Case Study: Dr. Ashita Tolwani’s Citrate Anticoagulation Innovation in CRRT

The “Citrate Queen” visits UAB SPARC on Oct 21st, 2025

CRRT Anticoagulation Challenges and the Risks of Systemic Heparin

Continuous renal replacement therapy (CRRT) is a dialysis modality used in critically ill patients with acute kidney injury, especially when hemodynamic instability makes traditional intermittent dialysis unsafe . A major challenge in CRRT is preventing the extracorporeal circuit from clotting without causing patient bleeding. Critically ill patients often have pro-thrombotic tendencies (activated coagulation cascades and reduced natural anticoagulants) yet are simultaneously at high risk of bleeding . Unfractionated heparin has been the conventional anticoagulant for CRRT, but systemic heparinization can lead to serious bleeding complications and heparin-induced thrombocytopenia in this fragile population. Frequent circuit clotting due to suboptimal anticoagulation shortens filter life, interrupts therapy, and causes blood loss, whereas aggressive heparin dosing may trigger hemorrhage. This trade-off highlighted an unmet need for a safer anticoagulation strategy in CRRT .

Regional citrate anticoagulation (RCA) emerged as an attractive solution. Instead of anticoagulating the patient’s entire bloodstream, citrate is infused into the dialysis circuit where it chelates ionized calcium – an essential cofactor in the coagulation cascade – thereby locally preventing clot formation . The patient receives a calcium replacement infusion downstream, so their systemic calcium levels (and coagulation) remain normal . Citrate is metabolized mainly by the liver (and muscle/kidney), generating bicarbonate as a byproduct, which can help buffer metabolic acidosis (though excess citrate can cause alkalosis if not properly adjusted) . This regional method maintains filter patency without exposing the patient to systemic anticoagulants. Studies have indeed shown that RCA prolongs circuit life and reduces bleeding events compared to heparin . By 2012, international guidelines (KDIGO) recommended RCA over systemic heparin for CRRT in patients without contraindications to citrate . In summary, the clinical problem driving Dr. Tolwani’s innovation was clear: how to deliver effective anticoagulation in CRRT that maximizes filter life and minimizes patient bleeding risk . RCA provided the conceptual solution, but early citrate protocols were complex and not widely adopted, setting the stage for a practical innovation.

A Simplified Citrate-Based Anticoagulation Protocol

Dr. Ashita Tolwani recognized that existing citrate anticoagulation methods, while promising, were too complicated and error-prone for routine clinical use . Early RCA protocols often required pharmacies to prepare custom high-concentration citrate solutions and involved multiple infusion pumps with frequent adjustments, increasing cost and nursing workload . In 2004, Tolwani and her colleagues at UAB (including pharmacist Dr. Rajesh Speer and nurse Brenda Stofan) developed a novel simplified citrate anticoagulation protocol to make CRRT safer and more “user-friendly” . The core innovation was a dilute 0.5% trisodium citrate solution that was isotonic and could double as a replacement fluid in CRRT . This meant that the same citrate solution could both prevent clotting in the filter and serve as the fluid for convection/dialysis, eliminating the need for multiple custom-mixed bags. The team paired this with a standardized 25 mM bicarbonate dialysate (to manage metabolic acid/base status) and a fixed-rate systemic calcium infusion to replenish calcium in the patient’s blood .

By standardizing fluids and concentrations, the protocol avoided patient-specific solution adjustments, greatly simplifying nursing tasks . The physiological principle remained the same – citrate in the pre-filter circuit binds calcium and prevents clotting, and calcium is infused back to the patient – but the deliverability was vastly improved. Importantly, the dilute 0.5% citrate was found to maintain acid–base balance better than more concentrated solutions: UAB’s trial showed that a 0.67% citrate fluid caused mild metabolic alkalosis, whereas 0.5% kept patients’ bicarbonate levels in normal range . In a prospective study of ICU patients, the UAB protocol achieved excellent results: adequate metabolic control, high solute clearance with an effluent rate ~35 mL/kg/hour, and markedly prolonged filter life (approximately 80% of filters lasted 48 hours, which was a major improvement over historical heparin therapy) . There were no bleeding complications attributed to anticoagulation, since systemic coagulation was intact. Dr. Tolwani’s team had effectively demonstrated that regional citrate could be implemented in a practical, safe, and cost-effective manner . As one publication noted at the time, no prior CRRT protocol had achieved this trifecta of effective anticoagulation, metabolic stability, and high clearance without complexity – making the UAB citrate protocol a significant advance .

