Estimating Time to ESRD in Children With CKD

doi:10.1053/j.ajkd.2017.12.011

American Journal of Kidney Diseases

Volume 71, Issue 6, June 2018, Pages 783-792

https://doi.org/10.1053/j.ajkd.2017.12.011 Get rights and content

Rationale & Objective

The KDIGO (Kidney Disease: Improving Global Outcomes) guideline for chronic kidney disease (CKD) presented an international classification system that ranks patients’ risk for CKD progression. Few data for children informed guideline development.

Study Design

Observational cohort study.

Settings & Participants

Children aged 1 to 18 years enrolled in the North American Chronic Kidney Disease in Children (CKiD) cohort study and the European Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) trial.

Predictor

Level of estimated glomerular filtration rate (eGFR) and proteinuria (urine protein-creatinine ratio [UPCR]) at study entry.

Outcome

A composite event of renal replacement therapy, 50% reduction in eGFR, or eGFR < 15 mL/min/1.73 m². eGFR was estimated using the CKiD-derived “bedside” equation.

Analytical Approach

Accelerated failure time models of the composite outcome using a conventional generalized gamma distribution. Likelihood ratio statistics of nested models were used to amalgamate levels of similar risk.

Results

Among 1,232 children, median age was 12 (IQR, 8-15) years, median eGFR was 47 (IQR, 33-62) mL/min/1.73 m², 60% were males, and 13% had UPCRs > 2.0 mg/mg at study entry. 6 ordered stages with varying combinations of eGFR categories (60-89, 45-59, 30-44, and 15-29 mL/min/1.73 m²) and UPCR categories (<0.5, 0.5-2.0, and >2.0 mg/mg) described the risk continuum. Median times to event ranged from longer than 10 years for eGFRs of 45 to 90 mL/min/1.73 m² and UPCRs < 0.5 mg/mg to 0.8 years for eGFRs of 15 to 30 mL/min/1.73 m² and UPCRs > 2 mg/mg. Children with glomerular disease were estimated to have a 43% shorter time to event than children with nonglomerular disease. Cross-validation demonstrated risk patterns that were consistent across the 10 subsample validation models.

Limitations

Observational study, used cross-validation rather than external validation.

Conclusions

CKD staged by level of eGFR and proteinuria characterizes the timeline of progression and can guide management strategies in children.

Section snippets

Study Participants and Design

Data in this analysis were pooled from CKiD and ESCAPE. CKiD is a prospective cohort study of children with CKD from 54 pediatric nephrology centers in North America who were aged 1 to 16 years with an estimated GFR (eGFR) of 30 to 90 mL/min/1.73 m². The study design and objectives have been previously reported.⁶ ESCAPE is a randomized trial at 33 pediatric nephrology centers in Western Europe in which 385 children 3 to 18 years of age with CKD (GFRs of 15-80 mL/min/1.73 m²) received fixed-dose

Results

Data were available for 1,269 children, 891 from CKiD and 378 from ESCAPE. Children missing baseline GFR or UPCR values (n = 26), having a baseline GFR < 15 mL/min/1.73 m² (n = 42), and having no follow-up data (n = 32) were excluded from analysis. Thus, analysis was restricted to 1,169 children, 857 from CKiD (73%) and 312 from ESCAPE (27%). Six CKiD children in this analysis died during study follow-up. Of those, 4 experienced an event before death; the other 2 were censored at their last CKID visit.

Discussion

The current KDIGO guideline for CKD classification is based almost entirely on adult data. To our knowledge, our study is the first to apply the principles of this classification to a large cohort of pediatric patients with CKD, combining 2 large multicenter studies using a multinational collaborative effort. To provide clinically useful measures of risk, we estimated the times by which 10%, 25%, and 50% of children in a given risk group will reach a clinically defined event (50% decline in

Acknowledgements

We acknowledge the contributions of Dr Alvaro Muñoz to the cross-validation methods used in this manuscript.

Peer Review: Received July 27, 2017. Evaluated by 3 external peer reviewers and a statistician, with editorial input from an Acting Editor-in-Chief (Editorial Board Member Giuseppe Remuzzi, MD). Accepted in revised form December 19, 2017. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with AJKD’s procedures for potential

