Pathology Student

Q. What triggers renin release? I know that it’s hypo-filtration of the juxtaglomerular apparatus (i.e. reduced fluid flow) but what is the actual trigger for renin release?

A. There are actually three different types of cells in the JGA: granular cells (which secrete renin), macula densa cells (which secrete a vasopressive substance that acts on the afferent glomerular arteriole) and mesangial cells (whose function is a little obscure).

Granular cells (also called juxtaglomerular cells) are little connective tissue cells surrounding glomerular arterioles. They secrete renin in response to three things: 1) beta-adrenergic stimulation, 2) decreased renal perfusion pressure (which is detected by the granular cells themselves) and 3) signals from the macula densa.

Macula densa cells are specialized cells within the wall of the distal tubule. They sense the salt content and the volume of fluid within the tubule (which is related to the glomerular filtration rate). If the salt content is high, or the volume of fluid is low, the macula densa cells do two things: 1) tell the granular cells to release renin, and 2) dilate the afferent arteriole of the glomerulus (by secreting a little vasopressive hormone).

Mesangial cells come in two types: those within the glomerulus (which provide structural support for the capillaries, and also secrete some hormones, like erythropoietin), and those outside the glomerulus (which are considered part of the juxtaglomerular apparatus). The two types are connected by gap junctions. The function of the extraglomerular cells is a bit obscure. They contract when they are stimulated by sympathetic nerves. In addition, they are located in between the macula densa and the afferent arteriole, so maybe they help these two structures communicate.

Systemic lupus erythematosus is one of a few diseases that have earned the name “the great imitator.” It is a chronic, systemic illness with many, many possible symptoms in many different organ systems, and widely varying disease courses in different patients. We’ll go through a short summary of lupus here and save the more detailed information for other posts.

The underlying cause of lupus is not known. To manifest the disease, you most likely need have two things: 1) a genetic predisposition, and 2) some environmental trigger (sun exposure, drugs, etc.). Whatever the underlying cause, patients with lupus all have autoantibodies against self antigens. All patients with lupus have anti-nuclear antibodies (antibodies against some part of the cell nucleus – like DNA, histones, RNA-bound proteins, or nucleoli). Some patients also have anti-RBC, anti-lymphocyte, anti-platelet and/or anti-phospholipid antibodies as well.

The autoantibodies cause damage by forming immune complexes with their corresponding antigens (in the case of anti-nuclear antibodies, there must be some type of cell destruction to expose the corresponding nuclear antigens!), and circulating around the body lodging in places they should not be (like glomeruli, skin, joints, the pericardium, etc.). Remember what type of hypersensitivity reaction this is? (See the bottom of the post for the answer. But try to remember before you look!)

Organ systems commonly affected (with common manifestations) are:
1. Renal system (wide variation in manifestations, from painless hematuria, to lupus nephritis, to end-stage renal failure. One histologic hallmark is membranous glomerulonephritis with a “wire-loop” appearance due to immune complex deposition.)
2. Skin (the classic manifestation is a malar, or “butterfly,” rash, but scaly patches, ulcers, and other skin lesions can occur)
3. Nervous system (headache, mood disorders, seizures, psychosis, focal neurologic deficits)
4. Musculoskeletal system (arthritis of small joints of hands, muscle pain)
5. Cardiovascular system (pericarditis, endocarditis (called Libman-Sacks endocarditis), atherosclerosis)
6. Hematopoietic system (anemia, thrombocytopenia, leukopenia, antiphospholipid antibody syndrome)

There are two main forms of lupus: discoid lupus and systemic lupus erythematosus. Patients with discoid lupus have only skin (not systemic) involvement, and they do not have anti-DS DNA antibodies (an antinuclear antibody frequently present in patients with systemic lupus). Systemic lupus erythematosus is just what the name says: a systemic form of the disease. It is the more common form, unfortunately.

The prognosis is difficult to predict for individual patients. Some patients have very few symptoms; rarely, the disease course is acute and rapid. Most patients suffer a relapsing and remitting course over a period of many years (the overall 10 year survival is 80%). Acute flare-ups can be treated with steroids – but as of now, there is no cure.

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The type of hypersensitivity reaction that is characterized by immune complex deposition is type III.

Photo credit: NIH (http://www.niehs.nih.gov/health/topics/conditions/lupus/index.cfm), under cc license.

Okay, we talked about how to remember the components of nephrotic syndrome and nephritic syndrome. But what causes these syndromes?

Let’s boil it down to the top causes.

Nephrotic syndrome can be caused by renal diseases or systemic diseases (like diabetes). We’ll just discuss the renal diseases here. All of these diseases are characterized by a loss of foot processes (look it up in a physiology textbook if you’ve forgotten what these are). The three main renal diseases are:

1. Minimal change disease. This is the number one cause of nephrotic syndrome in children. The pathogenesis is unknown. It’s called minimal change (or sometimes “nil”) disease because under light microscopy, the glomeruli look pretty normal! Prognosis is good.

