Integrating the Novel iCARE Estimated Glomerular Filtration Rate Equation for Youth Living With Type 2 Diabetes Into Care: Program Report

Abstract

Purpose of the program:

Youth living with type 2 diabetes (T2D) have high rates of early kidney disease and progression to kidney failure in early adulthood. Pediatric diabetes clinical practice guidelines have focused on screening for albuminuria and have not included recommendations for estimated glomerular filtration rate (eGFR) evaluation in children. In partnership with patients, families, and community partners, we are implementing a novel eGFR equation for youth with T2D into their diabetes care, with the aim of detecting youth with early kidney disease and providing appropriate interventions to slow disease progression.

Sources of Information:

The development of such a tool aligned with a priority-setting workshop in 2016, where early detection and prevention of kidney disease were identified as a key priority by people living with kidney disease. In response, our team developed the novel Improving renal Complications in Adolescents with type 2 diabetes through Research (iCARE) eGFR equation, which estimates kidney function over time in youth with T2D, and validated it in a cohort of youth in Colorado (US) and a secondary group of youth in Manitoba (Canada).

Methods:

To integrate the tool into clinical care, this study includes 4 separate phases. Phase 1: External validation of the iCARE eGFR equation in a cohort of children with obesity and T2D from Colorado, US, to assess the generalizability of the equation. Phase 2: Readiness Assessment of pediatric endocrinologists (a) quantitative survey in Canada (n = 40) and the United States (n = 75) to assess current practice for screening youth with T2D for diabetic kidney disease (DKD) and (b) qualitative focus groups (4 groups; 2 in Canada [n = 8] and 2 in the United States [n = 5]) to explore barriers and facilitators to implementation of the iCARE eGFR equation into the care for youth with T2D. Focus groups of youth living with T2D are underway and explore how youth and families wish to be educated regarding kidney health and what sources of information would be helpful to empower youth to ask about kidney health in clinical settings. Phase 3: Development and implementation of an iCARE eGFR equation toolkit, which will include the resources for providers and patient education materials and the inclusion of the novel eGFR equation into an app and local electronic medical record systems at 3 sites (Vancouver, Winnipeg, Toronto). Phase 4: Evaluation of the iCARE eGFR implementation toolkit, including audits at 3 centers in Canada, as well as patient and provider satisfaction surveys.

Key findings:

Phase 1: The validation study confirmed that the iCARE eGFR performed better than previously published eGFR equations in youth living with obesity and T2D. Relevant metrics were the highest P30 (% of eGFR values that fall within 30% of the measured glomerular filtration rate [GFR]) and the lowest bias. Phase 2: Survey results suggest that providers have strong adherence to existing T2D clinical practice guidelines, focused on albuminuria, but have limited experience and comfort with eGFR equations in general. Focus group discussions identified concerns about insufficient evidence indicating that eGFR metrics in childhood are associated with long-term outcomes and questions about generalizability and external validity. Key facilitators for improving uptake included development of a more comprehensive app or platform that presents eGFR findings in an accessible way for endocrinologists and development of clinical pathway guidelines to support follow-up treatment.

Implications:

Findings from phases 1 and 2 will be incorporated into the iCARE eGFR implementation toolkit, such that care providers and patients are able to utilize the most up-to-date evidence to screen for DKD and implement care strategies that will optimize the long-term kidney health of youth living with T2D.

Keywords

eGFR type 2 diabetes youth knowledge mobilization evaluation

Background/Introduction

Rates of youth onset type 2 diabetes (T2D) (diagnosed <18 years of age) are increasing worldwide, affecting predominantly children from disadvantaged backgrounds.^1,2 In Canada, First Nations children are at the highest risk, due largely to the ongoing socioeconomic impacts of colonial policies.^3-5 In the United States, the non-Hispanic black and American Indian populations have the highest rates.¹ Youth living with T2D have been shown to be at much higher risk for early chronic kidney disease (CKD),⁶ with rates of progression to kidney failure up to 50% in early adulthood.^7,8 As early intervention can slow or stop progression of kidney disease,⁹ the value of sensitive diabetic kidney disease (DKD) surveillance tools remains a major priority.^2,10

