Signs and Symptoms

A patient suffering from Minimal Change Disease will not experience any symptoms until the disease progresses to nephrotic syndrome and too much of the protein in their body is being lost into the urine.  Some of the major symptoms that a patient will notice once their body is in nephrotic syndrome and may cause them to seek treatment are as follows:

• Swelling.  You may hear the phrase 'pitting edema.'  Edema refers to the retention of fluid and swelling of the body.   'Pitting' refers to the way that the swelling is measured.  When a healthcare worker presses into the swollen area, their fingertip will leave a 'pit' that will not immediately disappear.

• Stretch marks (known medically as skin striae [STRY-ay]) are bands or lines on the skin that are due to a rapid growth.  The skin stretches to allow more space in the body.

• They can't pee!  Or at least the patient is not urinating very often.  This is called 'oliguria.' 

• Shortness of breath and chest pain.  Some of the fluid that is being kept in the body may get into the space between the lung and the lung cavity.  In a healthy person, this space is a negative pressure area which keeps the lung expanded.  Too much fluid in the potential space will cause the lung to collapse resulting in shortness of breath and pain in the chest.

• Often times, the fluid that is being retained will result in swelling specifically in the abdomen.  This is known as ascites (Uh-SIGH-tees) and it will look something like this...

• There may be an  unexplained, general weight gain.

• The individual may complain of a headache, fatigue and/or be irritable.

• Meuhrcke's lines - these lines are white bands that run parallel to one another and perpendicularly across the fingernail.  They are a result of low protein in the body.

• Anorexia.  This is just a general term for a loss of appetite or an inability to eat.

• Foamy or frothy urine.  This is caused by an excessive amount of protein being leaked into the urine. 

Signs of MCD

The main sign that medical professionals will be looking for is the presence of protein in the urine, otherwise known as proteinuria.  Healthy people will excrete a small amount of protein daily, however, once that amount is above a certain number (150mg for adults and 29-238mg for children) it is a medical problem and indicative of nephrotic syndrome.  The tentative diagnosis is then confirmed through a kidney biopsy.



References:

 http://web.b.ebscohost.com.offcampus.lib.washington.edu/ehost/pdfviewer/pdfviewer?vid=4&sid=15a322f7-c41c-48cc-8fc6-90a0fdbcaed7%40sessionmgr115&hid=125

https://www.kidney.org/atoz/content/nephrotic

http://www.merckmanuals.com/professional/genitourinary_disorders/glomerular_disorders/overview_of_nephrotic_syndrome.html

Diagnosis

Early diagnosis of this disease is extremely challenging.  Typically, the disease has already caused nephrotic syndrome and the patient is experiencing symptoms: frothy urine, weight gain from fluid retention, and edema (swelling due to fluid retention.) Once doctors are looking for reasons for the cause of nephrotic syndrome, the kidneys are biopsied (a small piece is removed to be viewed under a microscope.)

Diagnosis of this disease is essentially how the disease gets its name.  The third layer of the glomeruli, the podocytes, are visible under a regular standard light microscope, but it is nearly impossible to see detail and the way that the foot processes fit together.  So under this microscope, all elements are seen and the glomerulus shows minimal change.

 Glomerulus under a light microscope

However, if the same cells are put underneath an electron microscope, which will magnify cells to one million times their normal size, you can see the podocytes and their foot processes clearly.  It is very easy to see the way that they should uniformly fit together to form filtration slits..and as shown below, and the way that they look when they don't.

 Normal glomerulus under an electron microscope

A - close up of normal foot processes under electron microscope

B - close up of fused, raised and thinned foot processes under electron microscope

So once the symptoms start occuring the biopsy is taken and viewed and the abnormal podocyte fusion is discovered.  At this point, all symptoms can be attributed to MCD.  It is important to state here that MCD can be put into remission fairly easily once it is discovered.

However, biopsying a kidney is a fairly invasive procedure, so researchers are currently working on different methods of diagnosing MCD including the presence of certain proteins in urine, specifically transmembrane proteins that are present in large numbers in podocytes and low molecular weight proteins.  However, these diagnosis techniques are still in the early stage of research and kidney biopsy is currently the best way to make a certain diagnosis.

