Application of the updated International IgA Nephropathy Prediction Tool in children one- or two-years post-biopsy.

The pediatric International IgA Nephropathy (IgAN) Prediction Tool comprises two models with and without ethnicity and is the first method to predict the risk of a 30% decline in estimated glomerular filtration rate (eGFR) or kidney failure in children at the time of biopsy using clinical risk factors and Oxford MEST histology scores. However, it is unknown if the Prediction Tool can be applied after a period of observation post-biopsy. Using an international multi-ethnic cohort of 947 children with IgAN, 38% of whom were followed into adulthood, the Prediction Tool was updated for use one-year after biopsy. Compared to the original pediatric Prediction Tool, the updated post-biopsy Prediction Tool had a better model fit with higher R2D (51%/50% vs 20%), significant increase in 4-year C-statistics (0.83 vs 0.73/0.69, ΔC 0.09 [95% confidence interval 0.07-0.10] and ΔC 0.14 [0.12-0.15]) and better 4-year calibration with lower integrated calibration indices (0.74/0.54 vs 2.45/1.01). Results were similar after internal validation and when the models were applied two-years after biopsy. Trajectories of eGFR after a baseline one-year post-biopsy were non-linear and those at higher predicted risk started with a lower eGFR and experienced a more rapid decline over time. In children, eGFR had a variable rate of increase until 15-18 years old then decreased linearly with a more rapid decline in higher risk groups that was similar to young adults of comparable risk. Thus, the original pediatric Prediction Tool should be used in children at the time of biopsy, and the updated pediatric Prediction Tool should be used to revaluate risk one- or two-years after biopsy.

Kidney Failure Risk Equation in vascular access planning: a population-based study supporting value in decision making.

Background: The Kidney Failure Risk Equation (KFRE) can play a better role in vascular access (VA) planning in patients with chronic kidney disease (CKD) requiring hemodialysis (HD). We described the VA creation and utilization pattern under existing estimated glomerular filtration rate (eGFR)-based referral, and investigated the utility of KFRE score as an adjunct variable in VA planning. Methods: Patients with CKD aged ≥18 years with eGFR <20 mL/min/1.73 m2 who chose HD as dialysis modality from January 2010 to August 2020 were included from a population-based database in British Columbia, Canada. Modality selection date was the index date. Exposures were categorized as (i) current eGFR-based referral, (ii) eGFR-based referral plus KRFE 2-year risk score on index date (KFRE-2) >40% and (iii) eGFR-based referral plus KFRE-2 ≤40%. We estimated the proportion of patients who started HD on arteriovenous fistula/graft (AVF/G) within 2 years, indicating timely pre-emptive creation, and the proportion of patients in whom AVF/G was created but did not start HD within 2 years, indicating too-early creation. Results: Study included 2581 patients, median age 71 years, 60% male. Overall, 1562(61%) started HD and 276 (11%) experienced death before HD initiation within 2 years. Compared with current referral, the proportion of patients who started HD on AVF/G was significantly higher when KFRE-2 was considered in addition to current referral (49% vs 58%, P-value <.001). Adjunct KFRE-2 significantly reduced too-early creation (31% vs 18%, P-value <.001). Conclusions: KFRE in addition to existing eGFR-based referral for VA creation has the potential to improve VA resource utilization by ensuring more patients start HD on AVF/G and may minimize too-early/unnecessary creation. Prospective research is necessary to validate these findings.

Histologic and Clinical Factors Associated with Kidney Outcomes in IgA Vasculitis Nephritis.

BACKGROUND: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. METHODS: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. RESULTS: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. CONCLUSIONS: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

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.

Application of the International IgA Nephropathy Prediction Tool one or two years post-biopsy.

The International IgA Nephropathy (IgAN) Prediction Tool is the preferred method in the 2021 KDIGO guidelines to predict, at the time of kidney biopsy, the risk of a 50% drop in estimated glomerular filtration rate or kidney failure. However, it is not known if the Prediction Tool can be accurately applied after a period of observation post-biopsy. Using an international multi-ethnic derivation cohort of 2,507 adults with IgAN, we updated the Prediction Tool for use one year after biopsy, and externally validated this in a cohort of 722 adults. The original Prediction Tool applied at one-year without modification had a coefficient of variation (R2) of 55% and 54% and four-year concordance (C statistic) of 0.82 but poor calibration with under-prediction of risk (integrated calibration index (ICI) 1.54 and 2.11, with and without race, respectively). Our updated Prediction Tool had a better model fit with higher R2 (61% and 60%), significant increase in four-year C-statistic (0.87 and 0.86) and better four-year calibration with lower ICI (0.75 and 0.35). On external validation, the updated Prediction Tool had similar R2 (60% and 58%) and four-year C-statistics (both 0.85) compared to the derivation analysis, with excellent four-year calibration (ICI 0.62 and 0.56). This updated Prediction Tool had similar prediction performance when used two years after biopsy. Thus, the original Prediction Tool should be used only at the time of biopsy whereas our updated Prediction Tool can be used for risk stratification one or two years post-biopsy.

