis is usually provided 3 days per week in this setting on the basis that no clinical benefits have been demonstrated with more frequent hemodialysis. This should not detract from the importance of continually assessing and refining the hemodialysis prescription (including the need for extra treatments) according to dynamic changes in extracellular volume and other parameters, and ensuring that an adequate dose of hemodialysis is being delivered to the patient. Compared with other KRT modalities, the cardinal challenge encountered during intermittent hemodialysis is hemodynamic instability. This phenomenon occurs when reductions in intravascular volume, as a consequence of ultrafiltration and/or osmotic shifts, outpace compensatory plasma refilling from the extravascular space. Myocardial stunning, triggered by intermittent hemodialysis, and independent of ultrafiltration, may also contribute. The hemodynamic effect of intermittent hemodialysis is likely magnified in patients who are critically ill due to an inability to mount sufficient compensatory physiologic responses in the context of multiorgan dysfunction. Of the many interventions that have undergone testing to mitigate hemodynamic instability related to KRT, the best evidence exists for cooling the dialysate and raising the dialysate sodium concentration. Unfortunately, the evidence supporting routine use of these and other interventions is weak owing to poor study quality and limited sample sizes. Intermittent hemodialysis will continue to be an important and commonly used KRT modality for AKI in patients with critical illness, especially in jurisdictions where resources are limited. There is an urgent need to harmonize the definition of hemodynamic instability related to KRT in clinical trials and robustly test strategies to combat it in this vulnerable patient population.

The field of nephrology has been slow in moving beyond the utilization of creatinine as an indicator for chronic kidney disease and acute kidney injury (AKI). Early diagnosis and establishment of etiology, in particular, are important for treatment of AKI. In the setting of hospital-acquired AKI, tubular injury is more common, but acute interstitial nephritis (AIN) has a more treatable etiology. However, it is likely that AIN is under- or misdiagnosed due to current strategies that largely rely on clinical gestalt. In this issue of the JCI, Moledina and colleagues made an elegant case for the chemokine called C-X-C motif ligand 9 (CXCL9) as a biomarker of AIN. The authors used urine proteomics and tissue transcriptomics in patients with and without AIN to identify CXCL9 as a promising, noninvasive, diagnostic biomarker of AIN. These results have clinical implications that should catalyze future research and clinical trials in this space.

1Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada 2Kidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada Correspondence: Dr. Edward G. Clark, The Ottawa Hospital Riverside Campus, 1967 Riverside Drive, Ottawa, Ontario K1H 7W9, Canada. Email: [email protected] See related Patient Voice, “Patient Safety with Fluid Removal with In-Center Hemodialysis,” on pages 691–692, and related article, “Ultrafiltration Rate Levels in Hemodialysis Patients Associated with Weight-Specific Mortality Risks,” on pages 767–776.

Chronic kidney disease (CKD) confers a high risk of thrombosis and bleeding. However, little evidence exists regarding the optimal choice of postoperative thromboprophylaxis in these patients. We conducted a population-based, retrospective cohort study among adults ≥66 years old with CKD undergoing hip or knee arthroplasty who had filled an outpatient prophylactic anticoagulant prescription between 2010 and 2020 in Ontario, Canada. The primary outcomes of venous thrombosis (VTE) and hemorrhage were identified by validated algorithms using relevant diagnoses and billing codes. Overlap-weighted cause-specific Cox proportional hazard models were used to examine the association of direct oral anticoagulants (DOAC) on the 90-day risk of VTE and hemorrhage compared with low-molecular-weight heparin (LMWH). A total of 27  645 patients were prescribed DOAC (N = 22  943) or LMWH (N = 4702) after arthroplasty. Rivaroxaban was the predominant DOAC (94.5%), while LMWH mainly included enoxaparin (67%) and dalteparin (31.5%). DOAC users had higher eGFRs, fewer co-morbidities, and surgery in more recent years compared to LMWH users. After weighing, DOAC (compared with LMWH) was associated with a lower risk of VTE (DOAC: 1.5% vs. LMWH: 2.1%, weighted hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.59-0.94) and a higher risk of hemorrhage (DOAC: 1.3% vs. LMWH: 1.0%, weighted HR 1.44, 95% CI 1.04-1.99). Additional analyses including a more stringent VTE defining algorithm, different eGFR cut-offs, and limiting to rivaroxaban and enoxaparin showed consistent findings. Among elderly adults with CKD, DOAC was associated with a lower VTE risk and a higher hemorrhage risk compared to LMWH following hip or knee arthroplasty.