References:

 http://link.springer.com.offcampus.lib.washington.edu/article/10.1007/s00467-014-2915-3/fulltext.html

http://europepmc.org/abstract/med/10878397

What happens to the filter? (Pathophysiology)

The cause of this disease is still unknown.  They refer to it as 'idiopathic' which is a term they use to refer to any disease in which the cause is not known.  There are active studies being conducted now to determine why the foot processes of the podocytes don't fit together properly.



Here are a few factors that scientists believe could be potential contributing factors:

• Allergic reactions
• NSAID use
• Tumors
• Vaccinations
• Viral infections

Because scientists don't know why the disease happens, it is hard to gauge the progression of the disease.  Typically, it won't be picked up on until it has already progressed to nephrotic syndrome and there are symptoms visible in or on the body.  However, basically, the podocytes (the third layer of the glomerular filtration system) become effaced, which means soften, shorten and grow thinner and some fuse together and lift while too much space is left between others.  Protein, which is a molecule that is needed in large amounts for our bodies to move, fight off infection, balance our pH levels and many, many more things, is lost into the urine.


Here is how the glomerulus work in a normally functioning kidney:

 

Recall that the glomerulus is a three-layered filter.  In a person who is afflicted with minimal change disease, the third and outermost layer (foot processes of the podocytes) have fused together, thinned and raised and are no longer evenly spaced surrounding the capillaries, which makes it impossible for their foot processes to fit together properly and tightly.  They now allow some protein molecules to seep out and into the filtrate (the liquid that is the first stage of urine.)

When protein is lost, your body cannot regulate the processes that need protein.  You may end up suffering from:

• swelling
• shortness of breath
• needing to urinate more often
• hiccups
• fatigue
• trouble sleeping
• nausea and vomiting
• dry, itchy skin.

Eventually your body will begin to completely shut down.  However, once diagnosed, MCD is manageable.  


References:

 http://web.a.ebscohost.com.offcampus.lib.washington.edu/ehost/pdfviewer/pdfviewer?sid=07f2944c-cf4a-4486-a156-1b0c1d133dc2%40sessionmgr4002&vid=5&hid=4214

http://library.med.utah.edu/WebPath/RENAHTML/RENAL102.html

http://www.nlm.nih.gov/medlineplus/ency/article/000496.htm

Prevelance and Distribution (Epidemiology)

Who can get MCD?

Anyone can get Minimal Change Disease.  It is the number one cause of nephrotic syndrome* in children.  Most of the time, the disease affects children less than five years old and boys twice as often as girls.  However, adults can acquire MCD as well.  The average age of onset in adults is 40 years and the prevalence in both genders is equal.

*Nephrotic syndrome is another name for a disease of the kidney that includes edema (weight gain due to too much fluid in the body) and loss of protein into the urine.


MCD accounts for:

     70% - 90% of nephrotic syndrome in children under 10
     50% of nephrotic syndrome cases in children ages 10 - 18
     10% - 15% of primary nephrotic syndrome in adults

How does a person get MCD?

The cause of MCD is unknown.  It is a rare disease that was first identified in the early 1900s.  It was originally called lipoid nephrosis because of the amount of lipids in the tubules and urine. 

This disease may be related to the following:

• Allergic reactions
• NSAID use
• Tumors
• Vaccinations
• Viral infections

However, more research is currently being done to understand why the podocytes of the glomeruli fuse together and become unequally spaced.

How many people are afflicted with MCD?

MCD is more common in Asia than in North America and/or Europe, although it is not understood if this is due to more cases or diagnosis methods/biopsy practices.  2-7 new cases per 100,000 children are diagnosed annually.  The current prevalence is approximately 15 per 100,000.

References:

http://www.rarediseasesnetwork.org/neptune/patients/learnmore/MCD/

http://www.slideshare.net/avalliant?utm_campaign=profiletracking&utm_medium=sssite&utm_source=ssslideview

http://www.nlm.nih.gov/medlineplus/ency/article/000496.htm

http://emedicine.medscape.com/article/243348-overview#a0199

What is Minimal Change Disease?

Minimal Change Disease (MCD, for short) is a kidney disease in which large amounts of protein are lost in the urine.  It is the number one cause of nephrotic syndrome in children and a leading cause of nephrotic syndrome in adults worldwide. Nephrotic syndrome is a group of symptoms that include protein in the urine, low blood protein levels, high cholesterol levels, high triglyceride levels, and swelling.