In sum, the innovation introduced by Tolwani was not a brand-new drug but a simplified protocol – a combination of fluid formula and process improvements. The safety of the approach came from keeping anticoagulation regional (thus avoiding systemic heparin and bleeding) and from close monitoring of electrolytes (to catch any citrate accumulation early). The physiologic rationale was elegantly simple: use citrate to anticoagulate where needed and metabolize it to bicarbonate for a useful side effect. And the practical deliverability was addressed by standardizing solutions so that any ICU nurse could manage the therapy with a clear protocol. This innovation significantly lowered the barrier to adopting RCA in CRRT, turning it from an academic idea into a routine clinical practice at UAB and beyond.

Development Process: Team Science, Persistence, and Ownership

Translating this protocol from idea to bedside required extensive interdisciplinary collaboration and persistence. Dr. Tolwani assembled a team that included herself as the nephrologist, an ICU pharmacist (Dr. Speer), and an ICU dialysis nurse (Ms. Stofan) as co-developers . This team-based approach ensured that every facet of the protocol was workable in the real-world ICU setting. Pharmacist input was critical to formulate the citrate solution correctly and develop a reliable supply process in the hospital pharmacy. Nursing input was equally crucial – nurses would be the ones actually running CRRT 24/7, so the protocol had to be clear and feasible for them. By engaging these stakeholders from the start, Tolwani built a protocol that had frontline “buy-in.” In interviews, she emphasized how nurse-led deliverability was a focus: for example, creating a one-page primer and convenient flowcharts so that any nurse on a 3 AM shift could follow the steps confidently (paraphrased). The team conducted hands-on training sessions and iterative protocol refinements based on feedback, which fostered a sense of ownership among the staff.

Persistence and attention to detail were key to the development process. Tolwani often recounts how she made herself available “24/7” for the ICU team when the protocol was first implemented (paraphrased from personal communications). If a nurse had a concern at any hour, or if a lab value came back abnormal, she was there to troubleshoot. This constant presence built trust and allowed issues to be caught and corrected in real time – for example, fine-tuning the calcium infusion rate if ionized calcium levels drifted out of range. The protocol’s early success owed much to such vigilant monitoring and micro-adjustments, which Tolwani either handled herself or carefully taught to colleagues. Attention to detail meant rigorous protocols for monitoring electrolytes and acid-base status; the team instituted checks of serum calcium and bicarbonate at least every 6–8 hours initially, to ensure patient safety . When minor issues were identified (such as the slight alkalosis with 0.67% citrate), the team swiftly adjusted the protocol (switching to 0.5% citrate) and validated the change . This culture of continuous improvement exemplified translational research in action – moving back and forth between bedside observations and protocol refinements.

Tolwani’s leadership style in this project offers insights for successful innovation. She acted as a translational champion, taking personal responsibility for the outcome. Rather than expecting nurses or fellows to “figure it out,” she remained deeply involved in every case using the new protocol until it was running smoothly. Her presence also helped overcome resistance; ICU staff knew the nephrologist who designed the protocol was backing it fully, which gave them confidence. Moreover, by crediting and involving co-inventors from nursing and pharmacy, she created a sense of shared mission. All three inventors are named on the patent (highlighting the true interdisciplinary nature of the innovation) . This collegial environment meant that potential pitfalls (from formulation errors to user errors) were anticipated and addressed collectively. In short, the development process was characterized by meticulous attention, team-centered problem solving, and relentless persistence. These qualities were as vital to the innovation’s success as the citrate chemistry itself.

