Minimal change disease

URL of this page: http://www.nlm.nih.gov/medlineplus/ency/article/000496.htm

Minimal change disease is a kidney disorder that can lead to nephrotic syndrome, although the
nephrons of the kidney look normal under a regular microscope.

Causes
Each kidney is made of more than a million units called nephrons, which filter blood and
produce urine.

In minimal change disease, there is damage to the glomeruli -- the tiny blood vessels inside the
nephron. The disease gets its name because this damage isn't visible under a regular microscope.
It can only be seen under an electron microscope.

Minimal change disease is the most common cause of nephrotic syndrome in children. It is also
seen in adults.

The cause is unknown, but the disease may occur after:

 Allergic reactions
 Recent immunizations
 Viral infection

Symptoms
There may be symptoms of nephrotic syndrome:

 Foamy appearance of the urine

 Poor appetite
 Swelling (especially around the eyes, feet, and ankles, and in the abdomen)
 Weight gain (from fluid retention)

Minimal change disease does not reduce the amount of urine produced. It rarely progresses to
kidney failure.

Exams and Tests

The doctor may not be able to see any obvious outward signs of the disease, other than swelling.
Blood and urine tests reveal signs typical of nephrotic syndrome, including:
  High cholesterol
 High levels of protein in the urine
 Low levels of albumin in the blood

A kidney biopsy and examination of the tissue with an electron microscope can show signs of
minimal change disease. An immunofluorescence exam of the biopsied kidney tissue is negative.

Treatment
Corticosteroids can cure minimal change disease in most children. Some patients may need to
stay on steroids to keep the disease in remission.

Adults do not respond to steroids quite as well as children, but many still do find steroids
effective. Adults may have more frequent relapses and steroid dependence.

Patients who have three or more relapses may do better with cytotoxic therapy. In most cases,
this involves a medication called cyclophosphamide. Other medicines that have been used
include cyclosporine and chlorambucil.

Swelling may be treated with:

 ACE inhibitor medicines

 Blood pressure control
 Diuretics (water pills)

You may also be told to reduce the amount of salt in your diet.

Outlook (Prognosis)
Minimal change disease usually responds well to corticosteroids, often within the first month. A
relapse can occur, but patients may improve after prolonged treatment with corticosteroids and
medications that suppress the immune system (immunosuppressive medications).

Possible Complications
 Nephrotic syndrome
 Side effects of medications

When to Contact a Medical Professional

Call for an appointment with your health care provider if you develop symptoms of minimal
change disease.
If you have this disorder, call for an appointment with your health care provider if your
symptoms worsen or you develop new symptoms, including side effects from the medications
used to treat the disorder.

Prevention
There is no known prevention.

Alternative Names
Minimal change nephrotic syndrome; Nil disease; Lipoid nephrosis; Idiopathic nephrotic
syndrome of childhood

References
Appel GB. Glomerular disorders and nephrotic syndromes. In: Goldman L, Ausiello D, eds.
Cecil Medicine. 23rd ed. Philadelphia, Pa: Saunders Elsevier; 2007: chap 122.

http://www.nlm.nih.gov/medlineplus/ency/article/000496.htm
What is nephrotic syndrome?

Nephrotic syndrome is a set of signs or symptoms that may point to kidney problems. The
kidneys are two bean-shaped organs found in the lower back. Each is about the size of a fist.
They clean the blood by filtering out excess water and salt and waste products from food.
Healthy kidneys keep protein in the blood, which helps the blood soak up water from tissues. But
kidneys with damaged filters may leak protein into the urine. As a result, not enough protein is
left in the blood to soak up the water. The water then moves from the blood into body tissues and
causes swelling.

Both children and adults can have nephrotic syndrome. The causes of and treatments for
nephrotic syndrome in children are sometimes different from the causes and treatments in adults.
For information about nephrotic syndrome in adults, see the National Institute of Diabetes and
Digestive and Kidney Diseases (NIDDK) publication Nephrotic Syndrome in Adults.

Childhood nephrotic syndrome can occur at any age but is most common between the ages of 1½
and 5 years. It seems to affect boys more often than girls.

A child with nephrotic syndrome has these signs:

 high levels of protein in the urine, a condition called proteinuria

 low levels of protein in the blood
 swelling resulting from buildup of salt and water
 less frequent urination
 weight gain from excess water

Nephrotic syndrome is not itself a disease. But it can be the first sign of a disease that damages
the kidney’s tiny blood-filtering units, called glomeruli, where urine is made.

