Patient monitoring in a pragmatic, multicenter trial of incremental hemodialysis: early experience from the TwoPlus randomized controlled trial

Abstract

Background

Pragmatic randomized controlled trials (RCTs) must be embedded within routine clinical workflows, which require monitoring strategies that are feasible in everyday practice. Incremental hemodialysis—initiating treatment twice weekly in patients with preserved residual kidney function and escalating frequency as needed—differs from conventional thrice-weekly initiation. Implementing this approach in a pragmatic trial among providers and dialysis staff unfamiliar with incremental dialysis necessitated additional preparation and oversight. The TwoPlus trial is a multicenter pragmatic RCT evaluating incremental versus conventional initiation of chronic hemodialysis. We describe the patient monitoring framework developed for TwoPlus, which integrates digital infrastructure, human touchpoints, and provider engagement to ensure participant safety.

Methods/Design

TwoPlus is an ongoing multicenter RCT enrolling adults initiating chronic hemodialysis with residual kidney function (urine urea clearance ≥ 2.0 mL/min and urine output ≥ 500 mL/24 hours). Participants are randomized to incremental hemodialysis—twice-weekly treatment supported by diuretics and sodium bicarbonate, with transition to thrice-weekly as clinically indicated—or conventional thrice-weekly initiation. The primary outcome is a composite of all-cause death, hospitalization, or emergency department visits. Secondary outcomes include preservation of residual kidney function and treatment adherence. The monitoring framework combines automated dialysis data downloads, manual data abstraction, assessments conducted by investigators or clinical research coordinators and reviewed at the site level, structured team reviews, and regular communication with treating providers.

Discussion

This layered monitoring model balances feasibility, safety, and fidelity in a pragmatic trial where provider engagement and site-specific adaptation were essential. The monitoring approach adopted in TwoPlus will inform the design of monitoring frameworks for future pragmatic nephrology trials.

Trial registration

NCT05828823.

Supplementary information

The online version contains supplementary material available at 10.1186/s12882-025-04659-2.

Introduction

Pragmatic randomized controlled trials (RCTs) are designed to evaluate interventions under real-world conditions and must operate within routine clinical workflows [1]. This design increases the involvedness of trial operations—particularly patient monitoring—because oversight must be integrated into standard care processes rather than layered on top of them [2]. Traditional safety monitoring, which often relies on retrospective reporting of serious adverse events to Institutional Review Boards or Data and Safety Monitoring Committees, may be insufficient in this setting [3]. Beyond traditional oversight, proactive, real-time strategies are required—especially when the intervention alters foundational aspects of care delivery [4].

In many RCTs, interventions remain fixed after randomization, and safety oversight is narrowly focused on predefined outcomes. By contrast, trials involving emerging interventions that employ existing tools and knowledge and that need to be embedded in routine care require more flexible and layered monitoring frameworks [2]. This adaptability not only enhances participant safety but also supports continuous learning across diverse clinical sites.

Here, we describe the operationalization of the monitoring strategy in the TwoPlus trial—a multicenter pragmatic RCT comparing incremental versus conventional initiation of chronic hemodialysis [5]. The rationale for evaluating the effectiveness of incremental hemodialysis versus conventional thrice-weekly initiation has been detailed elsewhere [5]. Briefly, incremental hemodialysis leverages residual kidney function and adjuvant therapies, allowing a gradual transition to full-dose therapy. Tailored to clinical manifestations and residual kidney function, incremental hemodialysis is supported by growing evidence for its potential to improve quality of life, reduce treatment burden, and preserve residual function [6], without compromising clinical safety [7]. However, most prior studies were conducted at institutions where clinicians were already familiar and comfortable with prescribing and monitoring patients on incremental hemodialysis [8, 9]. In routine practice, this approach challenges entrenched norms and relies heavily on the experience and engagement of treating nephrologists and dialysis staff, many of whom are unaccustomed to deviating from the thrice-weekly standard [10]. The current manuscript focuses on the patient monitoring framework of the TwoPlus trial, which has not previously been described in detail, and aims to provide a model for safety oversight in pragmatic nephrology research.