From Patent to Global Impact: Commercialization Journey

Having proven the efficacy of her citrate protocol, Dr. Tolwani moved to protect and disseminate the innovation. In November 2005, UAB’s tech transfer office filed a U.S. patent application for the citrate solution and CRRT method; it was published in 2007 and later issued as U.S. Patent 7,884,132 (February 2011)  . This patent, titled “Process for metabolic control and high solute clearance and solutions for use therein,” covered the standardized 0.5% citrate replacement fluid and associated protocol. The UAB Research Foundation (UABRF) was listed as the assignee, reflecting UAB’s ownership of the IP . Notably, the inventors on the patent are Dr. Tolwani, Dr. Speer, and Ms. Stofan – the nephrologist-pharmacist-nurse trio – underscoring how integral the team was to the innovation’s creation .

Early on, there was strong interest in this regional citrate method from the nephrology industry. UABRF entered into licensing discussions with medical device and solution companies to bring the citrate protocol to market. International licensing became a key strategy, as CRRT technology companies in Europe were quick to see the value. One challenge, however, was that the team did not file a PCT (Patent Cooperation Treaty) application within one year of the U.S. filing – an important lesson in IP strategy. Missing this window meant the invention wasn’t patented outside the United States. In practical terms, UAB could secure a U.S. patent but had limited protection overseas. Despite this, the innovation still found a path to global commercialization through partnerships. Gambro AB (a Swedish CRRT equipment manufacturer, later acquired by Baxter International) was an early adopter of Tolwani’s citrate concept. Prismocitrate 18/0 (naming it for 18 mmol/L citrate, roughly 0.5%) was developed and introduced into the international market, allowing Gambro’s Prismaflex CRRT machines to use pre-packaged citrate solution. This was essentially Tolwani’s solution scaled up. By the late 2000s and early 2010s, Prismocitrate 18 had become available in Europe, Canada, India, Australia, New Zealand and many other countries . In those regions, regional citrate anticoagulation rapidly moved from a niche idea to standard practice, largely enabled by the availability of this solution. An ICU nurse could now spike a bag of Prismocitrate and run Tolwani’s protocol without needing pharmacy compounding on-site.

Within the United States, adoption lagged due to regulatory hurdles – commercial citrate solutions for CRRT had not been FDA-approved. U.S. centers (including UAB) resorted to compounding citrate fluids in-house in their pharmacies to use the protocol . It wasn’t until the COVID-19 pandemic (when CRRT demand surged) that the FDA granted emergency use authorization for Baxter’s solution, now branded Regiocit, in 2020. Baxter Healthcare, having acquired Gambro, became the global industry partner for Tolwani’s invention. In fact, Baxter ultimately purchased the license to UAB’s 0.5% citrate solution patent . This acquisition validated the innovation’s significance – a major dialysis company invested to secure the rights and integrate the solution into its product line. The commercial success of the citrate protocol is evident: what started as a local quality improvement has become a global standard of care in CRRT. “That anticoagulant, Prismocitrate 18, is now used in continuous dialysis around the world,” UAB News reported in 2020 .

Dr. Tolwani’s institution benefited as well. Although the missed PCT filing meant UAB couldn’t patent-protect the solution abroad, licensing agreements still generated royalty income. Tolwani channeled these royalties back into research by endowing the Tolwani Innovation Fund in Nephrology to support new translational projects . In UAB’s words, “Tolwani’s invention has allowed us to perform CRRT in critically ill patients in a much safer way,” and the proceeds are now fueling further innovation (paraphrased from UAB news). The patent journey had some twists – a lesson in the importance of early international patent strategy – but ultimately the innovation reached patients worldwide. Today, Dr. Tolwani is often referred to by colleagues as UAB’s “Citrate Queen” for her pioneering work , and she holds an endowed professorship in Nephrology. The commercialization story, from a 2007 patent to global adoption through Prismocitrate/Regiocit, exemplifies how a university innovation can scale up and transform clinical practice globally.

Lessons Learned for Academic Innovators and Institutions

Dr. Tolwani’s citrate anticoagulation project offers several important lessons for clinical and translational researchers:

• The Power of a Translational Champion: Breakthrough ideas need a champion to drive them from bench to bedside. Tolwani’s persistent 24/7 leadership was crucial – her hands-on approach and unwavering commitment ensured the protocol succeeded in practice. A dedicated individual (or team) who “owns” the project can navigate obstacles, inspire collaborators, and maintain momentum.

