Machine learning for prediction of chronic kidney disease progression: Validation of the Klinrisk model in the CANVAS Program and CREDENCE trial.

AIM: To validate the Klinrisk machine learning model for prediction of chronic kidney disease (CKD) progression in patients with type 2 diabetes in the pooled CANVAS/CREDENCE trials. MATERIALS AND METHODS: We externally validated the Klinrisk model for prediction of CKD progression, defined as 40% or higher decline in estimated glomerular filtration rate (eGFR) or kidney failure. Model performance was assessed for prediction up to 3 years with the area under the receiver operating characteristic curve (AUC), Brier scores and calibration plots of observed and predicted risks. We compared performance of the model with standard of care using eGFR (G1-G4) and urine albumin-creatinine ratio (A1-A3) Kidney Disease Improving Global Outcomes (KDIGO) heatmap categories. RESULTS: The Klinrisk model achieved an AUC of 0.81 (95% confidence interval [CI] 0.78-0.83) at 1 year, and 0.88 (95% CI 0.86-0.89) at 3 years. The Brier scores were 0.020 (0.018-0.022) and 0.056 (0.052-0.059) at 1 and 3 years, respectively. Compared with the KDIGO heatmap, the Klinrisk model had improved performance at every interval (P < .01). CONCLUSIONS: The Klinrisk machine learning model, using routinely collected laboratory data, was highly accurate in its prediction of CKD progression in the CANVAS/CREDENCE trials. Integration of the model in electronic medical records or laboratory information systems can facilitate risk-based care.

Kidney outcomes in children with primary focal segmental glomerulosclerosis from a low- and middle- income country.

BACKGROUND: Limited data exists regarding the clinical course and outcomes of children with primary focal segmental glomerulosclerosis (FSGS) from low- and middle- income countries. METHODS: Children aged 1-18 years with biopsy-proven primary FSGS followed from January 2010-June 2023 in a tertiary-care center were enrolled and their clinical profile, histological characteristics, kidney outcomes, and predictors of adverse outcomes were determined. RESULTS: Over 13 years, 73 (54.8% boys) children with median (IQR) age at FSGS diagnosis 6.7 (3,10) years were recruited and followed up for median 4 (2.5,8) years. FSGS-not otherwise specified (NOS) was the most common histological subtype, in 64 (87.6%) children, followed by collapsing variant in 5 (6.8%) children. At last follow-up, 43 (58.9%), 2 (2.7%) and 28 (38.3%) children were in complete remission (CR), partial remission (PR), and no remission (NR) respectively. Calcineurin inhibitors led to CR or PR in 39 (62%) children. Overall, 21 (28.7%) children progressed to chronic kidney disease (CKD) stage 2-5 (19 from NR vs. 2 from PR group; p = 0.03); with 41% of those NR at 12 months progressing to CKD 4-5 by last follow-up. On multivariable analysis, collapsing variant [adjusted HR 2.5 (95%CI 1.5, 4.17), p = 0.001] and segmental sclerosis > 25% [aHR 9.9 (95%CI 2.2, 45.2), p = 0.003] predicted kidney disease progression. CONCLUSIONS: In children with FSGS, response to immunosuppression predicts kidney survival as evidenced by nil to lower progression to CKD 2-5 by median follow-up of 4 (2.5,8) years in children with CR and PR, compared to those with no remission at 12 months from diagnosis. Segmental sclerosis > 25% and collapsing variant predicted progression to advanced CKD.

Association of serum 25-hydroxyvitamin D with cardiovascular mortality and kidney outcome in patients with early stages of CKD.

PURPOSE: While serum 25-hydroxyvitamin D (25[OH]D) deficiency is prevalent in chronic kidney disease (CKD), the effects of 25(OH)D deficiency on cardiovascular mortality and kidney outcomes in patients with early-stage CKD remain incompletely understood. METHODS: This multicenter retrospective cohort study included adult patients with stages 1-3 CKD from 19 medical centers across China between January 2000 and May 2021. The primary outcome was cardiovascular mortality. The secondary study outcome included CKD progression (defined as a sustained > 40% eGFR decrease from baseline or progress to end-stage kidney disease), and annual percentage change of eGFR. RESULTS: Of 9229 adults with stages 1-3 CKD, 27.0% and 38.9% had severe (< 10 ng/mL) and moderate (10 to < 20 ng/mL) serum 25(OH)D deficiency, respectively. Compared with patients having 25(OH)D ≥ 20 ng/mL, a significantly higher risk of cardiovascular mortality (hazard ratio [HR] 1.90, 95% CI 1.37-2.63), CKD progression (HR 2.20, 95% CI 1.68-2.88), and a steeper annual decline in eGFR (estimate - 7.87%; 95% CI - 10.24% to - 5.51% per year) was found in those with serum 25(OH)D < 10 ng/mL. Similar results were obtained in subgroups and by sensitivity analyses. CONCLUSIONS: 25(OH)D deficiency is associated with increased risks of cardiovascular mortality and CKD progression in patients with early-stage CKD. Studies are needed to determine whether early intervention for 25(OH)D deficiency could improve the prognosis of patients with early-stage CKD.

