Outer Limits - Renal
Welcome to the third installment of this metabolic panel series, where we're exploring what happens when these lab values hit their limits, or beyond. Previously we've explored Cations (located here) and Anions (located here), but don't feel like you need to read these in any particular order.
These blogs are meant as a reference for you to come back to. There's a lot of information in each, so they might be better absorbed in chunks. I'm writing these as the reference I wish I had when I started learning lab values.
This week we're going to tackle the renal values on our chemistry panel! Renal physiology can be more than a little intimidating, but you're going to totally understand these labs by the time we're done! Because this renal section is a little different than the other sections, I'm going to start us off with a little refresher on the nephron, using a couple of illustrations.
A Quick Primer on Renal Physiology
I think of a nephron (the functional unit of the kidney) like cleaning out your garage by having a garage sale. You start by taking all of the boxes out of the garage, but you leave the big things in - like your cars, riding lawnmower, and beer fridge.
You open up all of the boxes from the garage, and you sort through the things you want to keep, and the things you wish to sell. Anything you want to keep goes back in the garage, and anything you wish to sell goes out into the driveway for a huge discount - guaranteed to sell! How does this apply to the nephron?
The nephron accepts all the little stuff. All those little boxes are like ions and waste molecules. But, large stuff like cells stays in the blood, as the cars stayed in the garage.
Then, through a sorting process (like sorting through the boxes) the nephron decides what it wants to sell and what the blood should keep. Anything that the blood should keep gets reabsorbed (like putting something back into the garage where it came from). Anything that the body should get rid of stays in the nephron (like keeping it out in the driveway for the sale).
Through this process of filtration, we can measure a few things to determine how well the renal system is working.
How fast is this filtration process occurring? (GFR)
Is it excreting Creatinine? (Creat)
Is it excreting/reabsorbing Blood Urea Nitrogen? (BUN)
Glomerular filtration rate (GFR) makes sense because this tells us at what rate the filtration is actually flowing through the nephron. Any reduction in the rate would clearly have a negative impact on the efficiency of filtering our blood. But why do we specifically use blood urea nitrogen (BUN) and creatinine as our other two markers for renal health? Consider another illustration.
Imagine you have three kids, and they all have chores to do before you get home from work.
Tyler has to vacuum.
Brittany has to dust.
Brian has to take out the trash.
When you get home, the house is vacuumed, there isn’t a speck of dust, but the garbage is overflowing. Which kid is in trouble? Brian! This is essentially how we look at BUN and Creatinine - they’re the trash, and only kidneys take them out. So, when they elevate, it's pretty likely to be the renal system that is having trouble.
Now that we've had a little refresher on how the lab values relate to our kidney function, let's focus on a few values that we'll commonly see. We'll tackle the GFR first because the Creat and BUN are going to make more sense after that.
Outer Limits: GFR
I’m going to take us through what a GFR is, and then bring us down to a simplified version of it called eGFR (e = estimated).
The renal system works as a filter, and just like any filter, you have to have flow going through it in order to get any benefit. We estimate or measure that filtration rate through the glomerulus to figure out how well the kidneys are working. This average filtration rate is the product of at least a couple of things (1,2,3):
The average pressure exerted on the glomerulus
The permeability and surface area of the glomerulus in contact with Bowman’s capsule.
Let’s first talk about the pressure that’s causing flow through the glomerulus.
Just like any traditional filter, the more pressure that is exerted on the semi-permeable membrane, the faster things will filter. The most obvious source of this pressure is our systemic blood pressure. We’ve heard this before - a certain amount of pressure is needed to not only maintain perfusion to the kidneys themselves but also for the kidneys to continue filtering out waste products and make urine. However, theres’ a little more that goes into the pressures exerted on this filter than just blood pressure.
We also have colloid oncotic pressure (COP) wanting to hold everything inside of the blood (causing it to stay in the blood and not go through filtration). Colloid pressure is a little different than our serum osmolality. If you remember from previous blogs in this series, the serum osmolality is made up of substances like sodium, BUN, and glucose. However, all of those things get passed pretty freely into filtration because of their small size. Colloid pressure is caused by bigger things in the blood - like plasma proteins such as albumin (albumin makes up about 80% of the colloid oncotic pressure). So, while blood pressure is wanting to send things through filtration, the albumin is fighting in the other direction to keep things inside of our blood. Then, there’s just one more thing as well, which is our capsular hydrostatic pressure. This pressure is pretty easy to understand. The kidneys can only accept so much flow, so if they get overloaded, they overflow and cause a lot of back-pressure. This is like a shower drain that doesn’t drain as fast as the water coming from the shower - the water starts to build up until you’re standing in it (anyone who has shared a bathroom with someone who has long hair knows what I’m talking about). Averaging all of these pressures gives us our net filtration rate (NFP)(1,2,3).
Glomerulus filtration pressure - (Capsular hydrostatic pressure + Colloid osmotic pressure) = Net filtration pressure.
or you can abbreviate that… GFP - (CHP + COP) = NFP.
Can you picture how altering any one of those variables would affect the NFP? If the blood pressure goes down, If the colloid oncotic pressure goes up, if the capsular pressure goes up, these will all equal a situation where the filtration rate will go down. That seems like almost everything… but there are just a couple more. What are they?
We can go back to our example of the filter. Which of the following will have the higher flow through it?
A. A filter that is thick and narrow.
B. A filter that is thin and wide.
Clearly, B is the correct answer. Surface area and thickness are factors that will affect the GFR. If the surface area is small, and the membrane in which substances have to pass through is thick, this will lead to a reduction inflow. The surface and the thickness of the membrane make up something called our filtration coefficient (KF). Now, we have all of the things necessary for our GFR (1,2,3).