A Pilot Study to Predict Risk of IgA Nephropathy Progression Based on miR-204 Expression.

INTRODUCTION: Immunoglobulin (Ig)A nephropathy (IgAN) is the most frequently diagnosed primary glomerulonephritis worldwide. Despite the common diagnostic feature of mesangial IgA-containing immune complex deposition, the clinical course of the disease is extremely variable, with 30% of patients developing end-stage kidney disease within 20 years of diagnosis. Therefore, identifying which patients are likely to progress is paramount. RESULTS: In this pilot study, we found that urinary exosomal miR-204 expression was significantly reduced in IgAN compared with healthy subjects. However, there was no difference in miR-204 expression between IgAN and non-IgAN chronic kidney disease controls. Analysis of miR-204 expression in kidney biopsy cores by next-generation sequencing followed by quantitative polymerase chain reaction validation in independent cohorts demonstrated that expression of miR-204 was significantly lower in IgAN compared with thin-membrane nephropathy but not compared with membranous nephropathy. Patients with IgAN at high risk of future progression had significantly lower expression of miR-204 than those at low risk of progression. Cortical localization indicated that miR-204 was preferentially expressed in the interstitium compared with glomeruli in IgAN nonprogressors and that this distribution was lost in IgAN progressors. Receiver operating characteristic curve analysis between the 2 IgAN cohorts revealed an area under the curve of 0.82. In addition, miR-204 expression correlated with known clinicopathological prognostic risk factors. Importantly, incorporating miR-204 into the International IgAN risk prediction tool improved the diagnostic power of the algorithm to predict risk of progression. CONCLUSION: Additional large-scale studies are now needed to validate the additive value of miR-204 in improving risk prediction in IgAN and more broadly in chronic kidney disease.

Differential expression of microRNA miR-150-5p in IgA nephropathy as a potential mediator and marker of disease progression.

Understanding why certain patients with IgA nephropathy progress to kidney failure while others maintain normal kidney function remains a major unanswered question. To help answer this, we performed miRNome profiling by next generation sequencing of kidney biopsies in order to identify microRNAs specifically associated with the risk of IgA nephropathy progression. Following sequencing and validation in independent cohorts, four microRNAs (-150-5p, -155-5p, -146b-5p, -135a-5p) were found to be differentially expressed in IgA nephropathy progressors compared to non-progressors, and patients with thin membrane nephropathy, lupus nephritis and membranous nephropathy, and correlated with estimated glomerular filtration rate, proteinuria, and the Oxford MEST-C scores (five histological features that are independent predictors of clinical outcome). Each individual microRNA increased the discrimination score of the International IgAN Prediction Tool, although due to the small number of samples the results did not reach statistical significance. miR-150-5p exhibited the largest amplitude of expression between cohorts and displayed the best discrimination between IgA nephropathy progressors and non-progressors by receiver operating curve analysis (AUC: 0.8). However, expression was similarly upregulated in kidneys with established fibrosis and low estimated glomerular filtration rates at the time of biopsy. Consistent with a more generic role in kidney fibrosis, in situ hybridization revealed that miR-150-5p was found in lymphoid infiltrates, and areas of proliferation and fibrosis consistent with the known drivers of progression. Thus, miR-150-5p may be a potential functional mediator of kidney fibrosis that may add value in predicting risk of progression in IgA nephropathy and other kidney diseases.

External Validation of International Risk-Prediction Models of IgA Nephropathy in an Asian-Caucasian Cohort.

INTRODUCTION: Two prediction models for IgA nephropathy (IgAN) using clinical variables and the Oxford MEST scores were developed and validated in 2 multiethnic cohorts. Additional external validation is required. METHODS: Biopsy-proven Chinese and Argentinian patients with IgAN were included. The primary outcome was defined as a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage renal disease. C-statistics and stratified analyses were used for model discrimination, coefficient of determination (R2 D) for model fit, and calibration plots for model calibration. Baseline survival function was also evaluated. RESULTS: A total of 1275 patients were enrolled, with a mean age of 34 (interquartile range: 27-42) years, 50% of whom (638 of 1275) were men. Use of renin-angiotensin system blockers was higher than in previously reported cohorts, whereas other variables were comparable. The C-statistic of the models was 0.81, and R2 D was higher than reported. Survival curves in the subgroups (<16th, ∼16th to <50th, ∼50th to <84th, and ≥84th percentiles of linear predictor) were well separated. Most of the predictor variables, including hazard ratio, predicted 5-year risk, and eGFR decline slope, were worse with risk increasing. The baseline survival function was comparable in our cohort and the reported cohorts. The calibration was acceptable for the full model without race. However, the risk probability over 3 years was overestimated in the full model with race included. CONCLUSION: The prediction models showed good performance on personalized risk assessment, which may be used as drug-specific, precision-medicine approaches to treatment decisionmaking.

Evaluating a New International Risk-Prediction Tool in IgA Nephropathy.