Association between cholinesterase inhibitors and kidney function decline in patients with Alzheimer's dementia.

Preclinical evidence shows that activation of the cholinergic anti-inflammatory pathway (CAP) may have direct and indirect beneficial effects on the kidney. Cholinesterase inhibitors (ChEIs) are specific Alzheimer's dementia (AD) therapies that block the action of cholinesterases and activate CAP. Here, we explored a plausible effect of ChEIs on slowing kidney function decline by comparing the risk of CKD progression among patients with newly diagnosed AD that initiated ChEI or not within 90 days. Using complete information of routine serum creatinine tests, we evaluated changes in estimated glomerular filtration rate (eGFR) and defined the outcome of chronic kidney disease (CKD) progression as the composite of an eGFR decline of over 30%, initiation of dialysis/transplant or death attributed to CKD. A secondary outcome was death. Inverse probability of treatment-weighted Cox regression was used to estimate hazard ratios. Among 11, 898 patients, 6,803 started on ChEIs and 5,095 did not. Mean age was 80 years (64% women) and the mean eGFR was 68 ml/min/1.73m2. During a median 3.0 years of follow-up, and compared to non-use, ChEI use was associated with 18% lower risk of CKD progression (1,231 events, adjusted hazard ratio 0.82; 95% confidence interval 0.71-0.96) and a 21% lower risk of death (0.79; 0.72-0.86). Results were consistent across subgroups, ChEI subclasses and after accounting for competing risks. Thus, in patients with AD undergoing routine care, use of ChEI (vs no-use) was associated with lower risk of CKD progression.

Long-term Visit-to-Visit Variability in Hemoglobin A1c and Kidney-Related Outcomes in Persons With Diabetes.

RATIONALE & OBJECTIVE: To characterize associations between long-term visit-to-visit variability of hemoglobin A1c (HbA1c) and risk of adverse kidney outcomes in patients with diabetes. STUDY DESIGN: Observational study. SETTING & PARTICIPANTS: 93,598 adults with diabetes undergoing routine care in Stockholm, Sweden. EXPOSURES AND PREDICTORS: Categories of baseline and time-varying HbA1c variability score (HVS, the percentage of total HbA1c measures that vary by>0.5% [5.5mmol/mol] during a 3-year window): 0-20%, 21%-40%, 41%-60%, 61%-80%, and 81%-100%, with 0-20% as the reference group. OUTCOME: Chronic kidney disease (CKD) progression (composite of>50% estimated glomerular filtration rate [eGFR] decline and kidney failure), acute kidney disease (AKI by clinical diagnosis or transient creatinine elevations according to KDIGO criteria), and worsening of albuminuria. ANALYTICAL APPROACH: Multivariable Cox proportional hazards regression. RESULTS: Compared with persons showing low HbA1c variability (HVS 0-20%), any increase in variability was associated with a higher risk of adverse kidney outcomes beyond mean HbA1c. For example, for patients with a baseline HbA1c variability of 81%-100%, the adjusted HR was 1.6 (95% CI, 1.47-1.74) for CKD progression, 1.23 [1.16-1.3] for AKI, and 1.28 [1.21-1.36] for worsening of albuminuria. The results were consistent across subgroups (diabetes subtypes, baseline eGFR, or albuminuria categories), in time-varying analyses and in sensitivity analyses including time-weighted average HbA1c or alternative metrics of variability. LIMITATIONS: Observational study, limitations of claims data, lack of information on diet, body mass index, medication changes, and diabetes duration. CONCLUSIONS: Higher long-term visit-to-visit HbA1c variability is consistently associated with the risks of CKD progression, AKI, and worsening of albuminuria. PLAIN-LANGUAGE SUMMARY: The evidence for current guideline recommendations derives from clinical trials that focus on a single HbA1c as the definitive measure of efficacy of an intervention. However, long-term visit-to-visit fluctuations of HbA1c may provide additional value in the prediction of future kidney complications. We evaluated the long-term fluctuations in glycemic control in almost 100,000 persons with diabetes undergoing routine care in Stockholm, Sweden. We observed that higher long-term HbA1c fluctuation is consistently associated with the risks of chronic kidney disease progression, worsening of albuminuria and acute kidney injury. This finding supports a role for long-term glycemic variability in the development of kidney complications and illustrates the potential usefulness of this metric for risk stratification at the bedside beyond a single HbA1c test.

Cardiorenal Outcomes Among Patients With Atrial Fibrillation Treated With Oral Anticoagulants.