[Top]

How is childhood nephrotic syndrome diagnosed?

To diagnose childhood nephrotic syndrome, the doctor may ask for a urine sample to check for
protein. The doctor will dip a strip of chemically treated paper into the urine sample. Too much
protein in the urine will make the paper change color. Or the doctor may ask for a 24-hour
collection of urine for a more precise measurement of the protein and other substances in the
urine.

The doctor may take a blood sample to see how well the kidneys are removing wastes. Healthy
kidneys remove creatinine and urea nitrogen from the blood. If the blood contains high levels of
these waste products, some kidney damage may have already occurred. But most children with
nephrotic syndrome do not have permanent kidney damage.
A strip of chemically treated paper will change color when dipped in urine with too much
protein.

In some cases, the doctor may want to examine a small piece of kidney tissue with a microscope
to see if something specific is causing the syndrome. The procedure of collecting a small tissue
sample from the kidney is called a biopsy, and it is usually performed with a long needle passed
through the skin. The child will be awake during the procedure and receive calming drugs and a
local painkiller at the site of the needle entry. A child who is prone to bleeding problems may
require open surgery for the biopsy. General anesthesia will be used if surgery is required. For
any biopsy procedure, the child will stay overnight in the hospital to rest and allow the health
care team to address quickly any problems that might occur.

[Top]

What conditions are associated with childhood nephrotic syndrome?

Minimal Change Disease

The condition most commonly associated with childhood nephrotic syndrome is minimal change
disease. Doctors do not know what causes it. The condition is called minimal change disease
because children with this form of the nephrotic syndrome have normal or nearly normal
appearing kidney biopsies. If a child is diagnosed with minimal change disease, the doctor will
probably prescribe prednisone, which belongs to a class of drugs called corticosteroids.
Prednisone stops the movement of protein from the blood into the urine, but it does have side
effects that the doctor will explain. Following the doctor’s directions exactly is essential to
protect the child’s health. The doctor may also prescribe another type of drug called a diuretic,
which reduces the swelling by helping the child urinate more frequently.

When protein is no longer present in the urine, the doctor will begin to reduce the dosage of
prednisone. This process takes several weeks. Some children never get sick again, but most
experience a relapse, developing swelling and protein in the urine again, usually following a viral
illness. However, as long as the child continues to respond to prednisone and the urine becomes
protein free, the child has an excellent long-term outlook without kidney damage.

Children who relapse frequently, or who seem to be dependent on prednisone or have side effects
from it, may be given a second type of drug called a cytotoxic agent. The agents most frequently
used are cyclophosphamide and chlorambucil. After reducing protein in the urine with
prednisone, the doctor may prescribe the cyclophosphamide or chlorambucil for 8 to 12 weeks.
Alternatively, cyclosporine, a drug also used in transplant patients, may be given. Treatment with
cyclosporine frequently continues over an extended period.

In recent years, doctors have explored the use of mycophenolate mofetil (MMF) instead of
cytotoxic agents for children who relapse frequently. MMF is an immunosuppressant used to
treat autoimmune diseases and to keep the body from rejecting a transplanted organ. MMF has
not been tested for treating minimal change disease in large clinical trials, but doctors report
promising results with small numbers of patients. MMF has milder side effects than cytotoxic
agents, but taking immunosuppressants can raise the risk of infection and other diseases. The
good news is that most children outgrow minimal change disease by their late teens with no
permanent damage to their kidneys.

Focal Segmental Glomerulosclerosis (FSGS) and Membranoproliferative Glomerulonephritis

(MPGN)

In about 20 percent of children with nephrotic syndrome, a kidney biopsy reveals scarring or
deposits in the glomeruli. The two most common diseases that damage these tiny blood-filtering
units are FSGS and MPGN.

Because prednisone is less effective in treating these diseases than it is in treating minimal
change disease, the doctor may use additional therapies, including cytotoxic agents. Recent
experience with another class of drugs called ACE inhibitors, usually used to treat high blood
pressure, indicates these drugs can help decrease the amount of protein leaking into the urine and
keep the kidneys from being damaged in children with FSGS or MPGN.

Congenital Nephropathy

Rarely, a child may be born with congenital nephropathy, a condition that causes nephrotic
syndrome. The most common form of this condition is congenital nephropathy of the Finnish
type (CNF), inherited as an autosomal recessive trait—meaning the gene for CNF must be
inherited from both parents.

Another condition that causes nephrotic syndrome in the first months of life is diffuse mesangial
sclerosis (DMS). The pattern of inheritance for DMS is not as clearly understood as the pattern
for CNF, although the condition does appear to be genetic.

