Renal failure: Pathology review

Definitions & Key takeaways

Renal failure is a condition in which the kidneys are no longer able to function properly. There are two main types of renal failure: acute renal failure and chronic renal failure. Acute renal failure, also known as acute kidney injury (AKI), is when the kidney isn't functioning at 100% and that decrease in function develops relatively quickly, typically over a few days. AKI is commonly caused by anything that causes acute damage to the kidneys, such as infection, injury, toxins, and certain medications. The symptoms include swelling, decreased urine output, and changes in the color and smell of urine.

In chronic kidney failure, which is now called chronic kidney disease (CKD), kidney function gradually decreases over a minimum of three months. CKD is most commonly caused by chronic disorders like diabetes mellitus and hypertension. Other causes of CRF include glomerulonephritis, polycystic kidney disease, and chronic obstructive uropathy. The symptoms of CRF can include fatigue, anemia, and signs of fluid retention.

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Case Study0:00–0:37

On the Nephrology ward, two people came in. The first one is 55 year old Matilda, who came in with oliguria, fever and a rash on her arm.
Matilda also has a history of taking NSAIDs for her knee-pain. The second one is 34 year old George, which came in with oliguria, hypotension, tachycardia and cold extremities.
George says that he’s also been having diarrhea for a few days now. BUN and creatinine levels were high for both of them.
Both Matilda and George have renal failure. Now, renal failure is when the kidneys aren’t functioning properly.

Physiology0:37–2:01

Before talking specifics, let’s remember some basic renal physiology. Now the kidney’s job is to regulate what’s in the blood, so they might remove waste, or make sure electrolyte levels are steady, or regulate the overall amount of water, and even make hormones, such as erythropoietin, which stimulates red blood cell production.
Okay, so blood gets into the kidney through the renal artery, into tiny clumps of arterioles called glomeruli where filtration happens.
After filtration, the stuff that’s filtered out, called the filtrate, moves into the renal tubules, where reabsorption and secretion of fluid and electrolytes happens.
Along with fluid and electrolytes, though, waste-containing compounds are also filtered, like urea and creatinine, although some urea is actually reabsorbed back into the blood, whereas only a little bit of creatinine is reabsorbed.
In fact, in the blood, the normal ratio of blood urea nitrogen, or BUN, to creatinine is between 5 and 20 to 1—meaning the blood carries 5 to 20 molecules of urea for every one molecule of creatinine, and this is a pretty good way to assess kidney function!
So, when we want to check renal function, we look at BUN and creatinine levels and if there’s something wrong, then levels of both BUN and creatinine will be high.Now, back to renal failure.

Pathology2:01–5:42

There are two types of renal failure: acute and chronic. Now, acute renal failure is now called acute kidney injury.
This is when the kidney isn’t functioning at 100% and that decrease in function develops relatively quickly, typically over a few days.
In this case, the individual typically presents with oliguria, even anuria and levels of BUN and creatinine will be high.
Then there’s chronic kidney failure, which is now called chronic kidney disease. This is when the kidney function gradually decreases over a minimum of three months.
This is usually caused by hypertension, diabetes mellitus, or congenital renal conditions. Both acute and chronic renal failure has some pretty dire consequences.
A lot of the things that the kidneys normally excrete are now stuck in the body. First, H+ ion secretion is impaired and this can lead to metabolic acidosis.
Secondly, potassium excretion is also impaired and this can lead to hyperkalemia. Now, in certain cases, such as heart failure, pulmonary edema or hypertension, the kidney will retain more water and sodium, and so the individual can present with peripheral or periorbital edema.
Next, there’s uremia, which is caused by the accumulation of uremic toxins, including urea itself. Symptoms include nausea and anorexia.
Another sign of uremia is bleeding and easy bruising, and that’s due to platelet dysfunction. There’s also uremic pericarditis- which is the inflammation of the pericardium.
Next, there’s uremic neuropathy affecting the central and peripheral nervous system. Clinically, there’s progressive encephalopathy - that causes asterixis, which is a tremor in the hand when the wrist is extended, just like a bird flapping its wings.
Finally, Renal failure can also increase lipid synthesis in the liver, causing hyperlipidemia, especially hypertriglyceridemia.
Now, chronic kidney disease can lead to even more problems over a long period of time. If a child is affected, it can lead to growth retardation and developmental delay, especially in individuals that had to undergo dialysis.
Another important fact for your exams is that there’s also erythropoietin deficiency and this leads to anemia. Finally, there’s renal osteodystrophy.
This happens for a number of reasons and it’s important to memorize all of them. First, the kidneys can’t excrete phosphate, leading to hyperphosphatemia.
Next, the kidneys are needed to convert 25- hydroxyvitamin D to active 1,25 dihydroxyvitamin D, or calcitriol, which is the active form of vitamin D which helps with intestinal calcium reabsorption.
As a result, there will be hypocalcemia. Now, since there’s too much phosphate and too little calcium, this can affect the bones and they can become thinner and more prone to break.
Hyperphosphatemia and hypocalcemia also triggers the parathyroid glands to release more parathyroid hormone, a hormone that causes increased bone break down to release more calcium.
Finally, the extra phosphate in the blood can also bind to calcium and they can deposit in various tissues, such as the vascular tissue.
Okay, now that we’ve gone over the general pathology, let’s look at some specific causes of acute kidney injury. There are three types of acute kidney injury or AKI: prerenal AKI, intrarenal AKI and postrenal AKI.