Participants, interventions, outcomes

The TwoPlus trial is an ongoing multicenter RCT comparing incremental versus conventional initiation of chronic hemodialysis in patients with kidney dysfunction requiring dialysis [5]. Eligibility criteria, recruitment settings, interventions, and outcomes are fully described in the published TwoPlus protocol [5] and are also summarized in the Supplementary Material accompanying this manuscript. In brief, adults initiating chronic hemodialysis who have residual kidney function based on timed urine collection of kidney urea clearance ≥ 2.0 mL/min and urine output ≥ 500 mL/24 hours, and who meet other clinical eligibility criteria, are randomized across multiple academic and community dialysis units to either incremental hemodialysis or conventional thrice-weekly initiation (Fig. 1).

Fig. 1.

TwoPlus trial schema. Participants with new-onset chronic hemodialysis undergo prescreening, informed consent, screening, and randomization to either incremental hemodialysis (n = 175) or conventional hemodialysis (n = 175). In the incremental hemodialysis group, a minimum treatment duration of 4 hours per session was prescribed immediately following randomization. In contrast, the conventional hemodialysis group was not required to meet this minimum duration at the outset. Throughout the follow-up period, dialysis session duration in both groups could be adjusted—either increased or decreased—based on clinical needs, at the discretion of the treating team or study investigators. Data collection and patient monitoring include timed urine collections, study-specific blood tests, and adjustments to dialysis prescriptions and medications as clinically indicated by the study team or treating providers

Participants randomized to the intervention group of incremental hemodialysis are treated with twice-weekly hemodialysis supported by adjuvant oral medications (diuretics, potassium binders and sodium bicarbonate if needed) and progress to thrice-weekly treatment when clinically indicated. The primary outcome is a composite of all-cause death, hospitalization, or emergency department visits, with secondary outcomes including residual kidney function and treatment adherence.

Statistical considerations

The planned sample size of 350 patient participants (175 per arm) provides ≥ 85% power to test non-inferiority for the primary composite outcome, assuming an event rate of 2.02 per person-year in the conventional group, an incidence-rate ratio of 0.94 for the incremental group, and a non-inferiority margin of 1.20 at a one-sided α = 0.025. The primary analysis will follow the intention-to-treat principle. The primary outcome—a composite of all-cause death, hospitalization, or emergency department visits—will be compared between study arms using time-to-event methods. Recurrent event models will be used for secondary analyses. Additional outcomes, including preservation of residual kidney function and treatment adherence, will be analyzed using mixed-effects and survival models, as appropriate. Time-to-event analyses will treat death, transplantation, withdrawal, and end of follow-up as censoring events, and recurrent-event analyses will use negative-binomial regression with over-dispersion adjustment. Missing data will be addressed using multiple imputations under the Missing at Random assumption for primary and secondary outcomes. Imputation models will incorporate baseline covariates, treatment assignment, and available longitudinal data to preserve variability and reduce bias. Sensitivity analyses will include inverse probability weighting and pattern-mixture models to evaluate the robustness of findings under alternative missingness mechanisms. For time-to-event analyses, participants will be censored at the time of withdrawal or loss to follow-up [5].

Data collection, management, and analysis

Clinical data in TwoPlus are collected through a hybrid model that combines automated downloads from dialysis electronic medical records (EMRs) with complementary manual data entry. Electronic dialysis data downloads (DDDs) are generated at participating dialysis organizations and transmitted on a standardized format and schedule to the Data Coordinating Center (DCC) (Fig. 2). When direct electronic extraction from dialysis EMR is not feasible, equivalent data are abstracted through structured dialysis EMR review and entered manually into the centralized TwoPlus database. Both electronic and manual streams capture treatment-level information from each dialysis session, including prescription details, vital signs, interdialytic weights, ultrafiltration volume, and delivered Kt/V.

Fig. 2.

Data flow and monitoring in the TwoPlus trial. Screening information, patient-reported outcomes, study-specific laboratory results, and adverse events (e.g., hospitalizations and emergency department [ED] visits) are obtained through structured, protocol-driven processes, including review of healthcare system electronic medical records (EMRs). Dialysis treatment data are sourced from dialysis EMRs either via automated Dialysis Data Downloads (DDD) or site-entered abstraction, depending on local capabilities. This hybrid approach ensures comprehensive and standardized data capture across diverse clinical environments. All data streams are transmitted to the Data Coordinating Center (DCC), where they undergo reconciliation and quality checks before integration into a centralized database. The DCC generates quarterly participant-level summaries—including kidney stdKt/V, dialysis stdKt/V, total stdKt/V, biochemical parameters, weight management metrics, and adherence indicators—which are returned to sites as structured monitoring reports to support ongoing oversight and protocol fidelity

To supplement treatment-level metrics, clinical research coordinators abstract data from non-dialysis healthcare institutions’ EMR, including emergency department visits, hospitalizations, and other adverse events. Patient-reported outcomes are also obtained through structured in-person or virtual assessments at regular study visits. This dual approach ensures that the monitoring framework incorporates both objective clinical parameters and contextual patient information.

