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kidney failure

An ‘Off-the-Shelf’ Replacement for Damaged Blood Vessels?

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human acellular vessel
Credit: Humacyte, Inc., Durham, NC

The object in the image above might look like an ordinary plastic tube. But this tube is neither plastic nor ordinary. It’s a bioengineered replacement human blood vessel that could one day benefit people who receive kidney dialysis or undergo coronary bypass surgery.

It’s called a human acellular vessel (HAV), and an NIH-funded team, led by Heather Prichard, Humacyte Inc., Durham, NC, grows these acellular vessels. They can run up to about 16-inches long with a diameter of 0.2 inches, which is well within the range of a human blood vessel.

Prichard and team start with a lightweight and biodegradable polymer mesh. They then seed the mesh scaffold with cells taken from human donor tissue within a 3D bioreactor system in the lab. The system is specially designed to provide nutrients and mechanical pulsations similar to those present in an intact human circulatory system.

After incubating the growing vessels for eight weeks, the researchers remove all the living cells, leaving behind mostly human collagen, a fibrous protein and major structural component of a blood vessel wall. It forms a non-living, replacement vessel that retains the physical and mechanical integrity of a human blood vessel. But, because these HAVs don’t have cells, they potentially can be surgically implanted into any human patient without risk of an immune reaction.

As reported recently in Science Translational Medicine, the best part is what happens after an HAV is implanted into the body [1]. The patient’s own cells infiltrate the HAVs. Over the course of many weeks, these cells produce multiple layers of living tissue to transform the acellular HAV into a functional, living blood vessel.

So far, HAVs have been tested in more than 240 people with end-stage kidney failure. The HAVs were implanted into the upper arms of participants and remained there from 16 to 200 weeks while these patients underwent dialysis three times per week to filter waste products from their blood. The early results indicate these bioengineered blood vessels were safe and fully functional. More research, though, will be needed to ensure that’s indeed the case.

For people who receive kidney dialysis, doctors now typically access the vasculature by linking an artery to a vein under the skin of the arm, making an “AV fistula.” But doctors can also use the HAV tube to make the needed connection.

What’s potentially game changing about HAVs is they offer the same “off-the-shelf” ease of a plastic tube but with the advantages of living tissue. Those advantages include the ability to fight infection and self-heal from the inevitable injury that comes with repeated needle pokes.

Though most of the work to date has focused on people undergoing kidney dialysis, an ongoing clinical trial is testing the potential of HAVs to improve blood flow when surgically implanted into the legs of patients with peripheral arterial disease [3]. Prichard also sees potential for HAVs in heart surgery. For example, HAVs might be useful during coronary bypass surgery to repair a narrowed or blocked blood vessel. They could also be used to replace blood vessels damaged or missing due to congenital defects or traumatic injuries. Not bad for an object that looks like an ordinary plastic tube.

References:

[1] Bioengineered human acellular vessels recellularize and evolve into living blood vessels after human implantation. Kirkton RD, Santiago-Maysonet M, Lawson JH, Tente WE, Dahl SLM, Niklason LE, Prichard HL. Sci Transl Med. 2019 Mar 27;11(485).

[2] Kidney Disease Statistics for the United States. National Institute of Diabetes and Digestive and Kidney Diseases/NIH

[3] Humacyte’s HAV for Femoro-Popliteal Bypass in Patients With PAD. Clinicaltrials.gov

Links:

Safety and Efficacy of a Vascular Prosthesis for Hemodialysis Access in Patients With End-Stage Renal Disease (ClinicalTrials.Gov)

Hemodialysis (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Tissue Engineering and Regenerative Medicine (National Institute of Biomedical Imaging and Bioengineering/NIH)

Humacyte (Durham, NC)

NIH Support: National Heart, Lung, and Blood Institute


Pursuing Precision Medicine for Chronic Kidney Disease

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Section of glomerular filters

Caption: Scanning electron micrograph showing a part of one of the kidney’s glomerular filters, which are damaged in people with chronic kidney disease (CKD). The cells with the lacy cytoplasmic extensions are called podocytes.
Credit: Kretzler Lab, University of Michigan Health System, Ann Arbor

Every day, our kidneys filter more than 30 gallons of blood to allow excretion of molecules that can harm us if they build up as waste. But, for more than 20 million Americans and a growing number of people around the world, this important function is compromised by chronic kidney disease (CKD) [1]. Some CKD patients are at high risk of progressing to actual kidney failure, treatable only by dialysis or kidney transplants, while others remain generally healthy with stable kidney function for many years with minimal treatment.

The dilemma is that, even when CKD is diagnosed early, there’s been no good way to predict which individuals are at high risk for rapid progression. Those individuals would potentially benefit from more intensive measures to slow or prevent kidney failure, such as drug regimens that tightly control blood pressure and/or blood glucose. So, I’m pleased to report that NIH-funded researchers have made some progress toward developing more precise strategies for identifying individuals at high risk for kidney failure. In recent findings published in Science Translational Medicine [2], an international research team has identified a protein, easily detectable in urine, which appears to serve as an early warning sign of CKD progression.