Importance: Although IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. Objective: To derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and Participants: We derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and Measures: Cox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R2D measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. Results: The study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R2D (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (ΔC, 0.04; 95% CI, 0.03-0.04 and ΔC, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R2D (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and Relevance: In this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.

External validation and clinical utility of a prediction model for 6-month mortality in patients undergoing hemodialysis for end-stage kidney disease.

BACKGROUND: End-stage kidney disease is associated with poor prognosis. Health care professionals must be prepared to address end-of-life issues and identify those at high risk for dying. A 6-month mortality prediction model for patients on dialysis derived in the United States is used but has not been externally validated. AIM: We aimed to assess the external validity and clinical utility in an independent cohort in Canada. DESIGN: We examined the performance of the published 6-month mortality prediction model, using discrimination, calibration, and decision curve analyses. SETTING/PARTICIPANTS: Data were derived from a cohort of 374 prevalent dialysis patients in two regions of British Columbia, Canada, which included serum albumin, age, peripheral vascular disease, dementia, and answers to the "the surprise question" ("Would I be surprised if this patient died within the next year?"). RESULTS: The observed mortality in the validation cohort was 11.5% at 6 months. The prediction model had reasonable discrimination (c-stat = 0.70) but poor calibration (calibration-in-the-large = -0.53 (95% confidence interval: -0.88, -0.18); calibration slope = 0.57 (95% confidence interval: 0.31, 0.83)) in our data. Decision curve analysis showed the model only has added value in guiding clinical decision in a small range of threshold probabilities: 8%-20%. CONCLUSION: Despite reasonable discrimination, the prediction model has poor calibration in this external study cohort; thus, it may have limited clinical utility in settings outside of where it was derived. Decision curve analysis clarifies limitations in clinical utility not apparent by receiver operating characteristic curve analysis. This study highlights the importance of external validation of prediction models prior to routine use in clinical practice.

Long-term patient and kidney survival after coronary artery bypass grafting, percutaneous coronary intervention, or medical therapy for patients with chronic kidney disease: a propensity-matched cohort study.

BACKGROUND: Revascularization in patients with chronic kidney disease (CKD) and coronary artery disease (CAD) is often deferred because of concern over progression of renal failure. HYPOTHESIS: Revascularization with either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) leads to progression of renal failure, but improves survival compared with medical therapy in patients with CKD. PATIENTS AND METHODS: Linkages between the British Columbia Cardiac Registry and the British Columbia Renal Registry of patients with established CAD and CKD who underwent CABG, PCI, or were treated medically were propensity matched. Overall patient survival was analyzed using a Cox proportional hazard model. Primary renal outcomes, defined as patients requiring long-term dialysis or progressive loss in kidney function, were analyzed using a competing risk approach. RESULTS: On the basis of the matched cohort, the risk of renal outcome in the first three months was the highest in the CABG group, but comparable between the PCI and the medical group (estimated probability at 3 months: 12.7% for CABG, 5.4% for PCI, 4.4% for medical; P<0.01). The estimated probability for the renal outcome at 24 months was similar across the groups: 37.9% for CABG, 37.6% for PCI, and 35.2% for medical therapy (P=0.62). The mortality risk at 24 months was lower for CABG (3.9%) compared with PCI (14.5%) or medical therapy (16.4%) (P<0.01). CONCLUSION: In patients with CAD and CKD who undergo the current practice of CABG, PCI, or are treated with medical therapy, progression of renal failure is higher in the first 3 months for CABG, but similar for all groups at 24 months. The 2-year mortality is lower in patients treated with CABG compared with PCI or medical therapy.

The Variability of Estimated Glomerular Filtration Rate Decline in Alport Syndrome.

BACKGROUND: A progressive trajectory toward renal failure is common in patients with Alport syndrome. Genotype-phenotype correlations have been well described; however, the natural history of the trajectory toward renal failure is not well described. OBJECTIVE: The objective of this study is to describe the natural history of renal function decline in a cohort of Alport syndrome patients. DESIGN: Retrospective observational cohort study. SETTING: British Columbia, Canada, chronic renal disease registry 1995-2012. PATIENTS: 37 biopsy proven Alport syndrome or hematuria with family history of Alport syndrome. MEASUREMENTS: Serial estimated glomerular filtration rate (eGFR) Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's eGFR measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2 /y decline), stable state (0-2 mL/min/1.73 m2 /y decline), and regressors (>2 mL/min/1.73 m2 /y incline). METHODS: In this retrospective observational cohort study, participants were identified through a chronic renal disease registry in British Columbia, Canada, from 1995 to 2012. Inclusion criteria were biopsy proven or hematuria with a family history of Alport syndrome. Individual patients and family group members were studied. Trajectory of renal decline described graphically by fitting a cubic smoothing spline to patient's serial estimated glomerular filtration rate (eGFR) measures. Various time points within a trajectory were indexed, randomly sampled, and followed for 2 years to estimate portion of progressors (>5 mL/min/1.73 m2/y decline), stable state (0-2 mL/min/1.73 m2/y decline), and regressors (>2 mL/min/1.73 m2/y incline). LIMITATIONS: Histological or genetic evidence of Alport syndrome is not available in all patients. RESULTS: Median follow-up time was 48.2 months of 37 patients (78% male), with a median age of 36 (interquartile range [IQR], 18-47) and a median age of renal replacement therapy commencement (n = 23) of 38 (IQR = 20-52). Renal function changes were found to be heterogeneous overall, intra-individual and within families. Portion of progressors in eGFR 45-60 mL/min/1.73 m2 was 73.7% (SD, 10.3), whereas 23.6% (SD, 11.0) remained stable. Within eGFR 30-45 mL/min/1.73 m2, 45.6% (SD, 7.0) were progressors, whereas 53.4% (SD, 7.4) remained stable. A large portion of eGFR 15-30 mL/min/1.73 m2 patients were stable (54.8%; SD, 8.4), whereas 25.7% (SD, 7.1) progressed and 19.5% (SD, 5.6) regressed. CONCLUSIONS: The renal decline in Alport syndrome patients is heterogeneous which has implications for designing clinical trials of interventions.

