Elaine S. Kamil, MD
A 2-year-old boy is brought to the office because of abdominal distention. He has just recovered from a runny nose that lasted 1 week, with no fever or change in activity. His mother reports that his eyelids were very swollen that morning, and she says that his thighs look “fat.” She has noticed that he has fewer wet diapers. He has always been a healthy child, and his immunizations are up to date. The family has a history of asthma and allergic rhinitis. Physical examination shows an active 2-year-old boy. Head and neck examination is clear, except for a few shotty anterior cervical lymph nodes and some minimal periorbital edema. Chest examination reveals some decreased breath sounds at the bases. The abdomen is moderately distended; bowel sounds are active, and a fluid wave is detectable. There is 2+ pitting edema of the lower legs, extending up to the knees. The urine has a specific gravity of 1.030; pH 6; 4+ protein; and trace, nonhemolyzed blood. Microscopic examination shows 4 to 6 red blood cells per high-power field and 10 to 20 hyaline and fine granular casts per low-power field.
1. What is the differential diagnosis of edema and ascites in previously healthy young children?
2. What criteria are used to determine if children with nephrotic syndrome require hospitalization or can be managed as outpatients?
3. What laboratory evaluation and therapy are instituted initially?
4. What are the important issues to address in parent/guardian education?
5. What is the prognosis of young children with nephrotic syndrome?
Although nephrotic syndrome is not a common childhood disease, every pediatrician can expect to care for 1 to 3 children with nephrosis at some time. Nephrotic syndrome may have serious or even fatal complications, and the disease tends to follow a chronic, relapsing course. Thus, it is important for the pediatrician to become familiar with the signs and symptoms of the disease and with the most current treatment modalities aimed at keeping affected children healthy and active.
Nephrotic syndrome occurs when an individual excretes a sufficient quantity of plasma proteins, primarily albumin, in the urine to cause hypoalbuminemia. Substantial urinary protein losses, hypercholesterolemia, and hypoalbuminemia characterize nephrotic syndrome. The condition is usually accompanied by obvious edema, but occasionally edema is not clinically detectable (Box 111.1).
In children, proteinuria of more than 40 mg/m2/hour (>50 mg/kg/ 24 hours) is considered nephrotic range proteinuria. (In adultsized patients, proteinuria of more than 3.5 g in 24 hours is associated with nephrotic syndrome.) Collection of a 24-hour urine sample is cumbersome in children, and the urinary total protein/ creatinine (TP/Cr) ratio done on a random urine sample, preferably a first morning urine, is a useful alternative. Whereas a ratio greater than 3.5 is considered nephrotic range proteinuria in adults with normal renal function, in children a ratio greater than 1.0 may signify nephrotic range proteinuria (see Chapter 110). Twenty-four– hour urine protein losses (g/m2/day) in children can be estimated by multiplying the urinary TP/Cr by 0.63.
Box 111.1. Diagnosis of Nephrotic Syndrome
•Heavy proteinuria (>40 mg/m2/hour or 50 mg/kg/24 hours in children)
Minimal change disease (MCD) is the most common form of nephrotic syndrome in childhood. The annual prevalence of new cases of nephrotic syndrome is 2 to 3 in 100,000 children in the population younger than 16 years. The cumulative prevalence of this chronic disease is estimated to be 16 in 100,000. Ninety percent of childhood cases are not associated with any systemic disease, and two-thirds of cases of childhood nephrotic syndrome present before age 5 years. The ratio of boys to girls in young children with nephrotic syndrome is 2:1. By late adolescence, both sexes are equally affected, and diseases other than MCD are much more prevalent in adolescents.
The typical child presenting with nephrotic syndrome is a preschool- age boy who is brought to the physician because he appears swollen to the parents or guardians. Some children are active and relatively asymptomatic despite the edema, whereas others may be very uncomfortable, with markedly swollen eyelids, abdominal discomfort, scrotal or labial edema, and even respiratory compromise. Usually children have a history of preceding infection, most typically an upper respiratory infection (URI). Children with nephrosis may develop diarrhea secondary to edema of the bowel wall.
Occasionally, children with nephrosis are critically ill because of peritonitis, bacteremia, or, rarely, a major thrombotic episode. Because their immune state is compromised, rapid evaluation and treatment of children with these complications of nephrotic syndrome are essential for survival. The primary peritonitis associated with nephrotic syndrome may be confused with an acute abdomen, such as may be seen with appendicitis. Some children who are experiencing a severe relapse have hypotensive symptoms secondary to intravascular volume depletion.
