Kidneys - Fundamentals

For those that don’t know I have still’s disease and end stage kidney failure, requiring a kidney transplant. Given the impact both conditions have on the quality of my life and general life expectancy, I have decided to explore solutions to both. I’m starting with kidneys first as that requires the most immediate attention right now.

To begin my search for a good solution to my kidney problem I will begin by understanding what a healthy kidney does and how it develops. I will then try to understand where my kidneys fall short and why, with the goal of identifying the specific problems I need to be focusing on.

The purpose for writing publicly about my learnings are as follows:

1. Writing clarifies my thinking, however, given my lack of background in this field, writing alone won’t be enough to actually learn. I have found that the best way to learn something completely outside of my domain is to put my “understanding” up to debate and criticism. This forces me to ensure that my understanding is as good as can be due to fear of publicly embarrassing myself.

1. I know that there will be gaps and misunderstandings in my learning, so by “opening” it up it allows others to identify these issues and correct me.

Disclaimer

To reiterate, my interest in exploring this problem is not an altruistic one, or driven by scientific curiosity. I want to be absolutely honest about my intentions and motivations, which is to give myself a high quality of life again *(with my life pre-illness being the bar) and increase my life expectancy **(with my life expectancy pre-illness being the bar). This may mean that the problems I identify as high priority, may not be seen as a general high priority problem for the majority of kidney failure issues.

How to read this

As you read through this document I highly encourage you to:

• Actively look for mistakes and inconsistencies. In the likely case that you find them please mention them, publicly if possible, as this could probably help someone else with their understanding

• Think of questions you think I ought to ask myself. In order to make fast progress towards my desired solution I need to be asking better questions, so any help here would be appreciated

• If you think there is a better way I could approach my learning and problem solving, please do reach out, again publicly would be preferred

Text written in italics are questions I have but am unable to answer at this moment.

What does the Kidney do?

• Most people are born with 2 kidneys each found on either side of spine just below rib cage

• They constantly remove waste and water from blood to make up urine

• The kidneys also removes acid from the blood, maintains balance between water and salts and minerals (including sodium, calcium, phosphorus and potassium)

• If this balance isn’t maintained it impacts nerves, muscles and other tissues. Too much sodium causes high blood pressure. Too much potassium leads to irregular heartbeat, vomiting, nausea, muscle weakness. Too little potassium could lead to low blood pressure

• Kidneys make hormones that maintain blood pressure, create red blood cells, keep your bones strong and healthy

  • Where and how does the kidney make these hormones?

• Kidneys are made up of approximately 1 million filtering units (each) called nephrons. A nephron is a two part unit made up of 1) glomerulus and 2) tubule. The glomerulus filters your blood and the tubule returns your needed substances bad to your blood such as important minerals, and removes extra waste.

  • Is there a minimum number of nephrons a kidney needs to be functional, if so what is it?

  • Is it possible to have too many nephrons, if so what is the impact?

  • Does the 3d structure of the kidney impact its function, if so?

  • Does the outside layer of the kidney serve any function, if so, what is it, and how does it do it?

  • Does the size of the kidney matter? If it does, why?

  • Does the shape of the kidney matter? If it does, why?

• The glomerulus is a cluster of tiny blood vessels with thin walls that act as a filter. This allows smaller molecules and water to pass through. Bigger things like proteins and blood cells can’t pass through.

  • What are the material properties of the glomerulus and why?

  • Does the 3d nature of the glomerulus have an impact on its function, if yes, how so?

  • What is the glomerulus dependent on to do its job?

  • What regulates the glomerulus as it does its job?

• The tubule runs alongside the glomerulus and filters the blood in there, reabsorbing nearly all the water and minerals. It removes excess acid from the blood too. The remaining fluid in the tubule is waste + water, also known as urine.

  • Why is extra water filtered out in the tubule? Why doesn’t all of the filtering happen in the glomerulus?

  • What are the material properties of the tubules and why?

  • Does the 3d nature of the tubules have an impact on its function, if yes, how so?

  • What is the tubule dependent on to do its job?

  • What regulates the tubule as it does its job?

• Blood flows into the kidney through the renal arteries, and flows out of the kidney through the renal vein.

The kidney is developed at the same time as the urinary tract system from the cloaca and mesoderm in the embryo.

• The cloaca is the only opening for the urinary tracts

• The mesoderm is a germ layer in animal embryos that gives rise to specialised tissue types. This is where you find pluripotent stem cells (stem cells that can turn into any type of adult cell, but not any embryonic cell). It is the middle layer in the germ layer (a group of cells formed during embryonic development)

  • Why does the kidney start developing at the same time as the urinary tract?

  • What is it about the mesoderm layer that creates kidneys?

Kidney development happens in 3 stages (in order):

1. Pronephros

2. Mesonephros

3. Metanephros.

Pronephros - Summary

• This is the first stage of kidney development within the embryo.

• This process starts 22 days after conception in the embryo

• You can think of this as a non-functional early version of the kidney

  • At this stage of kidney development what can this version  of the kidney do / not do? 

  • What is the primary purpose of this stage, especially since it is non functional?

  • Why does this process happen 22 days in and what triggers it to happen?

• By day 26 it grows to meet the cloaca (a hole for the urinary tract to release feaces), to become the mesonephric duct which helps the formation of the urinary bladder

  • Why does it take 4 days for this to happen?

• By day 28 the cells die

  • Which cells actually die and why?

  • What is left behind after these cells die?

  • Why does it take 2 days for these cells to die?