Prerenal Acute Kidney In5:42–7:57

With prerenal AKI, the cause is decreased blood flow into the kidneys. Now, since less blood’s going to the kidneys, this means that less blood is being filtered, so there’s a decrease in the glomerular filtration rate, or GFR, which is how much blood, usually in mL, the kidneys filter through their glomeruli per minute.
If less blood is being filtered, that means less urea and creatinine are filtered out, and more stays in the blood, so levels of BUN and creatinine will be high.
Also with less blood being filtered, the kidneys activate the renin-angiotensin system, which causes aldosterone release by the adrenal glands.
This hormone tells the kidneys to reabsorb sodium. When sodium gets reabsorbed, water gets reabsorbed as well.
Water and sodium reabsorption is also tied to urea reabsorption, so in this situation, urea gets reabsorbed and so even more urea gets into the blood, resulting in a BUN to creatinine ratio of greater than 20:1.
Now, looking at the urine, more sodium is being retained, so the urine sodium is usually less than 20 mEq/L. The ratio of sodium excreted to total sodium filtered, or FENa, is usually less than 1%, and finally that urine is more concentrated because less water is excreted, so typically the urine’s greater than 500 milliosmoles per kilogram.
Prerenal AKI can happen in hypovolemic states like an acute hemorrhage, gastrointestinal losses- like with diarrhea and vomiting, renal losses- like with diuretics.
All this can lead to hypovolemic shock. In a hypovolemic states, the individual presents with tachycardia, hypotension, reduced skin turgor, and cool extremities.
Now, prerenal AKI can also happen with hypervolemic states where there’s a low effective circulating volume. One example is severe systolic heart failure leading to not enough blood getting pumped to the kidneys.
When this happens, it’s called cardiorenal syndrome. Finally, systemic vasodilation, like with sepsis, can lead to prerenal AKI.
Next there’s intrinsic or intrarenal AKI, which is due to damage to the tubules, the glomerulus, or the kidney interstitium, which is the space between tubules.

Intrarenal Acute Kidney 7:57–8:45

In general, with intrarenal AKI, there’s kidney damage, causing them to lose the ability to filter blood, and secrete or reabsorb materials like normal.
If urea isn’t reabsorbed, less urea stays in the blood relative to creatinine, and the BUN to creatinine ratio falls to less than 20:1.
Also, renal tubule cells can’t reabsorb sodium, meaning the urine Na+ goes above 40 mEq/L, and the FENa goes above 2%, and finally since water’s not being reabsorbed as much, urine osmolality falls below 350 mOsm/kg.
Okay, now, the most common cause of intrarenal AKI is acute tubular necrosis or ATN, which causes damage to the tubules.