All data streams feed into a secure, web-based system managed by the DCC (Fig. 2). The DCC reconciles incoming DDDs and manual entries against expected participant lists, generates automated alerts for discrepancies, and ingests validated datasets into the central repository. Logic and range checks are applied at the point of entry to enhance data quality (see Supplementary material). Curated participant-level summaries—including residual kidney function, dialysis stdKt/V, kidney stdKt/V, total stdKt/V, and routine laboratory values—are produced quarterly and returned to sites to support ongoing monitoring and intervention fidelity. Access is role-restricted, and all transmissions are encrypted.

Patient monitoring in the TwoPlus trial

Drawing on best practices from prior pragmatic trials [2], the TwoPlus monitoring framework integrates electronic health records, human-centered follow-up, and team-based decision-making to support safe implementation of an emerging intervention across varied practice settings. Monitoring in TwoPlus extends beyond detecting adverse events. It is designed to:

1. Identify early signs of clinical instability.

2. Support adjustments to the dialysis prescription.

3. Assess adherence to treatment assignments.

4. Provide guidance and reassurance to treating providers.

5. Safeguard trial equipoise across diverse practice settings.

These goals require that providers remain well-informed and supported, and that study teams maintain close, ongoing collaboration with treating nephrologists and dialysis unit staff. As illustrated in Fig. 3, patient monitoring in TwoPlus spans five interconnected domains:

1. Provider engagement — active involvement of treating nephrologists to confirm eligibility, approve randomization, and maintain ongoing communication about clinical status.

2. Human touchpoints — monthly participant check-ins, informal communication with dialysis staff, and structured tracking logs that provide context beyond electronic data.

3. Team-based review — structured meetings at the site and investigator level where clinical research coordinators and investigators assess longitudinal data, discuss cases, and recommend adjustments in treatment or monitoring.

4. Digital surveillance — near real-time monitoring through dialysis EMR downloads, Admission-Discharge-Transfer (ADT) alerts, and interoperability with regional health information exchanges, integrated with quarterly reports from the Data Coordinating Center.

5. Site-level adaptation — tailoring implementation to local infrastructures, workflows, and patient populations, including cultural and language considerations, to ensure feasibility and fidelity across diverse care environments.

Fig. 3.

Layered patient monitoring framework in the TwoPlus trial. The TwoPlus monitoring framework spans five interconnected domains: provider engagement, human touchpoints, team-based review, digital surveillance, and site-level adaptation. Each domain incorporates specific activities to ensure participant safety, intervention fidelity, and trial feasibility. Examples include treating nephrologist approval and communication with providers (provider engagement); monthly participant check-ins and dialysis staff input (human touchpoints); standardized tracking logs and case discussions at investigators’ meetings (team-based review); EMR-integrated admission–discharge–transfer (ADT) alerts and monitoring of dialysis, volume management, and laboratory metrics (digital surveillance); and tailoring for underserved populations, variable infrastructures, and workflow integration across academic and community practices (site-level adaptation)

The following sections describe how these principles have been operationalized across participating TwoPlus sites.

Provider engagement

In pragmatic trials, provider engagement functions as both a safety mechanism and a key determinant of adherence to the trial protocol [11]. In TwoPlus, the treating nephrologist is often not a study investigator. Successful implementation of the intervention—and protection of participant safety—therefore depends heavily on the engagement and support of non-research clinicians. Positioning providers as partners, rather than passive recipients of study protocols, was critical to enhancing both intervention safety and fidelity—an approach previously advocated for pragmatic trials [12].

To address limited prior experience with incremental hemodialysis among many treating nephrologists and dialysis staff, structured training sessions were conducted at each site before recruitment began (Fig. 4). Training and engagement were implemented through a cascaded model, beginning with centralized sessions led by the principal investigators and the Clinical Coordinating Center (CCC) for site investigators and research coordinators, who then trained local treating teams and dialysis staff. For sites lacking automated EMR data transfer, tailored training was provided on manual data extraction and entry workflows.