The exact cause of MCD and focal segmental glomerulosclerosis (FSGS) is not known. Recent genetic and biomarker studies suggest that MCD and FSGS are different diseases, although they both exhibit intrinsic structural defects in the glomerular podocyte. For MCD, the best current theory postulates that some stimulus (usually infectious) causes a clone of cells to proliferate and produce 1 or more soluble factors that are toxic to the glomerular epithelial cells (ie, podocytes), which are the cells that maintain the glomerular basement membranes. Active MCD shows a reduction in the net negative charge across the glomerular basement membrane and causes a diffuse abnormality in capillaries throughout the body, resulting in leakage of albumin in the peripheral capillaries and increases in interstitial fluid. The constituents of the glomerular basement membrane and chemicals coating the glomerular epithelial and endothelial cells normally bear a net negative charge. The presence of these negatively charged chemicals creates a charge-selective barrier to filtration. This barrier plays a significant role in the ultrafiltration of macromolecules present in the plasma, enhancing the filtration of molecules bearing a positive electrical charge and retarding the filtration of molecules bearing a negative electrical charge. During episodes of relapse, patients with MCD show a breakdown in the normal charge-selective barrier to filtration, often resulting in massive proteinuria. Kidney biopsies from patients with nephrotic syndrome demonstrate a net reduction in anionic sites during periods of relapse. Additionally, some children have mutations in podocyte proteins (eg, nephrin, podocin) that result in nephrotic syndrome. Children presenting with nephrosis before 1 year of age have a high likelihood of having a genetic mutation causing nephrotic syndrome, and any child with steroid-resistant nephrotic syndrome should also be screened for such genetic mutations.
Recent studies have shown evidence that the soluble factors in FSGS and MCD likely are different. For example, although 70% of patients with FSGS have been shown to have elevated plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR), in patients with MCD the levels are undetectable. Considerable evidence exists indicating that the proteinuria in the patient with
MCD or FSGS may be caused by soluble factors. Some patients who develop end-stage renal disease from idiopathic nephrotic syndrome (particularly FSGS) have experienced a relapse of the nephrotic syndrome with massive proteinuria immediately after transplantation of a normal kidney. In 1 instance, a patient with end-stage renal disease from FSGS developed an immediate severe relapse after transplant. The kidney was removed and transplanted into another patient without FSGS, and the kidney functioned normally without proteinuria. Infusion of peripheral blood mononuclear cell products from children with nephrosis induces albuminuria in rats. Removal of serum proteins by adsorption to a protein A Sepharose column or by plasmapheresis has resulted in remission of proteinuria in some patients who have experienced a recurrence of nephrotic syndrome after transplantation. Mixing plasma from a patient in relapse with FSGS with glomeruli in vitro can cause swelling of the glomeruli. The remission of the proteinuria after treatment with immunosuppressive medication provides further evidence that nephrotic syndrome is mediated in some way by the immune system. Children with MCD have been shown to have higher helper T/regulatory T cell ratios than in healthy children.
Normal adults are able to synthesize 12 g (0.4 oz) of albumin per day in the liver, and adults with nephrotic syndrome may synthesize 14 g (0.5 oz) of albumin per day. Therefore, the hypoproteinemia characteristic of nephrotic syndrome cannot be explained completely by measured amounts of urinary protein losses (approximately 3.5 g/day [0.1 oz/day]). The difference between the hepatic synthetic capacity for albumin and measured urinary losses can be explained by protein catabolism in the kidney. Renal tubular epithelial cells reabsorb filtered plasma proteins and catabolize them to amino acids, which then reenter the amino acid pool of the body. Thus, the magnitude of losses of plasma proteins at the glomerular level is far greater than the amount measured in a 24-hour urine sample.
The hypoalbuminemia that occurs in nephrotic syndrome is a result of the massive proteinuria, and the hypercholesterolemia occurs as a consequence of the hypoalbuminemia. The hyperlipidemia is partially the result of a generalized increase in hepatic protein synthesis that also involves overproduction of lipoproteins. Additionally, less lipid is transported into the adipose tissue because the activity of lipoprotein lipase is reduced in adipose tissue during active nephrotic syndrome. Hyperlipidemia is most pronounced in children with MCD. Serum albumin levels and serum cholesterol levels are generally inversely correlated. The hyperlipidemia is the last biochemical abnormality to clear after the child achieves remission from an episode of nephrotic syndrome.
Nephrotic syndrome is considered primary or secondary. Primary nephrotic syndrome is not associated with a systemic disease, whereas secondary nephrotic syndrome is a feature of a systemic disease, such as anaphylactoid purpura, immunoglobulin (Ig) A nephropathy, or systemic lupus erythematosus (SLE). Most young children with nephrotic syndrome have the primary form of the disease and secondary causes become more prevalent during adolescence.
Children with primary nephrotic syndrome are also classified according to their response to steroid therapy. Affected individuals may be categorized as steroid-sensitive, steroid-dependent, or steroid-resistant. Typically, children who are steroid-sensitive and remain so have MCD; however, a renal biopsy must be performed before the diagnosis of MCD is made. Sensitivity to or dependence on corticosteroids is a critical factor in determining a child’s prognosis.