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PRESERVE seeks to provide new knowledge to inform shared decision-making regarding blood pressure (BP) management for pediatric chronic kidney disease (CKD). PRESERVE will compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; expand the National Patient-Centered Clinical Research Network (PCORnet) common data model by adding pediatric- and kidney-specific variables and linking electronic health record data to other kidney disease databases; and assess the lived experiences of patients related to BP management.
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BP measurements (clinic-based and 24-hour ambulatory BP); urine protein; and antihypertensive treatment by therapeutic class.
The primary outcome is a composite event of a 50% reduction in eGFR, eGFR of <15 mL/min/1.73 m², long-term dialysis or kidney transplant. Secondary outcomes include change in eGFR, adverse events, and PROs.
Longitudinal models for dichotomous (proportional hazards or accelerated failure time) and continuous (generalized linear mixed models) clinical outcomes; multivariable linear regression for PROs. We will evaluate heterogeneity of treatment effect by CKD etiology and degree of proteinuria and will examine variation in hypertension management and outcomes based on socio-demographics.
Causal inference limited by observational analyses.
PRESERVE will leverage the PCORnet infrastructure to conduct large-scale observational studies that address BP management knowledge gaps for pediatric CKD, focusing on outcomes that are meaningful to patients.
Hypertension is a major modifiable contributor to loss of kidney function in chronic kidney disease (CKD). The purpose of PRESERVE is to provide evidence to inform shared decision-making regarding blood pressure management for children with CKD. PRESERVE is a consortium of 16 health care institutions in PCORnet, the National Patient-Centered Clinical Research Network, and includes electronic health record data for >19,000 children with CKD. PRESERVE will (1) expand the PCORnet infrastructure for research in pediatric CKD by adding kidney-specific variables and linking electronic health record data to other kidney disease databases; (2) compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; and (3) assess the lived experiences of patients and caregivers related to blood pressure management.
Predicting pediatric kidney disease progression—are 3 variables all you need?
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Accurate estimation of chronic kidney disease (CKD) progression risk is vital for clinical decision-making. Existing risk equations lack validation in pediatric CKD populations. Ng et al. developed new risk equations using the CKD in Children and European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients cohorts. The elementary model, incorporating estimated glomerular filtration rate, urine protein-creatinine ratio, and diagnosis, exhibited excellent discrimination and calibration at external validation. External validation of enriched models is pending. The equations have the potential to aid pediatric CKD centers in patient counseling and care planning.
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Clinicians need improved prediction models to estimate time to kidney replacement therapy (KRT) for children with chronic kidney disease (CKD). Here, we aimed to develop and validate a prediction tool based on common clinical variables for time to KRT in children using statistical learning methods and design a corresponding online calculator for clinical use. Among 890 children with CKD in the Chronic Kidney Disease in Children (CKiD) study, 172 variables related to sociodemographics, kidney/cardiovascular health, and therapy use, including longitudinal changes over one year were evaluated as candidate predictors in a random survival forest for time to KRT. An elementary model was specified with diagnosis, estimated glomerular filtration rate and proteinuria as predictors and then random survival forest identified nine additional candidate predictors for further evaluation. Best subset selection using these nine additional candidate predictors yielded an enriched model additionally based on blood pressure, change in estimated glomerular filtration rate over one year, anemia, albumin, chloride and bicarbonate. Four additional partially enriched models were constructed for clinical situations with incomplete data. Models performed well in cross-validation, and the elementary model was then externally validated using data from a European pediatric CKD cohort. A corresponding user-friendly online tool was developed for clinicians. Thus, our clinical prediction tool for time to KRT in children was developed in a large, representative pediatric CKD cohort with an exhaustive evaluation of potential predictors and supervised statistical learning methods. While our models performed well internally and externally, further external validation of enriched models is needed.
Data quality control in longitudinal epidemiologic studies: conditional studentized residuals from linear mixed effects models for outlier detection in the setting of pediatric chronic kidney disease
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Quality control in longitudinal cohort studies is critical for valid epidemiologic inference. Conditional studentized residuals (CSRs) derived from linear mixed effects models offer efficient individual-specific quality control. We present the utility of CSRs for outlier detection in an applied example using data from the Chronic Kidney Disease in Children cohort.
Longitudinal linear mixed effects models with glomerular filtration rate (GFR) as the outcome were fit for observations prior to kidney replacement therapy, stratified by nonglomerular or glomerular diagnosis, and for a subset after receiving a kidney transplant. For each model, CSRs were calculated and values ≥±5 were considered potential outliers for further investigation.
A total of 1096 participants contributed 6881 annual measures of GFR across the two diagnostic groups and after transplant. In all models, the fixed effects captured progressive GFR decline. CSRs provided measures of individual-level deviations from the modeled trajectories (random + fixed effects) and were easily visualized in longitudinal plots. A total of 38 potential outliers from 32 participants were detected and further investigated for quality control.
This example demonstrated how longitudinal models can provide CSRs to detect individual-specific outliers. CSRs should be considered as part of quality control for longitudinal epidemiologic studies.
Revisiting the Application of an Adult Kidney Failure Risk Prediction Equation to Children With CKD
2023, American Journal of Kidney Diseases