MISE EN CONTEXTE: Les patients atteints du syndrome d'Alport voient souvent leur état de santé évoluer vers l'insuffisance rénale. La corrélation entre le génotype et le phénotype est bien établie. Par contre, l'histoire naturelle de la trajectoire menant à l'insuffisance rénale demeure mal connue. OBJECTIFS DE L'ÉTUDE: Le principal objectif de cette étude était de caractériser l'histoire naturelle du déclin de la fonction rénale chez une cohorte de patients atteints du syndrome d'Alport. CADRE ET TYPE D'ÉTUDE: Une étude de cohorte observationnelle rétrospective effectuée entre 1995 et 2012 à partir du registre provincial des maladies rénales chroniques de la Colombie-Britannique, au Canada. PATIENTS: Une cohorte de 37 patients dont le diagnostic avait été confirmé par biopsie ou qui présentaient une hématurie conjointement à un historique familial de syndrome d'Alport. MESURES: Le débit de filtration glomérulaire estimé (DFGe) a été mesuré à plusieurs reprises. La trajectoire du déclin de la fonction rénale a été représentée graphiquement en ajustant une méthode d'interpolation cubique par splines de lissage à la série de mesures du débit de filtration glomérulaire estimé (eGFR) du patient. Plusieurs périodes suivant une trajectoire déterminée ont été indexées, échantillonnées aléatoirement et suivies pendant deux ans afin d'évaluer la proportion de cas de progression de la maladie (>5 mL/min/173m2/année de déclin), de patients stationnaires (0 à 2 mL/min/1,73 m2/année de déclin) et de cas de régression (>2 mL/min/1,73 m2/année de remontée). MÉTHODOLOGIE: Les patients qui ont participé à cette étude de cohorte observationnelle et rétrospective ont été recrutés entre 1995 et 2012 au sein d'un registre des patients souffrant d'insuffisance rénale chronique de la Colombie-Britannique, au Canada. La sélection des participants s'est effectuée sur la base d'un diagnostic posé par biopsie OU d'une hématurie en présence d'un historique familial de syndrome d'Alport. Les patients eux-mêmes, ainsi que des membres de leurs familles respectives ont été observés. La trajectoire du déclin de la fonction rénale a été représentée graphiquement en ajustant une méthode d'interpolation cubique par splines de lissage à la série de mesures du débit de filtration glomérulaire estimé (eGFR) du patient. Plusieurs périodes suivant une trajectoire déterminée ont été indexées, échantillonnées aléatoirement et suivies pendant deux ans afin d'évaluer la proportion de cas de progression de la maladie (>5 mL/min/173m2/année de déclin), de patients stationnaires (0 à 2 mL/min/1,73m2/année de déclin) et de cas de régression (>2 mL/min/1,73m2/année de remontée). LIMITES DE L'ÉTUDE: Les données génétiques ou histologiques nécessaires pour la confirmation du syndrome d'Alport étaient absentes pour certains patients. RÉSULTATS: Le suivi s'est effectué auprès de 37 patients dont 78% étaient des hommes et s'est échelonné sur une période moyenne de 48,2 mois. L'âge médian des participants était de 36 ans (Ecart Interquartile [EI] 18, 47) et l'âge médian où ceux-ci avaient commencé une thérapie de remplacement de la fonction rénale était de 38 ans (EI 20, 52). Les changements dans la fonction rénale se sont avérés hétérogènes tant de façon globale pour l'étude que chez les individus ou au sein de leurs familles. La proportion de progression de la maladie pour les patients présentant des valeurs de eGFR entre 45 et 60 mL/min/1,73m2 était de 73,7% (Écart-type [ÉT]: 10,3) tandis que 23,6% (ÉT: 11,0) sont demeurés stables. Dans le groupe de patients dont les valeurs de eGFR se situaient entre 30 et 45 mL/min/1,73m2, une proportion de 45,6% (ÉT: 7,0) était en progression alors que 53,4% (ÉT: 7,4) sont demeurés stables. Une forte proportion des patients présentant des valeurs de eGFR entre 15 et 30 mL/min/1,73m2 soit 54,8% (ÉT: 8,4) sont demeurés stables, tandis que 25,7% (ÉT: 7,1) étaient en progression et 19,5% (ÉT: 5,6) étaient en régression. CONCLUSIONS: Le déclin de la fonction rénale chez les patients atteints du syndrome d'Alport est hétérogène ce qui entraîne des répercussions sur la façon de concevoir les essais d'intervention cliniques.

