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Now, That’s What I Call High-Yield: Renal Function

Ask any nephrologist – they will tell you that renal function is all that matters. Well, it’s pretty important for your Step 1 studying, too. There’s so much wonderful physiology, pathophysiology, medications, mechanisms of action. A truly exciting organ system. Let’s talk about some basic renal framework before jumping into details.


Our Tips for High-Yield Renal Function Study for the USMLE:

The kidneys are composed of a couple million nephrons. The nephron contains an entrance, the glomerulus, and an egress, the collecting duct. Blood pressure drives blood through the glomerulus, some of which makes its way through to become filtrate, the rest of which exits via the efferent arteriole.

Through the tubule, substances are secreted and reabsorbed. The filtrate then heads from collecting duct to ureter to bladder to toilet (or foley or diaper).

Like all organs, to prevent ischemia and subsequent injury, the kidney needs oxygen. Oxygen comes from blood, which is delivered to the kidneys by cardiac output. We will talk more about kidney ischemia when we get to renal failure. If anything gets too complex, think back to this: your basic understanding of the structure of the kidney.

Calculations (7) – Are they actually high-yield? Not really. But I couldn’t eschew them because they are the easiest of points on the test, if you remember the equations. Unlike the 3-step questions that comprise most of Step 1, questions about calculating filtration fraction or GFR are usually a means of simple division. Devote a little bit of mind space to memorizing these equations. They are certainly crammable, and can be reviewed just before Test Day.

Nephron Physiology (8.5) – The name of the game when it comes to compartmentalizing the nephron is knowing the type of ion channel and the drug(s) that work there. The proximal collecting tubule is the main site of reabsorption. It is here that all of the glucose (in a non-diabetic) and most of the sodium, chloride, bicarb, phosphate, water, and potassium get reabsorbed. The thick ascending loop (of Henle) contains the almighty Na/K/2Cl channel; ions can pass through, water cannot. As it’s a loop, it’s where loop diuretics like furosemide work. The distal (convoluted) tubule has a Na/Cl channel and again, no water channel. Thiazides work here. The collecting tubule a specialized sodium channel (ENaC) and the V2 channel. Potassium-sparing diuretics work here to excrete sodium and water, and hang onto potassium. ADH acts here to hold onto water.

Renin-Angiotensin-Aldosterone system (9) – This system is so important that a relatively in-depth description is necessary. Renin is a protease, so naturally, it cleaves proteins. It is generated in response to low BP, low NaCl detection, or a sympathetic surge. It cleaves angiotensinogen into Angiotensin I. The lungs secrete ACE, which turn Angiotensin I into Angiotensin II. Angiotensin II itself is a vasoconstrictor; it tells the kidneys to hold onto sodium and water, causes ADH secretion, and leads to aldosterone secretion. Aldosterone then acts at the distal tubule to spill potassium and hang onto sodium. The whole purpose of the system is to drive up blood pressure. ACE inhibitors act early on in the cycle to prevent Angiotensin II from ever being created. Aldosterone inhibitors act later in the process to prevent sodium and water absorption. Key connection: Sympathetic overactivity and activation of the RAAS system is implicated in the pathogenesis of heart failure. The body hangs onto too much water because of poor kidney perfusion, causing congestion and increased afterload/fluid overload for the already suffering heart.

Electrolyte abnormalities (7.5) – Good luck admitting your medicine patient and not coming across at least a few electrolyte derangements in their problem list. Let’s talk about the ones that really matter:

HYPOnatremia is a dangerous abnormality that, if severe and/or acute, can lead to seizures and coma. If corrected too quickly, it can lead to permanent neurological damage.

Another true foil is HYPERkalemia. This can destabilize cardiac cellular membranes and lead to EKG changes and lethal arrhythmias. Correct quickly with diuretics (pee it out), insulin (drive it into cells), beta-agonists, and prevent untoward cardiac issues with calcium. If you are in a real bind, dialysis can get the potassium out of the blood. Magnesium, when too high, can depress deep tendon reflexes, cause hypotension, and even cardiac arrest. The classic case is a pre-eclamptic who is on too high a magnesium infusion. When it comes to calcium, high levels lead to the classic “bones (pain), groans (GI discomfort), (kidney) stones, and psych overtones;” low levels cause muscle spasm and tetany.

Casts (7) – While cast formation in urine might not be of the highest yield, its ability to cinch a questionable diagnosis make casts too juicy to pass up.

In order for a cast to form, a certain substance must coalesce inside the tubules in the kidney. Therefore, there must be an intrinsic renal process occurring for a cast to form. This is best illustrated by WBC casts. WBC in the urine means a likely “urinary tract infection,” but not until there are white blood cells in the kidney itself (pyelonephritis), do we get casts. RBC casts mean blood making its way into the tubule, usually from glomerulus breakdown from glomerulonephritis. Muddy brown/granular casts are the result of tubular cells sloughing into the ducts, seen in acute tubular necrosis (ATN).

Nephrotic and Nephritic Syndrome (8.5) – The spectrum of these two has a lot of overlap, making diagnosis a bit trickier. By definition, nephritis means inflammation at the level of the nephron, and nephrosis means 3.5+ grams/day of proteinuria.

Pure nephritic syndromes to commit to memory include PSGN, IgA nephropathy, and rapidly progressing glomerulonephritis (including Goodpasture and Wegener’s/granulomatosis with polyangiitis).

High-yield nephrotic syndromes include minimal change disease (very common, usually in children), amyloidosis (multi-organ involvement), FSGS, and diabetic glomerulonephropathy. There’s a lot of nitty gritty detail contained in these diseases, and many others that we haven’t talked about. More than electron microscope and other esoteric findings, focus on the disease process and pathophysiology. The rest will come with each pass through the material.