Fig. 4.

Training structure for implementation of the TwoPlus trial. Training for TwoPlus was delivered through a stepwise inter- and intra-institutional structure that cascaded across stakeholders. Multi–principal investigators (MPIs) trained local study teams, including site investigators and clinical research coordinators. Local study teams, in turn, trained local treating teams such as faculty attendings, nephrology fellows, and advanced practice practitioners (e.g., nurse practitioners, physician assistants). Finally, local study teams and treating providers provided training and orientation to dialysis staff, including nurses, dietitians, and social workers at participating dialysis centers

All patients initiating chronic hemodialysis at participating centers are prescreened for eligibility with input and approval from the treating nephrologist to confirm appropriateness for incremental therapy—for example, adequate volume status and the ability to follow dynamic medical instructions. At randomization, treating providers are notified of the assigned study arm, and for participants randomized to the incremental arm, this communication emphasizes the need for closer monitoring and offers an opportunity to raise safety concerns.

To sustain engagement, study teams maintain regular communication with providers throughout follow-up. Some sites use recurring email updates or designate liaisons to ensure timely information flow, while others involve study-affiliated nephrologists as consultants when dialysis staff express discomfort with non-standard schedules. These arrangements provide peer-to-peer support and reinforce decision-making while respecting provider autonomy.

In some cases, coverage providers unfamiliar with the trial temporarily overruled randomization assignments or delayed intervention implementation. Such episodes underscored the importance of continuous communication and rapid clarification. Ultimately, consistent provider engagement has improved protocol adherence, facilitated timely treatment adjustments, and supported the safe delivery of incremental hemodialysis across diverse dialysis settings.

Human touchpoints

Digital systems alone cannot ensure participant safety in a pragmatic trial [4, 13, 14]. Human touchpoints—structured, intentional interactions between study staff, participants, and dialysis teams—are essential to gather insights into participant experiences and clinical changes that are not consistently documented in electronic records.

At all sites, trained clinical research coordinators conduct monthly in-person with patient participants. These checkpoints use a conversational approach, asking open-ended questions such as “How are you feeling?” or “Have you been to the hospital since we last spoke?” These touchpoints uncover issues that may not be evident in the medical record—such as fluid imbalance, missed treatments, or medication changes—and foster rapport, which supports retention and adherence.

Patient-reported outcomes are collected during study visits using validated instruments. These include Illness Intrusiveness Rating Scale and Time to Recovery from a Dialysis Session, administered monthly, and EuroQoL-5 Dimensions-5 Level (EQ-5D-5 L) and SONG-HD Fatigue, administered quarterly [5]. These questionnaires are completed with the assistance of a study team member. A noted limitation is that the team member administering the instruments is not blinded to the participant’s assigned intervention. While these tools provide valuable insights into patient experiences, they are not used in a strictly objective manner to guide changes in dialysis prescriptions. Adjustments to treatment are made based on clinical judgment by the treating team or study investigators.

Individual sites also maintain internal tracking logs for participants in the incremental arm. These typically include treatment dates, prescribed and achieved weights, blood pressures, and medication adjustments. Study teams review these logs regularly—often weekly or biweekly—during structured meetings involving the site investigator and clinical research coordinator. This facilitates early recognition of clinical drift, such as rising interdialytic weight gains or unexplained weight adjustments.

Informal communication with dialysis staff further enhances monitoring. Nurse managers and front-line dialysis staff frequently notify the study team about missed treatments, evolving symptoms, or social barriers. In some cases, treating nephrologists initiate discussions about patient eligibility or reassess suitability for continued participation in the incremental arm.

Team-based decision-making

Decisions to maintain or escalate dialysis frequency in TwoPlus are informed by structured, collaborative reviews that integrate both clinical context and laboratory data. Parameters guiding progression from twice- to thrice-weekly hemodialysis are summarized in the Supplementary Material. These include thresholds for residual kidney function, biochemical parameters, volume status, and clinical events, and are used to support individualized treatment decisions in collaboration with treating providers.