Since medicines have little effect on congenital nephropathy, transplantation is usually required
by the second or third year of life, when the child has grown enough to receive a kidney. To keep
the child healthy, the doctor may recommend infusions of the protein albumin to make up for the
protein lost in urine and prescribe a diuretic to help eliminate the extra fluid that causes swelling.
The child’s immune system may be weakened, so antibiotics should be given at the first sign of
infection.

Congenital nephropathy can disturb thyroid activity, so the child may need the substitute
hormone thyroxine to promote growth and help bones mature. Some children with congenital
nephropathy have excessive blood clotting, or thrombosis, which must be treated with a blood
thinner like warfarin.

A child with congenital nephropathy may need tube feedings to ensure proper nutrition. In some
cases, the diseased kidneys may need to be removed to eliminate proteinuria. Dialysis will then
be required to replace kidney function until the child’s body is big enough to receive a
transplanted kidney. Peritoneal dialysis is preferable to hemodialysis for young children.

In peritoneal dialysis, a catheter is surgically placed in the abdomen and then used to introduce a
solution into the abdominal cavity, or peritoneum. The solution draws wastes and extra fluid
from the bloodstream. After a few hours, the solution is drained and replaced with a fresh supply.
The drained solution carries the wastes and extra fluid out of the body.

[Top]

Points to Remember

 Nephrotic syndrome is a set of signs or symptoms that may point to kidney problems.
 Childhood nephrotic syndrome is most common between the ages of 1½ and 5 years.
 Nephrotic syndrome causes proteinuria, low levels of protein in the blood, less frequent
urination, and swelling and weight gain from the buildup of fluid.
 Diagnosis of nephrotic syndrome requires urine and blood samples and may include a kidney
biopsy.
 Most cases of childhood nephrotic syndrome result from minimal change disease.
 The two most common diseases that damage the kidneys’ tiny blood-filtering units and cause
nephrotic syndrome are focal segmental glomerulosclerosis (FSGS) and membranoproliferative
glomerulonephritis (MPGN).
 Congenital nephropathy is a rare condition that causes nephrotic syndrome in newborns.

[Top]

Hope through Research

The NIDDK conducts and supports research to help people with kidney disease, including
children. The NIDDK’s Division of Kidney, Urologic, and Hematologic Diseases (DKUHD)
maintains the Pediatric Nephrology Program, which supports research into the causes, treatment,
and prevention of kidney disease in children. In 2002, the DKUHD initiated the Focal Segmental
Glomerulosclerosis Clinical Trial to learn more about the best way to treat FSGS. Then, in 2003,
the DKUHD began the Prospective Study of Chronic Kidney Disease in Children to learn more
about the negative effects of pediatric kidney disease, including cardiovascular disease and
neurocognitive impairment.

People interested in participating in clinical trials of new treatments for nephrotic syndrome can
find a list of centers recruiting patients at www.ClinicalTrials.gov.

The U.S. Government does not endorse or favor any specific commercial product or company.
Trade, proprietary, or company names appearing in this document are used only because they are
considered necessary in the context of the information provided. If a product is not mentioned,
the omission does not mean or imply that the product is unsatisfactory.

[Top]

http://kidney.niddk.nih.gov/kudiseases/pubs/childkidneydiseases/nephrotic_syndrom/
Introduction
Background
Nephrotic syndrome is kidney disease with proteinuria, hypoalbuminemia, and edema. Nephrotic range
proteinuria is 3 grams per day or more. On a single, "spot" urine collection, it is 2 grams of protein per
gram of urine creatinine.

There are many specific causes of nephrotic syndrome. These include kidney diseases such as minimal-
change nephropathy, focal glomerulosclerosis, and membranous nephropathy. Nephrotic syndrome can
also result from systemic diseases that affect other organs in addition to the kidneys, such as diabetes,
amyloidosis, and lupus erythematosus. A schematic drawing of the glomerular barrier is shown below.

Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement
membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often
referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid
across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125
mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being
20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of
albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from
Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American
Physiological Society (www.the-aps.org).
[ CLOSE WINDOW ]
Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement
membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often
referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid
across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125
mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being
20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of
albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from
Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American
Physiological Society (www.the-aps.org).

Nephrotic syndrome may affect adults and children, of both sexes and of any race. It may occur in
typical form, or in association with nephritic syndrome. The latter connotes glomerular inflammation,
with hematuria and impaired kidney function.
Classification

Nephrotic syndrome can be primary, being a disease specific to the kidneys, or it can be
secondary, being a renal manifestation of a systemic general illness. In all cases, injury to
glomeruli is an essential feature.

