MCNS & FSGS
MCNS, or minimal change nephrotic syndrome, is the most frequent diagnosis causing nephrotic syndrome in children. Nephrotic syndrome (NS) can be caused by many diseases--MCNS< FSGS (focal segmental glomerulosclerosis), which is the second most common cause, MPGN (membranoproliferative glomerulonephritis), MGN (membranous glomerulopathy), lupus nephritis, HSP nephritis, and other diseases. Children who have nephritis from lupus, HSP, or MPGN do not always have NS as part of their disease. They may have proteinuria (protein in the urine) but in quantities less than one sees in NS. In NS one sees heavy (i.e. lots of) proteinuria, low blood protein levels, high blood cholesterol levels and swelling (edema), generally around the eyes, the extremities and the abdomen.
MCNS generally comes on fairly fast, over days, and often the first thing noted is puffy eyes in the morning. Mild swelling usually first shows up in the eyes in the morning. The tissues around the eyes are loose and so there is room to hold water between the cells of these tissues, and when one has been lying flat all night, fluid goes to the site of least resistance, around the eyes. As the child is up and around and the day goes on, gravity pulls that fluid down, and the abdomen seems big and the feet swell. When the edema gets bad, everything swells.
The first thing that goes wrong is that the kidney filters, the glomeruli, become leaky for protein. They continue to do everything else normally. As protein is lost into the urine, the liver can't keep up making new protein and the blood protein level falls. Protein in the blood, particularly albumin, acts as a sponge to keep fluid in the blood vessels, so when the albumin level is low, fluid leaks out of the blood vessels into the tissues and causes swelling. Then the blood fluid volume is low, which means that blood flow through the blood vessels in the heart and kidneys is low. Special receptors sense this, and two hormones appear on the scene that tell the kidneys to retain water and salt in the blood stream. Urine volume decreases, salt concentration in the urine decreases proportionately, and salt and water are retained in the body. The salt and water don't stay in the blood vessels because of lack of the sponge effect (oncotic pressure) but rather leaks out into the tissues and causes swelling. Thereafter, the more salt and water the child takes, the more goes out into the tissues and causes swelling. Another effect of these hormones is to make one thirsty, since the perception of the body is that fluid is needed, so the child wants to drink--and proportionately take in salt. With thirst turned on, the child can all of a sudden get thirsty and seem to balloon up overnight.
At the beginning the child just seems to have eyes that are puffy in the morning but get better through the day. It is common to think that the problem is allergies with the culprit being something in the bedroom. After a few more days, it becomes obvious that the child is swollen all over. A urine test shows that the urine is concentrated--high concentration of waste products to water, and also that the urine contains lots of protein. There may be a little blood in the urine too. Most of the time the blood pressure is normal, but it can be a little elevated. The creatinine (marker waste product measured to evaluate kidney filtration function) is usually normal, but it may be a little high related to the low blood volume (creatinine is measured as a concentration in blood and if the fluid is low in blood, but there is a normal amount of creatinine, the concentration of creatinine in that fluid will calculate to be high). This sequence of events is most frequent in children between ages 1 and 6 years, but can happen older, very rarely in the first year of life.
The protein leak comes about, we think, because of some abnormal immune substance in the blood that affects the filters and causes them to leak protein into the urine. Medications that blunt some of the actions of the immune system are useful in MCNS. The first medication used, which is effective in the great majority of children, is prednisone, a steroid medication. It is given as a dose of about 2 mg/kg body weight (1 kg=2.2 pounds) per day, in one or more divided doses, and it usually works within a month to eradicate the protein in the urine. The prednisone dose is then switched to every other day and it is stopped after another 1-3 months. Each of us nephrologists have our favorite way to taper the prednisone.
The chances are high that the child will have another episode, necessitating that the prednisone dose be raised back to the high daily dose. This may happen as the prednisone dose is tapered or after it is stopped. If the child ends up staying on prednisone most of the time because of relapse (i.e. recurrence of proteinuria) then that child is called steroid -dependent. If the child does not respond to prednisone at all, remaining nephrotic, then that child is termed steroid-resistant. The child who is steroid-resistant is likely to have another cause of NS for example, focal segmental glomerulosclerosis (FSGS). That situation can be very difficult.
