A previously well 5 year old male presents to your office with the chief complaint of facial puffiness. His mother noticed this a few days ago and it seems to be worsening. He has no other symptoms, but about two weeks ago had "a bad cold."
Exam: VS T 37, HR 90, RR 20, BP 92/55. He is alert and cooperative with the examination. His face shows moderate periorbital edema. His eyes are non-injected, his conjunctiva are not edematous and his throat is not red. His heart is regular without murmurs. Heart sounds are normal. His lung exam shows good aeration, with no crackles or rhonchi. Abdomen is soft, non-tender, non-distended and without masses or shifting dullness. No hepatosplenomegaly. He has normal male genitalia with no scrotal edema. The dorsal surfaces of his hands and feet have mild pitting edema. He has brisk capillary refill and 2+ pulses. No rashes are noted.
Urinalysis shows 4+ protein, and a specific gravity of 1.030. His chemistry panel is remarkable for protein of 2 g/dL, serum albumin of 1.4 g/dL and cholesterol of 350 mg/dL. BUN and creatinine are normal.
He is not ill enough to require hospitalization. He is started on oral prednisone BID. He is followed as an outpatient clinically and by daily urine dipsticks. His edema and proteinuria gradually resolve with treatment. His corticosteroids are tapered off and he remains stable.
Nephrotic syndrome describes the collection of clinical and laboratory findings secondary to glomerular dysfunction, resulting in proteinuria. The diagnostic criteria are marked proteinuria, generalized edema, hypoalbuminemia, and hyperlipidemia (with hypercholesterolemia). The proteinuria in nephrotic syndrome is severe, exceeding 50 mg of excreted protein for every kilogram of body weight over 24 hours. Primary nephrotic syndrome refers to diseases limited to the kidney, whereas secondary nephrotic syndrome indicates systemic diseases that include kidney involvement (e.g., diabetic nephropathy).
In healthy children (less than 18 years of age), the annual incidence of nephrotic syndrome is 2-7 new cases per 100,000. The prevalence is approximately 16 cases per 100,000 children, making nephrotic syndrome one of the most frequent reasons for referral to a pediatric nephrologist. Also, the most common type of nephrotic syndrome is recurrent to some degree, so cases will often manifest repeatedly over time. The peak age for the onset of nephrotic syndrome is 2-3 years of age. In early childhood, males outnumber females about 2:1 for new cases of nephrotic syndrome. In adolescence and adults, the gender distribution is more equal. Primary nephrotic syndrome is more common in children less than six years of age, while secondary nephrotic syndrome predominates for patients older than six. The disease inheritance is usually sporadic, although there is a congenital form of nephrotic syndrome, called Finnish type congenital nephrosis, which is inherited in an autosomal recessive manner. This abnormality has been mapped to a defect in the nephrin gene on chromosome 19q13.1 that codes for a protein in the glomerular basement membrane.
The main pathogenic abnormality in nephrotic syndrome is an increase in glomerular capillary wall permeability, resulting in pronounced proteinuria. The normal glomerular wall is remarkably selective for retaining protein in the serum. Once this selectivity is lost, the excretion of large amounts of protein will follow. This increase in permeability is related to the loss of negatively charged glycoproteins within the capillary wall that usually repel negatively charged proteins. The predominant protein lost is albumin, although immunoglobulins are also excreted. The pathophysiology for the formation of edema is incompletely understood. A simplification of the predominant theory is that after the plasma albumin concentration drops, secondary to protein excretion, the plasma oncotic pressure drops. With the decrease in oncotic pressure, fluid moves from the intravascular space to the interstitial space causing edema. The liver has a very large capacity to synthesize protein, so the persistent hypoalbuminemia is likely not due entirely to increased losses. Reduction of the intravascular volume results in activation of the renin-angiotensin-aldosterone system. Sodium and water are retained, which further increases the edema. There are likely other factors involved in the formation of edema, because some patients with nephrotic syndrome have normal or increased intravascular volume.
The hyperlipidemia in nephrotic syndrome is characterized by elevated triglycerides and cholesterol and is possibly secondary to two factors. The hypoproteinemia is thought to stimulate protein synthesis in the liver, including the overproduction of lipoproteins. Also lipid catabolism is decreased due to lower levels of lipoprotein lipase, the main enzyme involved in lipoprotein breakdown.