Primary causes of nephrotic syndrome include, in approximate order of frequency:

 Minimal-change nephropathy
 Focal glomerulosclerosis
 Membranous nephropathy
 Hereditary nephropathies

Secondary causes include, again in order of approximate frequency:

 Diabetes mellitus
 Lupus erythematosus
 Amyloidosis and paraproteinemias
 Viral infections (eg, hepatitis B, hepatitis C, human immunodeficiency virus [HIV] )
 Preeclampsia

Nephrotic-range proteinuria may occur in other kidney diseases, such as IgA nephropathy. In
that common glomerular disease, one third of subjects may have nephrotic-range proteinuria.1
Nephrotic syndrome may occur in persons with sickle cell disease and evolve to renal failure.
Membranous nephropathy may complicate bone marrow transplantation, in association with
graft versus host disease. Kidney diseases that affect tubules and interstitium, such as interstitial
nephritis, will not cause nephrotic syndrome.

The above causes of nephrotic syndrome are largely those for adults, and this article will
concentrate primarily on adult nephrotic syndrome.

However, nephrotic syndrome in infancy and childhood is an important entity. A study from
New Zealand found the incidence of nephrotic syndrome to be almost 20 cases per million
children under age 15 years.2 In specific populations, such as those of Finnish or Mennonite
origin, congenital nephrotic syndrome may occur in 1 in 10,000 or 1 in 500 births, respectively.3
According to the International Study of Kidney Diseases in Childhood (ISKDC), 84.5% of all
children with primary nephrotic syndrome have minimal-change nephrotic syndrome (MCNS),
9.5% have focal segmental glomerulosclerosis (FSGS), 2.5% have mesangial proliferation, and
3.5% have membranous nephropathy or another cause of the disease.4,5 Increasing trends of
FSGS incidence are being reported, but MCNS remains the most important cause of chronic
renal disease in children.

From a therapeutic perspective, nephrotic syndrome may be classified as steroid sensitive,

steroid resistant, steroid dependent, or frequently relapsing.
Recent studies

In a retrospective study, Vivarelli et al investigated whether, in children with idiopathic

nephrotic syndrome, the period of time between the onset of steroid therapy and syndrome
remission can serve as a prognostic indicator. The study included 103 patients with idiopathic
nephrotic syndrome and had a median follow-up time of 43 months. The authors found that in
patients who did not suffer relapse or who relapsed infrequently, the median period between
treatment onset and remission was less than 7 days. In patients who frequently relapsed or who
developed steroid-dependent nephrotic syndrome, the median time to remission was more than 7
days after treatment began. The authors concluded that the length of time between steroid
treatment onset and remission is an early prognostic indicator for patients with idiopathic
nephrotic syndrome.6

Pathophysiology

Glomerular permeability

In a healthy individual, less than 0.1% of plasma albumin may traverse the glomerular filtration
barrier.7 Controversy exists regarding the sieving of albumin across the glomerular permeability
barrier. Specifically, it is proposed that there is ongoing albumin passage into the urine, in many
grams per day, with equivalent substantial tubular uptake of albumin, the result being that the
urine has 80 mg per day or less of daily albumin.8 This controversy is based on studies in
experimental animals. However, studies of humans with tubular transport defects suggest that the
glomerular urinary space albumin concentration is 3.5 mg/L.9 With this concentration, and a
normal daily glomerular filtration rate (GFR) of 150 liters, one would expect no more than 525
mg per day of albumin in the final urine. Amounts above that level point to glomerular disease.

The glomerular capillaries are lined by a fenestrated endothelium that sits on the glomerular
basement membrane, which in turn is covered by glomerular epithelium, or podocytes, which
envelops the capillaries with cellular extensions called foot processes. In between the foot
processes are the filtration slits. These 3 structures—the fenestrated endothelium, glomerular
basement membrane, and glomerular epithelium—are the glomerular filtration barrier. A
schematic drawing of the glomerular barrier is seen in the image below.
Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement
membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often
referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid
across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125
mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being
20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of
albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from
Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American
Physiological Society (www.the-aps.org).
[ CLOSE WINDOW ]
Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement
membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often
referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid
across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125
mL/min. The plasma flow rate (Qp) is close to 700 mL/min, with the filtration fraction being
20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of
albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from
Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American
Physiological Society (www.the-aps.org).