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: CKiD Investigators: Joshua Samuels, MD (University of Texas, Houston); Susan Furth, MD, PhD (Children's Hospital of Philadelphia); Meredith Atkinson, MD (Johns Hopkins Children’s Center); Amy Wilson, MD (Riley Hospital for Children at Indiana University Health); Alejandro Quiroga, MD (DeVos Children’s Hospital at Spectrum); Susan Massengill, MD (Carolinas Medical Center); Dave Selewski, MD (University of Michigan, Mott Hospital); Maria Ferris, MD (University of North Carolina, Chapel Hill); Amy Kogon, MD (Nationwide Children’s Hospital, Ohio State University); Frederick Kaskel, MD, PhD (Children’s Hospital at Montefiore); Marc Lande, MD, George Schwartz, MD (University of Rochester Medical Center, Golisano Children’s Hospital at Strong); Jeffrey Saland, MD (Icahn School of Medicine at Mount Sinai); Victoria Norwood, MD (University of Virginia); Tej Matoo, MD (Children’s Hospital of Michigan); Guillermo Hidalgo, MD (East Carolina University); Poyyapakkam Srivaths, MD (Texas Children's Hospital, Baylor); Joann Carlson, MD (Rutgers-Robert Wood Johnson Medical School); Craig Langman, MD (Ann & Robert H. Lurie Children’s Hospital of Chicago); Susan Mendley (University of Maryland); Eunice John, MD (University of Illinois, Chicago); Kiran Upadhyay, MD (University of Florida); Patricia Seo-Mayer, MD (INOVA Fairfax Hospital for Children); Larry Patterson, MD (Children’s National Medical Center); Rulan Parekh, MD, Lisa Robinson, MD (Hospital for Sick Children [Sick Kids]); Adam Weinstein, MD (Children’s Hospital at Dartmouth); Dmitry Samsonov, MD (Maria Fareri Children’s Hospital at Westchester); Juan Kupferman, MD (Maimonides Medical Center); Jason Misurac, MD (University of Iowa); Anil Mongia, MD (State University of New York, Downstate Medical Center); Steffan Kiessling, MD (University of Kentucky); Cheryl Sanchez-Kazi, MD (Loma Linda University); Allison Dart, MD, MSc, FRCPC (Children’s Hospital of Winnipeg); Sahar Fathallah, MD (Children’s Hospital of Alabama); Donna Claes, MD, Mark Mitsnefes, MD (Cincinnati Children’s Hospital and Medical Center); Tom Blydt-Hansen, MD, FRCPC (British Columbia Children’s Hospital); Bradley Warady, MD (Children’s Mercy Kansas City); Larry Greenbaum, MD, PhD (Egleston Children's Hospital, Emory University); Joseph Flynn, MD (Seattle Children's Hospital); Craig Wong, MD, MPH (University of New Mexico Children’s Hospital); Isidro Salusky, MD, Ora Yadin, MD (University of California, Los Angeles); Katherine Dell, MD (Case Western Reserve University); Randall Jenkins, MD (Northwest Pediatric Kidney Specialist); Cynthia Pan, MD (Medical College of Wisconsin); Elaine Ku, MD, MAS (UCSF Children’s Hospital); Amira Al-Uzri, MD, Randall Jenkins, MD (Oregon Health and Science University); Nancy Rodig, MD (Boston Children’s Hospital); Cynthia Wong, MD (Stanford University Medical Center); Keefe Davis, MD (St. Louis Children’s Hospital); Martin Turman, MD, PhD (Phoenix Children’s Hospital); Sharon Bartosh, MD (University of Wisconsin); Colleen Hastings, MD (LeBonheur Children’s Medical Center); Anjali Nayak, MD (University of Oklahoma Health Sciences Center); Mouin Seikaly, MD (University of Texas Southwestern Medical Center); Nadine Benador, MD, Robert Mak, MD, PhD (University of California, San Diego); Ellen Wood, MD (Cardinal Glennon Hospital); Randall Jenkins, MD (Children’s Kidney Specialists, Idaho); Gary Lerner, MD (Children’s Hospital of Los Angeles); Gina Marie Barletta, MD (Arizona Kidney Disease and Hypertension Center).