RATIONALE & OBJECTIVE: Direct oral anticoagulants (DOACs) have progressively replaced vitamin K antagonists (VKAs) for stroke prevention in patients with nonvalvular atrial fibrillation (AF). DOACs cause fewer bleeding complications, but their other advantages, particularly related to kidney outcomes, remain inconclusive. We studied the risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) after DOAC and VKA administration for nonvalvular AF. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Cohort study of Swedish patients enrolled in the Stockholm Creatinine Measurements (SCREAM) project with a diagnosis of nonvalvular AF during 2011-2018. EXPOSURE: Initiation of DOAC or VKA treatment. OUTCOME: Primary outcomes were CKD progression (composite of >30% estimated glomerular filtration rate [eGFR] decline and kidney failure) and AKI (by diagnosis or KDIGO-defined transient creatinine elevations). Secondary outcomes were death, major bleeding, and the composite of stroke and systemic embolism. ANALYTICAL APPROACH: Propensity score weighted Cox regression was used to balance 50 baseline confounders. Sensitivity analyses included falsification end points, subgroups, and estimation of per-protocol effects. RESULTS: We included 32,699 patients (56% initiated DOAC) who were observed for a median of 3.8 years. Their median age was 75 years, 45% were women, and 27% had an eGFR <60mL/min/1.73m2. The adjusted HRs for DOAC versus VKA were 0.87 (95% CI, 0.78-0.98) for the risk of CKD progression and 0.88 (95% CI, 0.80-0.97) for AKI. HRs were 0.77 (95% CI, 0.67-0.89) for major bleeding, 0.93 (95% CI, 0.78-1.11) for the composite of stroke and systemic embolism, and 1.04 (95% CI, 0.95-1.14) for death. The results were similar across subgroups of age, sex, and baseline eGFR when restricting to patients at high risk for thromboembolic events and when censoring follow up at treatment discontinuation or change in type of anticoagulation. LIMITATIONS: Missing information on time in therapeutic range and treatment dosages. CONCLUSIONS: Among patients with nonvalvular AF treated in routine clinical practice compared with VKA use, DOAC use was associated with a lower risk of CKD progression, AKI, and major bleeding but a similar risk of the composite of stroke, systemic embolism, or death.

Association of the Urine-to-Plasma Urea Ratio With CKD Progression.

RATIONALE & OBJECTIVES: The urine-to-plasma (U/P) ratio of urea is correlated with urine-concentrating capacity and associated with progression of autosomal dominant polycystic kidney disease. As a proposed biomarker of tubular function, we hypothesized that the U/P urea ratio would also be associated with progression of more common forms of chronic kidney disease (CKD). STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: 3,723 adults in the United States with estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2, enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: U/P urea ratio, calculated from 24-hour urine collections and plasma samples at baseline. OUTCOME: Associations of U/P urea ratio with eGFR slope, initiation of kidney replacement therapy (KRT), and CKD progression, defined as 50% decline in eGFR or incident KRT. ANALYTICAL APPROACH: Multivariable linear mixed-effects models tested associations with eGFR slope. Cox proportional hazards models tested associations with dichotomous CKD outcomes. RESULTS: The median U/P urea ratio was 14.8 (IQR, 9.5-22.2). Compared with participants in the highest U/P urea ratio quintile, those in the lowest quintile had a greater eGFR decline by 1.06 mL/min/1.73 m2 per year (P < 0.001) over 7.0 (IQR, 3.0-11.0) years of follow-up observation. Each 1-SD lower natural log-transformed U/P urea ratio was independently associated with CKD progression (HR, 1.22 [95% CI, 1.12-1.33]) and incident KRT (HR, 1.22 [95% CI, 1.10-1.33]). Associations differed by baseline eGFR (P interaction = 0.009). Among those with an eGFR ≥30 mL/min/1.73 m2, each 1-SD lower in ln(U/P urea ratio) was independently associated with CKD progression (HR, 1.30 [95% CI, 1.18-1.45]), but this was not significant among those with eGFR <30 mL/min/1.73 m2 (HR, 1.00 [95% CI, 0.84-1.20]). LIMITATIONS: Possibility of residual confounding. Single baseline 24-hour urine collection for U/P urea ratio. CONCLUSIONS: In a large and diverse cohort of patients with common forms of CKD, U/P urea was independently associated with disease progression and incident kidney failure. Associations were not significant among those with advanced CKD at baseline.

