Are patients with primary glomerular disease at increased risk of malignancy?

Over the past decade, several observational studies and case series have provided evidence suggesting a connection between glomerular diseases (GN) and the development of malignancies, with an estimated risk ranging from 5%-11%. These malignancies include solid organ tumors as well as hematologic malignancies such as lymphoma and leukemia. However, these risk estimates are subject to several sources of bias, including unmeasured confounding from inadequate exploration of risk factors, inclusion of GN cases that were potentially secondary to an underlying malignancy, misclassification of GN type, and ascertainment bias arising from an increased likelihood of physician encounters compared to the general population. Consequently, population-based studies that accurately evaluate the cancer risk in GN populations are lacking. While it is speculated that long-term use of immunosuppressive medications and GN disease activity measured by proteinuria and estimated glomerular filtration rate may be associated with cancer risk in patients with GN, the independent role of these risk factors remains largely unknown. The presence of these knowledge gaps could lead to (i) lack of awareness of cancer as a potential chronic complication of GN, (ii) under-utilization of routine screening practices in clinical care that allow early diagnosis and treatment of malignancies, and (iii) under-recognition 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 GN, 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.

Impaired Renal Function and Major Cardiovascular Events in Young Adults.

BACKGROUND: Cardiovascular (CV) disease in young adults (aged 18-39 years) is on the rise. Whether subclinical reductions 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 m2; 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 m2 in young adults (eg, for MACE, at eGFR 70-79 mL/min/1.73 m2, 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.

Risk of venous thromboembolism or hemorrhage among individuals with chronic kidney disease on prophylactic anticoagulant after hip or knee arthroplasty.

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.

A Population-Based Analysis of the Risk of Glomerular Disease Relapse after COVID-19 Vaccination.

BACKGROUND: Although case reports have described relapses of glomerular disease after COVID-19 vaccination, evidence of a true association is lacking. In this population-level analysis, we sought to determine relative and absolute risks of glomerular disease relapse after COVID-19 vaccination. METHODS: In this retrospective population-level cohort study, we used a centralized clinical and pathology registry (2000-2020) to identify 1105 adult patients in British Columbia, Canada, with biopsy-proven glomerular disease that was stable on December 14, 2020 (when COVID-19 vaccines first became available). The primary outcome was disease relapse, on the basis of changes in kidney function, proteinuria, or both. Vaccination was modeled as a 30-day time-varying exposure in extended Cox regression models, stratified on disease type. RESULTS: During 281 days of follow-up, 134 (12.1%) patients experienced a relapse. Although a first vaccine dose was not associated with relapse risk (hazard ratio [HR]=0.67; 95% confidence interval [95% CI], 0.33 to 1.36), exposure to a second or third dose was associated with a two-fold risk of relapse (HR=2.23; 95% CI, 1.06 to 4.71). The pattern of relative risk was similar across glomerular diseases. The absolute increase in 30-day relapse risk associated with a second or third vaccine dose varied from 1%-2% in ANCA-related glomerulonephritis, minimal change disease, membranous nephropathy, or FSGS to 3%-5% in IgA nephropathy or lupus nephritis. Among 24 patients experiencing a vaccine-associated relapse, 4 (17%) had a change in immunosuppression, and none required a biopsy. CONCLUSIONS: In a population-level cohort of patients with glomerular disease, a second or third dose of COVID-19 vaccine was associated with higher relative risk but low absolute increased risk of relapse.

The value of repeat kidney biopsy during an atypical course of membranous nephropathy.

BACKGROUND: The clinical trajectory for patients with primary membranous nephropathy ranges widely from spontaneous remission to a rapid decline in kidney function. Etiologies for rapid progression with membranous nephropathy include concurrent bilateral renal vein thrombosis, malignant hypertension, and crescentic membranous nephropathy. Given the wide heterogeneity in prognosis, timing of immunosuppressive therapy is often challenging and centers around an individual patient's perceived risk for rapidly progressive disease. CASE PRESENTATION: Herein, we describe the clinical course of a young patient who initially developed a typical presentation of membranous nephropathy with consistent kidney biopsy findings. Given clinical stability, a six month observation period was undertaken prior to initiating immunosuppression. Within this observation window, the patient developed community acquired pneumonia followed several weeks later by a sudden, rapid decline in kidney function requiring dialysis. Repeat kidney biopsy revealed post-infectious glomerulonephritis superimposed upon a background of membranous nephropathy. Immunosuppressive therapy resulted in a favorable long-term outcome with normalization of kidney function and remission of nephrotic syndrome. To our knowledge, this is the first report of the simultaneous occurrence of these two glomerular disease processes. CONCLUSION: This case illustrates the value of repeat kidney biopsy during an atypical course of membranous nephropathy. Superimposed glomerular disease processes should be considered during a course of rapidly progressive membranous nephropathy.