More than 90% of children with primary nephrotic syndrome have idiopathic nephrotic syndrome and this will be the focus of this chapter. The etiology of this condition remains largely unknown, but some have postulated an immunologic mechanism. Supporting evidence for this theory include the characteristic response to corticosteroids and cytotoxic agents, an observed increased incidence of concurrent allergic conditions, and spontaneous remissions with natural measles infections (known to induce suppression of cell-mediated immunity). Evidence against an immunologic etiology is a failure to identify immune reactants or inflammation in kidney biopsies.
There are three morphological patterns of idiopathic nephrotic syndrome, with minimal change disease (also called "nil disease") making up 80-85% of the cases. In this condition, the glomeruli appear normal or have a minimal increase in the mesangial cells or matrix. As well as being the most common form of primary nephrotic syndrome, minimal change disease also has the mildest clinical course. The rest of this chapter will focus on this disease entity after briefly describing the other forms of primary nephrotic syndrome as well as secondary nephrotic syndrome. The less commonly seen types of primary idiopathic nephrotic syndrome are focal segmental glomerular sclerosis, membranous glomerulonephritis and membranoproliferative glomerulonephritis.
Focal segmental glomerular sclerosis is found in about 7-15% of patients with nephrotic syndrome, making it the second most common primary renal lesion. It tends to have a more severe clinical course with persistent proteinuria, progressive decline in glomerular filtration rate and hypertension that can be unresponsive to therapy. Renal failure occurs, with dialysis or transplant being the only treatment options. Unfortunately, the recurrence rate of focal segmental glomerular sclerosis can be as high as 40% after renal transplant.
Membranoproliferative glomerulonephritis accounts for roughly 7% of primary idiopathic nephrotic syndrome. These patients often have hematuria, hypertension and mild azotemia. Another characteristic finding is persistently depressed C3 levels. The clinical course is variable with only a small percentage of patients going into remission.
Membranous glomerulopathy is rare in the pediatric age group, but becomes more common into adolescence and adulthood. It is often associated with infections, with hepatitis B being the most common. The clinical course is variable, but the overall prognosis is good, with spontaneous remission of proteinuria occurring in 50-60% of cases.
There are many different causes of secondary nephrotic syndrome in children. These include multisystemic diseases such as systemic lupus erythematosus and Henoch-Schonlein purpura, malignancies such as Hodgkin disease or leukemia, drug or toxin exposures such as mercury, gold, penicillamine or bee sting, and infectious etiologies such as Epstein-Barr virus, cytomegalovirus and tuberculosis.
Children with idiopathic nephrotic syndrome secondary to minimal change disease usually present with edema. Clinically apparent edema usually is not seen until albumin levels drop below 2 g/dL. The edema is initially noted around the eyes and in the lower extremities. Over the course of a day, the edema often distributes from the eyes to more dependent areas. After time, the edema becomes more pronounced, generalizes and there can be weight gain. Patients or parents may notice tighter fit of clothes, belts and shoes and scrotal or labial edema often occurs. As the edema accumulates, pleural effusions, ascites and decreased urine output may develop. In many cases, there is a history of preceding upper respiratory symptoms. Anorexia, abdominal pain and diarrhea may be seen, possibly secondary to the formation of ascites. Blood pressure and renal function are usually normal.
The hallmark of nephrotic syndrome is severe proteinuria, most reliably diagnosed using a 24-hour urine collection. Spot urinalysis is also informative and reveals +3 to +4 proteinuria (300 to 1000 mg/dL), with a specific gravity usually greater than 1.020. Gross hematuria is not common. Blood samples show decreased albumin levels usually less than 2.0 mg/dL and elevated triglyceride and cholesterol levels. Because of the hypoalbuminemia, hypocalcemia is often seen, with calcium levels less than 9.0 mg/dL. Usually the ionized calcium will be normal. Hyponatremia and hyperkalemia can be seen, with hyperkalemia developing in patients who are oliguric. Serum C3 levels are normal in cases of minimal change disease.