• Interdisciplinary, Team-Centered Innovation: Complex clinical problems demand a team solution. Engaging end-users and experts across disciplines (nursing, pharmacy, etc.) from day one will improve the design and adoption of an innovation. Tolwani’s team included a nurse and pharmacist as co-inventors , illustrating how inclusive collaboration yields a product that is practical and readily adopted by the entire care team. For academic centers, fostering multidisciplinary teams and valuing all contributors (not just MDs or PhDs) is key to translational success.

• Early Intellectual Property (IP) Planning: Navigating patents and licensing is an integral part of translating a hospital innovation to broad use. This case underscores the importance of early and proactive IP strategy – had UAB pursued international patents (PCT) timely, they might have had even greater control over global commercialization. Academic innovators should work closely with their tech transfer offices to secure patent protections in major markets before presenting or publishing their ideas. That said, even if IP hurdles arise, creative licensing or partnership deals (as UAB did with industry) can still bring an innovation to the world.

• Persistence and Attention to Detail in Execution: The “last mile” of innovation – implementation in the real clinical environment – often determines success or failure. This requires champions to be detail-oriented and persistent. Tolwani’s meticulous monitoring and iterative refinements during the rollout prevented failures and built credibility for the new therapy. Future innovators should remain deeply involved during implementation, gather data, and refine their protocols. It’s a marathon, not a sprint, and success may depend on who is willing to troubleshoot the process on a weekend or overnight shift.

• Institutional Support and Recognition: Lastly, institutions benefit enormously from successful translational innovations and should actively support them. UAB eventually recognized Dr. Tolwani’s work with an endowed chair and public acknowledgment (even playfully nicknaming her the “CRRT Citrate Queen”) . The establishment of an innovation fund from her royalties is a great example of reinvestment in a culture of innovation . Academic centers should create incentives and provide resources for clinician-innovators – from protected time to seed funding and patent support – as these efforts can yield both improved patient care and institutional prestige. Recognizing and rewarding the teams behind such breakthroughs (not just the individual) also reinforces the collaborative spirit needed for translational research.

In conclusion, Dr. Ashita Tolwani’s citrate anticoagulation protocol for CRRT stands as a model case of translating an idea into a globally adopted therapy. It addressed a pressing clinical problem with a creative solution, was implemented through exemplary teamwork and perseverance, and navigated the path to patenting and commercialization despite hurdles. The outcome is improved safety for countless patients requiring CRRT around the world. This case study not only highlights a specific innovation in nephrology but also provides a roadmap for how academic clinicians can successfully bridge the “bench-to-bedside” gap to improve patient outcomes.

References

1. Davenport, A., & Tolwani, A. (2009). Citrate anticoagulation for continuous renal replacement therapy (CRRT) in patients with acute kidney injury admitted to the intensive care unit. NDT Plus, 2(6), 439–447.

2. Legrand, M., & Tolwani, A. (2021). Anticoagulation strategies in continuous renal replacement therapy. Seminars in Dialysis, 34(6), 416–422. doi:10.1111/sdi.12959

3. Tolwani, A. J., Prendergast, M. B., Speer, R. R., Stofan, B. S., & Wille, K. M. (2006). A practical citrate anticoagulation continuous venovenous hemodiafiltration protocol for metabolic control and high solute clearance. Clinical Journal of the American Society of Nephrology, 1(1), 79–87. doi:10.2215/CJN.00040505

4. Tolwani, A. J., Speer, R. R., & Stofan, B. S. (2011). Process for metabolic control and high solute clearance and solutions for use therein (U.S. Patent No. 7,884,132). Washington, DC: U.S. Patent and Trademark Office.

5. UAB Reporter. (2020, February 17). CRRT dialysis in the ICU — what patients and families want to know. University of Alabama at Birmingham News.

6. UAB Department of Medicine. (2019, January 16). Tolwani establishes Innovation Fund in Nephrology (Good News). UAB Medicine News.

7. Teixeira, J. P., Neyra, J. A., et al. (2023). Proceedings of the 2022 UAB CRRT Academy… Blood Purification, 52(1), 1–17. (Conflict of Interest disclosure notes Dr. Tolwani’s patent licensed to Baxter)