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Kidney functions and malfunctions

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Osmoregulation

 

Here’s a fancy topic of the newer spec… I’ve never done the kidney so I spent my post-A levels life in total kidney ignorance and utter lack of knowledge of my urination habits and their complexity, oh what a fool I have been. You on the other hand are going to have the damn honour of actually having a clue about how the brain and the kidneys freshen our blood up all the time. Oh ye enlightened children, rise.

 

 

Osmoregulation refers to the control of water potential of the blood. The blood is complicated, it has all these ions and proteins and stuff. Cells use various things up all the time and some more often than others at different times, night, day, sweat, tears, etc.

 

Molecules undergo deamination in the liver. This means they have an amino group removed. Since these amino group form ammonia which is toxic, it must be converted to safe urea in the blood before being excreted in urine by the kidneys. This is accomplished through the reaction with carbon dioxide.

 

 

There are systems in place that keep the blood at the right composition and pressure. The hypothalamus and posterior pituitary in the brain release a hormone into the blood that reaches the kidney and enables its cells to take up more water, to prevent it being wasted in urine as the case may be. This is detected by osmoreceptors.

 

The hormone is known as vasopressin or antidiuretic hormone (ADH), has a very short half life of 16-24 minutes as you can imagine since it regulates fast-changing things like water retention and blood pressure. It acts in the negative feedback loop that maintains optimal plasma concentration.

 

More specifically, the hypothalamus synthesises it while the posterior pituitary which is actually an extension of the hypothalamus, stores it for release into the blood.

 

 

ADH stimulates water retention by the kidney by:

 

1. Increasing water permeability in a part of the kidney cell which results in retaining more water and excreting more concentrated urine

2. Increasing urea permeability by another part of the kidney cell which results in its concentration in the urine

3. Increasing sodium absorption across the section of the kidney cell which circulates the solution, resulting in reabsorption of water

 

This uses the principles of osmosis where water moves from a higher water potential (less concentrated solution) to a lower water potential (more concentrated solution). Here urea is the solute and water is the solvent. Guess the solution! …pee.

 

Ok let’s look at the actual kidney cell and all this mystery of the different “parts” that do different things.

 

The nephron

The cell in the kidney that executes all this action is the nephron. It looks a bit weird and has all these tubes hanging off it. A kidney has about a million of these bad boys.

 

The path that the fluid takes via the nephron and to becoming urine is threefold: filtration, reabsorption and secretion. This means that there is a middle section that allows for reabsorption into the bloodstream before releasing the contents into urine.

 

 

Oooh almost got poked by that loop of Henle… keep to yourself loop.

 

Let’s start at the top with the glomerulus. It’s a scrunched up bunch of capillaries that allow the high pressure needed to filter the blood forwards. The fluid passes from the capillaries into the capsule that surrounds them, Bowman’s capsule.

 

 

Oooh creepy. This is where the subsequent glomelural filtrate is formed. Still similar to blood plasma, but minus all those proteins and large molecules. Capillaries consist of a squamous endothelium (flat, single-celled layer). The wall of Bowman’s capsule contains podocytes (spider-like cells that prevent proteins from passing though).

 

 

Next, water and glucose are reabsorbed by the proximal convoluted tubule (in yellow)… At least it’s honest about being convoluted. Unlike the distal convoluted tubule, it doesn’t have many mitochondria. The distal convoluted tubule needs many mitochondria to generate ATP for active transport of ions such as sodium ions back from the filtrate. As the useful minerals get absorbed back into circulation, waste materials such as urea accumulate in the fluid (urea is produced in the liver from excess amino acids by joining two ammonia molecules with one carbon dioxide molecule in what is termed the ornithine cycle).

 

The distal and proximal convoluted tubules are made of cuboidal epithelium (single-celled layer of cuboidal cells with large, centrally-located nuclei). The proximal tubule cells contain a high concentration of mitochondria, villi and basal invaginations.

 

For the water to be reabsorbed, a countercurrent exchange system needs to exist. This is provided by the loop of Henle which has a downwards part and an upwards part. The upwards part is impermeable to water, enabling the countercurrent exchange and the pumping out of the sodium ions.

 

 

Its job is to maintain a gradient of sodium ions to enable the water potential gradient underpinning water movement and reabsorption. This is carried away in the distal tubule and collecting ducts. The water and waste is then excreted via urine.