Your kidneys are responsible for cleaning your blood and filtering out waste products.  To do this, all the blood is filtered in the functional units of the kidneys call nephrons.  The nephrons contain two parts, glomeruli (multiple glomerulus) and tubules.  The glomerulus (one single unit) of each nephron is the first filter.  Waste products of the blood are pushed out of the glomerulus through holes.  Larger and important parts of the blood, red blood cells and protein, are kept inside the glomerulus and go back into circulation.

Here is a short video on how the parts of your kidneys function to keep your blood clean.  He talks about the kidney, nephron and glomerulus from 3:44 - 4:48.

The system in this video is normally functioning.  In MCD, the third layer of the glomerulus filter, the podocytes, have foot processes that are not shaped properly.  Typically, they are very symmetrical and fit together perfectly (kind of like interlacing your fingers together tightly) so as to not allow anything important to pass through and leave our blood stream.  MCD presents in foot processes that don't fit together, are too thin and are slightly elevated. 









The protein is filtered out of the glomerulus, lost to the blood and voided from the body in urine.  The presence of protein in the urine is called proteinuria.  The picture to the right shows the holes in the glomeruli, and more specifically the slits between the foot processes of the podocytes, allowing protein to pass through along with the waste products. 




References:

http://www.unckidneycenter.org/kidneyhealthlibrary/minimalchange.html

http://www.nature.com/ki/journal/v83/n3/full/ki2012412a.html#close

http://www.edren.org/pages/edreninfo/minimal-change-disease.php

Terminology

Some terms that you'll need to know to understand just what minimal change disease is...


 Kidney - Almost every human being has two kidneys.  They are small, bean-shaped organs (about the size of a fist) that are located on either side of the spine and below the rib cage.  Kidneys are responsible for constantly cleaning all of our blood and getting rid of the waste by producing urine. It is made up of about a million tiny filters that our blood flows through called nephrons.



Nephron - A nephron (NEF-ron) is a tiny filter within the kidney.  There are approximately a million nephrons in each kidney.  Each nephron works through a two different filter processes, the glomerulus and the tubule.






Glomerulus - The glomerulus (glom-AIR-you-lus) is the first filter in the kidney.  It works kind of like a pasta strainer.  A large, circular area called Bowman's capsule that allows blood to enter and has specifically sized holes in it that allow waste particles to pass through the holes into the tubules but keep blood cells and protein molecules in the body's circulation.  The glomerulus is actually composed of three different layers of filters: fenestrated endothelium, a basement membrane and epithelial cells called podocytes.


The three layers of the glomerulus:


1. Fenestrated endothelium -The innermost cells of the glomerulus.  Endothelial cells of the capillary (which carries the blood into Bowman's capsule) that are fenestrated or have holes in them to allow waste products to pass through.  These holes in the fenestrated endothelium do not allow red blood cells or large particles of protein to pass through, however, they are the largest holes and some particles that are important to the body are able to pass through this first layer.


2. Basement membrane - This second and center layer of the filter is an area made of collagen fibers and other proteins that are fused together but leave small holes to allow waste products to pass through. The space between the fibers and proteins of the basement membrane are smaller than the fenestrated endothelium and they are able to recapture particles of protein and put them back into circulation.

3. Podocytes (with foot processes) -These epithelial cells that surround the outside of Bowman's capsule have foot processes or small projections of the cell itself that are very close together.  In a normally functioning glomerulus, these podocytes are all separated from one another and aligned perfectly to form tiny slits that allow waste products to squeeze through but recapture all proteins.  The podocytes are the smallest and final layer of the filter.  In minimal change disease, the podocyte is the part of the cell that is malformed. 

The three layers of the glomerulus: 

fenestrated endothelium, basement membrane, and podocytes.  

Light (standard) microscope -A typical microscope that magnifies cells to 100 times their normal size.

Electron microscope -A powerful microscope that magnifies cells to 1 million times their normal size.



References:

http://www.nlm.nih.gov/medlineplus/ency/article/000496.htm

http://kidney.niddk.nih.gov/kudiseases/pubs/yourkidneys/

 http://courses.washington.edu/conj/bess/filtration/filtration.htm