At each site, assessments are conducted by clinical research coordinators or investigators and reported to the site principal investigator. These reviews occur weekly or biweekly and focus on key indicators such as interdialytic weight gain, dry weight changes, blood pressure patterns, diuretic use, hospitalizations, and relevant laboratory results. Many sites employ pre-populated tracking templates to visualize longitudinal trends, enabling early recognition of clinical drift or emerging safety concerns.

In some instances, treating providers identified clinical instability and adjusted dialysis prescriptions before the study team’s scheduled review. In these cases, the study team documented the rationale, confirmed alignment with trial protocol, and incorporated the adjustment into ongoing monitoring. In other instances, findings from site-level reviews were communicated to treating providers along with recommendations to maintain the current regimen or to adjust diuretics, potassium binders, sodium bicarbonate dosing, target weight, or dialysis frequency. Final prescribing decisions always rested with the treating providers, ensuring that adjustments reflected both clinical judgment and trial objectives.

Cross-site learning was promoted through biweekly investigator meetings, where teams presented cases, shared challenges, and exchanged solutions. These peer discussions fostered consistency in protocol implementation while allowing flexibility to adapt to local clinical environments. Collectively, this multi-level review process supported treatment decisions that were patient-centered, evidence-informed, and faithful to the intent of the trial.

Digital infrastructure and surveillance

EMR systems form the backbone of safety monitoring in the TwoPlus trial. Participating sites implemented automated tools to capture dialysis session data and clinical events in near real-time, ensuring close alignment between study monitoring and routine clinical care.

A key element is the deployment of research-specific ADT alerts within institutional EMRs. These alerts notify study teams of hospitalizations or emergency department visits involving enrolled participants and prompt chart review and documentation of adverse events. Several sites enhanced surveillance further by leveraging interoperability with regional EMR networks—such as CRISP and EPIC’s CareEverywhere—to capture events occurring outside their home health systems. This cross-institutional visibility strengthened monitoring in regions with fragmented care networks.

When safety events were identified, responses could be initiated either by treating providers—who sometimes adjusted dialysis prescriptions immediately—or by the study team following review of alert data. In both cases, the study team documented the event, verified consistency with trial protocol, and integrated the information into ongoing monitoring.

At the coordinating level, the DCC supports oversight by generating quarterly participant-level reports. These reports summarize key metrics including residual kidney function, dialysis stdKt/V, kidney stdKt/V, total stdKt/V, volume management parameters, and routine laboratory values. Investigators use these reports to obtain a high-level overview of each participant’s trajectory, allowing for early recognition of concerning trends and for timely discussions with treating providers. In addition, dialysis adherence is monitored using a Fidelity Monitoring Tool, which evaluates outpatient treatment patterns including missed sessions, shortened durations, and adherence to recommended transitions. Details of the adherence metrics and scoring methodology are provided in the Supplementary Material. Fidelity data are not only collected but actively used to support trial implementation. Site investigators receive regular reports from the DCC summarizing adherence metrics, including missed treatments, shortened sessions, and protocol deviations. These reports are reviewed to identify performance gaps and guide site-level quality improvement efforts, ensuring consistent delivery of the intervention and enhancing trial fidelity.

Site-specific adaptations

Although all sites follow a unified TwoPlus protocol, implementation required local adaptations to maintain safety, support provider engagement, and ensure fidelity in diverse clinical environments. These differences reflected variability in institutional infrastructure, dialysis organization, geography, and patient populations. While most participating sites are embedded within academic medical centers, several involve collaborations with private nephrology practices which will enhance the relevance and generalizability of TwoPlus findings across real-world settings.

At many sites, study activities follow highly structured workflows. Digital tools, physician-led consent, and weekly team reviews are coordinated through centralized tracking systems. One or more clinical research coordinators visit dialysis units in person, and physician investigators are actively engaged across all phases—from prescreening and consent to ongoing patient monitoring.

Some sites faced distinct challenges, including caring for largely underserved populations, high proportions of patients with limited English proficiency, and many participants with undocumented status. In these settings, frequent communication with treating providers, close collaboration with social work and pharmacy teams, and flexible approaches to medication access and transportation were critical to increase recruitment and sustain intervention adherence.

Operational challenges also influenced study conduct. At some sites, dialysis centers experienced temporary holds on onboarding new patients due to staffing shortages. In other instances, the addition of new dialysis centers was required—and is anticipated to remain a recurring need—depending on local operational workflows and recruitment rates.