 

 

Microscope slides of the kidney and nephron reveal these structures. Under scanning electron microscopy (right), the glomeruli look particularly striking.

 

Urine analysis practicals

“Mock” urine can be used to test the solution for various biologically relevant compounds such as protein composition. The analysis begins with a simple colour and smell assessment, as well as how clear or opaque it appears.

 

 

Protein concentration is significant, as a failure in kidney function can result in it leaking into urine. The solution can be prepared by adding egg whites to the blank mock urine solution. The mock urine can be heated up for several minutes. If it becomes cloudier, it suggests there is protein present.

 

Glucose can also be tested in urine. Glucose can be added to the mock urine prior to testing. Benedict’s reagent is used in this case, which turns brick red when positive for (reducing) sugars. You’ll remember Benedict’s test from the early days learning about carbohydrates!

 

Endocrine functions of the kidney

The kidney executes various homeostatic functions in the body via secretion of erythropoietin and renin.

 

 

Erythropoitein (EPO) is a protein that regulates red blood cell (RBC) production from bone marrow. It has a background level to make up for the turnover rate of RBCs (erythrocytes) every few months, and can increase in the event of hypoxia experienced in tissues. Hypoxia is a low level of oxygen, and since red blood cells contain the haemoglobin that binds and carries oxygen around the body, it’s no surprise that a reaction to that might be to produce more RBCs!

 

 

Renin is another protein that takes part in the homeostasis of arterial blood pressure. It is one side of the renin – angiotensin aldosterone system (RAAS) which regulates the volume of fluid outside cells and the constriction of blood vessels.

 

Kidney disease

 

Kidney disease, whether acute or chronic, is usually a symptom of underlying causes including high blood pressure and diabetes. One of the endpoints of this disease is kidney failure where its function of clearing waste products from blood no longer takes place. The symptoms of this include fatigue, swelling, nausea, diarrhoea, less or more frequent urination, bone damage, muscle cramping, irregular heart beat and others, depending on severity and other factors.

 

The mechanisms of development of these symptoms are high levels of urea in the blood (nausea, weight loss, bloody urine), build-up of phosphates in the blood (itching, bone damage, muscle cramps), buildup of potassium in the blood (arrhythmia, paralysis), and failure to remove excess fluids (swelling, shortage of breath).

 

 

Alongside this, the effects of renin and EPO changes can affect health. Lack of adequate EPO secretion can cause anaemia while failure of the RAAS can lead to a lack of blood pressure homeostasis.

 

Diagnosis can be accomplished via urine and blood tests, such as blood urea nitrogen (BUN) and creatinine. Other tests include scans and biopsies. Commonly, urine is tested for blood and protein presence. If creatinine is present, is indicates a failure in kidney filtering. Normally, creatinine as with other protein should be kept out of urine.

 

BUN is a measure of the waste products in blood. Of course, kidney function should remove this.

 

Addressing the underlying issues priming kidney disease, such as lifestyle factors like diet can revert kidney disease in its incipient stage. Once kidney function has ceased, kidney failure can be treated with dialysis or a kidney transplant.

 

Dialysis comes in two flavours: hemodialysis and peritoneal dialysis.

 

 

Hemodialysis requires a machine and is usually done out of home, a few times a week. The machine cleans the blood which is drawn out of the patient and then returned back through a tube connected between an artery and a vein. Hemodialysis requires a commitment to trips out at specific intervals to undergo dialysis, but is advantageous due to no participation required on the part of the patient during the procedure.

 

Peritoneal dialysis involves using the abdominal cavity as the site of filtering. The abdominal cavity has a membrane called the peritoneal membrane which acts as a filter between the fluid in the abdomen (around the intestines) and blood circulation. A tube is placed through the membrane, and a special fluid is delivered into the cavity by the patient at home. This is then collected back after around 30 minutes in a waste bag, and repeated a few time daily. Alternatively, it can be done at night on a special machine called a cycler which switches the fluid to renew it several times automatically while the patient sleeps.

 

This method requires extreme caution keeping the tube insertion site in the abdomen clean as to avoid infection. Both methods require a strict diet, water intake and certain vitamins, and both methods might not be available to all patients, depending on their specific health situation.