Renal biopsy is not necessary for the child with newly diagnosed nephrotic syndrome and the initial treatment will be the same, regardless of the cause. How the disease responds to corticosteroids may help dictate the need for biopsy. If the response is good and renal function is normal, the diagnosis of minimal change disease may be presumed. If relapses respond to corticosteroids and there is no proteinuria during disease free periods, this diagnosis is strengthened. Biopsy is generally obtained in cases where there is poor or no response to corticosteroids, the patient is less than 1 year old (high likelihood of congenital nephrotic syndrome) or over 10 years old, secondary nephrotic syndrome is suspected, there is corticosteroid toxicity, or the use of a cytotoxic agent is being considered. Patients with low serum complement levels or hypertension on presentation may require biopsy since these conditions are not characteristic of minimal change disease and may indicate other renal lesions.
The treatment of primary idiopathic nephrotic syndrome of childhood is corticosteroid therapy and supportive care. Steroid therapy will be discussed below. Many patients may be treated on an outpatient basis, although the newly diagnosed patient is sometimes admitted for diagnostic and educational purposes. Edema is managed with sodium restriction (the "no added salt diet") and diuretics such as hydrochlorothiazide. If hypokalemia develops, an oral potassium supplement or spironolactone may be added. Aggressive use of loop diuretics may be harmful since most patients initially presenting with nephrosis are hypovolemic. The use of diuretics necessitates close monitoring of patients. Patients need to monitor their weight closely and consume adequate amounts of protein.
Conditions that require immediate attention and hospitalization are severe scrotal edema, dehydration (more than 10% dehydrated), respiratory compromise due to pulmonary edema or pleural effusions, and peritonitis or suspected bacterial infection. Despite their edematous appearance, most patients have decreased intravascular volumes. Therapy is aimed at the restoration of intravascular volume and preventing volume overload. Intravenous fluids are used, sometimes with the infusion of albumin to increase the serum oncotic pressure. The albumin must be given slowly, over 8-12 hours, to prevent fluid overload from rapid intravascular volume expansion. There is some debate over the use of albumin, since the effect seems to be transient and it is presumably excreted rapidly (1). Electrolyte levels and renal function must be closely monitored. Once the intravascular volume is restored, diuretic therapy is used to mobilize the fluid and prevent volume overload. Paracentesis is performed if there is respiratory compromise secondary to severe ascites. Antibiotic therapy to cover for the most common pathogens should be started if there is evidence of bacterial infection (discussed below).
Minimal change disease is characteristically responsive to corticosteroid therapy and once the diagnosis is confirmed with laboratory testing, steroid therapy should be started. Prednisone is initiated with a dose of 60 mg/sq-meter/day or 2 mg/kg/day divided in 2-3 doses. The daily dose is continued until the proteinuria resolves, usually in 2-3 weeks. Some sources suggest continuing the daily dose for 4-6 weeks (1). Regardless, the corticosteroids are continued and then tapered over the course of 3-6 months. In patients with minimal change nephrotic syndrome, approximately 98% will eventually have satisfactory therapeutic responses. This disease is one of frequent relapse, with two thirds of patients having a single relapse and roughly one third experiencing repeated relapses over many years. Most patients with steroid-responsive nephrotic syndrome will continue to have relapses until they are in their late teens. Relapses are treated the same as the initial presentation. With repeated relapses or severe steroid toxicity (growth retardation, elevated blood pressure), cytotoxic agents such as cyclophosphamide are added to a lower corticosteroid dose. This agent has been shown to prevent relapses and to increase the duration of remission. Chlorambucil and less commonly cyclosporine have also been used for remission induction. Another regimen for patients refractory to corticosteroids is indomethacin and an angiotensin-converting enzyme (ACE) inhibitor.
The most common complications of nephrotic syndrome are bacterial infection and thromboembolism. There are also complications secondary to medications such as the gastric irritation and insulin resistance seen with corticosteroids or the hemorrhagic cystitis, sterility and leukopenia seen with cyclophosphamide. The tendency to develop infections, especially "primary peritonitis" (a type of pneumococcal sepsis), is thought to be due to IgG excretion, decreased complement function, and diminished splanchnic blood flow. The organisms causing peritonitis are most commonly Streptococcus pneumoniae and Escherichia coli. Peritonitis should always be considered in a patient who has nephrotic syndrome and abdominal pain or fever. Antibiotics such as ampicillin or vancomycin with a third generation cephalosporin or an aminoglycoside would provide good empiric coverage. Other infections such as sepsis, cellulitis, pneumonia and urinary tract infection are also seen. The signs of infection may be masked if the patient is currently on corticosteroid therapy. Any child with nephrotic syndrome and a fever must be thought of as having an infection until proven otherwise, since they are at high risk for sepsis, similar to splenectomy patients. Because of their predilection for S. pneumoniae infection, polyvalent pneumococcal vaccine should be administered to children over two years of age.