Heart Failure-Type Symptom Score Trajectories in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Quality of life in chronic kidney disease (CKD) is impaired by a large burden of symptoms including some that overlap with the symptoms of heart failure (HF). We studied a group of individuals with CKD to understand the patterns and trajectories of HF-type symptoms in this setting. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,044 participants in the Chronic Renal Insufficiency Cohort (CRIC) without prior diagnosis of HF. PREDICTORS: Sociodemographics, medical history, medications, vital signs, laboratory values, echocardiographic and electrocardiographic parameters. OUTCOME: Trajectory over 5.5 years of a HF-type symptom score (modified Kansas City Cardiomyopathy Questionnaire [KCCQ] Overall Summary Score with a range of 0-100 where<75 reflects clinically significant symptoms). ANALYTICAL APPROACH: Latent class mixed models were used to model trajectories. Multinomial logistic regression was used to model relationships of predictors with trajectory group membership. RESULTS: Five trajectories of KCCQ score were identified in the cohort of 3,044 adults, 45% of whom were female, and whose median age was 61 years. Group 1 (41.7%) had a stable high score (minimal symptoms, average score of 96); groups 2 (35.6%) and 3 (15.6%) had stable but lower scores (mild symptoms [average of 81] and clinically significant symptoms [average of 52], respectively). Group 4 (4.9%) had a substantial worsening in symptoms over time (mean 31-point decline), and group 5 (2.2%) had a substantial improvement (mean 33-point increase) in KCCQ score. A majority of group 1 was male, without diabetes or obesity, and this group had higher baseline kidney function. A majority of groups 2 and 3 had diabetes and obesity. A majority of group 4 was male and had substantial proteinuria. Group 5 had the highest proportion of baseline cardiovascular disease (CVD). LIMITATIONS: No validation cohort available, CKD management changes in recent years may alter trajectories, and latent class models depend on the missing at random assumption. CONCLUSIONS: Distinct HF-type symptom burden trajectories were identified in the setting of CKD, corresponding to different baseline characteristics. These results highlight the diversity of HF-type symptom experiences in individuals with CKD.

Nutritional Epidemiology and Dietary Assessment for Patients With Kidney Disease: A Primer.

Nutritional epidemiology seeks to understand nutritional determinants of disease in human populations using experimental and observational study designs. Though randomized controlled trials provide the strongest evidence of causality, the expense and difficulty of sustaining adherence to dietary interventions are substantial barriers to investigating dietary determinants of kidney disease. Therefore, nutritional epidemiology commonly employs observational study designs, particularly prospective cohort studies, to investigate long-term associations between dietary exposures and kidney disease. Due to the covarying nature and synergistic effects of dietary components, holistic characterizations of dietary exposures that simultaneously consider patterns of foods and nutrients regularly consumed are generally more relevant to disease etiology than single nutrients or foods. Dietary intakes have traditionally been self-reported and are subject to bias. Statistical methods including energy adjustment and regression calibration can reduce random and systematic measurement errors associated with self-reported diet. Novel approaches that assess diet more objectively are gaining popularity but have not yet fully replaced self-report and require refinement and validation in populations with chronic kidney disease. More accurate and frequent diet assessment in existing and future studies will yield evidence to better personalize dietary recommendations for the prevention and treatment of kidney disease.

Association of an Acute Kidney Injury Follow-up Clinic With Patient Outcomes and Care Processes: A Cohort Study.

RATIONALE & OBJECTIVE: To determine whether attendance at an acute kidney injury (AKI) follow-up clinic is associated with reduced major adverse kidney events. STUDY DESIGN: Propensity-matched cohort study. SETTING & PARTICIPANTS: Patients hospitalized with AKI in Ontario, Canada, from February 1, 2013, through September 30, 2017, at a single clinical center, who were not receiving dialysis when discharged. EXPOSURE: Standardized assessment by a nephrologist. OUTCOMES: Time to a major adverse kidney event, defined as death, initiation of maintenance dialysis, or incident/progressive chronic kidney disease. ANALYTICAL APPROACH: Propensity scores were used to match each patient who attended an AKI follow-up clinic to 4 patients who received standard care. Cox proportional hazards models were fit to assess the association between the care within an AKI follow-up clinic and outcomes. To avoid immortal time bias, we randomly assigned index dates to the comparator group. RESULTS: We matched 164 patients from the AKI follow-up clinic to 656 patients who received standard care. During a mean follow-up of 2.2±1.3 (SD) years, care in the AKI follow-up clinic was not associated with a reduction in major adverse kidney events relative to standard care (22.1 vs 24.7 events per 100 patient-years; HR, 0.91 [95% CI, 0.75-1.11]). The AKI follow-up clinic was associated with a lower risk of all-cause mortality (HR, 0.71 [95% CI, 0.55-0.91]). Patients aged at least 66 years who attended the AKI follow-up clinic were more likely to receive ß-blockers (HR, 1.34 [95% CI, 1.02-1.77]) and statins (HR, 1.35 [95% CI, 1.05-1.74]), but not angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (HR, 1.21 [95% CI, 0.94-1.56]). LIMITATIONS: Single-center study and residual confounding. CONCLUSIONS: Specialized postdischarge follow-up for AKI survivors was not associated with a lower risk of major adverse kidney events but was associated with a lower risk of death and increased prescriptions for some cardioprotective medications.

Proteomic signature associated with chronic kidney disease (CKD) progression identified by data-independent acquisition mass spectrometry.