Time to revisit the problem of CIN? The low incidence of acute kidney injury with and without contrast in hospitalized patients: an observational cohort study.

BACKGROUND: Acute kidney injury (AKI) following imaging procedures with contrast medium in hospitalized patients is commonly attributed to contrast-induced nephropathy (CIN). This study sought to establish a benchmark of the incidence of AKI in hospitalized patients who underwent computed tomography (CT) scans, with and without intravenous contrast administration. METHODS: This was a multi-center observational cohort study. Hospitalized patients in four hospitals with CT scans during two time periods in 2012 and 2013 were included. AKI post-scan was defined as a change in serum creatinine (sCr) in absolute terms of ≥26.5 µmol/L (≥0.3 mg/dl), occurring within 7 days of the CT scan. AKI incidence was examined by study phases and CT-scan types using logistic regression models. Multinomial logistic regression was used to examine the proportions of sCr availability between two study phases. RESULTS: Three hundred and twenty-five patients in Period 1 and 518 patients in Period 2 were included in the study. The incidence of AKI in Period 1 was similar in those who received contrast and in those who did not (11.6 % [95 % C.I.: 6.5, 18.7] vs. 10.1 % [95 % C.I.: 5.1, 17.3]; p = 0.38). The incidence of AKI remained not significantly different between the two periods in those who received contrast (11.6 % [95 % C.I.: 6.5, 18.7] vs. 10.7 % [95 % C.I.: 6.8, 15.8]; p = 0.89) and those who did not (10.1 % [95 % C.I.: 5.1, 17.3] vs. 9.1 % [95 % C.I.: 5.2, 14.6]; p = 0.54). Among those who received contrast, there was a significant increase in the availability of both pre- and post- CT scan sCr in Period 2 compared to Period 1 (73.6 % [95 % C.I.: 67.7, 80.6] vs. 79.8 % [95 % C.I.: 75.2, 84.7]; p = 0.006). LIMITATIONS: Our study was not targeted to specifically assess the impact of a prevention protocol on the incidence of AKI and was limited to settings within one health authority in the province. CONCLUSION: In hospitalized patients, the incidence of AKI is low, not different between those who did and did not receive contrast, and was not impacted by improvement in the monitoring of sCr in at risk patients. A better understanding of the determinants of AKI post-contrast scan is required to improve strategies to reduce the incidence of AKI.

DONNÉES CONNUES: L'occurrence d'un épisode d'insuffisance rénale aiguë (IRA) à la suite d'examens d'imagerie médicale avec administration d'un agent de contraste est fréquemment attribuée à une néphropathie induite par l'agent de contraste lui-même. La présente étude a cherché à établir des bases de référence susceptibles d'aider à mesurer l'incidence des épisodes d'IRA chez les patients hospitalisés qui ont à subir un examen par tomodensitométrie (scanner), avec ou sans administration intraveineuse d'un agent de contraste. MÉTHODOLOGIE: Cette étude observationnelle a été réalisée sur des cohortes de patients hospitalisés sélectionnés dans les unités de néphrologie de quatre centres hospitaliers différents. Ces patients ont subi des examens par tomodensitométrie au cours de deux périodes distinctes en 2012 et en 2013. Il a été décrété que les patients étaient atteints de néphropathie post-scanner lorsque leur taux de créatinine sérique augmentait de plus de 26.5 µmol/L ou à 0.3 mg/dl dans les 7 jours suivant l'examen. L'incidence d'insuffisance rénale aiguë a été analysée à l'aide d'un modèle de régression logistique en fonction de la phase de l'étude et du type de tomodensitomètre utilisé pour l'examen. Une régression logistique multinomiale a été utilisée pour présenter les taux de créatinine sérique mesurés entre les phases de l'étude. RÉSULTATS: La cohorte de la phase 1 comptait 325 patients et celle de la phase 2 en comptait 518. Il en est ressorti que l'incidence d'IRA post-scanner était similaire chez tous les patients de la phase 1, qu'ils aient ou non reçu un agent de contraste par intraveineuse avant l'examen (11.6 % [95 % I.C: 6.5, 18.7] vs 10.1 % [95 % I.C: 5.1, 17.3]; p = 0.38). L'incidence des épisodes d'IRA post-scanner est demeurée similaire dans les deux phases pour les patients ayant reçu un agent de contraste (11.6 % [95 % I.C: 6.5, 18.7] vs 10.7 % [95 % I.C: 6.8, 15.8]; p = 0.89) de même pour les patients n'en ayant pas reçu (10.1 % [95 % I.C: 5.1, 17.3] vs 9.1 % [95 % I.C: 5.2, 14.6]; p = 0.54). Chez les sujets ayant reçu un produit de contraste, il y avait une plus grande disponibilité des mesures de créatinine sérique pré ­ et post-scanner dans la période 2 par rapport à la période 1 (73.6 % [95 % I.C: 67.7, 80.6] vs 79.8 % [95 % I.C: 75.2, 84.7]; p = 0.006). LIMITES DE L'ÉTUDE: La présente étude ne visait pas à évaluer de façon systématique l'impact d'un protocole de prévention sur l'incidence d'un épisode d'IRA, étant donné qu'elle s'est limitée aux paramètres établis dans un seul cadre régional. CONCLUSION: L'incidence d'un épisode d'IRA chez les patients hospitalisés subissant un examen en tomodensitométrie demeure faible, et n'apparait pas significativement différente qu'ils reçoivent ou non un agent de contraste au préalable. Une surveillance plus rigoureuse des taux de créatinine sérique chez les patients à risque n'a pas non plus mené à des différences marquées dans l'incidence d'un épisode d'IRA post-scanner. Ainsi, une meilleure compréhension des facteurs susceptibles de provoquer des épisodes d'IRA post-scanner est requise afin d'améliorer les stratégies visant la réduction de leur incidence.