A wide range of conditions, from diabetes to hypertension to the autoimmune disease lupus, can contribute to the gradual loss of kidney function seen in people with CKD. But research suggests that once kidney damage reaches a critical threshold, it veers off to follow a common downhill course, driven by shared cell signaling pathways and almost independent of the conditions causing it. If there was an easy, reliable way to determine when a CKD patient’s kidneys are approaching this threshold, it could open the door to better strategies for protecting them from kidney failure.

With this need in mind, a team, led by Matthias Kretzler and Wenjun Ju of the University of Michigan, began analyzing gene activity in kidney biopsy samples donated by 164 CKD patients and stored in the European Renal cDNA Bank. Specifically, the researchers looked for patterns of gene activity that corresponded with the patients’ estimated glomerular filtration rates, an indicator of renal function frequently calculated as part of a routine blood workup. Their first pass produced a list of 72 genes that displayed varying levels of activity that corresponded to differences in the patients’ estimated glomerular filtration rates. Importantly, the activity of many of those genes is also increased in cell signaling pathways thought to drive CKD progression.

Further study in two more groups of CKD patients, one from the United States and another from Europe, whittled the list down to three genes that best predicted kidney function. The researchers then zeroed in on the gene that codes for epidermal growth factor (EGF), a protein that, within the kidney, seems to be produced specifically in tubules, which are key components of the waste filtration system. Because EGF appears to enhance tubular repair after injury, researchers had a hunch that it might serve as a positive biomarker of tubular function that could be combined with existing tests of glomerular filtration to detect progression of CKD at an earlier stage.

In groups of CKD patients from the United States and China, the researchers went on to find that the amount of EGF in the urine provides an accurate measure of the protein’s activity in the kidney, making it a promising candidate for a simple urine test. In fact, CKD patients with low levels of EGF in their urine were four times more likely than those with higher EGF levels to have their kidney function worsen within a few years.

These lines of evidence suggest that, if these findings are replicated in additional studies, it may be possible to develop a simple EGF urine test to help identify which individuals with CKD would benefit the most from aggressive disease management and clinical follow-up. Researchers also plan to explore the possibility that such a urine test might prove useful in the early diagnosis of CKD, before there are any other indications of kidney disease. These are very promising new findings, but much remains to be done before we can think of applying these results as standard of care in the clinic. For example, the EGF work needs to be replicated in larger groups of CKD patients, as well as CKD patients with diabetes.

Beyond their implications for CKD, these results demonstrate the power of identifying new biologically important indicators directly from patients and then testing them in large, diverse cohorts of people. I look forward to the day when these sorts of studies will become possible on an even larger scale through our U.S. Precision Medicine Initiative Cohort.

References:

[1] National Chronic Kidney Disease Fact Sheet, 2014. Centers for Disease Control and Prevention.

[2] Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker. Ju W, Nair V, Smith S, Zhu L, Shedden K, Song PX, Mariani LH, Eichinger FH, Berthier CC, Randolph A, Lai JY, Zhou Y, Hawkins JJ, Bitzer M, Sampson MG, Thier M, Solier C, Duran-Pacheco GC, Duchateau-Nguyen G, Essioux L, Schott B, Formentini I, Magnone MC, Bobadilla M, Cohen CD, Bagnasco SM, Barisoni L, Lv J, Zhang H, Wang HY, Brosius FC, Gadegbeku CA, Kretzler M; ERCB, C-PROBE, NEPTUNE, and PKU-IgAN Consortium. Sci Transl Med. 2015 Dec 2;7(316):316ra193.

Links:

Chronic Kidney Disease: What Does it Mean to Me? (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

Personalized Molecular Nephrology Research Laboratory (University of Michigan)

C-Probe (University of Michigan)

Precision Medicine Initiative Cohort Program (NIH)

NIH Support: National Center for Advancing Translational Sciences; National Institute of Diabetes and Digestive and Kidney Diseases


Metabolomics: Taking Aim at Diabetic Kidney Failure

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Patients with red tubes attached to their arms

iStock
Caption: Dialysis is often used to treat kidney failure related to diabetes.

My own research laboratory has worked on the genetics of diabetes for two decades. One of my colleagues from those early days, Andrzej Krolewski, a physician-scientist at the Joslin Diabetes Center in Boston, wondered why about one-third of people with type 2 diabetes eventually develop kidney damage that progresses to end-stage renal disease (ESRD), but others don’t. A stealthy condition that can take years for symptoms to appear, ESRD occurs when the kidneys fail, allowing toxic wastes to build up. The only treatments available are dialysis or kidney transplants.