Acute Tubular Necrosis8:45–11:13

Often ATN is due to ischemia from a prerenal acute kidney injury. On your tests, make sure you don’t confuse this with prerenal AKI where there’s decreased filtration of blood, but the kidneys are not damaged.
In ATN, there’s severe ischemia leading to the death of tubular cells. The proximal tubular cells and thick ascending limb cells are highly susceptible to injury.
That’s because these cells receive their blood from vasa recta which are tiny capillaries located in the medulla of the kidney.
In this particular zone, the blood flow is relatively slow to allow for the countercurrent multiplication mechanism to work properly.
The other way tubules can be damaged is via nephrotoxins such as contrast dyes, aminoglycosides antibiotics, cisplatin, heavy metals like lead, myoglobin from damaged muscles - like in rhabdomyolysis, ethylene glycol or radiocontrast dye, and hemoglobinuria that’s usually associated with hemolytic anemia.
The proximal tubule cells are particularly susceptible to nephro toxin injury. Now, ATN usually has three stages.
The first one is the inciting event or the trigger that causes damage in the tubules. Next there’s a maintenance phase, also called the oliguric phase, which usually lasts from 1 to 3 weeks.
This is when the kidneys aren’t working and here there’s a risk for developing electrolyte disturbances, like hyperkalemia, because potassium isn’t effectively secreted, metabolic acidosis, because acid excretion is impaired and uremia, which is when there are too many waste products retained.
Finally, there’s the recovery phase, which is when the kidneys start working, because the tubular cells begin a process of re-epitheliazation, meaning new functional cells are born.
As a result, creatinine and BUN levels fall, and there’s polyuria. Also for your tests, remember that in this phase, there’s a risk for developing hypokalemia, because too much potassium is excreted this time.
There can be wasting of other electrolytes or minerals as well. Remember for your exams that on microscopy, there are muddy brown granular, epithelial cell casts, along with renal tubular epithelial cells.Okay, moving onto another cause of intrarenal AKI, which is acute interstitial nephritis.

Acute Interstitial Nephr11:13–12:23

This is an inflammation of the renal interstitium over the course of days to weeks. It is thought to be a type I or type IV hypersensitivity reaction, and is typically a response to a medication like NSAIDs- in which case, it’s called analgesic nephropathy, penicillin, rifampin, proton pump inhibitors and diuretics.
After the cessation of the offending medication, symptoms of acute interstitial nephritis typically resolve completely. In rare cases, the inflammation in the interstitium can be caused by systemic infections, such as infections with Mycoplasma or by autoimmune conditions, like Sjogren syndrome, sarcoidosis or systemic lupus erythematosus.
It can be asymptomatic, but for your exams, remember that it can also present symptoms like fever, rash, hematuria, pyuria and costovertebral angle tenderness.
With acute interstitial nephritis, the blood count shows eosinophilia and the urine microscopy shows white cells, white cell casts, and red blood cells.

Acute Glomerulonephritis12:23–13:08

Another type of intrarenal AKI is acute glomerulonephritis, which is when the glomeruli are damaged by inflammation. Acute glomerulonephritis can be caused by rapidly progressive glomerulonephritis, which is when inflammation in the glomerulus is so severe, that it breaks the glomerular basement membrane and as a result, the kidney function decreases rapidly in a matter of days to weeks.
Another cause of acute glomerulonephritis is hemolytic-uremic syndrome, which is caused by bacteria like E.coli O157:H7.
For your exam, remember it’s characterised by hemolytic anemia, thrombocytopenia, and acute kidney injury. Another clue is that the person might have had bloody diarrhea for a few days prior to the oliguria.
Next up, there’s diffuse cortical necrosis, which is when there’s generalized cortical infarction of both kidneys. This happens because of a combination of vasospasm and disseminated intravascular coagulation, or DIC, where tiny thrombus block some of the arteries in the kidney and so, the kidneys won’t get any blood in that area.

Diffuse Cortical Necrosi13:08–13:42

This can be associated with obstetric complications like abruptio placentae, where there’s massive blood loss, that can lead to both vasospasm and DIC.
It can also be associated with septic shock, which also causes DIC.Okay, next, there’s renal papillary necrosis, where the renal papillae are damaged and tiny parts of them can be eliminated in the urine, so there’s sloughing of the renal papillae.