Filtration of plasma water and solutes is extracellular and occurs through the endothelial fenestrae and
filtration slits. The importance of the podocytes and the filtration slits is shown by genetic diseases.
Thus, in congenital nephrotic syndrome of the Finnish type, the gene for nephrin, a protein of the
filtration slit, is mutated, leading to nephrotic syndrome in infancy . Similarly, podocin, a protein of the
podocytes, may be abnormal in a number of children with steroid-resistant focal glomerulosclerosis.

The glomerular structural changes that may cause proteinuria are (1) damage to the endothelial surface,
(2) damage to the glomerular basement membrane, and/or (3) damage of the podocytes. One or more
of these mechanisms may be seen in any one type of nephrotic syndrome. Albuminuria alone may
occur, or, with greater injury, leakage of all plasma proteins, (ie, proteinuria) may take place.

Proteinuria that is more than 85% albumin is selective proteinuria. Albumin has a net negative charge,
and it is proposed that loss of glomerular membrane negative charges could be important in causing
albuminuria. Nonselective proteinuria, being a glomerular leakage of all plasma proteins, would not
involve changes in glomerular net charge but rather a generalized defect in permeability. This construct
does not permit clear-cut separation of causes of proteinuria, except in minimal-change nephropathy, in
which proteinuria is selective.

Pathogenesis of edema

An increase in glomerular permeability leads to albuminuria and eventually to hypoalbuminemia. In

turn, hypoalbuminemia lowers the plasma colloid osmotic pressure, causing greater transcapillary
filtration of water throughout the body and thus the development of edema.

Capillary hydrostatic pressure and the gradient of plasma to interstitial fluid oncotic pressure
determine the movement of fluid from the vascular compartment to the interstitium. The oncotic
pressure is mainly determined by the protein content. The flux of water across the capillary wall
can be expressed by the following formula:

Qw = K ([Pc - Pi] - [pp - pi]

In this formula, Qw is net flux of water, K is the capillary filtration coefficient, Pc is capillary
hydrostatic pressure, and Pi is the interstitial fluid hydrostatic pressure, while pp is the plasma
oncotic pressure, and pi is the interstitial fluid oncotic pressure. With a high enough capillary
hydrostatic pressure or a low enough intravascular oncotic pressure, the amount of fluid filtered
exceeds the maximal lymphatic flow, and edema occurs. In patients with nephrotic syndrome,
this causes a reduction in plasma volume, with a secondary increase of sodium and water
retention by the kidneys.

An alternate hypothesis is that a condition of renal sodium retention occurs because of the
proteinuria, but this is not related to intravascular volume or to serum protein concentration. The
evidence supporting this hypothesis includes the fact that (1) sodium retention is observed even
before the serum albumin level starts falling and (2) intravascular volume is normal or even
increased in most patients with nephrotic syndrome. This could occur if intraluminal protein
directly stimulated renal epithelial sodium reabsorption.10

A third possible mechanism is an enhanced peripheral capillary permeability to albumin, as

shown by radioisotopic technique in human studies of 60 patients with nephrotic syndrome.11
This would then lead to increased tissue oncotic pressure and fluid retention in the peripheral
tissues.

Metabolic consequences of proteinuria

In the nephrotic syndrome, levels of serum lipids are usually elevated. This can occur via (1)
hypoproteinemia that stimulates protein, including lipoprotein, synthesis by the liver, and (2)
diminution of lipid catabolism caused by reduced plasma levels of lipoprotein lipase.

The loss of antithrombin III and plasminogen via urine, along with the simultaneous increase in
clotting factors, especially factors I, VII, VIII, and X, increases the risk for venous thrombosis
and pulmonary embolism. In the first 6 months that a patient has nephrotic syndrome, the
occurrence rate of venous thrombosis may reach 10%.12

Vitamin D–binding protein may be lost in the urine, leading to hypovitaminosis D, with
malabsorption of calcium and development of bone disease.13

Urinary immunoglobulin losses may lower the patient's resistance to infections and increase the
risk of sepsis and peritonitis.