A primary method for monitoring kidney function is the estimated glomerular filtration rate (eGFR), which utilizes readily available patient characteristics and endogenous filtration markers, such as serum creatinine (Cr).¹¹ However, eGFR equations were not designed for, nor validated in youth with obesity or hyperfiltration, such as youth living with T2D. Our team therefore sought to develop and validate a novel eGFR equation specifically for monitoring the kidney health of youth with T2D, as part of the improving Renal Complications in Adolescents with T2D through Research cohort (iCARE).¹² The iCARE is a multisite cohort study in Canada¹³ and a part of the patient-oriented research network, Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD).¹⁴ Patient partners and researchers specifically identified early detection and prevention of kidney disease as part of a network-wide priority-setting initiative in 2016. iCARE’s research is focused on early identification of kidney disease and guided by a Participant and Family Advisory Group (iCARE PAG). Given the disproportionate burden of kidney disease in First Nations communities, the iCARE PAG has strong representation from these groups, providing guidance on how we can take a culturally competent approach to our work that aligns with the needs of their communities.

In 2019, the iCARE study group published the development and validation of a novel equation, which was created from iohexol GFRs (iGFRs) performed in 100 youth with T2D and 26 overweight/obese controls.¹² The iCARE equation performed better than all previously published creatinine-based eGFRs, including the CKiD (Chronic Kidney Disease in Children Study) equation¹⁵ which supported the improved accuracy of this equation in this unique population.¹² Despite the publication of the iCARE eGFR in 2019, it was, however, not integrated into current diabetes or kidney disease clinical practice guidelines.^10,16

To facilitate implementation of the equation into the care of children living with T2D, our team designed this knowledge mobilization project. As many youth with T2D are cared for by pediatric endocrinologists in Canada, our efforts for this initial implementation project focused on implementation into pediatric diabetes clinics.¹⁷ The project involves four phases, including external validation, a readiness assessment, the design of an iCARE eGFR equation toolkit, and evaluation. We present the preliminary results of the first two phases, including barriers and facilitators to implementation identified by the readiness assessment, and how they will be used to design our implementation toolkit in future work. Detailed results from phase 1 (validation) and phase 2 (survey and focus groups of pediatric endocrinologists) are being concurrently submitted for publication to other journals.

Methods

Phase 1: External Validation of the iCARE Glomerular Filtration Rate Equation

To assess the generalizability of the equation, we evaluated the performance of the iCARE eGFR in four cohorts of youth from Colorado, United States. We also compared performance to other eGFR equations currently in clinical use in children and adults with CKD, including the bedside CKiD,¹⁵ full age spectrum equation (FAS),^18-20 Chronic Kidney Disease in Children (CKiD) Under 25 (years) eGFR (U25),²¹ Modification of Diet in Renal Disease equation (MDRD),²² and Chronic Kidney Disease Epidemiology Collaboration (CKD-epi)²³ equations. The validation cohorts included youth with obesity, type 1 diabetes (T1D) and T2D diabetes from the Renal Hemodynamics, study Energetics and Insulin Resistance in Youth Onset Type 2 Diabetes (Renal-HEIR),²⁴ Impact of Metabolic Surgery on Pancreatic, Renal and CardiOVascular HEalth in Youth with Type 2 Diabetes (IMPROVE-T2D),²⁵ Copeptin in Adolescent Participants with Type 1 Diabetes and Early Renal Hemodynamic Function (CASPER),²⁶ and Evaluation of Coffee Therapy for Improvement of Renal Oxygenation (COFFEE)²⁷ studies with iohexol GFR data available. In total, there were 20 youth with obesity, 63 with T1D, and 67 youth with T2D available for analysis.