Fluid balance, change in serum creatinine and urine output as markers of acute kidney injury post cardiac surgery: an observational study.

BACKGROUND: Acute kidney injury (AKI) is defined as oliguria or rise in serum creatinine but oliguria alone as a diagnostic criterion may over-diagnose AKI. OBJECTIVES: Given the association between fluid overload and AKI, we aimed to determine if positive fluid balance can complement the known parameters in assessing outcomes of AKI. DESIGN: Prospective observational study. SETTING: Teaching hospital in Vancouver, Canada. PATIENTS: 111 consecutive patients undergoing elective cardiac surgery from January to April 2012. MEASUREMENTS: Outcomes of cardiac surgery intensive care unit (CSICU) and hospital length of stay (LOS) in relation to fluid balance, urine output and serum creatinine. METHODS: All fluid input and output was recorded for 72 hours post-operatively. Positive fluid balance was defined as >6.5 cc/kg. Daily serum creatinine and hourly urine output were recorded and patients were defined as having AKI according to the AKIN criteria. RESULTS: Of the patients who were oliguric, those with fluid overload trended towards longer LOS than those without fluid overload [CSICU LOS: 62 and 39 hours (unadjusted p-value 0.02, adjusted p-value 0.58); hospital LOS: 13 and 9 days (unadjusted p-value: 0.05, adjusted p-value: 0.16)]. Patients with oliguria who were fluid overloaded had similar LOS to patients with overt AKI (change in serum creatinine ≥ 26.5 µmol/L), [CSICU LOS: 62 and 69 hours (adjusted p value: 0.32) and hospital LOS: 13 and 14 days (adjusted p value: 0.19)]. Patients with oliguria regardless of fluid balance had longer CSICU LOS (adjusted p value: 0.001) and patients who were fluid overloaded in the absence of AKI had longer hospital LOS (adjusted p value: 0.02). LIMITATIONS: Single centre, small sample, LOS as outcome. CONCLUSIONS: Oliguria and positive fluid balance is associated with a trend towards longer LOS as compared to oliguria alone. Fluid balance may therefore be a useful marker of AKI, in addition to urine output and serum creatinine.