Frequency

United States

The figure below shows the incidence per million population of important causes of nephrotic
syndrome. Diabetic nephropathy with nephrotic syndrome is most common, at an estimated rate
of at least 50 cases per million population. That is an underestimation, however, since the rate of
end-stage renal disease from diabetes has reached 100 cases per million population in some
Western countries. In children, nephrotic syndrome may occur at a rate of 20 cases per million
children.2
Incidence of important causes of nephrotic syndrome, in number per million population. The
left panel shows systemic causes, and the right panel lists primary renal diseases that can
cause nephrotic syndrome. fgs = focal glomerulosclerosis, MN = membranous nephropathy,
min change = minimal-change nephropathy. Data are in part from Swaminathan et al and
Bergesio et al.
[ CLOSE WINDOW ]

Incidence of important causes of nephrotic syndrome, in number per million population. The
left panel shows systemic causes, and the right panel lists primary renal diseases that can
cause nephrotic syndrome. fgs = focal glomerulosclerosis, MN = membranous nephropathy,
min change = minimal-change nephropathy. Data are in part from Swaminathan et al and
Bergesio et al.

International

Biopsy studies in children with nephrotic syndrome have shown similar types of histology in
India and Turkey, compared with what one would expect in Western countries.14,15 In Pakistani
adults with nephrotic syndrome, the spectrum of histologies of kidney biopsies has been found to
be similar to that seen in western countries.16

Glomerular disease may be associated with schistosomal infection, as could occur in Egypt.17
So-called "tropical nephrotic syndrome" may not be a true entity. Doe et al summarized the
evidence for causes of nephrotic syndrome in African children.18 All of the typical histologies
may be found on kidney biopsy. The connection of nephrotic syndrome to quartan malaria is not
well-established. Indeed, Pakasa and Sumaili call attention to the apparent decline of parasite-
associated nephrotic syndrome in the Congo.19,20 It is possible that the perceived
association between nephrotic syndrome and parasitic infections was coincidental, as supported
by the ongoing and probably increasing occurrence of chronic kidney disease in the Congo.20

Mortality/Morbidity

 In the preantibiotic era, infection was a major factor in the mortality rate among patients with
nephrotic syndrome.21 Treatments for nephrotic syndrome and its complications appear to have
reduced the morbidity and mortality once associated with the syndrome.
 A study by Donadio et al of 140 patients with idiopathic membranous nephropathy, 89 of whom
received no treatment with corticosteroids or immunosuppressive drugs and 51 of whom were
treated primarily with short-term courses of prednisone alone, found that the patients' survival
rates were  the same as those expected for the general population.22 This supports the clinical
practice of expectant management for the first 6 months, without immunosuppression,
in persons with membranous nephropathy and a low risk for progression. 23
 The prognosis may worsen because of (1) an increased incidence of renal failure and the
complications secondary to nephrotic syndrome, including thrombotic episodes and infection, or
(2) treatment-related conditions, such as infectious complications of immunosuppressive
treatments.
 In secondary nephrotic syndromes, morbidity and mortality are related to the primary disease
process, such as diabetes or lupus, although in diabetic nephropathy, the magnitude of
proteinuria itself relates directly to mortality.24

Race

 Because diabetes is major cause of nephrotic syndrome, American Indians, Hispanics, and
African Americans have a higher incidence of nephrotic syndrome than do white persons.
 HIV nephropathy is a complication of HIV that is unusual in whites; it is seen with greater
frequency in African Americans.25
 Focal glomerulosclerosis appears to be overrepresented in African American children, as
compared with white children, as a cause of nephrotic syndrome. 26

Sex

 There is a male predominance in the occurrence of nephrotic syndrome, as there is for chronic
kidney disease in general. This male overrepresentation is also seen in paraneoplastic
membranous nephropathy.27
 However, lupus nephritis affects mostly women.
Age

The image below shows typical ages at which a given cause of nephrotic syndrome may occur. It
does not show every possible cause of nephrotic syndrome, such as lupus nephritis, which
typically affects young black women. The ages shown are averages.

A schema of the average patient ages associated with various common forms of nephrotic
syndrome.
[ CLOSE WINDOW ]
A schema of the average patient ages associated with various common forms of nephrotic
syndrome.

Clinical
History

 The first sign of nephrotic syndrome in children is usually swelling of the face; this is followed by
swelling of the entire body.
 Adults can present with dependent edema.
 Foamy urine may be a presenting feature.
 A thrombotic complication, such as deep vein thrombosis of the calf veins or even a pulmonary
embolus, may be the first clue indicating nephrotic syndrome.
 Additional historical features that appear can be related to the cause of nephrotic
syndrome. Thus, the recent start of a nonsteroidal anti-inflammatory drug (NSAID) or a 10-year
history of diabetes may be very relevant.