BACKGROUND: Halting progression of chronic kidney disease (CKD) to established end stage kidney disease is a major goal of global health research. The mechanism of CKD progression involves pro-inflammatory, pro-fibrotic, and vascular pathways, but pathophysiological differentiation is currently lacking. METHODS: Plasma samples of 414 non-dialysis CKD patients, 170 fast progressors (with ∂ eGFR-3 ml/min/1.73 m2/year or worse) and 244 stable patients (∂ eGFR of - 0.5 to + 1 ml/min/1.73 m2/year) with a broad range of kidney disease aetiologies, were obtained and interrogated for proteomic signals with SWATH-MS. We applied a machine learning approach to feature selection of proteins quantifiable in at least 20% of the samples, using the Boruta algorithm. Biological pathways enriched by these proteins were identified using ClueGo pathway analyses. RESULTS: The resulting digitised proteomic maps inclusive of 626 proteins were investigated in tandem with available clinical data to identify biomarkers of progression. The machine learning model using Boruta Feature Selection identified 25 biomarkers as being important to progression type classification (Area Under the Curve = 0.81, Accuracy = 0.72). Our functional enrichment analysis revealed associations with the complement cascade pathway, which is relevant to CKD as the kidney is particularly vulnerable to complement overactivation. This provides further evidence to target complement inhibition as a potential approach to modulating the progression of diabetic nephropathy. Proteins involved in the ubiquitin-proteasome pathway, a crucial protein degradation system, were also found to be significantly enriched. CONCLUSIONS: The in-depth proteomic characterisation of this large-scale CKD cohort is a step toward generating mechanism-based hypotheses that might lend themselves to future drug targeting. Candidate biomarkers will be validated in samples from selected patients in other large non-dialysis CKD cohorts using a targeted mass spectrometric analysis.

Total cortical interstitial inflammation predicts chronic kidney disease progression in patients with lupus nephritis.

BACKGROUND: End-stage kidney disease (ESKD) from lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Kidney biopsy is the gold standard for diagnosis and prognostication of LN. While interstitial fibrosis and tubular atrophy (IFTA) predict progression to ESKD, the National Institutes of Health (NIH) classification of interstitial inflammation in unscarred cortical parenchyma is not predictive of chronic kidney disease (CKD) progression. The objective of this study was to determine whether total cortical interstitial inflammation that accounts for inflammation in the entire cortical parenchyma could predict CKD progression in patients with LN. Early identification of at-risk patients may improve outcomes. METHODS: This retrospective cohort study included 125 SLE patients with LN class III, IV, V or mixed (III/V, IV/V) on the index biopsy (2005-2018). Kidney biopsies were reviewed and assigned based on the 2018 NIH Activity Index (AI) and tubulointerstitial lesion categories. Total interstitial inflammation in the entire cortical parenchyma was graded as 0, 1, 2 or 3, corresponding to <10%, 10-25%, 26-50% and >50%, respectively, of the total cortical parenchyma containing an inflammatory infiltrate (similar to the definition used in the Banff total inflammation score). CKD progression was defined as an estimated glomerular filtration rate decrease of ≥30% within 5 years after the index biopsy. Kaplan-Meier survival curves and Cox proportional hazards models were performed to compare the two scoring systems, the total cortical intestinal inflammation score and the NIH interstitial inflammation score as predictors of CKD progression. RESULTS: Of 125 patients, 46 experienced CKD progression; 21 of 46 subsequently developed ESKD, 28 (22.4%) had moderate-severe total cortical interstitial inflammation and 8 (6.4%) had moderate-severe NIH interstitial inflammation. There were no differences in baseline characteristics between progressors and nonprogressors. Total cortical interstitial inflammation was associated with CKD progression in time-dependent analyses [hazard ratio 2.45 (95% confidence interval 1.2-4.97)] adjusted for age at biopsy, race, sex, LN class and hypertensive vascular change on kidney biopsy. The NIH interstitial inflammation was not associated with CKD progression. CONCLUSIONS: In contrast to the current NIH interstitial inflammation classification, accounting for interstitial inflammation in the entire cortical parenchyma allows identification of patients at risk for CKD progression in LN.

Design and population of the VALOR-CKD study: a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of veverimer in slowing progression of chronic kidney disease in patients with metabolic acidosis.

BACKGROUND: Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progression of CKD. METHODS: The VALOR-CKD trial is an international, randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the effect of once-daily veverimer on kidney disease progression in patients with metabolic acidosis and CKD. Eligibility criteria include a serum bicarbonate in the range of 12-20 mmol/L and an estimated glomerular filtration rate (eGFR) of 20-40 mL/min/1.73 m2. The primary outcome is kidney disease progression defined as the development of end-stage kidney disease, a sustained decline in eGFR of >40% from baseline or death due to kidney failure. Key secondary endpoints include effects on physical function. RESULTS: Between December 2018 and December 2021, 1480 participants were randomized. The mean age at baseline was 65.1 years and 42% of the patients were female. The mean baseline eGFR was 29.1 mL/min/1.73 m2 and mean serum bicarbonate was 17.5 mmol/L. The median urine albumin-to-creatinine ratio at screening was 201 mg/g and the median 5-year predicted risk of kidney failure was 32%. Diabetes and hypertension were present in 56% and 98% of participants, respectively. CONCLUSIONS: VALOR-CKD has recruited a large population of people with metabolic acidosis at high risk for CKD progression to determine the effects of veverimer on the risk of progressive loss of kidney function.