GFR = NFP x KF.
That’s all it is (lol). Clearly, renal physiology is pretty complex, and there is a lot of anatomy and pressures that I could have included in this section to really increase our understanding, but this is enough information for us to understand what our GFR actually is. Now that we have an understanding of what goes into a normal GFR, what about the eGFR?
Estimated GFR takes your creatinine and then includes some variables to estimate how well your kidneys should be working, given your age, sex, height, muscle mass, etc... Essentially, the less creatinine you filter out the lower your eGFR is going to be, and vice versa.
High serum creatinine = Low eGFR
Low or normal serum creatinine = High or normal eGFR
Seems a lot more simple than the regular one, right? Even though the eGFR only takes into account the serum creatinine with adjustments for some variables, it’s still affected by all the other stuff we mentioned. All of that blood pressure, oncotic pressure, capsular pressure, membrane thickness, and surface area - that stuff will impact your creatinine as well (which is why this estimation can be made) (4).
One last thing about GFR before we wrap up. A rather odd thing you'll see on a lab report is two eGFR numbers - one for African American patients, and one for everyone else. Wait, what? It's complicated, and there's some history involved. It's clearly controversial since biologically there should not be any difference in kidney function based on skin color. The national kidney foundation sounds like they're changing their approach to this. You can read their statement HERE.
Outer Limits: Creatinine
Creatinine sounds a lot like "Creatine" - and that's because creatinine comes from the breakdown of creatine in our muscles and protein from our diet. It's normal to have creatinine in our blood because muscle is always being used, damaged, and replaced. For this reason, a higher creatinine is common in someone who has a large amount of muscle mass. This doesn't just mean bodybuilders - younger people, in general, have more muscle mass. It's said that we lose anywhere from 3-8% of our lean muscle mass per decade after the age of 30, and then that rate increases again after the age of 60 (5,6). (All the more reason to do resistance training throughout your life.) Speaking of individuals who do resistance training, they will frequently supplement with Creatine Monohydrate because it increases water retention in the muscles, and will generally increase strength through more storage of phosphocreatine. Phosphocreatine, through the release of phosphate via creation kinase, provides the muscles with energy (this is similar to how cells release energy from converting ATP to ADP from releasing a phosphate) (7). You can probably guess that the inverse is true as well - those with very low muscle mass are generally on the low side of the creatinine. Where is the renal system actually getting rid of the creatinine?
Most of the creatinine that's excreted comes from that initial filtration through the glomerulus, and then creatinine will continue to enter the nephron from the bloodstream in the proximal convoluted tubule. Because this is a waste product, the bloodstream really doesn't want to reabsorb any of it at all once the creatinine has entered the nephron.
Not only will your lab result look at creatinine, but it might also look at something called creatinine clearance (CrCl). There's a pretty simple calculator HERE that shows you what factors are involved in deciding how much creatinine you should be clearing through your kidneys. What's the difference between regular creatinine and creatinine clearance? A normal creatinine is a serum creatinine, which means that it's looking at how much creatinine that's in your blood. For our purposes, this is typically what we're measuring. Creatinine clearance is how much you're eliminating in urine over a given amount of time (24 hours). The creatinine clearance value comes out to be measured in mL/min, which sounds very familiar to our (estimated) glomerular filtration rate, right? Correct. Creatinine clearance is considered to be an estimate of GFR (an eGFR). However, the creatinine clearance is noted to overestimate our glomerular filtration rate because creatinine also enters the nephron through the proximal convoluted tubule. Thus, it's using two places to enter the urine instead of just one. This adds some creatinine after the glomerulus, which is why it overestimates the GFR (typically by 10-20%)(8).
Like I noted earlier, the reason we're looking at creatinine specifically for renal function is that without the renal system, our creatinine would rise sharply - indicating renal failure.
Outer Limits: BUN
Why the question mark after the "Hypouremia"? A high BUN is referred to as "Uremia". What's the opposite of uremia? No one seems to know. If you know, please tell me. One might say that it's the 'azo' terms, such as "hyperazotemia" and "hypoazotemia", but I would disagree. Hypo/hyperazotemia refers to any nitrogen-containing compound in the blood, even creatinine - it's not specific to blood urea nitrogen the way that the term "Uremia" is. One other thing that I'll mention is that if you pronounce this lab "BUN" like a hamburger BUN, people will ridicule you mercilessly. You have to say "BEE, YOU, EHN"... I'm not really sure why. Alright, I'm done now. Let's get back on track.
Just like we had to understand creatine to understand creatinine, we have to understand ammonia to understand blood urea nitrogen. Metabolism of proteins (from inside or outside of the body) will result in the production of ammonia. As you can probably guess, the build-up of ammonia is not a good thing. The body tries to keep ammonia levels very low at approximately 15 to 45 µ/dL - higher levels will result in neurotoxicity and other problems. How does it manage to keep the ammonia this low? The liver metabolizes ammonia into blood urea nitrogen - a less toxic waste product that can be excreted by the renal system (9).
As you can see, there is some leftover nitrogen. This nitrogen will probably combine with more hydrogen to make more ammonia, and the process of the liver making these into BUN by adding oxygen and carbon will continue. That BUN will travel to the kidneys for excretion.
Before we move further, can you see how liver failure could cause a low BUN level? If the liver will not make BUN, ammonia will likely build up because it cannot be converted. However, if ammonia was normal and BUN was high, we would then suspect renal failure was the issue.