Another complication, thromboembolism is thought to be more common secondary to increased platelet aggregation, increased fibrinogen concentration, decreased antithrombin III concentrations, increased blood viscosity and decreased blood flow. Venous thrombosis is most common, especially in the renal vein, pulmonary artery, and deep vessels of the extremities. In patients with refractory nephrosis, low dose anticoagulants are sometimes used.
The prognosis for children with minimal change nephrotic syndrome is good, with most patients ultimately becoming disease free and living a normal life. Mortality is approximately 2% with the majority of deaths being secondary to complications such as peritonitis or thromboembolic disease.
1. The most common cause of primary idiopathic nephrotic syndrome is:
. . . . . a. Focal segmental glomerular sclerosis
. . . . . b. Membranoproliferative glomerulonephritis
. . . . . c. Membranous glomerulopathy
. . . . . d. Minimal change disease
2. Common causes of mortality in primary nephrotic syndrome is/are:
. . . . . a. Acute renal failure
. . . . . b. Thromboembolism
. . . . . c. Congestive heart failure
. . . . . d. Peritonitis
. . . . . e. Seizure
3. True/False: A renal biopsy is necessary to confirm the diagnosis of primary idiopathic nephrotic syndrome.
4. The inheritance pattern of primary idiopathic nephrotic syndrome is/are:
. . . . . a. Autosomal recessive
. . . . . b. X-linked recessive
. . . . . c. Autosomal dominant
. . . . . d. Sporadic
5. Reasons for biopsy in a patient with nephrotic syndrome include:
. . . . . a. Continued proteinuria after a week of prednisone therapy.
. . . . . b. Age at onset of 10 months.
. . . . . c. Relapse 1 year after initial course of therapy.
. . . . . d. Cholesterol level greater than 400 mg/dL.
. . . . . e. A patient who has a history of systemic lupus erythematosus
1. Roth KS, Amaker BH, Chan JCM. Nephrotic Syndrome: Pathogenesis and Management. Pediatr Rev 2002;23(7):237-248.
2. Bergstein JM. Chapter 535 - Nephrotic Syndrome. In: Berhman RE, et al (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: WB Saunders Co, pp. 1592-1595.
3. Chesney RW. The Idiopathic Nephrotic Syndrome. Curr Opin Pediatr 1999;11(2):158-161.
4. Penaflor G. Congenital Nephrotic Syndrome. Pediatr Rev 2001;22(1):32.
5. Orth SR, Ritz E. The Nephrotic Syndrome. New Engl J Med 1998;338(17):1202-1211.
6. Kate C, Norman ME. Nephrotic Syndrome. In: Fleisher GR, Ludwig S (eds). Textbook of Pediatric Emergency Medicine, 4th edition. 2000, Baltimore: Lippincott, William & Wilkins, pp. 832-835.
Answers to questions
1. d. Minimal change disease or "nil disease" accounts for 80-85% of cases of primary idiopathic nephrotic syndrome in childhood.
2. b and d. Infection, especially peritonitis and thrombosis account for the majority to nephrotic syndrome mortality.
3. false. The decision to perform a renal biopsy is usually deferred until the initial course of corticosteroid is initiated, unless there are specific risk factors such as age below one or above 10, hypertension on presentation or decreased complement on presentation.
4. d. Primary nephrotic syndrome is sporadic in nature. Congenital nephrotic syndrome is passed in an autosomal recessive manner.
5. b and e. Nephrotic syndrome in a child less than 1 year old may indicate congenital nephrotic syndrome and renal biopsy is often performed. In a patient with SLE, the nephrotic syndrome is likely secondary and a renal biopsy is indicated.