Physical

 Edema is the predominant feature of nephrotic syndrome and initially develops around the eyes
and legs. With time, the edema becomes generalized and may be associated with an increase in
weight, the development of ascites, or pleural effusions.
 Hematuria and hypertension manifest in a minority of patients.
 Additional features on exam will vary according to cause and as a result of whether or not renal
function impairment exists. Thus, in the case of longstanding diabetes, there may be diabetic
retinopathy, which correlates closely with diabetic nephropathy. If the kidney function is
reduced, there may be hypertension and/or anemia.

Causes

 The usual causes of nephrotic syndrome are discussed above (see Background). They include
primary kidney diseases, such as minimal-change nephropathy, membranous nephropathy, and
focal glomerulosclerosis, as well as systemic diseases, such as diabetes mellitus, lupus
erythematosus, and amyloidosis.
 Congenital and hereditary focal glomerulosclerosis may result from mutations of genes that
code for podocyte proteins, including nephrin, podocin, or the cation channel 6 protein.
 Nephrotic syndrome can result from drugs of abuse, such as heroin.
 Nephrotic-range proteinuria occurring in the third trimester of pregnancy is the classical finding
of preeclampsia. In that condition, also known as toxemia, there is hypertension as well. It may
occur de novo or it may be superimposed on another chronic kidney disease. In the latter case,
there will have been preexisting proteinuria that will have worsened during pregnancy.
 Medication can cause nephrotic syndrome. This includes the very infrequent occurrence of
minimal-change nephropathy with NSAID use, and the occurrence of membranous nephropathy
with the administration of gold and penicillamine, which are older drugs used for rheumatic
 diseases; there have also been reports of focal glomerulosclerosis in association with
bisphosphonates. Although recognized, these associations have not yet been quantified.
 Nephrotic-range proteinuria could occur with the use of anticancer agents, such as
bevacizumab, that inhibit vascular endothelial growth factor (VEGF). 28 However, the clinical
picture of this complication is of a thrombotic microangiopathy rather than of nephrotic
syndrome per se.
 The association of membranous nephropathy with cancer is a clinical dilemma. This association
presumably results from immune complex injury to the glomerulus caused by cancer antigens.

While there are about 6000 new cases of membranous nephropathy per year in the United
States, there are 1.5 million new cases of nonskin cancer. Therefore, from the oncologist’s
standpoint, the problem of paraneoplastic membranous nephropathy is trivial. Nonetheless, a
carefully performed analysis from France suggested that the cancer rate in persons with
membranous nephropathy is approximately 10-fold higher than it is in the general population,
especially in individuals over age 65 years.27 In that study, 50% of membranous nephropathy
cases were diagnosed before the diagnosis of cancer. Thus, in some subjects with membranous
nephropathy, one should consider the possibility of an undiagnosed cancer.

http://emedicine.medscape.com/article/244631-overview
Introduction
Background

Minimal-change disease (MCD), also known as lipoid nephrosis or nil disease, is the most
common single form of nephrotic syndrome in children. It refers to a histopathologic lesion in
the glomerulus that almost always is associated with nephrotic syndrome. It typically is a disease
of childhood, but it also can occur in adults.

Pathophysiology

It is postulated that MCD is a disorder of T cells, which release a cytokine that injures the
glomerular epithelial foot processes. This, in turn, leads to a decreased synthesis of polyanions.
The polyanions constitute the normal charge barrier to the filtration of macromolecules, such as
albumin. When the polyanions are damaged, leakage of albumin follows. The identity of this
circulating permeability factor is uncertain, although it is postulated that it may be hemopexin.

Some of the cytokines that have been studied in MCD are interleukin-12 (IL-12) and interleukin-
4 (IL-4). IL-12 levels have been found to be elevated in peripheral blood monocytes during the
active phase and normalized during remission. Interleukin-18 (IL-18) can synergize with IL-12
to selectively increase the production of vascular permeability factor from T cells. In addition,
levels of IL-4 and CD23 (a receptor for immunoglobulin E [IgE]1 ) have been found to be
elevated in peripheral blood lymphocytes.

Synaptopodin is a proline-rich protein intimately associated with actin microfilaments present in

the foot processes of podocytes. Greater synaptopodin expression in podocytes is associated with
a significantly better response to steroid therapy. On the other hand, the expression of
synaptopodin does not predict progression of MCD or diffuse mesangial hypercellularity to focal
segmental glomerulosclerosis (FSGS). Thus, this marker could be used in the future to help
determine appropriate therapy.