The Risk of Cardiovascular Events in Individuals With Primary Glomerular Diseases.

RATIONALE & OBJECTIVE: Little is known about the risk of cardiovascular disease (CVD) in patients with various primary glomerular diseases. In a population-level cohort of adults with primary glomerular disease, we sought to describe the risk of CVD compared with the general population and the impact of traditional and kidney-related risk factors on CVD risk. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Adults with membranous nephropathy (n = 387), minimal change disease (n = 226), IgA nephropathy (n = 759), and focal segmental glomerulosclerosis (n = 540) from a centralized pathology registry in British Columbia, Canada (2000-2012). EXPOSURE: Traditional CVD risk factors (diabetes, age, sex, dyslipidemia, hypertension, smoking, prior CVD) and kidney-related risk factors (type of glomerular disease, estimated glomerular filtration rate [eGFR], proteinuria). OUTCOME: A composite CVD outcome of coronary artery, cerebrovascular, and peripheral vascular events, and death due to myocardial infarction or stroke. ANALYTICAL APPROACH: Subdistribution hazards models to evaluate the outcome risk with non-CVD death treated as a competing event. Standardized incidence rates (SIR) calculated based on the age- and sex-matched general population. RESULTS: During a median 6.8 years of follow-up, 212 patients (11.1%) experienced the CVD outcome (10-year risk, 14.7% [95% CI, 12.8%-16.8%]). The incidence rate was high for the overall cohort (24.7 per 1,000 person-years) and for each disease type (range, 12.2-46.1 per 1,000 person-years), and was higher than that observed in the general population both overall (SIR, 2.46 [95% CI, 2.12-2.82]) and for each disease type (SIR range, 1.38-3.98). Disease type, baseline eGFR, and proteinuria were associated with a higher risk of CVD and, when added to a model with traditional risk factors, led to improvements in model fit (R2 of 14.3% vs 12.7%), risk discrimination (C-statistic of 0.81 vs 0.78; difference, 0.02 [95% CI, 0.01-0.04]), and continuous net reclassification improvement (0.4 [95% CI, 0.2-0.6]). LIMITATIONS: Ascertainment of outcomes and comorbidities using administrative data. CONCLUSIONS: Patients with primary glomerular disease have a high absolute risk of CVD that is approximately 2.5 times that of the general population. Consideration of eGFR, proteinuria, and type of glomerular disease may improve risk stratification of CVD risk in these individuals. PLAIN-LANGUAGE SUMMARY: Patients with chronic kidney disease are known to be at high risk of cardiovascular disease. Cardiovascular risk in patients with primary glomerular diseases is poorly understood because these conditions are rare and require a kidney biopsy for diagnosis. In this study of 1,912 Canadian patients with biopsy-proven IgA nephropathy, minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy, the rate of cardiovascular events was 2.5 times higher than in the general population and was high for each disease type. Consideration of disease type, kidney function, and proteinuria improved the prediction of cardiovascular events. In summary, our population-level study showed that patients with primary glomerular diseases have a high cardiovascular risk, and that inclusion of kidney-specific risk factors may improve risk stratification.

Intravenous albumin for the prevention of hemodynamic instability during sustained low-efficiency dialysis: a randomized controlled feasibility trial (The SAFER-SLED Study).