CONTEXTE: L'insuffisance rénale aiguë (IRA) se définit comme une oligurie ou une élévation de la créatininémie. Par contre, l'oligurie comme unique critère diagnostique peut mener abusivement au diagnostic d'IRA. OBJECTIFS: Étant donné l'association entre l'hyperhydratation et l'IRA, nous cherchons à déterminer si une balance liquidienne positive peut complémenter les paramètres connus dans l'évaluation des résultats de l'IRA. TYPE D'ÉTUDE: Étude d'observation prospective. CONTEXTE: Hôpital universitaire à Vancouver, Canada. PARTICIPANTS: 111 patients consécutifs qui subissent une chirurgie cardiaque non urgente, entre janvier et avril 2012. MESURES: On a mis en parallèle les résultats de l'unité de soins intensifs en chirurgie cardiaque (USICC), de même que la durée de l'hospitalisation (soins actifs), avec la balance liquidienne, la diurèse et la créatininémie. MÉTHODES: On a mesuré les ingesta et excreta durant les 72 heures postopératoires. On a défini une balance liquidienne positive à >6,5 cc/kg. On a enregistré la créatininémie quotidienne et la diurèse aux heures, et on a déterminé que les patients souffraient d'IRA en nous basant sur les critères de l'Acute Kidney Injury Network (AKIN). RÉSULTATS: Parmi les patients oliguriques, ceux qui avaient une surcharge liquidienne tendaient davantage vers une hospitalisation prolongée que ceux qui n'en avaient pas [durée de soins actifs à l'USICC: 62 et 39 heures (valeur de p non ajustée: 0,02, valeur de p ajustée: 0,58); durée de soins actifs à l'hôpital: 13 et 9 jours (valeur de p non ajustée: 0,05, valeur de p ajustée: 0,16)]. Les patients présentant une oligurie qui présentaient aussi une surcharge liquidienne requéraient une durée de soins actifs similaire aux patients souffrant d'IRA (modification de la créatininémie ≥ 26,5 µmol/L), [soins actifs USICC: 62 et 69 heures (valeur de p ajustée: 0,32) soins actifs à l'hôpital: 13 et 14 jours (valeur de p ajustée: 0,19)]. Les patients présentant une oligurie, indépendamment de la balance liquidienne, bénéficiaient d'une durée de soins actifs à l'USICC prolongée (valeur p ajustée: 0,001), tandis que les patients en surcharge liquidienne, mais ne souffrant pas d'IRA bénéficiaient davantage de soins actifs à l'hôpital (valeur de p ajustée: 0,02). LIMITES DE L'ÉTUDE: Un seul centre, un échantillon restreint, les soins actifs considérés comme une issue. CONCLUSION: Les patients avec oligurie et une balance liquidienne positive ont nécessité des soins actifs prolongés à l'USICC, comparativement aux patients ne présentant qu'une oligurie. La balance liquidienne peut donc constituer un marqueur d'IRA, en plus de la diurèse et la créatininémie.

Urinary NGAL levels before and after coronary angiography: a complex story.

BACKGROUND: We describe urinary neutrophil gelatinase-associated lipocalin (uNGAL) values in association with clinical characteristics and urinary parameters in adults undergoing coronary angiography. METHODS: This is an observational study of consecutive patients who underwent elective coronary angiography during a 4-month period in a large urban tertiary care hospital. RESULTS: One hundred and thirteen patients were enrolled, and 100 had sufficient data to be included in the analyses. A large range of preprocedural uNGAL levels were observed (range 1-269 ng/mg Cr). Median preprocedural uNGAL was 8 ng/mg Cr. Age (P = 0.009), serum creatinine (P = 0.077) and albumin excretion (P = 0.009) were significant predictors of baseline uNGAL. Half the cohort demonstrated an increase and half a decrease in the absolute values of uNGAL after angiography, irrespective of preprocedural levels. CONCLUSIONS: We observed variable, but relatively low absolute levels of uNGAL prior to angiography in this 'cardiac' cohort. Only age, serum creatinine and albumin excretion could explain some of this variability. When designing studies of at-risk individuals where uNGAL may be used as a marker for acute kidney injury, this variability should be taken into account.

Elevated osteoprotegerin is associated with all-cause mortality in CKD stage 4 and 5 patients in addition to vascular calcification.

BACKGROUND: Cardiovascular disease is the leading cause of death in the chronic kidney disease (CKD) population. The mechanisms of vascular damage are not fully understood. The objective of this study was to prospectively investigate the importance of novel mediators of vascular damage, in conjunction with vascular calcification (VC), on survival. METHODS: A total of 134 subjects [60 haemodialysis (HD), 28 peritoneal dialysis (PD) and 46 CKD stage 4] were studied. All survivors completed 40 months of follow-up. VC was measured using multi-slice spiral CT of the superficial femoral artery. Circulating osteoprotegerin (OPG), Fetuin-A and high sensitivity C-reactive protein (hs-CRP) were measured in addition to standard clinical biochemical analysis. RESULTS: After a 40-month follow-up, 31 patients had died (27 men and 4 women). Of 31 subjects, 31 had evidence of significant VC. The majority of deaths were in the HD group (48%), 36% were PD subjects and 16% were CKD subjects. The outcome of interest was survival at the end of follow-up. Multivariate logistical regression analysis revealed male gender [OR 8.06 (1.34-48.450) P = 0.02], OPG >25 pmol/L [OR 5.31(1.35-20.88) P = 0.02] and hypoalbuminaemia [OR 0.26 (0.12-0.56) P < 0.01], were associated with increased odds of death. CONCLUSION: We have previously reported that VC and low albumin predict death in CKD stages 4 and 5 over a 2-year follow-up period. These data show that OPG, independent of CRP, is also associated with a negative outcome. The mechanisms remain to be elucidated; however, it is likely that they are associated with vascular damage through mechanisms in addition to VC.

A comparison of the predictive performance of different methods of kidney function estimation in a well-characterized HIV-infected population.