 

The membranes used in dialysis are semipermeable and allow the filtering of waste products and salts by diffusion across certain concentration gradients. This ensures that some contents like sugars and proteins remain the blood, while excess salts and urea are removed, simulating kidney function as closely as possible.

 

 

Kidney transplantation involves using a dead or live donor’s kidney to rescue kidney function of a patient on dialysis, or preemptively before they require dialysis. It is a 3-hour operation that attaches the new kidney to the patient’s blood supply, without removing the old kidneys (their removal has been shown to increase surgery outcome problems). Kidney transplants successfully increase lifespan, with better results seen the sooner it is performed relative to time on dialysis.

 

Donors are relatives, friends, altruistic strangers or sellers on the kidney market which is legal and supported in some parts of the world, such as Iran. Different locations have different approaches to kidney donation, with some prohibiting payment, and others openly encouraging donation through financial incentives. Successful donation chains have been established in some countries. They work by passing on incompatible kidneys from donors aimed at their relatives, onto strangers who are compatible with their kidney. In exchange, they get a compatible kidney from another stranger, and so on and so forth, creating a donation chain that addresses compatibility issues while encouraging kidney donation and extending the available organ pool.

 

Patients reach healthy kidney function following the transplant within a few days to weeks, and must adhere to a strict immunosuppressant drugs course indefinitely to maximise the success of their transplant.

 

Advanced tissue technologies

As seen previously, stem cells can be used to construct tissues of a specific nature, such as kidney tissue. Therapeutic cloning refers to handling cells and tissues in a new environment, such as a lab, in order to create organs that may be used for transplantation. They are not part of a whole organism.

 

 

Reproductive cloning involves whole organism handling i.e. full body cloning. The prospect of this technology as used for transplantation purposes is troublesome to say the least. Experiments have taken place to grow human organs inside pig bodies, but thankfully they do not work. Only around 1 in 1,000 cells in the pig embryo were maintained as human. Aside from the glaring ethical issues of this proposition, the biological reality is that if an organ is to be human, then its environment would have to be human, and ultimately the organism as a whole. Pigs are already close to humans in that they are mammals, but the closer biochemical interactions are fine-tuned enough to be different.

 

Any successful tissue technology would have to take account of its sustainability, source, accessibility and safety. A proof-of-principle artificial or hybrid organ may be an impressive feat for the cover of Nature journal, but the reality of millions of patients in need around the globe can only be changed by affordable, ethically-sourced and developed treatments.

 

Limitations of using stem cells for replacing damaged tissues and organs include delivery, integration into existing tissue, compatibility with host tissue, and sourcing and production.

 

Using a patient’s own cells gets around the issue of compatibility and rejection, but raises challenges in terms of extracting the cells and growing them and differentiating them for the target tissue type. The balance of transplanted cells versus present tissue in a patient is an issue. Introducing few therapeutic cells causes little disturbance to the tissue, but may overpower the new cells and simply reprogram them into cells similar to the diseased cells. Introducing too many new cells can be traumatic to existing tissue, similar to surgery or implantation of synthetic devices or structures.

 

Questions around cell proliferation are also important if the tissue or organ seeking replacement is large or spread out, or deep into tissue. Sourcing and production (including scalability) are also limiting because growing and differentiating stem cells for certain tissue types can take a long time (many months for nerve cells), and can use up large amounts of biological materials. Some of these materials (used as food for the cells; no, they do not grow by magic) are sourced from slaughtered animals e.g. blood of calves, various other chemicals and proteins collected as a byproduct of the animal industry.

 

 

In terms of using stem cells for organ transplants, the issue is one of the extracellular matrix of organs. This is the solid, shape-giving structures made of collagen for example, that cells grow in. Hearts have had their cells (red) removed, and the scaffold used to populate with new stem cells, which spread throughout the heart successfully. There are many synthetic, bio-compatible materials being tested in combination with stem cells to make muscle, bone or skin tissues, as well as livers, kidneys, hearts, etc.

 

The issue is one of making the cells adhere to the artificial scaffold and proliferate in a way that leads to the normal development of organ function. 3D printing and other methods are used to create these scaffolds, sometimes at the same time as seeding them with stem cells.

 

Ok byeeeeee

 

 

 

 

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