Written by Rebecca Dewhurst @becky_dewhurst from the @SayerLab

How can urine help us understand kidney diseases?

Everyday thousands of healthy kidney cells are shed into our urine. Under the right conditions, these cells, known as urine-derived renal epithelial cells, or hURECs for short, can be collected as a liquid biopsy, and used to study a wide range of rare genetic kidney diseases without a traditional painful invasive biopsy.

isolating kidney cells from urine to study kidney diseases
Figure 1. Simplified method of isolating and culturing human urine-derived renal epithelial cells (hURECs).

What do the Kidneys do?

The kidneys are bean shaped organs found towards the back of the upper abdomen involved in the ultrafiltration of our blood. Our kidneys are vital in maintaining appropriate water levels, and produce waste products like urea which is excreted in urine.

Who is affected by kidney disease?

In the UK alone, one in ten people have Chronic Kidney Disease (CKD); this equates to around 3 million patients in total (1). There are a number of reasons for the onset of kidney disease, including poor control of blood sugar levels in diabetes, high blood pressure or inherited causes.

What diseases can we study using these cells?

In our Newcastle University Renal Genetics group, we predominantly study a group of diseases known as ciliopathies, which occur due to cilia defects. Found on the surface of almost all cells, cilia are finger-like protrusions acting like radio antennae feeding information back to the control centre of the cell, known as the nucleus. Ciliopathies can affect a number of organ systems, including the eyes, brain, liver and kidneys. Examples of ciliopathies affecting the kidneys include Joubert Syndrome, Oral-facial-digital Syndrome, Nephronophthisis and Autosomal Dominant Polycystic Kidney Disease, all of which we can study using hURECs.

Figure 2. Basic structure of a primary cilium. Cilia are finger-like protrusions which are found on the surface of almost all cells, and are involved in key cellular signalling processes. Ciliopathies can result in extra-long, short, or curly cilia. Figure adapted from (2).

How have these cells been used?

For many years, the Newcastle University Renal Genetics group we have been using hURECs to further understand how and why kidney disease develops in ciliopathies like Joubert Syndrome (3; 4) and Nephronophthisis (5). These hURECs allow us to investigate both the phenotype (characteristics that we can see) and the genotype (the genetic blueprint including genes and DNA) which are involved in renal ciliopathies, giving much desired answers to patients and their families.

Remarkably, hURECs have been used in our hands to generate 3D cell models known as organoids which can be considered as ‘kidneys in a dish’. These renal organoids, known as tubuloids (6) or nephrospheres (7), have allowed for more complex kidney disease modelling.

Figure 3. Images of human urine-derived renal epithelial cells (hURECs) from Wild Type and Joubert Syndrome urine samples. Cell nuclei are shown in blue with cilia shown in green. Image taken, with permission from  (4).

What does this mean for patients?

One of the main benefits of using hURECs is that we can gain a kidney organ specific snapshot of how the renal cilia are affected, which can sometimes be missed using other cell types like fibroblasts, which are derived from skin biopsies. Urine sample collection in order to grow hURECs is also quick, easy and most importantly pain free, meaning multiple samples can be taken.  Exciting opportunities in the development of patient-specific hUREC generated disease models highlight why urine samples, a waste product, may hold the key to developing our understanding of kidney diseases.  

References

1. Kidney Research UK. Annual Reports and Accounts. Kidney Research UK. [Online] 2020. [Cited: 26 06 2020.] https://kidneyresearchuk.org/about-us/annual-reports/.

2. Ciliopathies: an expanding disease spectrum. Waters, A M and Beales, P L. 7, 2011, Pediatric Nephrology, Vol. 26, pp. 1039-1056.

3. A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies. Srivastava, S, et al. 23, 2017, Human Molecular Genetics, Vol. 26, pp. 4657-4667.

4. Targeted exon skipping of a CEP290 mutation rescues Joubert syndrome phenotypes in vitro and in a murine model. Ramsbottom, S A, et al. 49, 2018, PNAS, Vol. 115, pp. 12489-12494.

5. Human urine-derived renal epithelial cells provide insights into kidney-specific alternate splicing variants. Molinari, E, et al. 2018, European Journal of Human Genetics, Vol. 26, pp. 1791-1796.

6. Tubuloids derived from human adult kidney and urine for personalized disease modeling. Schutgens, F, et al. 2019, Nature Biotechnology, Vol. 37, pp. 303-313.

7. Urinary nephrospheres indicate recovery from acute kidney injury in renal allograft recipients – a piolet study. Knafl, D, et al. 251, 2019, BMC Nephrology, Vol. 20.

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