BACKGROUND: Glomerular filtration rate (GFR) estimation equations have never been validated in the HIV population. This pilot study aimed to compare all currently available methods of kidney function assessment with nuclear GFR in HIV-infected adults. METHODS: Patients underwent GFR measurement with (99m)Tc-diethylenetriaminepentaacetic acid (Tc-99m Pentetate), and measured values were compared with results of creatinine-based estimation equations [abbreviated 4-variable Modification of Diet in Renal Disease (MDRD) formula and Cockcroft-Gault (CG) formulae], 24-hour urine creatinine clearance and estimated cystatin C GFR. RESULTS: Twenty-seven HIV-infected adults were studied. Most were male and Caucasian, with a mean age of 52 years. Median CD4 was 290 cells/mm(3), 70% of patients had HIV RNA <50 copies/ml and all were receiving highly active antiretroviral therapy (median 5 drugs). Median Tc-99m Pentetate-GFR was 91 ml/min/1.73 m(2). Despite greater bias and similar accuracy, the MDRD formula was more precise than the CG formula, regardless of whether CG estimations were corrected for ideal body weight or body surface area. Relative accuracy within 30% of nuclear GFR was greater for the MDRD formula than for all other methods. The performance of 24-hour urine creatinine clearance was similar to that of the MDRD formula for patients with GFR <90 ml/min/1.73 m(2), although it performed less well at higher GFR. The performance of cystatin C GFR was inferior to that of all the creatinine-based methods. CONCLUSIONS: While no method of kidney function estimation performed highly, both 24-hour urine creatinine clearance and the MDRD formula performed with a level of precision and accuracy sufficient for clinical decision making. Our findings support the preferential use of the MDRD formula in the treated HIV population and suggest that there are no HIV-specific factors that limit equation applicability. Larger validation studies are needed to confirm our findings and allow generalization to the HIV population at large.

Exploration of association of 1,25-OH2D3 with augmentation index, a composite measure of arterial stiffness.

BACKGROUND AND OBJECTIVES: Abnormalities in mineral metabolism [calcium, phosphate, and immunoreactive parathyroid hormone (PTH)] and vitamin D have been linked to increases in central arterial stiffness. Central arterial stiffness can be measured using noninvasive technologies, including augmentation index (AIx), a composite measure of arterial stiffness. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: In 131 outpatients identified from individual cardiac or kidney disease clinics, we examined conventional demographic and laboratory risk factors, vitamin D levels (1,25-OH2D3 and 25-OHD3), and markers of inflammation or endothelial function [C-reactive peptide (hsCRP), matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), and IL-6] in relationship to AIx. RESULTS: The median eGFR was significantly different between clinics (range 25-81 ml/min). Subjects with higher phosphate or MMP-9 levels were found to have a higher AIx (P = 0.02 and 0.07, respectively). Lower 1,25-OH2D3 levels or reduced eGFR were associated with higher AIx (P = 0.002 and 0.005, respectively). The associations between 1,25-OH2D3 and phosphate levels and AIx were observed for values within the normal range. No association was noted for calcium, iPTH, 25-OHD3, or hsCRP and AIx. Adjusting for potential confounders [eGFR, calcium, phosphate, and (log) iPTH] the association of lower 1,25-OH2D3 with AIx remained statistically significant. CONCLUSION: This exploratory study demonstrates a significant association between AIx and 1,25-OH2D3 in a diverse group with cardiac, kidney disease, or both. These increasing understanding of the role of vitamin D in vascular health lends a context to these findings and raises questions as to additional modifiable risk factors in complex patients. Further studies are required.

Coronary artery calcification scores in patients with chronic kidney disease prior to dialysis: reliability as a trial outcome measure.

BACKGROUND: Coronary artery calcification (CAC) is prevalent in patients with chronic kidney disease (CKD). Data on the reliability and validity of high-resolution computerized tomography (HRCT) in patients with CKD is lacking. The purpose of this study was to evaluate the inter- and intra-reviewer agreement and inter-scan reproducibility of CACS measurement with HRCT in a cohort of patients with CKD prior to dialysis, and to compare the change in CACS at 30 minutes to the change in CACS over 1 year. METHODS: Thirty-three patients with CKD not yet on dialysis underwent an HRCT scan at baseline and 1 year to assess for CAC and CAC progression. Two radiologists independently reviewed films and each radiologist re-reviewed a randomly selected subset of films they had previously viewed, to assess for inter-reviewer and intra-reviewer reliability, respectively. Patients underwent a repeat scan within 30 min of the first baseline scan to assess for inter-scan reproducibility. RESULTS: At baseline, eight patients (24%) had no CAC. Of the 25 patients (76%) with CAC, 10 (40%) had severe calcification. Intra-reviewer agreement was 83%. Inter-reviewer agreement ranged between 77 and 94%. Six (27%) of the patients with >30 baseline CACS had >15% change in CACS following repositioning. Four of these patients had an increase in CACS with position change [18% (95% CI: 5-40%)]. Of the 21 patients who underwent a follow-up scan at 1 year, 7 (33%) demonstrated CACS progression. CONCLUSIONS: There is significant imprecision in HRCT-derived CACS in CKD patients. This suggests a need for standardization of methods of CACS measurement with HRCT.