Across all sites, strong rapport with dialysis staff has proved critical. Dialysis nurses frequently act as informal liaisons, alerting the study team to clinical instability or emerging concerns. At certain sites, medical directors have served as study champions, reinforcing awareness and engagement across dialysis unit personnel. In others, close coordination between investigators and treating nephrologists on sharing kidney clearance results—including dialysis and kidney stdKt/V calculations—to inform hemodialysis prescriptions in the incremental arm.

Importantly, evaluating the effectiveness of patient approach in both academic and non-academic environments is essential to understanding its potential for broader implementation. On average, 30% of study participants receive care from private practice dialysis providers, with site variation ranging from 0% to 100%. The remaining 70% are managed within academic institutions. Importantly, while site investigators are affiliated with academic institutions, all participating dialysis centers in the TwoPlus trial serve both private and academic physician practices. Across these centers, dialysis staff follow similar workflows and clinical protocols regardless of physician affiliation. This consistency in care delivery across settings strengthens the scalability of the monitoring framework and supports its feasibility in diverse real-world dialysis environments.

Discussion

The TwoPlus trial offers a unique opportunity to evaluate incremental hemodialysis in a pragmatic, multicenter setting, and the monitoring framework described here is central to its safe implementation. Unlike conventional efficacy trials, pragmatic designs require oversight systems that are embedded within routine workflows and adaptable to diverse care environments. For example, the NIH Pragmatic Trials Collaboratory has implemented regular, rigorous data quality checks and ongoing monitoring of intervention adherence directly within health system operations, rather than through parallel research structures [4, 15, 16]. These trials leverage electronic health records for outcome ascertainment, but must address challenges such as data standardization, aggregation across sites, and integration of patient-reported outcomes, often necessitating tailored solutions at each participating center. Additionally, the Collaboratory emphasizes early and ongoing engagement with health system leaders and front-line clinicians to adapt protocols in response to operational changes, as seen during the COVID-19 pandemic and in the planning and execution phases of demonstration projects [4, 15, 16]. Our experience highlights several principles that may be relevant to future pragmatic nephrology trials.

First, provider engagement emerged as most effective element in participant monitoring and protocol fidelity. Active communication with treating nephrologists and dialysis staff supported adherence and facilitated timely adjustments, whereas lapses in engagement led to delays or protocol drift. Embedding provider engagement as a core element of monitoring may therefore improve both safety and intervention delivery. Other investigators similarly emphasized the importance of human oversight to ensure participant safety. Curtis et al. highlight that while digital systems are integral to pragmatic trial monitoring, human oversight is crucial for ensuring participant safety [4].

Second, the integration of digital and human monitoring touchpoints provided complementary strengths. Automated dialysis data downloads allowed for near real-time tracking of treatment-level variables, while manual data entry and structured patient check-ins collects adverse events and patient concerns not always captured in the dialysis EMRs. Likewise, Marsolo et al. note that electronic health record–based monitoring faces challenges from system variability and updates, necessitating additional human involvement [13]. Huang et al. demonstrate that automated EMR monitoring may miss important adverse events, emphasizing the continued need for traditional, human-centered safety approaches [14].

Third, team-based decision-making and site-specific adaptations proved essential in translating the protocol into varied practice settings. Structured case reviews, cross-site investigator meetings, and informal communication channels created a learning network that promoted consistency while allowing flexibility to accommodate local contexts. Such adaptability is particularly important for emerging interventions that challenge established norms of dialysis delivery. Prior research demonstrates that site-level customization facilitates the implementation of innovative strategies across heterogeneous clinical environments [17, 18]. Canadian initiatives have increased home dialysis uptake by deploying tailored educational tools and feedback reports aligned with local workflows [19, 20]. The COVID-19 pandemic accelerated the use of telehealth, facilitated by regulatory waivers and policy changes, expanding access to home dialysis and supporting remote patient management [21–23]. Adaptation also occurs at the patient level, as seen with personalized cognitive behavioral therapy for dialysis patients and flexible peritoneal dialysis prescriptions based on residual kidney function [24]. These examples underscore that successful innovations in dialysis are best conceptualized as adaptive frameworks rather than rigid protocols, to enable customization to local resources, patient needs, and system constraints.