We evaluated bias, precision, and accuracy of the eGFR equations for each cohort. We evaluated the following properties for each equation, consistent with previous eGFR studies: 1. Percentage of eGFR values that were within 30% and 10% of the corresponding iGFR values (P30 and P10 respectfully) and the mean absolute error (MAE). 2. Bland-Altman analyses including mean bias with 95% confidence intervals (CI) (mean discrepancy = mean [observed − predicted] and 95% limits of agreement [mean ± 1.96SD]). 3. We also developed scatter plots including the best-fit regression line and the line of identity to graphically compare the performance of the iCARE equation against the other eGFR equations.

Phase 2: Readiness Assessment

Quantitative survey of pediatric endocrinologists

An anonymous survey was sent to pediatric endocrinologists through the Canadian Pediatric Endocrine Group (CPEG) and the Pediatric Endocrine Society (PES) email listservs in 2023/24. Forty surveys were completed by CPEG members and 75 by PES members. The survey was designed to evaluate three themes of inquiry: (1) current standard of practice for screening for DKD and hypertension in youth with T2D; (2) comfort level and competency in interpreting and managing evidence of early kidney dysfunction, including proteinuria, and eGFR in youth with T2D; and (3) perceived barriers and facilitators to implementation of the iCARE eGFR into routine T2D clinical practice for the purpose of early DKD screening.

Surveys were distributed in both English and French in Canada and in English in the United States. Units were adjusted to the standard in each country. Descriptive statistics were performed to present results.

Qualitative focus groups of pediatric endocrinologists and youth living with type 2 diabetes and their caregivers

Provider groups

Interest to participate was elicited at the end of the survey for both Canadian and United States providers. A semi-structured focus group guide administered by a single interviewer, and informed by the Consolidated Framework for Implementation Research (CFIR) framework,²⁸ was used. The guide focused on the following topics: (1) DKD screening practices in youth with T2D, (2) clinical utility of eGFR, (3) barriers and facilitators to the implementation of the iCARE eGFR into practice, (4) potential use of the iCARE eGFR equation, and (5) evaluation of the implementation process. A total of four virtual focus groups were performed; two in Canada (n = 8) and two in the United States (n = 5) from a total of seven centers, at which point saturation was reached.

Patients

Current iCARE participants (16-22 years old) who had previously indicated consent to be contacted for future research opportunities were approached for this ancillary study by research teams. A semi-structured focus group guide was also utilized and focused on exploring the following topics: (1) understanding of eGFR, (2) familiarity with testing to assess kidney health in general, (3) comfort discussing kidney health with their doctor/provider and how they have previously learned about kidney health, and (4) optimal messaging for the implementation toolkit. To date, a total of three focus groups have been held with youth participants and their caregivers (two groups in Manitoba [n = 8], one group in Toronto [n = 4]). Recruitment is ongoing.

Discussions were recorded and transcribed for all focus groups. Thematic analysis will be done with a combination of inductive and deductive approaches.

Phase 3: Implementation of an iCARE Estimated Glomerular Filtration Rate Equation Toolkit

Following the principles of the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance),²⁹ our knowledge mobilization and implementation strategies are directed toward the development of a toolkit. Care provider and patient-facing resources, with multilevel stakeholder collaboration, will be integrated into electronic medical records (EMRs) for use in clinical practice. Once all data from the readiness assessments are complete, learnings from the survey and the provider and patient focus groups will be synthesized to design the optimal implementation toolkit for implementing the eGFR equation.

Key components will include the following. (1) Implementation of the iCARE equation into an existing app to be used by care providers to facilitate efficient calculation of the eGFR. Three local individual EMR systems at three centers (Vancouver, Winnipeg, Toronto) will incorporate the eGFR equation to automatically generate the results when patient sex, height, weight, and serum creatinine are available. (2) Development of provider and patient education materials to guide interpretation of the equation and management of DKD. These will include both infographics and short videos that can be easily shared on social media or housed on the DREAM website (dreamdiabetesresearch.com).

