Urinalysis as a ‘liquid biopsy of the kidney’

As nephrologists, we're obsessed with urine for a lot of different reasons. It holds a lot of answers, and in some ways we think of it as a liquid biopsy of the kidney. When we're called to evaluate a person who has a nephrology problem, not only acute kidney injury but even some electrolyte disorders, we can really look to the urine to begin our evaluation. That can help us with building our differential diagnosis and even identifying some causes as the most likely.

One of the anatomic compartments of the kidney that can be damaged is the glomerulus, and there are a few different types of glomerular injury. We separate these into either nephritic syndromes or nephrotic syndromes, and the big piece that separates the two is the magnitude or the presence of protein or albumin in the urine. The urine dipstick or the formal urinalysis can give us a very early and quick indication that there is protein, and then we can do additional urine studies to further quantify that. If that number, when we quantify it, is very high—the cutoff that we use is over 3 or 3.5 g—we're thinking about a nephrotic syndrome, while lower than that, we might think about a nephritic syndrome. If there's no protein in the urine at all, then we're thinking about nonglomerular causes of kidney injury.

There are other compartments in the kidney that we might think about. There are blood vessels that can be injured, there are tubules that can be injured, and there's the interstitial space that can be injured. We can again look to the urine to find clues that those compartments might have some problem going on. Another example of that is if there is interstitial injury, we tend to see the infiltration of inflammatory cells into that interstitial space. And how does that manifest in the urine? We can see white blood cell casts, and that might be picked up even on a dipstick as leukocyte esterase, which is an enzyme present inside of white blood cells. Without having to even get to the kidney biopsy, we might have a very early clue just from an initial urine dipstick.

Also, a few components of the urinalysis can really be helpful for a few specific diagnoses that sometimes might be ignored. The first one is specific gravity, a marker of how concentrated the urine is. The specific gravity of water is 1. A very high urine specific gravity suggests to us that the urine is very concentrated, so the urine might actually even appear dark. Even visual assessment of the urine can sometimes be helpful. When we talk about high specific gravity, we're talking about 1.3, as an example.

In the context of acute kidney injury, if the kidney has a low effective circulating volume, it's really going to try to concentrate that urine to try to conserve everything that it can for water and salt, so we would expect to see a very high specific gravity. On the flip side of that, if the urine specific gravity is very low, it tells us, in the setting of acute kidney injury, that unless the patient is on diuretics, or some other medicine that would impair urinary concentration, the kidney is injured. When the tubules are injured, they don't concentrate urine as well. When we're making a diagnosis of acute tubular necrosis, or acute tubular injury, if I see a very dilute urine specific gravity, I can really feel confident that my assessment and my evaluation have some support that the tubules are not working.

Another scenario where I use specific gravity in my clinical practice is for patients who are presenting with sodium disturbances. Hyponatremia and hypernatremia are both disorders of water imbalance for the most part. When we're evaluating these patients, a common question that we ask is, what is the urine osmolality? We're using that to try to understand the level of antidiuretic hormone (ADH) activity. If there are very, very high levels of ADH, then we expect the urine osmolality to be very high.

If I have a patient with hyponatremia, and I'm wondering is this somebody who has a low effective circulating volume, I would expect there to be an elevated specific gravity, a very concentrated urine, because of this very high activity of antidiuretic hormone. On the flip side of that, if I have a patient who has developed hyponatremia because of primary polydipsia or excessive water intake, then I would expect the urine specific gravity to be to be fairly low because the ADH should be shut off. The kidneys should be producing as dilute urine as they can.

Again, visual inspection is another way to do this. If I'm evaluating a patient for the first time and they have a Foley catheter or happen to have a urine sample by the bedside, I can tell by the color of the urine, if it's clear or on the darker yellow/amber spectrum, some estimate of ADH activity.

A second useful aspect [of urinalysis] is the urine pH. It's usually reported at the end of the urinalysis, maybe right under or above the specific gravity. The urine pH can be very helpful for two reasons. If a person has kidney stones or crystals that are seen on microscopy, the urine pH can really help you understand their makeup. With a low urine pH, so less than 6 or less than 5.5, we think about uric acid stones. With a higher pH, over 6.5 or over 7, we think about calcium phosphate stones. pH can also be very helpful in the assessment of acid-base disturbances and specifically renal tubular acidosis. We can use the urine pH to make a fairly quick assessment of whether a type 1, type 2, or type 4 renal tubular acidosis (RTA) is more likely. For type 1 RTA, we expect a very high pH, and since we just talked about calcium phosphate stones, it's not surprising that type 1 RTA is associated with their formation. In contrast, type 4 RTA has a very low pH, and those individuals tend to have uric acid stones or crystals. With type 2 RTA, the pH can be a little bit variable. I find that urine pH can be very helpful in patients who have both stones or crystals, as well as renal tubular acidosis, which often go hand in hand.