Association between serum total cholesterol and chronic kidney disease progression in children: results from the KNOW-PedCKD.

BACKGROUND: Dyslipidemia can cause cardiovascular disease and increase the fatality rate among children with chronic kidney disease (CKD); this makes early screening and treatment of dyslipidemia crucial. This study aimed to assess the association between the changes in serum total cholesterol levels over time and the degree of CKD progression in children. METHODS: From April 2011 to August 2021, 379 of the 432 participants enrolled in the KoreaN cohort study for Outcomes in patients With Pediatric CKD (KNOW-PedCKD) were included and divided into 4 categories based on total cholesterol levels (< 170 mg/dL, acceptable; 170-199, borderline; 200-239, high; and ≥ 240, very high). Survival analysis using conventional and time-dependent Cox proportional hazards model were performed for a composite event of CKD progression (≥ 50% decrease in estimated glomerular filtration rate from baseline, a twofold increase in creatinine, or the occurrence of dialysis or kidney transplantation). RESULT: The incidence of composite event of CKD progression was 96.3, 90.4, 87.3, and 270.6 cases per 1000 person-years in the acceptable, borderline, high, and very high categories, respectively. On using the time-dependent Cox proportional hazards model, the hazard ratio of the very high category was significantly higher than that of the acceptable category by 3.13 times as per univariate analysis and 2.37 times as per multivariate analysis. CONCLUSIONS: Very high serum total cholesterol is a significant risk factor for CKD progression in children. Lowering total cholesterol levels below the very high category in children with CKD may delay the progression of CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.

Biomarkers of eGFR decline after cardiac surgery in children: findings from the ASSESS-AKI study.

BACKGROUND: Children who require surgery for congenital heart disease have increased risk for long-term chronic kidney disease (CKD). Clinical factors as well as urine biomarkers of tubular health and injury may help improve the prognostication of estimated glomerular filtration rate (eGFR) decline. METHODS: We enrolled children from 1 month to 18 years old undergoing cardiac surgery in the ASSESS-AKI cohort. We used mixed-effect models to assess the association between urinary biomarkers (log2-transformed uromodulin, NGAL, KIM-1, IL-18, L-FABP) measured 3 months after cardiac surgery and cyanotic heart disease with the rate of eGFR decline at annual in-person visits over 4 years. RESULTS: Of the 117 children enrolled, 30 (24%) had cyanotic heart disease. During 48 months of follow-up, the median eGFR in the subgroup of children with cyanotic heart disease was lower at all study visits as compared with children with acyanotic heart disease (p = 0.01). In the overall cohort, lower levels of both urine uromodulin and IL-18 after discharge were associated with eGFR decline. After adjustment for age, RACHS-1 surgical complexity score, proteinuria, and eGFR at the 3-month study visit, lower concentrations of urine uromodulin and IL-18 were associated with a monthly decline in eGFR (uromodulin ß = 0.04 (95% CI: 0.00-0.09; p = 0.07) IL-18 ß = 0.07 (95% CI: 0.01-0.13; p = 0.04), ml/min/1.73 m2 per month). CONCLUSIONS: At 3 months after cardiac surgery, children with lower urine uromodulin and IL-18 concentrations experienced a significantly faster decline in eGFR. Children with cyanotic heart disease had a lower median eGFR at all time points but did not experience faster eGFR decline. A higher-resolution version of the Graphical abstract is available as Supplementary information.

Nephrology Referral Based on Laboratory Values, Kidney Failure Risk, or Both: A Study Using Veterans Affairs Health System Data.

