Predicting progression in acute kidney injury

Last month the final study from my time at NIH was published. This study explored a promising, and relatively new, biomarker for acute kidney injury during critical illness. Although the biomarker had been previously tested in humans we were able to develop a potential refinement in a preclinical model.

During critical illness, such as sepsis, organ failure is a major complication increasing the risk of death. For the kidneys, treatment is limited to more focused management. This means avoiding further harm and keeping the patient alive long enough for kidney function to return.

The sooner kidney injury is detected the better the likely outcome but this can be surprisingly difficult. Some significantly improved options have been developed but further, even better, options are still desired. A new approach is giving the kidney something to do and measuring how well it performs. This idea is similar to the treadmill stress test commonly used to detect cardiovascular disease such as angina.

The test that was developed gave a dose of a drug called furosemide that is actively excreted by the kidneys and stimulates urine production. If the kidneys are healthy, the furosemide will be excreted and the amount of urine produced will increase. In a human clinical study this approach performed very well and there have been several subsequent studies in different settings.

Urine volume is altered by a variety of factors and we decided to investigate whether further improvements in performance would be possible by measuring furosemide excretion directly. When used in ideal conditions results were comparable. However, when we gave a drug called vasopressin that is commonly used to manage blood pressure during critical illness measuring urine volume gave erroneous results while furosemide excretion remained reliable.

The study is published in Critical Care Explorations and is freely available.

Exploring the onset of acute kidney injury during sepsis

In an earlier post I discussed the damage sepsis can do. It has been a focus of many of the projects I have been involved with for the past few years even though the group I am with is tasked with studying kidney disease. We are interested in sepsis because it is a major cause of acute kidney injury.

We do not yet know all the details of this link. Knowing exactly when kidney function falls after sepsis and what triggers the fall could be very important. It would help in developing clinical procedures and therapies to manage patients with sepsis at risk of acute kidney injury.

I recently published a study exploring one potential cause of falling kidney function during sepsis. The kidney filters the blood and removes excess fluid, solutes, and toxins from the body. The blood passes through the glomerulus where fluid can leak out. The volume at this stage is very large and includes many good things the body wants to keep. This fluid then passes through other specialized structures including the tubules where most of the fluid and useful solutes are re-absorbed. To prevent the body from losing too much fluid if the tubules are not working there is a feedback loop that stops the glomeruli producing filtrate.

Using a genetic model I tested whether this feedback loop is activated during sepsis. The results have just been published in the American Journal of Physiology. Renal Physiology.

Technique and review articles on exosomes

I've studied exosomes since the Summer of 2007 when I did my MSc dissertation project and then PhD in the laboratory of James Dear. When it came time to move on I was fortunate in finding my current position where I could explore new areas without moving away entirely from the exosome field where I had so much experience.

An opportunity to revisit the exosomal field came at the beginning of 2016 when we were invited to write three separate book chapters and review articles on exosomes. The third manuscript, a chapter in the book "Drug Safety Evaluation", has just been published online.

Inevitably the manuscripts have some overlap but they each focus on different aspects of exosomes and their study. The highlight was having a figure from our article in the journal of cellular physiology on the front cover of the issue.

The three manuscripts are:

Urine Exosome Isolation and Characterization is focused on the methods we use to collect, process, and characterize exosomes.

Urine Exosomes: An Emerging Trove of Biomarkers is a review of the potential and challenges in bringing exosome based biomarkers into clinical use.

Quantification of Exosomes is a review of the options available for determining the concentration of exosomes.

Regulation of vesicle uptake

A lipid bilayer, called the plasma membrane, surrounds every cell. This protects the cell from the environment and keeps the insides in. Keeping material contained is important for many aspects of biology. Lipid bilayers form organelles and vesicles within the cell to contain specialized components. For example, powerful enzymes recycle old material in the cell. If not contained these enzymes would wreak havoc. To prevent this lysosomes contain the enzymes, protecting the cellular contents. Material from all over the cell can get added to lysosomes.

Vesicles move material from one place to another. Endosomes move material from the plasma membrane. Endosomes either fuze with lysosomes or recycle back to the plasma membrane. The lipid bilayer of an endosome will join with the plasma membrane. The contents of the endosome exit the cell. The endosome can contain even smaller vesicles. Outside the cell we call these vesicles exosomes.

During my PhD I discovered that exosomes can transfer proteins between kidney cells. Wilna Oosthuyzen continued this work by asking what regulates this process. She discovered that vasopressin regulates exosome uptake in collecting duct cells of the kidney.

It is very gratifying when a study builds on work I published earlier, and particularly when executed so well. I was very pleased to be able to contribute.

Inflammatory responses to sepsis

In an earlier post (TLR4) I discussed the TLR4 receptor. This receptor detects microbes and starts an inflammatory response. TLR4 is not the only receptor that detects microbes. There are many receptors the immune system uses. This redundancy prevents microbes going undetected and matches the response to the microbe. At least, when everything works. An excessive response can cause sepsis. In sepsis the response is so strong that it damages tissues and can even cause organ failure.

I have recently collaborated with Oliver Voss and John Coligan from the National Institute of Allergy and Infectious Diseases. They were studying CD300b. This is another receptor that binds lipopolysaccharides (LPS) like TLR4. CD300b then binds to TLR4 and enhances its signaling. This enhanced signaling can then cause more tissue damage, leading to sepsis.

Inhibiting TLR4 does not work well for treating sepsis in humans. This might be because some TLR4 signaling helps combat infecting microbes. Inhibiting CD300b might strike a healthy balance between continuing to fight the infection and the excessive signaling causing tissue injury.