Patient partners (O.A.-G., J.L.), along with the iCARE PAG, will play a critical role in the interpretation of survey and focus group findings and the design of the toolkit. Specific considerations will be made to ensure that the videos are relevant for First Nations populations in Canada and non-Hispanic black populations in the United States. Images and media will be tailored based on feedback.

“To make kidney resources more relevant to First Nations families, we should put things in local languages, especially for families living in more remote communities.”—Jacqueline Linklater, Four Arrows Regional Health Authority First Nation Research Liaison.

“It is important that the eGFR toolkit be co-designed with patients and families because making this toolkit together builds trust and strong relationships between patients and health care providers, reduces misunderstanding, ensures that everyone is heard, and encourages patients to speak openly about their concerns. The eGFR toolkit should be easy to understand and practical for everyone, and the best way to achieve this is by having health care providers and patients work together.”—Onalee Garcia-Alecio, Patient Partner

Site champions (J.H., S.B., E.A.C.S.) will be critically important to support site-specific implementation at the three initial sites in Canada, including facilitating integration of the equation with local EMR systems, as well as encouraging uptake of the tool among local colleagues caring for youth with T2D, and ultimately supporting the regulatory work required to implement audits and satisfaction surveys. Uptake into Clinical Practice Guidelines will be advocated for by study team members, based on their leadership positions in current guideline committees.

Phase 4: Evaluation of the iCARE Glomerular Filtration Rate Implementation Toolkit

After implementation of the toolkit, an evaluation based on the RE-AIM framework is planned for three centers in Canada (Vancouver, Winnipeg, Toronto). Evaluation will include chart audits at one and four months after implementation and patient and provider satisfaction surveys, which will be performed at four months after implementation at each site. Specifically, Reach of the intervention will include the number and characteristics of care providers utilizing the tool at each site, as well as the proportion of patients where it is documented in their chart. Perceived Effectiveness will be assessed by the surveys of providers and patients. Adoption will be assessed by the proportion of staff that consistently utilize the tool in their practice (>80% of eligible patients). Implementation will be evaluated by patient and caregiver understanding of eGFR results. Maintenance/sustainment will be more likely to be successful if the implementation is perceived to be useful and endorsed by Canadian and International Guidelines, such as the International Society of Pediatric and Adolescent Diabetes (ISPAD).

Preliminary Findings

The Can-SOLVE CKD network created a Pathway to Implementation guide, which has been adapted for this project in Figure 1. At this stage, the iCARE eGFR implementation team has completed Phase 2 and is actively working on the implementation toolkit (Phase 3 of the project). We have prepared and are concurrently submitting three separate papers, summarizing the results of validation, the survey³⁰ and the focus group findings from pediatric endocrinologists.³¹ The following key findings, identified to date and summarized in Table 1, will be utilized to design a successful implementation toolkit and optimize uptake and sustainability of the novel clinical tool into pediatric diabetes care.

Figure 1.

iCARE eGFR pathway from development to implementation.

Table 1.

Preliminary Findings from Each Phase of the iCARE eGFR Implementation Project.

Project phase
1. External Validation	- The iCARE eGFR equation provides the most accurate estimate of kidney function in youth ages 10-24 living with T2D, with high BMI, and increased GFR (P30 = 72.5% and bias = −15.6). - The iCARE eGFR should not be used in youth with T1D. - Additional research is required to evaluate the validity among youth from different ethnic backgrounds, as well as youth with lower iGFR.
2. Readiness Assessment Barriers and facilitators to implementation identified by diabetes care providers	Potential barriers 1. Discomfort and lack of certainty in the interpretation of eGFR by diabetes care providers. 2. Lack of longitudinal evidence that integration of eGFR into clinical decision-making (in addition to albuminuria) prior to eGFR decline will impact long-term outcomes of youth living with T2D. 3. Need for treatment algorithms to guide clinical decision-making based on eGFR results. Potential facilitators 1. Utilizing technology to simplify calculation of eGFR such as an existing medical app and EMR system. 2. Infographics and/or care pathways to guide interpretation of results in the low, normal, and high GFR ranges as well as treatment and referral recommendations. 3. Uptake into clinical practice guidelines.