BACKGROUND: Hemodynamic instability is a frequent complication of sustained low-efficiency dialysis (SLED) treatments in the ICU. Intravenous hyperoncotic albumin may prevent hypotension and facilitate ultrafiltration. In this feasibility trial, we sought to determine if a future trial, powered to evaluate clinically relevant outcomes, is feasible. METHODS: This single-center, blinded, placebo-controlled, randomized feasibility trial included patients with acute kidney injury who started SLED in the ICU. Patients were randomized to receive 25% albumin versus 0.9% saline (control) as 100 mL boluses at the start and midway through SLED, for up to 10 sessions. The recruitment rate and other feasibility outcomes were determined. Secondary exploratory outcomes included ultrafiltration volumes and metrics of hemodynamic instability. RESULTS: Sixty patients (271 SLED sessions) were recruited over 10 months. Age and severity of illness were similar between study groups. Most had septic shock and required vasopressor support at baseline. Protocol adherence occurred for 244 sessions (90%); no patients were lost to follow-up; no study-related adverse events were observed; open label albumin use was 9% and 15% in the albumin and saline arms, respectively. Ultrafiltration volumes were not significantly different. Compared to the saline group, the albumin group experienced less hemodynamic instability across all definitions assessed including a smaller absolute decrease in systolic blood pressure (mean difference 10.0 mmHg, 95% confidence interval 5.2-14.8); however, there were significant baseline differences in the groups with respect to vasopressor use prior to SLED sessions (80% vs 61% for albumin and saline groups, respectively). CONCLUSIONS: The efficacy of using hyperoncotic albumin to prevent hemodynamic instability in critically ill patients receiving SLED remains unclear. A larger trial to evaluate its impact in this setting, including evaluating clinically relevant outcomes, is feasible. Trial registration ClinicalTrials.gov (NCT03665311); First Posted: Sept 11th, 2018. https://clinicaltrials.gov/ct2/show/NCT03665311?term=NCT03665311&draw=2&rank=1.

Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy.

BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to <1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). RESULTS: During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. CONCLUSIONS: Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.

A Provincial Survey of the Contemporary Management of Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Recent years have witnessed an encouraging expansion of knowledge and management tools in the care of patients with autosomal dominant polycystic kidney disease (ADPKD), including measurement of total kidney volume as a biomarker of disease progression, stringent blood pressure targets to slow cyst growth, and targeted treatments such as tolvaptan. OBJECTIVES: We sought to evaluate clinicians' familiarity with, and usage of, novel evidence-based management tools for ADPKD. DESIGN: On-line survey. SETTING: British Columbia, Canada. PARTICIPANTS: Nephrologists in academic and community practice (excluding clinicians who practice exclusively in transplantation). MEASUREMENTS: Participants answered multiple-choice questions in 6 domains: sources of information, self-identified needs for optimal care delivery, prognostication, imaging tests, blood pressure targets, and use of tolvaptan. METHODS: An online survey was developed and disseminated via email to 65 nephrologists engaged in current clinical practice in British Columbia. RESULTS: A total of 29 nephrologists (45%) completed the questionnaire. The most popular source of information was the primary literature (83% of respondents). While 86% of respondents reported assessing the risk of disease progression before the onset of kidney function decline, most were using traditional metrics such as blood pressure and proteinuria rather than validated prediction tools such as the Mayo Classification. Although 90% of respondents obtained additional imaging after diagnosis in some or all of their ADPKD patients, only 1 in 5 reported being confident in their ability to interpret kidney size. The recommended blood pressure (BP) target of <110/75 mmHg was sought by 17% of respondents. All respondents reported being familiar with the literature regarding tolvaptan; however, only half were confident in their ability to identify suitable patients for treatment. The top 3 needs identified by clinicians were better access to medications (69%), clear management protocols (66%), and easier access to imaging tests (59%). LIMITATIONS: Funding mechanisms for tolvaptan can vary; therefore, clinicians' experience with the drug may not be generalizable. Although the response rate was acceptable, the survey is nonetheless subject to responder bias. CONCLUSION: This survey indicates that there is substantial variability in the usage of, and familiarity with, evidence-based ADPKD management tools among contemporary nephrologists, contributing to incomplete translation of evidence into clinical practice. Providing greater access to tolvaptan or imaging tests is unlikely to improve patient care without enhancing knowledge translation and education. TRIAL REGISTRATION: Not applicable as this was a survey.