Nephrotic syndrome is also classified by the appearance of the glomeruli on renal biopsy. A summary of the histologic lesions causing nephrotic syndrome appears in Table 111.1. Approximately 95% of young children with nephrotic syndrome have MCD. In these children, light microscopy shows normal-appearing glomeruli. Immunofluorescent microscopy typically is negative but may show some mesangial IgM deposits, and electron microscopy simply shows foot process effacement of the podocytes. In individuals with FSGS, light microscopy may show enlarged glomeruli and glomeruli with segments of sclerosis. Immunofluorescence may reveal some IgM and complement in the sclerotic segments, and electron microscopy shows areas of foot process effacement of podocytes. Biopsies performed later in the disease course show some totally sclerotic glomeruli, areas of interstitial fibrosis, and atrophy. Several recent series have noted an apparent increase in the incidence of FSGS among children with nephrosis.
Other primary renal diseases that can cause nephrotic syndrome in children include membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), IgA nephropathy and other forms of chronic glomerulonephritis, congenital nephrotic syndrome, and diffuse mesangial proliferative glomerulonephritis. Chronic hepatitis B infection may cause membranous nephropathy or MPGN. In endemic areas, the incidence of hepatitis B–associated membranous nephropathy has been reduced since the implementation of universal hepatitis B vaccination programs. Rarely, poststreptococcal acute glomerulonephritis and other forms of postinfectious acute glomerulonephritis may also cause nephrotic syndrome. With the exception of congenital nephrotic syndrome, all these diseases show the presence of immune deposits in the glomerular mesangial regions or along the glomerular basement membrane as well as some element of cellular proliferation, which may be severe. In these disease states, the presence of nephrotic syndrome is indicative of marked injury to the glomerular capillary wall. Neonates with congenital nephrotic syndrome Finnish type have a mutation of the gene encoding the nephrin molecule, a podocyte protein with a large extracellular domain that is an integral part of the glomerular slit diaphragm. These neonates have massive proteinuria beginning in utero and have severe nephrotic syndrome presenting in the first month after birth.
Abbreviations: FSGS, focal segmental glomerulosclerosis; GN, glomerulonephritis; MCD, minimal change disease; MN, membranous nephropathy; MPGN, membranoproliferative glomerulonephritis.
a MCD remains the dominant histologic type through mid-adolescence but becomes relatively less important in later childhood and adolescence.
Because of the varying distribution of edema fluid at presentation, nephrotic syndrome may be confused with sinusitis or an allergic reaction (eg, periorbital edema), obesity (eg, ascites), or an abdominal mass (eg, ascites). Other causes of generalized edema, such as congestive heart failure, hypoproteinemia from inflammatory bowel disease, or liver disease, can be easily excluded with routine laboratory testing.
The clinical evaluation should include a careful history (Box 111.2).
A complete physical examination is necessary. Blood pressure should be monitored, because hypertension or hypotension may occur. The extent of peripheral and central edema, including swelling of the eyelids, should be assessed. The physician should obtain a reliable, overall impression of the child’s level of comfort and activity. Examination also should include a careful search for infection, particularly life-threatening infections, such as pneumonia or peritonitis. Examination of the head and neck should focus on signs of recent infection, such as otitis media. The presence of dullness to percussion at the bases of the thorax is consistent with large pleural effusions. Ascites may be minimal or massive. With severe ascites, scrotal or labial edema may occur. The child with a history of abdominal pain should undergo a careful examination for signs of peritoneal irritation. The skin should be inspected for infection and rashes.
The laboratory evaluation of the child with nephrotic syndrome begins with a urinalysis. The dipstick shows 3+ or 4+ protein, although a dilute urine may be only 2+. Microscopic hematuria may be present in up to 25% of children with MCD. The presence of associated glycosuria in a child with nephrosis who is not on steroid therapy is concerning for FSGS. Careful microscopic examination of the urine is necessary. Casts are seen frequently, because urinary proteins precipitate in the tubules. The casts are hyaline, fine, and coarse granular. White blood cell (WBC) casts are sometimes seen, because some children with nephrotic syndrome may also have increased amounts of leukocytes in their urine. Large amounts of red blood cells (RBCs) and RBC casts are rarely seen in uncomplicated MCD and, if present, indicate another cause for the nephrotic syndrome. If RBC casts are seen together with substantial hematuria, an antistreptolysin O titer should be added to the preliminary evaluation outlined in this section. A random urinary TP/Cr should be done to determine whether the child has nephrotic range proteinuria.
Box 111.2. What to Ask
•Has the child recently had any infections, such as pharyngitis or an upper respiratory infection? Is the child from a group at high risk for hepatitis B or C infection?
•Are the child’s eyelids swollen? Do they look more puffy or less puffy at certain times during the day, especially on awaking or after crying?
•Does the child have a history of rashes characteristic of diseases that are associated with nephrotic syndrome?
•Is there a history of fever, oliguria, or abdominal pain?
•Is there a family history of nephrotic syndrome or kidney disease?
•Is the child playful and active, or is the edema so significant that movement is uncomfortable?
•Are the ascites and pleural effusions so severe that some respiratory compromise is evident?