NEPHRITIC
Glomerular Inflammation
Nephritic Syndrome is glomerular inflammation that causes bloody pee. The inflammation makes the glomerular capillaries and BM more permeable, allowing red blood cells to slip past. The inflammation also prompts the migration of Neutrophils (hypercellular appearance on histology). The cellular overcrowding chokes the flow of blood, and greatly diminishes the GFR. The reduced filtration causes oliguria. The low GFR will send the kidney into a panic (triggering the tubuloglomerular feedback mechanism), resulting in a lot of renin release from the JG cells. Renin turns on RAAS, causing some pretty serious salt retention, which leads to hypertension.
Nephritic syndrome is fundamentally due to a defect in size filtration. The size barrier is maintained by the endothelium and GBM. (In contrast, Nephrotic syndrome is a breakdown in the charge barrier).
Hematuria is the defining feature of nephritic syndromes. Importantly, the bleeding arises from the glomerulus, rather than the bladder or ureter or some other post-nephron structure. The fact that the bleeding starts up there is really important, because the passage of RBCs through the glomerulus and the nephron can leave some telltale signs! When RBCs are squished through the inflamed glomerulus, the high pressure often leaves them permanently distorted, and this finding is called “dysmorphic” red blood cells. And when enough RBCs fill up a nephron, they sometimes coalesce into a cast -- in fact, RBC casts are pathognomonic for nephritic syndrome.
On a urinalysis, look for 3+ hematuria, mild proteinuria and the aforementioned RBC casts. On blood work, look for azotemia (high creatinine and BUN).
GOODPASTURE’S SYNDROME
Autoimmune attack on type 4 collagen
Goodpasture’s Syndrome is an autoimmune attack on type 4 collagen (α3 chains), a major component of the BM. The antibodies coat the BM, neatly arranging themselves in a linear pattern. This linear pattern is visualized with immunofluorescent imaging (as smooth green lines). Keep in mind this is a type 2 hypersensitivity.
Goodpasture’s has unique symptoms. It causes hematuria and hemoptysis. If the BM is found everywhere in the body, why are the kidneys and lungs the only organs affected? Here’s an interesting theory I found. The BM is normally sequestered from the blood and its antibodies by endothelial cells. But the fenestrated nature of the glomerulus and the vulnerability of the alveoli (eg, to smoking) exposes their BMs.
It’s classically seen in young adult males. Untreated, it has a 50% mortality. Plasmapheresis treatment may help.
ALPORT SYNDROME
Defective type 4 collagen
Alport Syndrome is very similar to Goodpasture’s. But while Goodpasture’s was caused by an antibody attack against Type 4 Collagen, Alport is an inherited defect in the synthesis of Type 4 Collagen (specifically the α5 subunit). The defective collagen is thinner than healthy collagen, and it tends to split and fray the BM (visualized as a “basket-weave” appearance on EM). Alport is sometimes called “Thin GBM Disease.”
The BM is found all over the body. But for some reason most of the damage in Alport is isolated to the kidneys (nephritic), ears (deafness) and eyes (lenticonus and keratoconus). Can’t pee, can’t see, can’t hear a bee! The eye stuff is low yield, but for the curious readers, Lenticonus is a pointy lens and Keratoconus is a pointy cornea. Alport syndrome begins in childhood, and leads to renal failure after 20 or 30 years, necessitating a transplant.
Alport is one of the very few X-linked dominant diseases.
What's a more common cause of kidney problems plus sensorineural deafness?
Aminoglycoside toxicity!
IgA NEPHROPATHY
Berger Disease
IgA Nephropathy is straightforward. Some people naturally make extra IgA, and those extra IgA immune complexes tend to deposit in the glomerulus. This is a type 3 hypersensitivity reaction. It’s the most common Nephritic syndrome worldwide. We don’t know a lot about the mechanism.
IgA Nephropathy is episodic. IgA is the mucosal antibody. So a few days during and after a mucosal infection (cold, stomach bug), more IgA is made. Some of the excess IgA is deposited in the kidneys. In comparison, APSGN usually takes about 1 to 3 weeks to ramp up.
After about 20 or 30 years, half of patients develop kidney failure. They benefit from aggressive hypertension control, especially with renal protective drugs like ACE Inhibitors or ARBs.
ACUTE POST-STREPTOCOCCAL GLOMERULONEPHRITIS
Strep's revenge!
APSGN is an autoimmune attack on the glomerulus, taking place a few weeks after a Strep pyogenes (Group A Beta-hemolytic) infection. The exact MOA is fuzzy, but ultimately there is immune complex deposition in the glomerulus.
The immune complex deposits behave differently than in Membranous Nephropathy or Membranoproliferative Glomerulonephropathy. Instead of permanently lodging in the subendothelium, the glomerulus slowly pushes the deposits out into Bowman’s capsule (similar to how your skin gradually sheds a splinter). That shedding is why APSGN gets better without treatment. In between the time of deposition and then shedding, the deposits can be visualized as a dark blob within the podocytes (subepithelial). The overlying podocyte is often described as a “hump.” The deposit activates complement, which is an important distinguisher from IgA Nephropathy.
The timeline of events begins with a Strep pyogenes infection (typically impetigo, cellulitis or strep throat). The immune system fights back, and one of its tools is the production of antibodies. It takes about 1 to 3 weeks for new plasma cells to be made. But once they’re produced, a large number of anti-Strep antibodies begin to spill into the blood.
Here’s a typical case. A child has a sore throat. The sore throat is treated, and they improve. But 15 days later they develop HTN, edema (periorbital), and bloody or tea-colored pee. Their blood tests positive for Antistreptolysin O (ASO) Antibodies. They require IV hydration for a few days in the hospital due to dehydration, but their illness resolves spontaneously in a few weeks.
Strep pyogenes
LUPUS NEPHRITIS
The kidney gets hurt in 75% of patients with Lupus. Around 30% will die from their kidney disease. The severity and type of renal disease is quite variable however, ranging from microscopic hematuria to overt renal failure. On this page, I’ll focus on how Lupus can cause both a Nephritic or a Nephrotic syndrome.
Nephritic
Diffuse Proliferative Glomerulonephritis is the most common cause of kidney damage with Lupus. It’s a type 3 HSR -- there’s deposition of DNA immune complexes into the subendothelial layer of the glomerulus. The deposits activate the classical complement pathway. The damage results in thick vascular walls that are called “wire looping capillaries.” It often devolves into chronic kidney failure, and this is a pretty common cause of morbidity / mortality in Lupus. Treat with Steroids and / or Cyclophosphamide.
Nephrotic
Membranous Nephropathy is the 2nd most common cause of kidney damage from Lupus. It’s also a type 3 HSR, but the IC deposits are in the subepithelium, and it causes protein loss rather than a nephritic picture. The BM develops a thickened appearance.
RAPIDLY PROGRESSIVE CRESCENTIC GLOMERULONEPHRITIS
Worst case scenario
RPGN is the most severe manifestation of nephritic syndrome. Almost any cause of nephritic syndrome can devolve into RPGN. The prognosis is grim. The kidneys usually fail. The diagnosis is made once you take a biopsy from the dying kidney. You’ll see crescent-shaped scarring and lots of WBCs in the glomeruli. RPGN occurs whenever the glomeruli are damaged enough to allow fibrin inside. Fibrin scarring is usually permanent.