2. Focal segmental glomerulosclerosis. This disorder can be primary, or it may be associated with other conditions (like HIV, or heroin use). It’s called focal segmental glomerulosclerosis because if you look at a kidney biopsy, some (“focal”) glomeruli show partial (“segmental”) hyalinization. The prognosis is unknown, and unlike minimal change disease, the prognosis is generally poor.

3. Membranous glomerulonephritis. This type of glomerular disease is really an autoimmune reaction against some unknown renal antigen. Immune complexes are formed and are deposited along the glomerular basement membrane, which appears thickened on light microscopy. If you look at an electron micrograph, you’ll see subepithelial deposits, or “spikes.”

There are two main causes of nephritic syndrome. Both are immunologically mediated, and are characterized by proliferative changes and inflammation in the glomeruli. These causes are:

1. Postinfectious glomerulonephritis. This used to be called post-Streptococcal glomerulonephritis, because it most commonly occurs in children following a case of Strep throat. There’s a rather crude, but useful, mnemonic for this disease: sore throat (Strep infection), face bloat (edema), pee coke (patients often have brown-colored urine). Immune complexes are formed (the antigen is unknown, but probably is some type of Streptococcal protein) and deposited in the glomerular basement membrane (you can see the deposits on electron microscopy; they look like subepithelial humps). On light microscopy, the glomeruli look big and hypercellular, with lots of inflammatory cells. Recovery occurs in most children.

2. IgA nephropathy. This is also called Berger disease. It’s the most common glomerular disease worldwide, and it’s one of the most common causes of recurrent hematuria. It usually occurs in children or young adults, and it presents as hematuria following an upper respiratory infection. Patients with this disease produce abnormally high IgA levels; following an infection, you can see this IgA in the mesangium of the glomerulus (using immunofluorescent stains for IgA). Once IgA gets trapped there, complement is activated, and we all know what that does (bad stuff). The prognosis is variable.

There are, of course, other causes of nephrotic and nephritic syndrome (nothing is ever that easy!). But if you remember the main causes listed above, that should serve you very well.

Note: the photo of coca-cola bottles was taken by DeusXFlorida and can be found at http://www.flickr.com/photos/8363028@N08/3029152878/.

Here’s one of those things in pathology that will lead you to pull all your hair out: what is the difference between nephrotic and nephritic syndrome?

Ugh. They both involve the kidney, they both are syndromes so they’re probably both constellations of findings, and the names are maddeningly similar except for one stinking vowel. How can a person be expected to memorize these things?

Let’s start with the main features of each syndrome. We’ll pick four features for each, since it’s really hard to remember more than four of anything.

Nephrotic syndrome:

1. Massive proteinuria
2. Hypoalbuminemia
3. Edema
4. Hyperlipidemia/hyperlipiduria

Nephritic syndrome:

1. Hematuria
2. Oliguria
3. Azotemia
4. Hypertension

How do you make these lists hang together in a way that you can remember?

First, let’s take nephrotic syndrome. The thing to remember for this one is massive proteinuria. You might do this by remembering that nephrotic and protein both have an “o” in them. The massive proteinuria in these patients leads to hypoalbuminemia (they are peeing out albumin!), which results in edema (the oncotic pressure in the blood goes down, and fluid leaks out of the vasculature into the surrounding tissue). So right there, you have three of the four features, just by remembering one. The cause of the last feature, hyperlipidemia/hyperlipiduria, is less well-understood, so you’re just going to have to memorize that one. As an aside, nephrotic syndrome is often more dangerous than nephritic syndrome, so you might want to think of this syndrome as the “oh sh*t” syndrome (again – nephrotic has an o in it, nephritic does not). Crude, but if it works, who cares?

In nephritic syndrome, there is some proteinuria and edema, but it’s not nearly as severe as in nephrotic syndrome. The thing with nephritic syndrome is that the lesions causing it all have increased cellularity within the glomeruli, accompanied by a leukocytic infiltrate (hence the suffix “-itic”). The inflammation injures capillary walls, permitting escape of red cells into urine. Hemodynamic changes cause a decreased glomerular filtration rate (manifested clinically as oliguria and azotemia). The hypertension seen in nephritic syndrome is probably a result of fluid retention and increased renin released from ischemic kidneys.

If you really want to pare it down – if you only have enough brain space to remember one feature for each disorder – remember that nephrotic syndrome is characterized by massive proteinuria (the “o” in nephrotic), and nephritic syndrome is characterized by inflammation (the “-itic” in nephritic). Then at least you’ll have a shot at remembering the other features.

Note: The image above is of Streeter Seidell, a comedian, and was taken by Zach Klein. It can be found at http://www.flickr.com/photos/zachklein/54389823/.