Renal Papillary Necrosi13:42–14:57

This is usually a consequence of ischemia because the arteries supplying the renal papillae are tiny, so they’re prone to obstruction.
Now, renal papillary necrosis can be associated with sickle cell disease, because the abnormal red blood cells can build up and obstruct the arteries that supply blood to the renal papillae.
It can also be due to acute pyelonephritis, because the inflammation can obstruct those arteries. Another cause is the use of NSAIDs because they block the synthesis of prostaglandins that keep afferent arteriole dilated.
In other words, lack of these prostaglandins causes vasoconstriction of the afferent arteriole and therefore decreased glomerular filtration rate.
So, when there’s reduced blood flow through the renal artery, which is particularly common in the elderly and individuals with underlying heart, liver, or kidney disease, vasoconstriction of afferent arteriole can lead to renal papillary necrosis.
Finally, diabetes mellitus can lead to papillary necrosis, due to the vascular damage it induces. Let’s move on to postrenal AKI, which is caused by an obstruction in the outflow of urine from the kidneys, which causes a buildup of urine that backs up into the kidney.

Postrenal Acute Kidney I14:57–16:02

Now, BUN to creatinine ratio, FENa and urine sodium largely depend on if the tubules are working or not, so for your tests, simply remember that these 3 parameters can vary.
Just as with the others, less water and fluid being reabsorbed causes the urine to be less concentrated, and urine osmolality falls below 350 mOsm/kg.Postrenal AKI is most frequently due to benign prostatic hyperplasia or prostatic cancer in a male, both of which lead to compression of the urethra.
This can lead to frequent urination but a slow urinary stream and a low volume of urine excretion. Finally, there are kidney stones that can get stuck in either ureter or in the urethra.
Now, if only one ureter is obstructed, it’s called unilateral obstruction, and the other kidney is working fine, then renal function is usually preserved.
But if both ureters are obstructed, it’s called bilateral obstruction.Finally, let’s review! Consequences of renal failure includes metabolic acidosis, hyperkalemia, sodium and water retention, hyperlipidemia and uremia for both acute and chronic kidney failure.

Review16:02–17:32

Chronic renal failure leads to growth retardation and developmental delay, along with erythropoietin deficiency and renal osteodystrophy for chronic kidney disease.
Okay, now acute kidney injury can be prerenal, when there’s decreased blood flow to the kidneys. Labs here show high levels of BUN and creatinine, BUN to creatinine ratio of greater than 20:1, urine sodium is less than 20 mEq/L, FENa less than 1% and urine osmolality greater than 500 milliosmoles per kilogram.
Intrarenal AKI is due to damage to the tubules, the glomerulus, or the kidney interstitium. Labs show high levels of BUN and creatinine, BUN to creatinine ratio less than 20:1, urine sodium above 40 mEq/L, FENa goes above 2%, and urine osmolality falls below 350 milliosmoles per kilogram.
Causes of intrarenal AKI include ATN, acute interstitial nephritis and acute glomerulonephritis. With postrenal AKI, there’s an obstruction in the outflow of urine.
Labs show urine osmolality below 350 mOsm/kg but the other values might vary depending on if there’s damage to the kidneys themselves.Now back to our cases.

Summary17:32–18:46

Matilda came in with oliguria, a fever and a rash on her arm and labs showed that she had high levels of BUN and creatinine.
Oh, and she is also taking NSAIDs. Further lab work showed that she also had eosinophilia, BUN to creatinine ratio less than 20:1, urine sodium above 40 mEq/L, FENa above 2%, urine osmolality below 350 milliosmoles per kilogram.
She also had pyuria and white cell casts. So we can say that Matilda has a case of intrarenal AKI caused by interstitial nephritis which in turn is caused by NSAIDs, so this is analgesic nephropathy.
In this case, NSAIDs are stopped and the problem eventually resolved. Next, there’s George that came in with oliguria, hypotension, tachycardia and cold extremities and has also been having diarrhea for a few days.
BUN and creatinine were high and further lab work showed BUN to creatinine ratio greater than 20:1, urine sodium less than 20 mEq/L, FENa less than 1% and urine osmolality greater than 500 milliosmoles per kilogram.
So it’s a case of prerenal AKI caused by diarrhea. We should hydrate him!!