The child who is steroid-dependent may develop side-effects of the prednisone, which at some point in time, usually after 6 months or a year, may be cause for concern. At this point, treatment with an antimetabolite drug, one that has the effect of inhibiting rapidly dividing cells such as those of the immune system, is often tried. One of two drugs is usually used at this time, chlorambucil (Leukeran) or cyclophosphamide (Cytoxan), and is given as an 8-12 week course of the drug. After a course of the drug, it is likely that the child will still have episodes of the nephrotic syndrome, but they will be much less frequent. Each episode is then treated with prednisone, but the episodes are apt to be infrequent so that much less prednisone is given overall. It is preferred to use this in prepubertal children, since the closer the child is to puberty, the more likely is toxicity to the gonads, with a reduction in the sperm or egg count. This then may lead to decreased fertility. The other main option for a steroid dependent child is cyclosporine, which then usually ends up being used on a long term basis. It is added to prednisone, and the prednisone slowly tapered, leaving the cyclosporine. The child then usually is dependent on cyclosporine, although with time, eventually the child outgrows the MCNS and comes off all drugs.
The good news about MCNS is that most children outgrow it and are healthy adults. A few children go on having episodes of NS into adulthood.
MCNS episodes, both the first episode and subsequent ones, called relapses, often happen concomitant with a viral infection, such as an upper respiratory infection of one kind or another or flu. As I stated in part one, the problem is with the immune system and its interaction with the kidney but the exact cause that starts it all with each episode is unknown. There is a very slight tendency for the disease to happen more than once in a family, but it is slight and not worth any worry. If there is one child with the disease in a family; the chances of having a second child with the disease in the same family are only slightly higher than the uncommon chance of having one child with it. The incidence of the disease appears to be about one child in 100,000. Males have the disease twice as often as females.
A related disease is focal segmental glomerulosclerosis (FSGS), in which children usually present in the same manner, but they tend to be older. It does appear over time that we are seeing more FSGS than we used to see, and perhaps less MCNS. Many people including myself feel that the two diseases are really on a continuum with each other, with one end being the MCNS child who has discrete episodes of NS which respond to prednisone and who eventually, usually by the time puberty starts, outgrows the disease, and the other end being the child who has FSGS, responds to no therapy for the NS and then goes on to renal failure. In the middle is the steroid-dependent child, who needs lots of therapy to stay in remission, and on biopsy may have either MGNS or FSGS. The course of this child in the middle is much less predictable, but in any child who remains responsive to prednisone, no matter if the biopsy shows MCNS or FSGS, there is a chance of permanent remission with time.
The question of when or whether to do a biopsy is controversial, and I believe that there is no right answer. Certainly the child who is between one and six years old and behaves like he/she has MCNS does not need a biopsy. Beyond that, I am leaning to the feeling that we should biopsy often, because we don't know much about the disease and can only benefit from seeing more biopsies at different points in time of the evolution of the disease. I believe that biopsies are safe, and that is now well-documented in the medical literature. I wrote an editorial about renal biopsy in Pediatric Nephrology in December, 1996, and pointed out their safety and ease. Many of us are doing them as an outpatient procedure. They can and should be done with good intravenous sedation, and with that the child is comfortable throughout the procedure and does not remember the experience. We use ultrasound guidance and so know exactly where the needle is being placed, so that serious complications are very rare.
Some nephrologists do a biopsy before giving chlorambucil or cyclophosphamide, and I support that practice though I do not think that it is wrong not to do one in the child who appears to have frequently relapsing MCNS and I do not religiously do them in every such patient. There is no right or wrong answer as to when it is time to give a course of chlorambucil (Leukeran) or cyclophosphamide (Cytoxan), and there is no answer as to which to give, chlorambucil or cyclosphosphamide. The ideal patient for either drug is still several years before puberty and is having frequent relapses such that he/she is usually on prednisone. What a course of one of these drugs will do for 80-90% of children is to cut down the frequency of relapses, so that the child is less frequently on prednisone and prednisone side~ffects become less of a problem. Sometimes one gives a course of one of these drugs, the child then does well for 2-3 years with infrequent relapses, then starts having frequent relapses again. In this case, a second course of one of the drugs may be helpful. The main potential toxicity from these two drugs, which is a dose-dependent problem and depends on total lifetime dose, is gonadal toxicity, such that sperm count or number of viable eggs maybe reduced. Most, but not all children are OK with one course, but receiving two is more likely to be problematic. The other question is whether having had one of these drugs increases the chances of developing cancer in one's lifetime--theoretically yes; practically with all the other influences in our environment that can trigger cancer, I doubt that this is going to turn out to be that important.
The most difficult part of this disease is that there are no absolute guidelines or rules of therapy. We lack enough information. That is always frustrating for parents.