CONTEXTE: On a assisté au cours des dernières années à un élargissement prometteur des connaissances et des outils de gestion dans le domaine des soins prodigués aux patients atteints de maladie polykystique rénale autosomale dominante (MPRAD). On pense notamment à la mesure du volume rénal total comme biomarqueur de l'évolution de la maladie, à des cibles strictes en matière de pression artérielle visant à ralentir la croissance des kystes et à des traitements ciblés comme le tolvaptan. OBJECTIFS: Nous souhaitions évaluer la connaissance des cliniciens à l'égard de ces nouveaux outils fondés sur des données probantes et mesurer leur usage en contexte de MPRAD. TYPE D'ÉTUDE: Sondage en ligne. CADRE: Colombie-Britannique, Canada. PARTICIPANTS: Les néphrologues pratiquant en milieu hospitalier universitaire et communautaire (à l'exception des médecins pratiquant exclusivement en transplantation). MESURES: Les participants ont répondu à un questionnaire à choix multiples touchant six domaines précis: les sources d'information, les besoins autodéclarés pour une prestation de soins optimaux, le pronostic, les tests d'imagerie, les cibles de pression artérielle et l'utilization du tolvaptan. MÉTHODOLOGIE: Un sondage en ligne a été élaboré et distribué par courriel à 65 néphrologues pratiquant actuellement en Colombie-Britannique. RÉSULTATS: En tout, 29 néphrologues (45 %) ont répondu au questionnaire. La principale source d'information était la littérature (83 % des répondants). Bien que 86 % des répondants mentionnaient évaluer le risque de progression de la maladie avant les premières manifestations d'un déclin de la fonction rénale, la plupart recouraient à des indicateurs traditionnels comme la pression artérielle et la protéinurie plutôt qu'à des outils validés comme la classification de la clinique Mayo. Et bien que 90 % des répondants aient pu faire des tests d'imagerie supplémentaires après le diagnostic, chez certains ou chez tous leurs patients atteints de MPRAD, seul un médecin sur cinq s'est déclaré confiant en sa capacité d'interpréter la taille du rein. La cible recommandée de pression artérielle, soit moins de 110/75 mmHg, était recherchée par seulement 17 % des répondants. Tous les médecins ont mentionné être familiers avec la littérature portant sur le tolvaptan, mais la moitié des répondants doutaient de leur capacité à bien cerner les patients pour qui ce traitement est adéquat. Les cliniciens ont nommé trois principaux besoins: un meilleur accès aux médicaments (69 %), des protocoles de prise en charge clairs (66 %) et un accès plus facile aux tests d'imagerie (59 %). LIMITES: Les mécanismes de financement du tolvaptan sont variables et ainsi, l'expérience des cliniciens avec ce médicament pourrait ne pas être généralisable. Bien que le taux de réponse ait été jugé acceptable, le sondage demeure sujet à des biais de la part des répondants. CONCLUSION: Ce sondage indique qu'il existe une variabilité substantielle dans l'usage et la connaissance des outils de gestion de la MPRAD fondés sur les données probantes parmi les néphrologues. Cette situation contribue à l'application incomplète des résultats dans la pratique clinique. Offrir un accès accru au tolvaptan ou aux tests d'imagerie est peu susceptible d'améliorer les soins si l'application des connaissances et l'éducation ne sont pas améliorées. ENREGISTREMENT DE L'ESSAI: Sans objet puisqu'il s'agit d'une étude sous forme de sondage.

Socioeconomic Position and Incidence of Glomerular Diseases.

BACKGROUND AND OBJECTIVES: Social deprivation is a recognized risk factor for undifferentiated CKD; however, its association with glomerular disease is less well understood. We sought to investigate the relationship between socioeconomic position and the population-level incidence of biopsy-proven glomerular diseases. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective cohort study, a provincial kidney pathology database (2000-2012) was used to capture all incident cases of membranous nephropathy (n=392), IgA nephropathy (n=818), FSGS (n=375), ANCA-related GN (ANCA-GN, n=387), and lupus nephritis (n=389) in British Columbia, Canada. Quintiles of area-level household income were used as a proxy for socioeconomic position, accounting for regional differences in living costs. Incidence rates were direct standardized to the provincial population using census data for age and sex and were used to generate standardized rate ratios. For lupus nephritis, age standardization was performed separately in men and women. RESULTS: A graded increase in standardized incidence with lower income was observed for lupus nephritis (P<0.001 for trend in both sexes) and ANCA-GN (P=0.04 for trend). For example, compared with the highest quintile, the lowest income quintile had a standardized rate ratio of 1.7 (95% confidence interval, 1.19 to 2.42) in women with lupus nephritis and a standardized rate ratio of 1.5 (95% confidence interval, 1.09 to 2.06) in ANCA-GN. The association between income and FSGS was less consistent, in that only the lowest income quintile was associated with a higher incidence of disease (standardized rate ratio, 1.55; 95% confidence interval, 1.13 to 2.13). No significant associations were demonstrated for IgA nephropathy or membranous nephropathy. CONCLUSIONS: Using population-level data and a centralized pathology database, we observed an inverse association between socioeconomic position and the standardized incidence of lupus nephritis and ANCA-GN.

