Stage 1 – CKDu research planning and development

Consistent and transparent case definitions are essential to ensure comparability across regions and over time. The i3C framework recommends a pragmatic approach that prioritizes reproducibility while acknowledging the diagnostic uncertainty inherent in CKDu.

Population selection should:

• Apply standardized CKDu case definitions, typically based on reduced estimated glomerular filtration rate and/or markers of kidney damage in the absence of known causes (Caplin et al., 2019)
• Explicitly define exclusion criteria for known causes of CKD, recognizing that misclassification may occur in low-resource settings (Caplin et al., 2019)
• Consider age, sex, occupational exposure and geographic residence in defining the target population, particularly in known or suspected hotspots (Anand et al., 2019)
• Document screening pathways and referral mechanisms to ensure transparency and minimize selection bias.

Defining and assessing exposure is a central yet methodologically complex component of CKDu research. The i3C working group emphasize that exposure assessment should be guided by existing hypothesis, while also allowing for exploratory, hypothesis-generating analyses, and should be context-specific, and transparently reported. Given that CKDu likely arises from multiple interacting exposures rather than a single causal agent, study designs should, where feasible, support the collection of data and biosamples that enable testing of multiple potential exposure pathways over time.

Defining CKDu exposures

Exposure definitions should be informed by existing epidemiologic patterns and tailored to the local context. The i3C framework highlights the importance of clearly specifying what is being measured, its relevance, and its relationship to proposed disease mechanisms.

Given the cost of fieldwork, studies should distinguish between collecting data and biological samples and testing specific exposures, allowing samples and data to be retained for future analyses as hypotheses and evidence evolve.

Key principles include:

• Identification of environmental, occupational, behavioral, and social exposures plausibly linked to CKDu, such as heat stress, agricultural work practices, water sources, agrochemical use, and socioeconomic conditions.
• Explicit articulation of the etiological hypothesis underpinning exposure selection, avoiding exploratory testing without conceptual grounding.
• Clear definition of exposure timing, intensity and duration, particularly in relation to disease onset and progression.
• Recognition that exposures may differ across regions requiring locally relevant definitions rather than universal proxies.

Assessing CKDu exposures

The i3C framework emphasizes that exposure assessment should balance methodological rigor with feasibility, particularly in low-resource and rural settings. Multiple complementary approaches are often necessary to strengthen inference.

Approaches to exposure assessment may include:

• Structured questionnaires and interviews to capture occupational history, work practices, hydration patterns, and residential history, using standardized instrument where possible.
• Environmental assessment, including characterization of drinking water sources, workplace conditions, and ambient heat exposure, should account for logistical and temporal constraints.
• Use proxy measures (e.g., job category, geographic residence, seasonality) when direct measurement is not feasible, and report their limitations transparently.
• Incorporation of biological or molecular markers of exposure or effect (e.g., biomarkers of heat stress, nephrotoxic exposure, or early kidney injury) as adjuncts rather than replacements for traditional exposure data.

Integrating exposure assessment with study design

Exposure assessment should be integrated into the overall study design rather than treated as a standalone activity. The i3C framework underscores the importance of aligning exposure measurement, outcome definition, and analytic strategy.

Key integration considerations include:

• Ensuring exposure data collection is carried out in parallel with outcome assessment, particularly in longitudinal studies.
• Planning for repeat or cumulative exposure assessment where disease onset, progression or temporal relationships are of interest.
• Accounting for measurement error, recall bias, and misclassification, and addressing these limitations in analysis and interpretation.
• Avoid overinterpreting association when robust exposure characterization is lacking, particularly in the context of informing policy on interventions.

Ethical and practical consideration when assessing exposure

Assessment of CKDu exposure frequently intersects with sensitive issues related to labor conditions, livelihoods, and environmental justice. The i3C framework highlights the need for ethical vigilance throughout the exposure assessment process.

Considerations include:

• Minimizing potential harm or stigma associated with identifying high-risk occupations or communities.
• Ensure transparency with participants and communities regarding what exposure data can and cannot demonstrate.
• Aligning exposure assessment strategies with realistic pathways for intervention, so that data collected can meaningfully inform prevention and policy efforts.

Outcome definitions must align with study objectives and enable meaningful interpretation for both scientific and policy audiences. The i3C framework highlights the importance of harmonization while permitting staged outcome assessment.

Outcome planning should:

• Use standard kidney function measures (e.g., estimated glomerular filtration rate [eGFR], albuminuria/proteinuria, where available) consistent with international norms.
• Distinguish between prevalent disease, incident disease, and progression, particularly in longitudinal designs.
• Where biopsy is undertaken, integrate histopathologic findings using standardized reporting frameworks and clear indications.
• Anticipate downstream use of outcomes for intervention testing and health system planning.

Ethical considerations in CKDu research extend beyond formal approvals and must address participant vulnerability, uncertainty, and potential harm. The i3C framework underscores that ethical preparedness is an integral component of study design rather than a procedural afterthought.

Key requirements include:

• Early engagement with local ethics committees and regulatory authorities, accounting for country-specific governance structures.
• Explicit consideration of risk-benefit balance, particularly for invasive procedures or research with limited direct participant benefit.
• Clear plans for data governance, ownership, and sharing, including protection of community interests.
• Mechanisms for managing incidental findings and referral for clinical care.

Informed consent in CKDu research must be tailored to populations with varying levels of health literacy and trust in health systems. The i3C framework emphasizes that consent is a process rather than a single event.

Consent processes should:

• Use clear, culturally appropriate language that acknowledges uncertainty regarding etiology and prognosis.
• Address expectations related to results disclosure, follow up, and potential interventions.
• Include additional safeguards for biobanking, genetic testing, and kidney biopsy, where applicable.
• Be supported by trained personnel capable of responding to participant questions and concerns.

Early sustained engagement with policymakers increases the relevance and impact of CKDu research. The i3C framework highlights that research disconnected from policy contexts risks limited uptake, regardless of scientific quality.

Effective engagement should:

• Involve policy stakeholders during study planning, particularly when defining outcomes and data elements relevant to public health.
• Align research objectives with national surveillance, occupational health, and environmental priorities where possible.
• Communicate findings in formats accessible to non-academic audiences, without overstating causality.
• Support pathways from evidence generation to intervention testing and implementation.