RATIONALE & OBJECTIVE: Current guidelines for nephrology referral are based on laboratory criteria. We sought to evaluate whether nephrology referral patterns reflect current clinical practice guidelines and to estimate the change in referral volume if they were based on the estimated risk of kidney failure. STUDY DESIGN: Observational cohort. SETTING & PARTICIPANTS: Retrospective study of 399,644 veterans with chronic kidney disease (October 1, 2015 through September 30, 2016). EXPOSURE: Laboratory referral criteria based on Veterans Affairs/Department of Defense guidelines, categories of predicted risk for kidney failure using the Kidney Failure Risk Equation, and the combination of laboratory referral criteria and predicted risk. OUTCOME: Number of patients identified for referral. ANALYTICAL APPROACH: We evaluated the number of patients who were referred and their predicted 2-year risk for kidney failure. For each exposure, we estimated the number of patients who would be identified for referral. RESULTS: There were 66,276 patients who met laboratory indications for referral. Among these patients, 11,752 (17.7%) were referred to nephrology in the following year. The median 2-year predicted risk of kidney failure was 1.5% (interquartile range, 0.3%-4.7%) among all patients meeting the laboratory referral criteria. If referrals were restricted to patients with a predicted risk of ≥1% in addition to laboratory indications, the potential referral volume would be reduced from 66,276 to 38,229 patients. If referrals were based on predicted risk alone, a 2-year risk threshold of 1% or higher would identify a similar number of patients (72,948) as laboratory-based criteria with median predicted risk of 2.3% (interquartile range, 1.4%-4.6%). LIMITATIONS: Missing proteinuria measurements. CONCLUSIONS: The current laboratory-based guidelines for nephrology referral identify patients who are, on average, at low risk for progression, most of whom are not referred. As an alternative, referral based on a 2-year kidney failure risk exceeding 1% would identify a similar number of patients but with a higher median risk of kidney failure.

A Predictive Model for Progression of CKD to Kidney Failure Based on Routine Laboratory Tests.

RATIONALE & OBJECTIVE: Stratification of chronic kidney disease (CKD) patients at risk for progressing to kidney failure requiring kidney replacement therapy (KFRT) is important for clinical decision-making and trial enrollment. STUDY DESIGN: Four independent prospective observational cohort studies. SETTING & PARTICIPANTS: The development cohort comprised 4,915 CKD patients, and 3 independent validation cohorts comprised a total of 3,063. Patients were observed for approximately 5 years. EXPOSURE: 22 demographic, anthropometric, and laboratory variables commonly assessed in CKD patients. OUTCOME: Progression to KFRT. ANALYTICAL APPROACH: A least absolute shrinkage and selection operator (LASSO) Cox proportional hazards model was fit to select laboratory variables that best identified patients at high risk for KFRT. Model discrimination and calibration were assessed and compared against the 4-variable Tangri (T4) risk equation both in a resampling approach within the development cohort and in the validation cohorts using cause-specific concordance (C) statistics, net reclassification improvement, and calibration graphs. RESULTS: The newly derived 6-variable risk score (Z6) included serum creatinine, albumin, cystatin C, and urea, as well as hemoglobin and the urinary albumin-creatinine ratio. In the the resampling approach, Z6 achieved a median C statistic of 0.909 (95% CI, 0.868-0.937) at 2 years after the baseline visit, whereas the T4 achieved a median C statistic of 0.855 (95% CI, 0.799-0.915). In the 3 independent validation cohorts, the Z6C statistics were 0.894, 0.921, and 0.891, whereas the T4C statistics were 0.882, 0.913, and 0.862. LIMITATIONS: The Z6 was both derived and tested only in White European cohorts. CONCLUSIONS: A new risk equation based on 6 routinely available laboratory tests facilitates identification of patients with CKD who are at high risk of progressing to KFRT.

Biomarkers During Recovery From AKI and Prediction of Long-term Reductions in Estimated GFR.

RATIONALE & OBJECTIVE: The effects of acute kidney injury (AKI) on long-term kidney function, cardiovascular disease, and mortality are well documented. We aimed to identify biomarkers for the estimation of risk of new or worsening chronic kidney disease (CKD) following AKI. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adults from a single clinical center who experienced AKI between May 2013 and May 2016 and survived until 3 years after the hospitalization during which AKI occurred. Participants included those with and without preexisting CKD. PREDICTORS: Panel of 11 plasma biomarkers measured 3 months after hospitalization. OUTCOME: Kidney disease progression, defined as a≥25% decrease in estimated glomerular filtration rate (eGFR) combined with worsening CKD stage, assessed 3 years after the occurrence of AKI. ANALYTICAL APPROACH: Associations between biomarkers and kidney disease progression were evaluated in multivariable logistic regression models. Importance of predictor variables was assessed by constructing multiple decision trees, with penalized least absolute shrinkage and selection operator logistic regression for variable selection used to produce multivariable models. RESULTS: A total of 500 patients were studied. Soluble tumor necrosis factor receptor (sTNFR) 1, sTNFR2, cystatin C, neutrophil gelatinase-associated lipocalin, 3-month eGFR, and urinary albumin-creatinine ratio were independently associated with kidney disease progression and were more important than AKI severity or duration. A multivariable model containing sTNFR1, sTNFR2, cystatin C, and eGFR discriminated between those with and without kidney disease progression (area under the curve, 0.79 [95% CI, 0.70-0.83]). Optimizing the cutoff point to maximize utility as a "rule-out" test to identify those at low risk increased the sensitivity of the model to 95% and its negative predictive value to 92%. LIMITATIONS: Lack of external validation cohort. Analyses limited to patients who survived for 3 years after AKI. Mixed population of patients with and without baseline CKD. CONCLUSIONS: A panel of plasma biomarkers measured 3 months after discharge from a hospitalization complicated by AKI provides a potential opportunity to identify patients who are at very low risk of incident or worsening CKD. Further study is required to determine its clinical utility through independent prospective validation.