The layered monitoring framework described here holds broader relevance for routine dialysis care. Its structured design—integrating human touchpoints, digital surveillance, and site-specific adaptation—offers a model for enhancing patient safety and care quality beyond research settings. For example, systematic use of EMR-based alerts, combined with structured patient check-ins and collaborative decision-making, could help dialysis providers identify early signs of clinical instability, improve adherence, and support individualized treatment adjustments.

Despite these strengths, several challenges warrant consideration. The monitoring framework depends on the quality and completeness of electronic health record data, which may vary across institutions. Manual data entry, while critical for capturing contextual information, increases workload and may introduce variability in documentation. Compared with pragmatic trials conducted under the NIH Pragmatic Trials Collaboratory—which often benefit from integrated health systems and centralized data repositories—TwoPlus encountered distinct logistical challenges. Collaboratory trials typically operate within unified EMR platforms and embedded research infrastructures that streamline data capture and minimize manual processes. In contrast, TwoPlus was implemented across a heterogeneous network of dialysis providers and geographic regions, including sites with limited EMR interoperability. Some sites relied on tools such as EPIC’s CareEverywhere to track hospitalizations across unaffiliated hospitals, while others served patient populations with high proportions of uninsured individuals and non-English speakers. Implementing the intervention of incremental hemodialysis in the TwoPlus trial required added coordination, staff training time, and management oversight across sites. These reflect the real-world resource demands of embedding pragmatic trials into routine care. Similar considerations will apply to the broader implementation of incremental hemodialysis, which depends on staff training and data infrastructure to support patient monitoring. Future analyses from TwoPlus will examine these economic and logistical aspects to inform scalability and sustainability in research and practice. We also acknowledge that this report does not include quantitative performance indicators—such as fidelity scores, site-level adherence metrics, and workload assessments—are not yet included. These analyses are planned for future publications once the trial is complete and will provide deeper insight into the effectiveness and scalability of the monitoring model.

In summary, the TwoPlus monitoring strategy balances safety, feasibility, and fidelity through a layered approach that combines digital infrastructure with human-centered oversight. By embedding provider engagement and site-specific adaptations, this model may guide the design of future pragmatic nephrology trials testing real-world implementation of emerging interventions.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Abbreviations

ADT

Admission–Discharge–Transfer

CBT

Cognitive Behavioral Therapy

CCC

Clinical Coordinating Center

CRISP

Chesapeake Regional Information System for our Patients

DCC

Data Coordinating Center

DDD

Dialysis Data Download

EPIC

Electronic Medical Record system (Epic Systems Corporation)

EMR

Electronic Medical Record

EQ-5D-5L

EuroQoL 5 Dimensions, 5 Levels

ICMJE

International Committee of Medical Journal Editors

IRB

Institutional Review Board

Kt/V

Dialyzer clearance of urea × dialysis time/volume of distribution of urea

MPIs

Multi–Principal Investigators

PCORI

Patient-Centered Outcomes Research Institute

RCT

Randomized Controlled Trial

SONG-HD

Standardized Outcomes in Nephrology–Hemodialysis

Author contributions

SCG, ASA, and MM conceptualized the manuscript. SCG and MM wrote the first draft of the manuscript. All authors contributed to manuscript drafting or critical revision for intellectual content and approved the final version for submission.

Funding

The TwoPlus trial is funded by the Patient-Centered Outcomes Research Institute (PCORI), award number CER-2022C1-26300.

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

The TwoPlus trial and this monitoring protocol have been approved by the Institutional Review Boards (IRBs) of all participating institutions. Written informed consent is obtained from all participants prior to enrollment.

Consent for publication

Not applicable.

Trial status

The TwoPlus trial has been registered at ClinicalTrials.gov; NCT05828823; registration date: April 25, 2023. Recruitment for the TwoPlus trial began in January 2024 and was initiated in a staggered fashion across participating sites over the subsequent months. As of September 2025, enrollment and randomization remain ongoing at academic and community dialysis units throughout the United States.

Confidentiality

All data are handled in accordance with institutional and federal regulations. Identifiable information is stored only at the enrolling site. De-identified data are transferred to the Data Coordinating Center for analysis.

Dissemination policy

Study results will be disseminated through peer-reviewed publications, conference presentations, and engagement with stakeholders including dialysis providers, professional societies, and patient advocacy groups. Authorship will follow International Committee of Medical Journal Editors (ICMJE) guidelines. A lay summary will be prepared for participants and made publicly available.

Competing interests

The authors declare no competing interests.