Project phase

1. External Validation

- The iCARE eGFR equation provides the most accurate estimate of kidney function in youth ages 10-24 living with T2D, with high BMI, and increased GFR (P30 = 72.5% and bias = −15.6).
- The iCARE eGFR should not be used in youth with T1D.
- Additional research is required to evaluate the validity among youth from different ethnic backgrounds, as well as youth with lower iGFR.

2. Readiness Assessment
Barriers and facilitators to implementation identified by diabetes care providers

Potential barriers
1. Discomfort and lack of certainty in the interpretation of eGFR by diabetes care providers.
2. Lack of longitudinal evidence that integration of eGFR into clinical decision-making (in addition to albuminuria) prior to eGFR decline will impact long-term outcomes of youth living with T2D.
3. Need for treatment algorithms to guide clinical decision-making based on eGFR results.
Potential facilitators
1. Utilizing technology to simplify calculation of eGFR such as an existing medical app and EMR system.
2. Infographics and/or care pathways to guide interpretation of results in the low, normal, and high GFR ranges as well as treatment and referral recommendations.
3. Uptake into clinical practice guidelines.

Phase 1: Validity of the iCARE Glomerular Filtration Rate Equation

The age of youth in the validation studies was between 11 and 20 years, with a mean of 16.1 ± 2.5 years. Youth with T2D predominantly identified as Caucasian and Hispanic White (73.1%) and Black (14.9%) and had a mean body mass index (BMI) z-score of 2.4 ± 0.5. The obese group had a mean BMI z-score of 2.4 ± 0.4 and the youth with T1D had a median BMI z-score of 0.6 (IQR = −2.2 to 2.5). Body surface area (BSA) Corrected iGFRs were 165 ± 37 mL/min/1.73 m², 163 ± 45 mL/min/1.73 m², and 184 ± 30 mL/min/1.73 m² in the three groups respectfully.

We identified different agreements between the iGFR and eGFR equations for the T1D and T2D populations. There was essentially no agreement for T1D, and we therefore learned that the iCARE eGFR should not be used in this population. In the T2D population, all evaluated eGFR equations systematically underestimated the iGFR; however, the iCARE eGFR performed the best. Of the GFR’s estimated with the iCARE equation, 72.5% were within 30% of the measured iGFR (P30). Only 22.5% were within 10% of the iGFR (P10). The equation performed even better in the obese (non-diabetes) group, with 95% of the estimated GFRs falling within 30% of the iGFRs.

The Bland-Altman plots are presented in a separate validation paper (submitted), which reflect the prediction error or limits of agreement. The 95% limits of agreement of the iCARE eGFR are −43.2 to 15.7 mL/min/1.73 m² (bias −15.6). These findings were more optimal in the Manitoba validation group, which has already been published, with a P30 of 96.2% and P10 of 53.8%;¹² however, they reflect performance in an external population, with higher iGFRs (mean was 129 + 28 mL/min/1.73 m² in the original Manitoba validation cohort). Despite these limitations, the performance of the iCARE eGFR was better than all other available eGFRs and still is the best tool available to estimate kidney function in this population.

Phase 2: Endocrinologist Perspectives on Diabetic Kidney Disease Screening in Youth With Type 2 Diabetes

The readiness assessment revealed several barriers to implementation that need to be addressed. The survey identified that endocrinologists were rarely calculating eGFRs in their patients but rather almost universally ordering random urine tests for albumin:creatinine ratios (ACRs) for screening of DKD, as endorsed by clinical practice guidelines.^10,32 They were also rarely able to correctly interpret eGFR results when given clinical vignettes (ie, identify thresholds for high or low values). This suggests that more education is required for pediatric endocrinologists to properly utilize the iCARE eGFR, even once it is implemented into practice. Clinical support tools for providers and educational tools for youth will be part of the implementation toolkit that can facilitate knowledge sharing with patients.