Interleukin-13 (IL-13) has been implicated in the pathogenesis of MCD. In a study on Chinese
children in Singapore, it was shown that IL-13 genetic polymorphisms correlate with the long-
term outcome of MCD. An animal study by Lai et al suggested that IL-13 overexpression can
cause podocyte foot process fusion and proteinuria.2

In patients who develop acute renal failure, endothelin 1 expression is greater in the glomeruli,
vessels, and tubules than in the nonacute renal failure group. The glomerular epithelial cells
(podocytes) and the slit diaphragm connecting the podocyte foot processes play a primary role in
the development of proteinuria.

Nephrin is a major component of the slit diaphragm. The slit diaphragm is often missing in MC
nephrotic syndrome (MCD) kidneys. The role of nephrin and the slit diaphragm in MCD is not
known. However, genetic variants of a glomerular filter protein may play a role in some patients
with MCD.
Izzedine et al found a lack of glomerular dysferlin expression associated with minimal-change
nephropathy in a patient with limb-girdle muscular dystrophy type 2B.25 In the same study, 2 of 3
other patients with dysferlinopathy had microalbuminuria.

Although a multitude of studies have been published, the mechanism by which T cells increase
glomerular permeability has remained unproven.

Frequency

United States

In preadolescents, minimal-change nephrotic syndrome (MCNS) makes up 85-95% of all cases

of nephrotic syndrome. In adolescents and young adults, the prevalence is 50%, while in adults,
MCNS accounts for 10-15% of primary nephrotic syndrome cases. The incidence of nephrotic
syndrome is 2-7 new cases annually per 100,000 children, and the prevalence is 15 cases per
100,000 children.

Mortality/Morbidity

Very few patients progress to end-stage renal disease. These patients are those who have FSGS
that has been misdiagnosed as MCD.

 Hypovolemic shock is perhaps the most serious complication of MCD. Hypovolemic shock
typically occurs during the edema-forming phase of relapse and may be precipitated by
diarrhea, sepsis, drainage of ascitic fluid, or the use of diuretics.
 Hypertension, somewhat paradoxically, also may occur in approximately 9-14% of children.
Hypertension occurs in approximately 30% of adults, with a greater incidence in older patients
(>60 y).
 Thromboembolic events are serious complications of nephrotic syndrome. Peripheral
thrombosis may result in gangrene, and deep venous thrombosis in the legs or pelvic veins may
be a source of pulmonary emboli. Bacterial infections, especially peritonitis, occur with greater
frequency, partly because of the loss of immunoglobulin G (IgG) and complement factors B and
D in the urine. In fact, the largest reduction in mortality in these patients follows the
introduction of antibiotics rather than any specific therapy.

Race

 Asians may be at increased risk.

Sex

 It is found twice as frequently in boys than in girls.

 The frequency is the same between the sexes in adults.
Age

 The incidence peaks in children aged 2 years, with approximately 80% being younger than 6
years at the time of diagnosis.
 In adults, the mean age of onset is 40 years.

Clinical
History

 Edema may be preceded by an upper respiratory tract infection, an allergic reaction to a bee
sting, or the use of certain drugs or malignancies.
 Facial edema is noted first.
 Malaise and easy fatigability can occur.
 Weight gain often is an additional feature.
 The patient also may present with the following:
o Hypovolemia
o Hypertension
o Thromboembolism
o Infection

Physical

 The blood pressure usually is normal in children 3 but may be elevated in adults. (In addition, the
plasma creatinine in adults is often slightly elevated at presentation.)
 Dependent edema is the most prominent sign. The retina has a wet appearance. Subungual
edema with horizontal lines (called Muehrcke lines) also may occur.
 Hernias may be found, and the elasticity of the ears may be decreased.
 Heavy proteinuria over an extended period of time leads to a state of protein depletion with
muscle wasting, thinning of the skin, and growth failure.
 Pleural and ascitic fluid can accumulate. Rarely, cellulitis, peritonitis, or pneumonia may be the
first indication of an underlying nephrotic syndrome.
 Children may have growth failure.

Causes

Almost all cases are idiopathic, but a small percentage of cases (approximately 10-20%) may
have an identifiable cause. Causes may include the following:

 Idiopathic
 Secondary

o Drugs - Nonsteroidal anti-inflammatory drugs (NSAIDs), rifampin, interferon,

ampicillin/penicillin, trimethadione, mercury-containing cosmetic skin cream
o Toxins - Mercury, lithium, bee stings, fire coral exposure
o Infection - Infectious mononucleosis, HIV, immunization
 o Tumor - Hodgkin lymphoma (most commonly), carcinoma, other lymphoproliferative
diseases
o Posthematopoietic stem cell transplant

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