Mortality in Relation to Changes in a Healthy Aging Index: The Health, Aging, and Body Composition Study.

BACKGROUND: Baseline scores on a Healthy Aging Index (HAI), including five key physiologic domains, strongly predict health outcomes. This study aimed to characterize 9-year changes in a HAI and explore their relationship to subsequent mortality. METHODS: Data are from the Health, Aging, and Body Composition study of well-functioning adults aged 70-79 years. A HAI, which ranges from 0 to 10, was constructed at years 1 and 10 of the study including systolic blood pressure, forced expiratory volume, digit symbol substitution test, cystatin C, and fasting glucose. The relationships between the HAI at years 1 and 10 and the change between years and subsequent mortality until year 17 were estimated from Cox proportional hazards models. RESULTS: Two thousand two hundred sixty-four participants had complete data on a HAI at year 1, of these 1,122 had complete data at year 10. HAI scores tended to increase (i.e. get worse) over 9-year follow-up, from (mean [SD]) 4.3 (2.1) to 5.7 (2.1); mean within-person change 1.5 (1.6). After multivariable adjustment, HAI score was related to mortality from year 1 (hazard ratio [95% confidence interval] = 1.17 [1.13-1.21] per unit) and year 10 (1.20 [1.14-1.27] per unit). The change between years was also related to mortality (1.08 [1.02-1.15] per unit change). CONCLUSIONS: HAI scores tended to increase with advancing age and stratified mortality rates among participants remaining at year 10. The HAI may prove useful to understand changes in health with aging.

Kidney Disease in Women is Associated with Disadvantaged Childhood Socioeconomic Position.

BACKGROUND: Socioeconomic position (SEP) is an important determinant of health and it is dynamic across the entire lifespan. We sought to investigate the relationship between life-course SEP and chronic kidney disease (CKD) using 3 conceptual models: critical period, pathway and accumulation. METHODS: Cross-sectional analysis of 4,996 participants from The Irish Longitudinal Study on Ageing, a nationally representative cohort of community-dwelling adults aged ≥50 years. We defined childhood and adulthood SEP according to father's and respondent's occupation respectively. SEP was categorised as high (reference), intermediate, low and never worked. CKD was defined as a glomerular filtration rate < 60 mL/min/1.73 m2 estimated from the combination of creatinine and cystatin C. We used logistic regression to estimate the age-adjusted association between SEP and CKD separately in men and women. RESULTS: Low childhood SEP was strongly associated with CKD in women, after adjusting for adulthood SEP (OR 1.90 [95% CI 1.24-2.92]), supporting the critical period hypothesis. This association was not explained by traditional CKD risk factors. Women who experienced low childhood SEP and whose circumstances improved in adulthood also had increased odds of CKD, further supporting a critical period effect in childhood. There was comparatively less evidence in support of the pathway or accumulation models. We did not observe a statistically significant association between SEP and CKD in men. CONCLUSIONS: Our findings suggest that women exposed to disadvantaged SEP in childhood represent an at-risk group in whom there may be opportunities for identification of CKD and facilitation of health-promoting behaviours from an early age.

The relationship between kidney function and quality of life among community-dwelling adults varies by age and filtration marker.