“My hope is that the videos, infographics, and other materials we are creating about eGFR and kidney health will ensure that families and patients have a better understanding of overall kidney health and how to detect early signs of kidney issues. These resources are meant to educate and inform individuals to support their self-advocacy regarding their health and raise awareness.”—Jennifer Lopez, Patient Partner

The focus groups also identified some provider concerns with the clinical utility of the tool. While there have been many pediatric studies that support the association between albuminuria and CKD progression,^2,7 the importance of eGFR has not yet been evaluated. There was a perceived need for more evidence that modifying treatment based on eGFR in youth with T2D would result in improved long-term outcomes. As a result of this concern, our team is now additionally developing a risk prediction equation for CKD progression in youth with T2D. Results will be available in 2026. If eGFR is shown to add additional predictive value to urine ACR and other clinical characteristics, this will add additional justification for its implementation into practice.

Finally, endocrinologists, especially in the United States, expressed concern that the iCARE eGFR was not generalizable to other populations. While the iCARE eGFR has now been evaluated in small sample sizes of youth from a variety of racial groups, more study will be required to evaluate its performance in larger sample sizes of youth from different racial groups, ages, and stages of CKD.

Technology and integration into clinical practice guidelines were identified as important facilitators. Clinical tools that require complex calculations are often integrated into medical apps that can facilitate implementation. We therefore plan to build the calculation into a currently utilized app. We will also be working with site champions to incorporate the eGFR into local EMR systems in three sites. Finally, care providers expressed that they would be more likely to utilize the iCARE eGFR if it was endorsed by clinical practice guidelines. As our team is well situated to advocate for its implementation, this will also be an important strategy to scale up implementation beyond our three main study sites.

Implementation Reflections and Implications for Scale and Sustainability

This project is aiming to implement a tool, traditionally utilized by nephrologists, into the practice of pediatric endocrinologists. The readiness assessment performed prior to implementation of the novel iCARE eGFR equation into clinical practice highlighted several important barriers that will need to be addressed to facilitate uptake of this novel tool into the care of youth living with T2D prior to nephrology referral. Without addressing these barriers, implementation attempts will likely fail. It is important to acknowledge the scope of practice of different specialists when implementing interventions across disciplines. However, by working to improve collaboration and co-management, there is potential to improve identification and treatment of complications early to decrease rates of long-term kidney disease progression.

There was a clear understanding of the long-term risks of CKD and kidney failure in youth with T2D by pediatric endocrinologists and a universal diligence in following clinical practice guidelines for screening of albuminuria and timely referral to nephrology care. The surveys and focus groups were instrumental in identifying the need to address knowledge gaps in eGFR interpretation prior to meaningful implementation of this additional tool.

The team is well positioned to develop infographics and videos in collaboration with patients living with T2D, which will significantly improve the likelihood of achieving optional Reach, Adoption, Implementation, and Maintenance as we move toward the evaluation phase of the project.

Conclusion

This Knowledge mobilization project exemplifies the necessary steps to move new knowledge into clinical practice. The iCARE eGFR has the potential to provide diabetes care providers and patients additional knowledge about their kidney health, which can be used to guide treatment and follow responses to treatment and disease trajectories. By working actively with clinical research patient partners and community members, the deliverables from this initiative will be designed specifically for people who most benefit from them. Future research, including the evaluation of this implementation project, will also guide best practices for kidney care in youth-onset T2D.

Footnotes

Acknowledgements

We would like to acknowledge all the patients that have participated in the iCARE and the validation cohorts and focus groups, as well as all of the physicians that participated in the surveys and focus groups.

ORCID iDs

Allison B. Dart

J. Grace Zhou

Valerie Umaefulam

Kalie Tommerdahl

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding for iCARE has been provided by Research Manitoba, the Children’s Hospital Research Institute of Manitoba (CHRIM), Canadian Institute of Health Research (CIHR) Operating Grants and the Canadian Institutes for Health Research—Strategy for Patient-Oriented Research (CIHR-SPOR) through the Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) Network.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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