Decision-making algorithm shows early promise in guiding treatment of acute kidney injury

Acute kidney injury (AKI) is a common problem in hospitals across the country. In intensive care units, the condition often occurs as a result of low blood pressure and causes decreased blood flow to the kidneys. It can have serious consequences for patients, and is frequently associated with an increased risk of death and other severe complications. For physicians, AKI can be challenging to manage, in part because the evidence about when to begin treatment — namely, dialysis and other forms of renal replacement therapy (RRT) that artificially filter the blood — are quite limited and offer conflicting perspectives.

To help bring clarity to this problem, BWH nephrologist Mallika Mendu, MD, MBA, and her colleagues developed a decision-making algorithm to guide clinicians in deciding when to initiate RRT. It captures and integrates current data around AKI, including randomized controlled trials, observational studies as well as general clinical consensus. The algorithm (also called a Standardized Clinical Assessment and Management Plan or “SCAMP”) was tested in a prospective study of 176 patients in the Medical Intensive Care Unit (MICU) at BWH.

Recognizing the limits of existing evidence around AKI, Mendu and her colleagues also provided opportunities for clinicians to deviate from the algorithm and record those deviations, allowing the team to capture that data and incorporate them into future studies. For example, for patients whose blood pH is severely low (meaning acidic), the SCAMP recommends initiating RRT. Clinicians who deviate from this plan can indicate why they chose not to begin the therapy by choosing from a list of reasons or providing their own.

Mendu and her colleagues found that providers’ adherence to the algorithm is associated with lower in-hospital patient mortality in less severe cases of AKI. No significant association was found for patients with severe disease.

“Algorithm-based care can help improve how we care for patients with complex diseases,” said Mendu, assistant medical director for Quality and Safety at BWH. “What’s exciting here is that we have some preliminary evidence of a real benefit for patients with acute kidney injury — a condition that is not only devastating for patients but also often challenging for physicians to manage.”

Mendu and her colleagues are now working to extend their initial study by expanding the number and diversity of patients to include those in other intensive care settings.

Paper cited: Mendu ML et al. “A Decision-Making Algorithm for Initiation and Discontinuation of RRT in Severe AKI.” Clin J Am Soc Nephrol. DOI: 10.2215/CJN.07170716

New method harnesses ultrasound to deliver RNA-based therapies into gut cells

Delivering drugs to the right places in the body can present some formidable challenges, especially when the cells and tissues that require treatment lie in the gastrointestinal (GI) tract — a system honed for degradation, be it food or therapeutics. The conditions within the GI tract are particularly inhospitable to so-called biologic drugs, large molecules that include proteins and nucleic acids such as DNA and RNA. Yet these biologics hold enormous promise for treating a wide range of gastrointestinal disorders.

To overcome these challenges, BWH’s Giovanni Traverso, MB, BChir, PhD, and his colleagues developed a method for delivering RNA into the cells lining the colon that relies on ultrasound (a lower frequency form than that used for imaging). Remarkably, this method, described in Jan. 13th online issue of Gastroenterology, utilizes naked RNA — RNA that is not chemically modified from its original form — to reduce or “knock down” gene activity using small interfering RNAs (siRNAs). Knocking down genes is a powerful approach not only for understanding gene function but also for treating myriad diseases.

Using their ultrasound method, the researchers successfully delivered siRNA into colonic cells in mice in vivo. In mouse models of colitis, siRNAs directed against the Tnf-alpha gene, which helps promote inflammation, significantly reduced TNF-alpha protein levels in the colon and also alleviated inflammation. This proof of principle suggests the ultrasound-based approach could hold promise as a drug delivery method in humans.

“The remarkable thing about our approach is that is eliminates the need for engineering new molecules or creating special formulations that can withstand the harsh conditions of the gastrointestinal tract,” said Traverso, a gastroenterologist and biomedical engineer in the Division of Gastroenterology. “This could really help accelerate biomedical research and early-stage target discovery.”

Now, Traverso and his colleagues are exploring ways to extend this research and potentially translate it for clinical use.

Paper cited: Schoelhammer CM et al. “Ultra-sound Mediated Delivery of RNA to Colonic Mucosa of Live Mice.” Gastroenterology DOI: 10.1053/j.gastro.2017.01.002

New molecular ‘roadblock’ helps ensure the unidirectional development of T-cells

The development of immune cells is highly choreographed to produce the right types of cells, in the proper proportions and at the appropriate times. This is especially true in the case of T-cells, which play critical roles in defending the body from infection, as well as igniting inflammatory and autoimmune conditions. Although much is known about the molecular signals that help push T-cells down different developmental paths — becoming a Treg or a TH2 cell, for example — little is known about the molecules that act as roadblocks, preventing the cells from pursing alternative routes.

A new study by first author Chuan Wu, PhD, of the Evergrande Center for Immunologic Diseases at BWH, casts light on one of these molecular roadblocks. Known as musculin, the molecule works in mice to dissuade T-cells from choosing the path that leads them to become TH2 cells. Instead, the cells become Treg cells, which help organs such as the gut and lungs maintain a balanced immune system, preventing it from the kind of hyperactivity that can lead to allergic conditions, like asthma, or inflammatory disorders, such as inflammatory bowel disease.

Musculin, a type of transcription factor, provides a kind of brake on the developmental pathway leading to TH2 cells. Wu and his colleagues discovered that it cooperates with other regulators in mice to silence the genetic program that promotes the formation of TH2 cells. Further studies revealed that musculin exerts these effects in part by regulating how accessible — or not — genes are to the molecular machinery that activates them.

“Our work offers an important new perspective on T-cell differentiation,” says Wu, who conducted the work together with senior author Vijay Kuchroo, PhD, of the Evergrande Center for Immunologic Diseases, and their colleagues. “It also suggests some potential novel therapeutic strategies for inducing immune tolerance by inhibiting TH2 cells.”

Paper cited: Wu C et al. “The transcription factor musculin promotes the unidirectional development of peripheral Treg cells by suppressing the TH2 transcriptional program.” Nature Immunology DOI: 10.1038/ni.3667