Association of Time-Updated Anion Gap With Risk of Kidney Failure in Advanced CKD: A Cohort Study.

RATIONALE & OBJECTIVE: High anion gap acidosis frequently develops in patients with advanced chronic kidney disease (CKD) and might be involved in kidney injury. Its impact on kidney outcomes, however, has not been well studied. We sought to examine the association between time-updated anion gap and the risk of kidney failure with replacement therapy (KFRT) among patients with advanced CKD. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 1,168 patients with CKD glomerular filtration rate categories 3b-5 (G3b-G5) who had available data on anion gap. EXPOSURE: High time-updated anion gap defined as values ≥ 9.2 (top 25th percentile). OUTCOME: KFRT and death. ANALYTICAL APPROACH: Marginal structural models were fit to characterize the association between anion gap and study outcomes while accounting for potential time-dependent confounding. RESULTS: The mean baseline estimated glomerular filtration rate (eGFR) of the study participants was 28 mL/min/1.73 m2. Over a median follow-up period of 3.1 years, 317 patients progressed to KFRT (7.5 per 100 patient-years), and 146 died (3.5 per 100 patient-years). In the marginal structural models, a high anion gap was associated with a higher rate of KFRT (HR, 3.04 [95% CI, 1.94-4.75]; P < 0.001). This association was stronger in patients with a baseline eGFR of <30 mL/min/1.73 m2 (P for interaction = 0.05). High anion gap was also associated with a higher mortality rate (HR, 5.56 [95% CI, 2.95-10.5]; P < 0.001). Sensitivity analyses with different definitions of high anion gap showed similar results. LIMITATIONS: Observational study design and selection bias due clinical indications for measuring anion gap. CONCLUSIONS: Among patients with advanced CKD, high anion gap was associated with an increased risk of progression to KFRT and death.

CKD Progression From the Time of Estimated GFR-Based Waitlist Eligibility and Racial Disparities in Transplant Access.

RATIONALE & OBJECTIVE: Equations for estimated glomerular filtration rate (eGFR) that incorporate a term for race assign a higher value to Black individuals compared to non-Black individuals for the same sex, age, and serum creatinine concentration. This difference may contribute to racial disparities in kidney transplant access. We sought to (1) compare time from meeting a transplant eligibility threshold of eGFR ≤20 mL/min/1.73 m2 to kidney failure with replacement therapy (KFRT) among Black, Hispanic, and White patients, and (2) assess the impact of incorporation of race into eGFR expressions on establishment of waitlist eligibility and time from eligibility to KFRT. STUDY DESIGN: Retrospective cohort. SETTING & PARTICIPANTS: Using the OptumLabs Data Warehouse, we assembled a cohort of 40,042 White, 8,519 Black, and 3,569 Hispanic patients having at least one eGFR value between 20 and 60 mL/min/1.73 m2 within the preceding 2 years and an incident outpatient eGFR of ≤20 mL/min/1.73 m2 between 2008-2018, using the CKD-EPI creatinine equation that includes a term for race coded as Black or non-Black. We then reassembled a Black patient cohort based on incident eGFR ≤20 mL/min/1.73 m2 (n = 11,269) estimated using the same CKD-EPI equation but coding Black patients as non-Black. EXPOSURE: Race/ethnicity. OUTCOME: Time to KFRT. ANALYTICAL APPROACH: Unadjusted and adjusted Fine-Gray models; linear regression to compute eGFR slopes. RESULTS: By 3 years, the cumulative incidence of KFRT was 20.5% among White patients, 40.9% among Hispanic patients, 36% among Black patients whose GFR was estimated using a race term coded as Black, and 28.7% among Black patients whose GFR was estimated using a race term coded as non-Black. In fully adjusted analyses including 11,269 Black patients with an eGFR ≤20 mL/min/1.73 m2 based on coding them as non-Black, KFRT risk remained greater among Black (HR, 1.28 [95% CI, 1.15-1.43]) and Hispanic (HR, 1.66 [95% CI, 1.18-2.31]) patients than among White patients. Based on slopes of eGFR decline, coding Black patients as non-Black would allow earlier waitlist activation by an estimated median of 0.5 [interquartile range, 0.27-1.23] years. LIMITATIONS: Inability to exclude individuals who would not be kidney transplant candidates if comprehensively evaluated. CONCLUSIONS: A uniform eGFR threshold provides less opportunity for being placed on the transplant waitlist among Black and Hispanic patients. For many Black patients, estimation of GFR as if their race category were non-Black would allow substantially earlier waitlisting but would not eliminate their shorter time to KFRT and reduced opportunity for preemptive transplantation compared with White patients.