By Timothy E. Bunchman, MD

What is Nephrotic Syndrome?

Nephrotic syndrome (NS) is a serious medical condition characterized by swelling, protein in the urine, decreased protein in the blood and high cholesterol levels. It can occur at any age. The reason NS must be treated is based on two serious risk factors. The first major risk factor is that of infection. These infections are present in the fluid in the belly (peritonitis) or fluid in the skin (cellulitis) and can be caused by bacteria such as streptococcus or E. coli. This infection can be overwhelming and is life-threatening.

The second major risk factor for children with NS is the risk of blood clots. When a child loses massive amounts of protein in the urine, then the ability to appropriately clot blood is lost. Therefore, these children have an increased risk of developing blood clots. This clotting can be spontaneous or related to manipulation such as the placement of an intravenous catheter (IV) for infusions, IV contrast or other insults to the vascular space. These clots can be as mild as local clotting called thrombophlebitis, or as major as a pulmonary embolism causing death.

NS has the same symptoms at all ages, yet depending on the child’s age may have different causes and with varying outcomes.

Congenital Nephrotic Syndrome

Congenital NS occurs in infants who develop nephrotic syndrome within the first three months of life. Because babies are often pudgy at this age, it is very hard to notice puffiness or swelling in them. Typically, some of these newborns will present an abnormal thyroid screening, which is a screening that is done in every state to identify and treat hypothyroidism in the newborn. The thyroid screening measures a thyroid stimulating hormone (TSH) that is abnormal in congenital nephritic syndrome. This abnormal test result leads to further screening and aids in the diagnosis of congenital NS.

Congenital NS is usually related to genetic risk factors, but can be related to other diseases. Classic congenital NS has a 100 percent death rate because it doesn’t respond to any typical medical intervention. Therefore, the standard treatment worldwide for congenital NS is to remove the kidneys and place the infant on dialysis. The infant will remain on dialysis until he/she grows to an appropriate size for kidney transplant. By removing the kidneys, the congenital NS ceases; however, the trade off is the morbidity and mortality rate of an infant on dialysis is at least 30 percent. At the time of transplantation, there is a very low recurrence of NS in this population. In children who have not had their kidneys removed and are still nephrotic, transplantation should not occur due to the high risk of developing blood clots in the new kidney.

Infant Nephrotic Syndrome

Infant NS occurs in those children who become symptomatic after three months of age and before 12 months of age. This may be related to viral infections transferred from the mother, such as EBV, CMV, rubella or HIV, as well as other infant infections. A renal biopsy is necessary to look for the cause of the infection. Depending on the cause of the NS at this age, these children may respond to treatment for the underlying disease or may require immunosuppression for improvement of the NS itself.

Childhood Nephrotic Syndrome

Childhood NS typically presents at greater than one year and less than 13 years of age. Peak presentation is around three - five years of age. Three to four weeks prior to the diagnosis of childhood NS, usually these children will have been identified as having allergies or sinus disease due to facial swelling. Typically the family will see this facial swelling in the morning, but by the time they seek out medical care later in the day, the facial swelling will have resolved. This is because the patient has been standing, and due to gravity, the fluid has flowed to the legs and ankles, which have now become swollen.

Children with NS will often become symptomatic after respiratory infections, although there does not appear to be a seasonal variation in this disease. The common cold, immunizations and food allergies can all trigger NS. At presentation, these children will have significant facial swelling, anasarca (total body water retention) and scrotal or labial swelling. Whereas the genital swelling is quite alarming to families, there is no risk of sterility or damage to the ovaries or testes in these children. Blood pressure, urinalysis, a 24-hour urine collection or a random urine collection, and blood work will be completed. If the child has high urinary proteins, low albumin levels, swelling and elevated cholesterol, then the NS diagnosis is made.

Once NS has been diagnosed, then treatment is necessary. Since 1955, the standard treatment for NS is corticosteroid (prednisone) therapy. Corticosteroid therapy can be given either once, twice or three times a day depending on local standard of care. Children usually respond within seven - 21 days of starting the corticosteroids. The response is monitored at home with urinary protein screening, which slowly diminishes and then resolves completely. Once resolution has occurred, prednisone can be weaned or tapered. Patients then usually fall into one of three different categories. The first category, about 25 percent of children, will be able to wean off corticosteroids and remain off of them. The second group will often be able to wean off corticosteroids but will relapse within three - four weeks of coming off corticosteroids. If that occurs on a routine basis, these patients are referred to as having "frequent-relapsing nephrotic syndrome." A third group of patients will relapse during the weaning period of time. If that occurs on a routine basis, they are referred to as having "corticosteroid-dependent nephritic syndrome."

Regardless of a child’s grouping within childhood NS, 95 percent of them will respond to corticosteroids and will grow out of childhood NS after puberty. Since the peak age occurs between three – five years of age, the most common relapse trigger is respiratory infections. It is not unusual in the early years of life that three - five relapses to occur per year, which may put the child at risk for excessive complications of corticosteroid toxicity. This toxicity presents as cataracts, bone demineralization (which is difficult to measure), growth impairment, mood shifts, acne and obesity. The children who become corticosteroid toxic will be started on a secondary medicine such as Cytoxan to obtain resolution of the NS. Newer medicines such as tacrolimus can also be used as third line agents to obtain a remission.

Five percent of childhood NS patients do not respond to corticosteroid therapy. This group is referred to as having "corticosteroid-resistant nephrotic syndrome." Within that group, 65-70 percent of these children will develop kidney failure within five-10 years and require a kidney transplant. At the time of transplantation, these children have an 80 percent chance of recurrence of their NS.

Nephrotic Syndrome in children greater than 12 years of age

NS in children over the age of 12 is often considered to be "secondary nephrotic syndrome" as a presentation of glomerularonephritis. These children may have hypertension, hematuria and possibly abnormal renal function. If these children have any pulmonary symptoms including hemoptysis (coughing up blood), they must be evaluated for pulmonary renal diseases. In the comprehensive work-up of an adolescent with nephrotic syndrome, it may be necessary to perform a kidney biopsy and draw blood work. These results may lead to a diagnosis of Wegener’s Granulomatosis, Goodpasture’s syndrome (anti-GBM disease), systemic lupus erythematosus (SLE), Churg-Strauss disease, IgA nephropathy, membranous nephropathy or membranoproliferative glomerularonephritis (MPGN).

In infant and childhood NS, the family needs to be thoroughly educated on the risk factors of this therapy, such as infectious peritonitis, cellulitis, and other clotting causes because these are medical emergencies. The long term prognosis does not appear to have a higher incidence of coronary artery disease or other atherosclerotic disease in adulthood, despite the history of high cholesterol and high doses of steroids during childhood.

In all populations, the use of blood pressure medications (angiotensin converting enzymes and angiotensin receptor blockade medications) may be standard of care in order to decrease proteinuria. These may be used even when the child does not have hypertension.

It is incumbent upon the primary care physician to have children with NS, regardless of age, evaluated by a pediatric nephrologist. This pediatric nephrologist will work in consort with the primary care physician to identify a course of action that should be followed. Frequent evaluations and close monitoring by the pediatric nephrologist are necessary for a child with NS due to the unpredictability of the disease.

Timothy E. Bunchman, MD, is Professor of Pediatric Nephrology at Michigan State University College of Human Medicine and is the director of the pediatric nephrology, dialysis and transplantation program at Helen DeVos Children’s Hospital in Grand Rapids, Michigan. He also founded the non-profit Pediatric Continuous Renal Replacement Therapies Foundation.

This article originally appeared in the July 2007 issue of aakpRENALIFE.