The child who is having little problem with prednisone side-effects can also be carried by just giving the repeated courses of prednisone. However, most children who are on prednisone more than they are off of it will have slower than normal growth and will gain weight, with the extra fat going to the cheeks, bottom of the back of the neck (buffalo lump), and abdomen, with the extremities left thin. At the same time, prednisone may reduce muscle mass and strength. Prednisone also tends to cause salt and fluid retention, which is less of a problem if the diet is restricted in salt, causing high blood pressure. All of these changes are reversible once prednisone therapy is stopped. When significant amounts of prednisone are given over many years, then osteopenia (reduced bone mineral mass and strength), may be seen and the child is at risk for something called avascular necrosis of the hips, in which the top of the femur, the ball that fits into the hip socket, actually loses blood flow so the bone dies. This first causes pain, and then dysfunction of the hip joints. It is a bad problem and can be treated surgically if caught early, but can eventually require hip replacement.
Cyclosporine is another option. It can often be substituted for prednisone in the prednisone-dependent child and is usually less toxic long-term than is prednisone. It is not without its problems, which include hirsutism growing extra hair all over, which goes away when the drug is stopped) and more important nephrotoxicity, i.e. toxicity to the kidneys. The toxicity to the kidneys is dose dependent, so you always try to use the lowest effective dose, and also depends on the length of time the child is on the cyclosporine. A year or two of cyclosporine is probably not going to cause much problem, but longer periods of treatment may be problematic. Therapy in children who are prednisone-dependent is always a situation of weighing the pluses and minuses of all the options and making an individual decision. Levamisole is another option for the steroid-dependent patient, and perhaps for the steroid-resistant patient.
The child who is steroid-resistant may be a candidate for the Tune-Mendoza protocol, which consists of giving high dose methylprednisolone (Solumedrol, i.e. IV prednisone), intravenously three times a week or every other day for six doses, followed by weekly for eight doses and then slowly reducing frequency from there, along with oral prednisone and oral cyclosphosphamide. This therapy has worked in children resistant to all other therapies. It is potentially toxic, but is much better than remaining in the nephrotic state. Any child who remains nephrotic, untouched by any therapy, year after year, no matter what the initial lesion found on biopsy, will eventually go on to renal failure. I have seen the Tune-Mendoza protocol work in children where everyone had given up--I used to work with Dr. Tune, and I am a proponent of it for the right child.
Susan B. Conley, MD
St. Christopher’s Hospital for Children
Nephrotic syndrome is a constellation of findings and not a diagnosis
Minimal Change disease
Focal segmental glomerulosclerosis (FSGS)
Nephrotic syndrome consists of:
Heavy proteinuria (lots of protein in the urine)
Hypoproteinemia (low level of protein in the blood)
Edema (swelling, and also fluid in the abdominal cavity,
Hypercholesterolemia (high blood cholesterol)
Primary or idiopathic
Minimal change disease
Focal segmental glomerulosclerosis
Mesangial proliferative disease
Secondary to the other disease or part of another
Kidney disease like glomerulonephritis
Nephrotic vs Nephritic
Nephrotic (nephrosis is the verb)
Usually with proteinuria, but can be mild proteinuria
More children with FSGS
Shown in 2 studies
My perception is that those with MCNS recently have
More difficult disease
More often need to go to other drugs
Dense deposit disease
Occasionally post-infectious GN
Systemic disease with GN
Sickle Cell nephropathy
Monoclonal immunoglobulin deposit disease
HIV nephropathy (looks like FSGS)
Fluid in the abdomen (ascites)
Face, especially tissue around eyes which is called
Typical patient with nephrotic syndrome is a child:
1 – 6 years old
Presents with edema after a viral infection
Normal renal function
Has minimal change nephrotic syndrome
Minimal change nephrotic syndrome
Majority of cases of NS in children
But then often remit permanently in adolescence
10 – 15% of cases of NS in adults
Focal segmental glomerulosclerosis
Focal sclerosis or FSGS for short
25% of patients do fairly well and may eventuall
have a long-term remission
Majority have recurrent or persistent nephrotic syndrome
At least 25% go on to complete kidney failure
Immune system aberration > change in glomerular
Loss of many crucial proteins
Albumin > decreased oncotic pressure > edema
Antithrombin III > clotting (deep vein thromboses
Vitamin D binding protein
Binds the precursor chemical to activated Vitamin D
So can get rickets
IgG (gammaglobulin): blood levels often < 100 mg/dl>
Infection a major risk
TBG (thyroid binding globulin) > hypothyroidism
Other immune proteins
Adcites (fluid in the abdomen) is a great
Medium for bacterial growth
Cellulitis (infection of the skin and tissue underneath)
Especially in areas with edema
Prednisone 2 mg/kg for 1 month, then 2/kg qod
For 1 month, taper over 1 – 2 months
Give prednisone in dose
Recurrent episodes > 3 times/yr
No response to prednisone in 4wk
Nephritic signs at presentation
Ø 10 yr old at presentation
List serv for parents
Susan B. Conley, MD