BACKGROUND: The impact of a diminished level of kidney function on the well-being of an older individual is poorly understood. We sought to determine the association between estimated glomerular filtration rate (eGFR) and overall quality of life (QoL) among older adults. METHODS: Cross-sectional analysis of 4293 participants from the Irish Longitudinal Study on Ageing, a population-based study of community-dwelling adults ≥50 years of age. We used multivariable negative binomial regression to model the relationship between categories of cystatin C eGFR (eGFRcys) or creatinine eGFR (eGFRcr) and the number of QoL deficits from the Control, Autonomy, Self-realization and Pleasure (CASP-19) scale, a holistic measure of QoL among older adults (range 0-57). We further explored this relationship across age strata. RESULTS: Median age was 61 [interquartile range (IQR) 55-68] years, 53% were female, mean (SD) CASP-19 score was 44.8 (7.4) and median eGFRcys was 81 (IQR 68-93) mL/min/1.73 m2. After multivariable adjustment, participants with eGFRcys <45 mL/min/1.73 m2 had 14% greater QoL deficits {incidence rate ratio 1.14 (95% confidence interval 1.03-1.25)] relative to the reference group (eGFRcys ≥90 mL/min/1.73 m2). This relationship appeared linear across eGFRcys categories and was more pronounced in younger (50-64 years) compared with older participants (65-74 or ≥75 years). There was no substantive relationship between eGFRcr and CASP-19. CONCLUSIONS: Cystatin C but not creatinine eGFR was associated with clinically modest declines in QoL among a large sample of community-dwelling older adults. This relationship varied by age, suggesting that a diminished eGFR contributes little to overall QoL beyond middle age in this population.

Examining the utility of cystatin C as a confirmatory test of chronic kidney disease across the age range in middle-aged and older community-dwelling adults.

BACKGROUND: Cystatin C has been proposed as a confirmatory test of chronic kidney disease (CKD). This is most applicable to older individuals with CKD, the majority of whom have a creatinine-based estimated glomerular filtration rate (eGFR) of 45-59 mL/min/1.73 m2 (CKD stage 3a). We sought to examine the utility of cystatin C as a confirmatory test of CKD across the age range in the general population of older adults. METHODS: Cross-sectional analysis of 5386 participants from The Irish Longitudinal Study on Ageing, a cluster-sampled national cohort of community-dwelling adults aged ≥50 years. Cystatin C and creatinine were measured simultaneously using standardised assays. Using generalised additive models, we modelled the distributions of creatinine and cystatin C per year of age from four distributional parameters: location, dispersion, skewness, kurtosis. Among participants with CKD stage 3a, we estimated the predicted probability of cystatin C eGFR <60 mL/min/1.73 m2 ('confirmed CKD') as a function of age. RESULTS: Median age was 62 years, 53% were female and median cystatin C eGFR was 80 mL/min/1.73 m2. We observed progressive variability in cystatin C with increasing age. Compared with creatinine, cystatin C levels rose sharply beyond the age of 65. Among participants with CKD stage 3a (n=463), the predicted probability of 'confirmed CKD' increased steadily with age, from 15% at age 50 to 80% at age 80. CONCLUSIONS: The clinical utility of cystatin C may be maximised in middle-aged individuals, in whom the distribution of cystatin C is less variable than older adults, and the pretest probability of confirming CKD is lower.

Graded Association Between Kidney Function and Impaired Orthostatic Blood Pressure Stabilization in Older Adults.

BACKGROUND: Impaired orthostatic blood pressure (BP) stabilization is highly prevalent in older adults and is a predictor of end-organ injury, falls, and mortality. We sought to characterize the relationship between postural BP responses and the kidney. METHODS AND RESULTS: We performed a cross-sectional analysis of 4204 participants from The Irish Longitudinal Study on Ageing, a national cohort of community-dwelling adults aged ≥50 years. Beat-to-beat systolic and diastolic BP were measured during a 2-minute active stand test. The primary predictor was cystatin C estimated glomerular filtration rate (eGFR) categorized as follows (mL/min per 1.73 m2): ≥90 (reference, n=1414); 75 to 89 (n=1379); 60 to 74 (n=942); 45 to 59 (n=337); <45 (n=132). We examined the association between eGFR categories and (1) sustained orthostatic hypotension, defined as a BP drop exceeding consensus thresholds (systolic BP drop ≥20 mm Hg±diastolic BP drop ≥10 mm Hg) at each 10-second interval from 60 to 110 seconds inclusive; (2) pattern of BP stabilization, characterized as the difference from baseline in mean systolic BP/diastolic BP at 10-second intervals. The mean age of subjects was 61.6 years; 47% of subjects were male, and the median eGFR was 82 mL/min per 1.73 m2. After multivariable adjustment, participants with eGFR <60 mL/min per 1.73 m2 were approximately twice as likely to have sustained orthostatic hypotension (P=0.008 for trend across eGFR categories). We observed a graded association between eGFR categories and impaired orthostatic BP stabilization, particularly within the first minute of standing. CONCLUSIONS: We report a novel, graded relationship between diminished eGFR and impaired orthostatic BP stabilization. Mapping the postural BP response merits further study in kidney disease as a potential means of identifying those at risk of hypotension-related events.