  • What causes these cells to die?

Mesonephros - Summary

• This is the second stage of kidney development within the embryo, which starts around day 26 as the mesonephric duct begins to develop

• Functioning mesonephric tubules develop from the intermediate mesoderm (a section within the mesoderm layer) and start to excrete urine

  • Is the embryo actually urinating or is this just a way to test the functionality of the kidney?

  • Do these tubules work the same as fully developed adult tubules?

  • What triggers the development of these tubules?

• The artery from the dorsal aorta extends to meet the mesonephric tubule to form the glomerulus

  •  Are the glomeruli the same structure and functionality as those found in adult kidneys?

  • Why does this specific artery need to connect to this tubule? Is this artery used to create glomeruli in adult kidneys?

• Most of these cells also eventually die and are not part of the nephron unit found in adult kidneys

  • If these cells die then what was the point of them being created in the first place?

  • What causes these cells to die?

  • Does the death of these cells have an impact on the biological processes that come after this step?

Metanephros - Summary

• By day 35 the ureteral bud (an epithelial tube that branches repetitively to create the renal collecting duct system, whilst also causing nephrogenesis - the development of the adult kidney) branches from the tail of the mesonephric duct into the metanephric mesenchyme

• RET/The metanephric mesenchyme contains mesenchymal cells adjacent to the tips of the ureteric bud. These cells form the nephrons.

  • What cells exactly form the nephron?

  • Are the development of the cells found in the nephron dependent on any of the cells that came before it or cells that exist in a different part of the embryo? If so, how and why?

• This process is controlled by the GDNF/c-RET/WNT-11 pathway

• The interaction of the ureteral bud and metanephric mesenchyme causes branching morphogenesis and the elongation of the ureteral bud to create the primitive nephron

  • Branching morphogenesis is what leads to the transport of waste in the kidney

• The metanephros starts to function 6-10 weeks after fertilisation, with kidney development being complete by 36 weeks

  • Do the kidneys continue growing at this point? If so, is it all the cells that evolve or just some?

  • Do any cells die at this stage, if so, which ones and why? 

My medical diagnosis

• My kidney currently operates between 3-5%

  • How do we measure the functionality of a kidney?

• My nephrons have collapsed and I have scar tissue within my kidneys

  • What caused my nephrons to collapse and does this problem still exist within my body?

  • When the nephrons collapse does that mean the cells are dormant, dead or still active?

  • What function does a collapsed nephron prevent and why? 

  • If the cells of a nephron are dormant or dead, is it possible to revive them? 

  • What function does scar tissue inhibit?

  • What actually is scar tissue and can it be easily separated from desired cells?

  • Is it possible to remove scar tissue either through surgery or in vivo?

• I am on dialysis 3 times a week

  • Why do I only do dialysis 3 times a week? What would happen if I did it daily?

• Life expectancy of someone on dialysis (no transplant) is 5-10 years 

  • What causes this short life expectancy?

• Life expectancy of someone post transplant (living donor) is approximately 20 years

  • What causes this short life expectancy?

• Life expectancy of someone post transplant (deceased donor) is approximately 12 years

  • What causes this short life expectancy?

• I will be on immunosuppressants for life, due to the transplanted organ being a foreign object in my body, which come with its own complications

My quality of life as a kidney patient

When comparing my quality of life to how it used to be pre-illness, I would score it a 3/10, with 1/10 being that life is completely unbearable at the moment. Below I have provided a breakdown of my average day, habits and restrictions.

• Wake up 5am every Tuesday, Thursday and Saturday. 7.45am arrival. I can not miss any of these appointments or I could die from too much fluid and waste build up (because I don’t pee anymore) 

• I go to a far away hospital due to my underlying condition (still’s disease)

• 8am connected to the dialysis machine for 3hr30 minutes. Restricted to the bed. No reception, but there is wifi. In a room with 3 other people so everyone has to be quiet

  • Why does the dialysis machine have to be so big?

• Get home at 2pm

• Dialysis is very draining on the body, so I usually nap for 4 hours after that. 

  • Why is dialysis so draining? Why don’t healthy kidneys have this same effect?

• Restricted to 750ml a day, anymore and I become visibly swollen (my thirst does not reduce because of kidney failure, so it’s just something I have to manage)

• Permanent plastic tube inside on my right breast which restricts me from doing a few activities such as traveling, the way I shower, what I wear etc

• Daily nausea 

  • What causes my nausea?

• No international travel whilst on dialysis and a few years post transplant

• Travel within my own country is limited whilst doing dialysis (I can only go on the days I don’t have dialysis and need to be back for the days I have dialysis, so essentially weekend travel only)

Additional Questions

• Does the size of the kidney matter? If it does, why?

• Why is extra water filtered out in the tubule? Why doesn’t all of the filtering happen in the glomerulus?

• Is the material for all parts of the kidney the same?

• Do all parts of the kidney need to be 3d?

• Do adult kidney cells continuously evolve / grow?

• Can adult kidney cells repair itself?

• Does the age of an adult kidney impact its functionality, if so how?

My goal over the next few weeks will be to gain more clarity on the above questions and begin looking into the inner workings, pros and cons of current solutions. My reason for doing this is to understand what works and why, with the hopes of being able to borrow/build on top of some of these ideas.

*My quality of life pre-illness included no nausea, no liquid or food restriction etc. I was able to do whatever I wanted, whenever I wanted. I never smoked or drank before, and don’t aspire to.

** The average life expectancy for someone in the UK is approximately 81 years old