: ESCAPE Trial Investigators: A. Anarat (Cukurova University School of Medicine, Balcali, Adana, Turkey); A. Bakkaloglu, F. Ozaltin (Hacettepe University Faculty of Medicine, Sihhiye, Ankara, Turkey); A. Peco-Antic (University Children's Hospital, Belgrade, Serbia); U. Querfeld, J. Gellermann (Charité Children's Hospital, Berlin, Germany); P. Sallay (Semmelweis University Budapest, 1st Department of Pediatrics, Budapest, Hungary); D. Drożdż (Polish-American Children’s Hospital, Jagiellonian University Collegium Medicum, Krakow, Poland); K.-E. Bonzel, A.-M. Wingen (University Hospital Essen, Essen, Germany); A. Żurowska, I. Balasz (Department of Paediatric and Adolescent Nephrology and Hypertension, Medical University of Gdansk, Gdansk, Poland); A. Trivelli, F. Perfumo (G. Gaslini Institute, Genova, Italy); D.E. Müller-Wiefel, K. Möller (University Children’s Hospital Hamburg-Eppendorf, Hamburg, Germany); G. Offner, B. Enke (Hannover Medical School, Children's Hospital, Hannover, Germany); E. Wühl, C. Hadtstein, O. Mehls, F. Schaefer (Center for Pediatric and Adolescent Medicine, Heidelberg, Germany); S. Emre (University of Istanbul, Istanbul Medical Faculty, Capa, Istanbul, Turkey); S. Caliskan (Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey); S. Mir (Ege University Medical Faculty, Department of Pediatrics, Bornova, Izmir, Turkey); S. Wygoda (Urban Hospital St. Georg, Leipzig, Germany); K. Hohbach-Hohenfellner (University Children’s Hospital, Mainz, Germany); N. Jeck, G. Klaus (Philipps University Marburg, Department of Pediatrics, Marburg, Germany); G. Ardissino, S. Testa (IRCCS Ospedale Maggiore, Policlinico-Mangiagalli, Milano, Italy); G. Montini (Azienda Ospedaliera-Università di Padova, Padova, Italy); M. Charbit, P. Niaudet (Hopital Necker, Paris, France); A. Caldas-Afonso, A. Fernandes-Teixeira (Hospital S. Joao, Porto, Portugal); J. Dušek (University Hospital Motol, Department of Pediatrics, Prague, Czech Republic); M.C. Matteucci, S. Picca, A. Mastrostefano (Ospedale Pediatrico Bambino Gesù, Rome, Italy); M. Wigger (University Children's Hospital, Rostock, Germany); U.B. Berg, G. Celsi (Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden); M. Fischbach, J. Terzic (Hopitaux Universitaires de Strasbourg, Pediatrie 1, Strasbourg, France); J. Fydryk, T. Urasinski (Pomeranian Academy of Medicine, Szczecin, Poland); R. Coppo, L. Peruzzi (Ospedale Infantile Regina Margherita, Torino, Italy); K. Arbeiter (University Children's Hospital, Vienna, Austria); A. Jankauskiené (Vilnius University Children's Hospital, Vilnius University, Vilnius, Lithuania); R. Grenda, M. Litwin, R. Janas (Children's Memorial Health Hospital, Warsaw, Poland); T.J. Neuhaus (University Children's Hospital, Zürich, Switzerland).

: Authors’ Full Names and Academic Degrees: Susan L. Furth, MD, PhD, Chris Pierce, MS, Wun Fung Hui, MD, Colin A. White, MD, Craig S. Wong, MD, Franz Schaefer, MD, Elke Wühl, MD, Ali Abraham, PhD, and Bradley A. Warady, MD.

: Complete author and article information (including a list of the CKiD and ESCAPE Study Investigators) provided before references.

: Authors’ Contributions: Research idea and study design: SLF, CP, WFH, CAW, AA; data acquisition: SLF, CSW, FS, EW, BAW; data analysis/interpretation: SLF, CP, FS, EW, AA, BAW; statistical analysis: CP, AA; supervision or mentorship: SLF, FS, EW, BAW. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

: Support: The CKiD Study is supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, with additional funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute (U01-DK-66143, U01-DK-66174, U01DK-082194, and U01-DK-66116). ESCAPE was supported by grants from the Boehringer Ingelheim Stiftung; the European Commission (Fifth Framework Programme, QLRT-2001-00908); Kuratorium für Dialyse und Nierentransplantation, Neu-Isenburg; and the Baxter Extramural Grant Program. The funders of this study did not have any role in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication.

: Financial Disclosure: The authors declare that they have no relevant financial interests.

^∗: S.L.F. and C.P. contributed equally to this work.

^†: A.A. and B.A.W. contributed equally to this work.

View full text

Original InvestigationEstimating Time to ESRD in Children With CKD

Rationale & Objective

Study Design

Settings & Participants

Predictor

Outcome

Analytical Approach

Results

Limitations

Conclusions

Section snippets

Study Participants and Design

Results

Discussion

Acknowledgements

Lancet

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Am J Kidney Dis

J Clin Epidemiol

Am J Kidney Dis

Am J Kidney Dis

Kidney Int

Epidemiology of chronic kidney disease in children

Pediatr Nephrol

The Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease

Kidney Int Suppl

Design and methods of the Chronic Kidney Disease in Children (CKiD) prospective cohort study

Clin J Am Soc Nephrol

Strict blood-pressure control and progression of renal failure in children

N Engl J Med

Association of proteinuria with race, cause of chronic kidney disease, and glomerular filtration rate in the Chronic Kidney Disease in Children Study

Clin J Am Soc Nephrol

Original Investigation
Estimating Time to ESRD in Children With CKD