Kidney Function Estimated From Cystatin C, But Not Creatinine, Is Related to Objective Tests of Physical Performance in Community-Dwelling Older Adults.

BACKGROUND: The burden of chronic kidney disease is highest among older adults but the significance of a diminished level of kidney function in this heterogeneous population is poorly understood. We sought to examine the relationship between estimated glomerular filtration rate (eGFR) and objective physical performance in older adults. METHODS: Cross-sectional analysis of 4,562 participants from The Irish Longitudinal Study on Ageing, a national cohort of community-dwelling adults aged ≥50 years. We used multivariable linear or quantile regression to model the association between categories of cystatin C (eGFRcys) or creatinine eGFR (eGFRcr) and the following outcomes: gait speed, timed-up-and-go (TUG) and grip strength. Relationships were further explored using natural eGFR splines. We examined effect modification by age in the relationship between eGFR and gait speed. RESULTS: Mean (SD) age was 61.8 (8.3) years, 53.6% were female and median (IQR) eGFRcys was 82 (70-94) mL/min/1.73m2. In multivariable-adjusted models, participants in the lowest eGFRcys category (< 45 mL/min/1.73m2) had 3.32 cm/s (95% confidence interval [95%CI] 0.02-6.62) slower mean gait speed, 1.32 kg (95%CI 0.20-2.44) lower mean grip strength, and 0.31 seconds (95% CI -0.04 to 0.65) longer median TUG versus the reference group (eGFRcys ≥ 90 mL/min/1.73m2). The relationship between eGFRcys and outcomes appeared linear but varied by age. The association between eGFRcr and outcomes tended towards a U-shape. CONCLUSIONS: Cystatin C eGFR was linearly related to poorer physical performance beyond middle age among community-dwelling adults. The non-linear relationships observed with eGFRcr underscore the limitations of creatinine as a predictor of frailty outcomes in older individuals.

Spatial and Temporal Clustering of Anti-Glomerular Basement Membrane Disease.

BACKGROUND AND OBJECTIVES: An environmental trigger has been proposed as an inciting factor in the development of anti-GBM disease. This multicenter, observational study sought to define the national incidence of anti-GBM disease during an 11-year period (2003-2014) in Ireland, investigate clustering of cases in time and space, and assess the effect of spatial variability in incidence on outcome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We ascertained cases by screening immunology laboratories for instances of positivity for anti-GBM antibody and the national renal histopathology registry for biopsy-proven cases. The population at risk was defined from national census data. We used a variable-window scan statistic to detect temporal clustering. A Bayesian spatial model was used to calculate standardized incidence ratios (SIRs) for each of the 26 counties. RESULTS: Seventy-nine cases were included. National incidence was 1.64 (95% confidence interval [95% CI], 0.82 to 3.35) per million population per year. A temporal cluster (n=10) was identified during a 3-month period; six cases were resident in four rural counties in the southeast. Spatial analysis revealed wide regional variation in SIRs and a cluster (n=7) in the northwest (SIR, 1.71; 95% CI, 1.02 to 3.06). There were 29 deaths and 57 cases of ESRD during a mean follow-up of 2.9 years. Greater distance from diagnosis site to treating center, stratified by median distance traveled, did not significantly affect patient (hazard ratio, 1.80; 95% CI, 0.87 to 3.77) or renal (hazard ratio, 0.76; 95% CI, 0.40 to 1.13) survival. CONCLUSIONS: To our knowledge, this is the first study to report national incidence rates of anti-GBM disease and formally investigate patterns of incidence. Clustering of cases in time and space supports the hypothesis of an environmental trigger for disease onset. The substantial variability in regional incidence highlights the need for comprehensive country-wide studies to improve our understanding of the etiology of anti-GBM disease.