OBJECTIVE:To study age specific associations of modest reductions in estimated glomerular filtration rate (eGFR) with adverse outcomes. DESIGN:Retrospective, population based cohort study. SETTING:Linked healthcare administrative datasets in Ontario, Canada. PARTICIPANTS:Adult residents (18-65 years) with at least one outpatient eGFR value (categorized in 10 unit increments from 50 mL/min/1.73m2 to >120 mL/min/1.73m2), with no history of kidney disease. MAIN OUTCOME MEASURES:eGFRs and hazard ratios of composite adverse outcome (all cause mortality, any cardiovascular event, and kidney failure) stratified by age (18-39 years, 40-49 years, and 50-65 years), and relative to age specific eGFR referents (100-110 mL/min/1.73m2) for ages 18-39 years, 90-100 for 40-49 years, 80-90 for 50-65 years). RESULTS:From 1 January 2008 to 31 March 2021, among 8 703 871 adults (mean age 41.3 (standard deviation 13.6) years; mean index eGFR 104.2 mL/min/1.73m2 (standard deviation 16.1); median follow-up 9.2 years (interquartile range 5.7-11.4)), modestly reduced eGFR measurements specific to age were recorded in 18.0% of those aged 18-39, 18.8% in those aged 40-49, and 17.0% in those aged 50-65. In comparison with age specific referents, adverse outcomes were consistently higher by hazard ratio and incidence for ages 18-39 compared with older groups across all eGFR categories. For modest reductions (eGFR 70-80 mL/min/1.73m2), the hazard ratio for ages 18-39 years was 1.42 (95% confidence interval 1.35 to 1.49), 4.39 per 1000 person years; for ages 40-49 years was 1.13 (1.10 to 1.16), 9.61 per 1000 person years; and for ages 50-65 years was 1.08 (1.07 to 1.09), 23.4 per 1000 person years. Results persisted for each individual outcome and in many sensitivity analyses. CONCLUSIONS:Modest eGFR reductions were consistently associated with higher rates of adverse outcomes. Higher relative hazards were most prominent and occurred as early as eGFR <80 mL/min/1.73m2 in younger adults, compared with older groups. These findings suggest a role for more frequent monitoring of kidney function in younger adults to identify individuals at risk to prevent chronic kidney disease and its complications.

Introduction:Intraperitoneal (IP) vancomycin is often first-line empiric therapy and then maintenance therapy for peritoneal dialysis (PD) peritonitis. However, how vancomycin serum levels correlate with clinical outcomes remains unclear. Methods:We conducted a retrospective single-center adult cohort study of 98 patients with PD peritonitis treated with IP vancomycin between January 2016 and May 2022. The association between nadir vancomycin level and cure was evaluated in a logistic regression model, first unadjusted and then adjusted for age, sex, weight, glomerular filtration rate (GFR), and total number of days on PD. Vancomycin was assessed both as a continuous exposure (per 1 mg/l increase) and as a categorical exposure (<15 mg/l vs. ≥15 mg/l). A receiver operating characteristic curve (ROC) was created to explore nadir vancomycin level thresholds in an attempt to identify an optimal target level during treatment. Results:Of the patients, 81% achieved cure, and patients with nadir vancomycin level ≥15 mg/l were 7.5 times more likely to experience cure compared to those with a nadir level <15 mg/l (odds ratio [OR] 7.58, 95% confidence interval [CI] 1.71-33.57, P = 0.008). Weight, GFR, days on PD, sex, and age were not independently associated with outcome. The vancomycin level with the greatest discriminatory capacity for cure on the ROC analysis was 14.4 mg/l. Conclusion:Increasing IP vancomycin serum levels are associated with increased odds of cure; and maintaining vancomycin serum levels above 14-15 mg/l throughout the course of PD peritonitis treatment is likely to improve clinical outcomes.

BACKGROUND Cardiovascular (CV) disease in young adults (aged 18-39 years) is on the rise. Whether subclinical re-ductions in kidney function (ie, estimated glomerular filtration rate [eGFR] above the current threshold for chronic kidney disease but below age-expected values) are associated with elevated CV risk is unknown. OBJECTIVES The goal of this study was to examine age-specific associations of subclinical eGFR reductions in young adults with major adverse cardiovascular events (MACEs) and MACE plus heart failure (MACE+). METHODS A retrospective cohort study of 8.7 million individuals (3.6 million aged 18-39 years) was constructed using linked provincial health care data sets from Ontario, Canada (January 2008-March 2021). Cox models were used to examine the association of categorized eGFR (50-120 mL/min/1.73 m2) with MACE (first of CV mortality, acute coronary syndrome, and ischemic stroke) and MACE+, stratified according to age (18-39, 40-49, and 50-65 years). RESULTS In the study cohort (mean age 41.3 years; mean eGFR 104.2 mL/min/1.73 m(2); median follow-up 9.2 years), a stepwise increase in the relative risk of MACE and MACE+ was observed as early as eGFR <80 mL/min/1.73 m(2) in young adults (eg, for MACE, at eGFR 70-79 mL/min/1.73 m(2), ages 18-30 years: 2.37 events per 1,000 person years [HR: 1.31; 95% CI: 1.27-1.40]; ages 40-49 years: 6.26 events per 1,000 person years [HR: 1.09; 95% CI: 1.06-1.12]; ages 50-65 years: 14.9 events per 1,000 person years [HR: 1.07; 95% CI: 1.05-1.08]). Results persisted for each MACE component and in additional analyses (stratifying according to past CV disease, accounting for albuminuria at index, and using repeated eGFR measures). CONCLUSIONS In young adults, eGFR below age-expected values were associated with an elevated risk for MACE and MACE+, warranting age-appropriate risk stratification, proactive monitoring, and timely intervention. (J Am Coll Cardiol 2023;82:1316-1327) (c) 2023 by the American College of Cardiology Foundation.