And what about the Acid-Base balance and renal injury/failure? I’m glad you asked!

We will take a small digression from the BIG PICTURE subjects to delve a little deeper in a very high-yield subset of nephrology. Kidney Injury is common, and is a huge source of morbidity for both hospitalized patients and outpatients alike. I don’t make many promises when it comes to your USMLE exams, but I can promise you that some element of renal failure will show up on the test. 
It is important to elevate your consciousness on the subject of kidney injury. More important than understanding any particular lab values or etiology is comprehending what drives renal failure from the pathophysiologic perspective, how these patients present, and how the different etiologies are treated.

What exactly is renal failure/kidney injury?

(We will use these terms relatively interchangeably; in reality, renal failure is more of an end-stage kidney injury). Kidney injury represents a decrease in the filtering function of the kidney, a lowering of the glomerular filtration rate (GFR). While we can calculate a patient’s GFR based on age, weight, sex, height, and creatinine, usually we track a singular number, their creatinine, as the rest of the numbers stay pretty constant for a given patient. As the GFR (function) of the kidney worsens, the creatinine rises. Less creatinine is filtered into urine, and more hangs out in the blood, appearing on a basic metabolic panel blood test. For now, don’t worry about specific numbers and cutoffs, just realize that a rising creatinine represents poorer kidney functioning.
Why would the kidneys stop working as well as they once did? There are three big categories of renal failure, and to avoid frustration, you must understand that a particular patient’s kidney injury can fall into more than one category, and categories can overlap (more on that later). Your three big categories are “pre-renal,” “intrinsic renal,” and “post-renal.”

Post-renal failure

Let’s tackle post-renal, as it’s the most easily understood. As it sounds, the problem in POST-renal failure occurs AFTER blood is filtered through the kidney to form urine. If the passage of urine from the collecting duct to the toilet is obstructed, filtrate will back up in the tubule, flood the kidney, and injure it. Everything in the body depends on flow, and if filtrate can’t make its way out of the kidney, the kidney will get injured.
Working from distal-to-proximal, sources of obstruction can be clogged/clamped urinary catheter, obstructed distal urethra, obstructed prostatic urethra (BPH or cancer), renal calculus, or abdominal mass causing external compression of the ureter. Patient history and physical (and imaging, like renal ultrasound) will be most helpful in figuring out what is causing the problem.
Intrinsic kidney injury has to do with a direct injury to the kidney causing it to function more poorly. This is most commonly caused by renal ischemia or a nephrotoxin, resulting in “acute tubular necrosis (ATN),” a huge etiology of intrinsic kidney injury. Nephrotoxic drugs hurt the kidney directly and include Amphotericin, aminoglycosides, and vancomycin. Some drug classes hurt the kidney by compromising their blood flow, like NSAIDs and ACE inhibitors. Renal ischemia can be caused by any compromise in feeding the kidney oxygenated blood. Severe hypoxia, decrease forward flow (i.e., heart failure, hemorrhagic shock), anemia, and hypotension can all cause renal ischemia, ATN, and intrinsic kidney failure. Other important but less common causes of intrinsic kidney injury are tubulointerstitial nephritis, glomerulonephritis, and vasculitides.

Pre-renal failure

Pre-renal failure is a compromise of blood flow to the kidney, and is usually a function of dehydration. Your classic pre-renal patients are either suffering from a GI bug (vomiting and diarrhea), hyperemesis gravidarum, or overdiuresis. If lack of fluid/blood flow to the kidney continues long enough, the kidney can get ischemic, and start to have more of an ATN picture. The overlap of these two causes can drive students nuts. Don’t let it get you down, just realize that both can exist separately, but often overlap.

What would make you think a patient is suffering from renal failure?

Decreased urine output is the most classic of symptoms. Because the patient’s kidneys are having trouble making urine, you can expect to see fluid overload in the forms of peripheral edema, ascites, pulmonary edema, and pleural effusions. On labs, certainly look for a rising creatinine and BUN. When in doubt, always obtain urine studies, including a microscopic look at the urine itself. The presence of different types of casts can be pathognomonic for particular diseases.
Usually a patient’s history will point you in a particular direction. Started a new nephrotoxic medication? That’s an easy one – intrinsic.
Suffering from a newly diagnosed vasculitis on kidney biopsy? Intrinsic again.
Severely dehydrated G1P0 at 7w3d? Pre-renal all the way.
If you are not sure what’s going on, placing a Foley can help to take post-renal obstruction off the list, and will also help keep track of inputs and outputs while the patient is being treated.
Treatment of any etiology involves reversing and treating whatever the culprit is, and supporting the patient along the way. If something is obstructing, get it out of the way. Break up that too-big-to-pass stone, or call your urology colleagues to swiftly navigate a foley through the hypertrophied prostate. Your patient who was so fluid-down needs some IV fluids or blood. Give it back to them.
Intrinsic causes are often the hardest to treat; supportive care is king until the kidneys heal and start to put out urine again. Start by discontinuing any nephrotoxic agents, and working to encourage forward blood flow with inotropes if the heart is not functioning so well. Patients may need support with non-invasive positive pressure ventilation (or intubation) if their pulmonary status deems it so.
I know that’s a ton of information all at once, and we haven’t even talked about singular disease processes! But the goal was to fill in whatever gaps in a big-picture, forest-for-the-trees, 30,000-foot view that you had, in order to comprehend what’s going on in kidney injury. You are off to a great start, and have the framework to hang individual diseases onto. Annotate your brain!
A final tip in studying the renal system. Because it is so intimately intertwined with the cardiovascular system, do what you can to study these two systems close together. They are literally inseparable.
Check out Drs. Murdock and Hanson taking you through a high yield distillation of Renal Tubular Acidosis (RTA) and how it shows up on USMLE Steps 1 & 2.