VI. Nephrotic Syndrome (NS)

A.Definition. NS is a condition characterized by heavy proteinuria (>50 mg/kg/24 hours or by a urine total protein/creatinine ratio >3.5), hypoalbuminemia, hypercholesterolemia, and edema.

B.Epidemiology

1.Two-thirds of cases in children present before 5 years of age.

2.In young children, the ratio of boys to girls is 2:1. By late adolescence, both sexes are equally affected.

C.Classification. There are three categories of NS:

1.Primary NS, which refers to cases that are not a consequence of systemic disease. Primary NS accounts for 90% of all childhood cases of NS. The most common cause of primary NS in children is minimal change disease (MCD), which accounts for 95% of NS cases among young children and 50% of cases in older children and adolescents.

2.NS that results from other primary glomerular diseases, including focal segmental glomerulosclerosis (FSGS), MPGN, IgA nephropathy, and PSGN

3.NS that results from systemic diseases, including SLE and HSP

D.Pathophysiology

1.The basic physiologic defect is a loss of the normal chargeand size-selective glomerular barrier to the filtration of plasma proteins.

2.Excessive urinary protein losses lead to the hypoproteinemia of NS.

3.Hypercholesterolemia is a consequence of the hypoproteinemia.

a.Reduced plasma oncotic pressure induces increased hepatic production of plasma proteins, including lipoproteins.

b.Plasma lipid clearance is reduced because of reduced activity of lipoprotein lipase in adipose tissue.

E.Clinical features

1.Most children present with edema, which can range from mild periorbital edema to scrotal or labial edema to widespread edema. The edema often follows an upper respiratory infection (URI). Pleural effusions and hypotension may also occur.

2.Patients may rarely be asymptomatic at the time of diagnosis. In these patients, NS is diagnosed during an evaluation for asymptomatic proteinuria, and they are less likely to have MCD.

3.Patients are predisposed to thrombosis secondary to hypercoagulability. Rarely, patients may present with stroke or other thrombotic events such as renal vein thrombosis, deep vein thrombosis, and sagittal sinus thrombosis.

4.Patients are also at an increased risk for infection with encapsulated organisms, such as

Streptococcus pneumoniae, and therefore may present with spontaneous bacterial peritonitis, pneumonia, or overwhelming sepsis.

5.The clinical course for the child with MCD follows periods of relapses and remissions. About one-third of patients have only one episode, one-third have infrequent relapses, and one-third will have frequent relapses. For the latter two groups, the nephrotic syndrome is a chronic illness in which the side effects of medications have to be weighed against the complications of the disease.

6.Many, but not all, children with MCD achieve a sustained remission by adolescence.

F.Diagnosis. Diagnosis is on the basis of clinical features and on the following studies:

1.Urinalysis typically reveals 3+ to 4+ protein, sometimes microscopic hematuria, and a very elevated urinary TP/CR. The presence of RBC casts indicates a cause other than MCD.

2.CBC may show an elevated hematocrit as a result of hemoconcentration resulting from

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the hypoproteinemia. The platelet count may also be elevated.

3.Routine chemistries (electrolytes) may demonstrate metabolic acidosis, which may be caused by acquired renal tubular acidosis (in severe cases the heavy proteinuria of nephrotic syndrome may cause RTA). Hypoalbuminemia and elevated serum cholesterol are present. BUN and creatinine should be measured to assess for renal impairment.

4.C3, ANA, and antistreptococcal antibodies are indicated during an initial evaluation to rule out causes of NS other than MCD.

5.Renal ultrasound often shows enlarged kidneys.

6.Renal biopsy is rarely indicated in the young child with typical NS, unless the creatinine clearance is impaired or initial management with corticosteroids is ineffective.

7.Genetic testing for mutations associated with nephrotic syndrome may be indicated in the child who presents with nephrotic syndrome before their first birthday and in the steroid-resistant child.

G.Management. Treatment is dictated by the underlying cause of the NS.

1.Most children are hospitalized for initial treatment, although a relatively asymptomatic child with a reliable caregiver can be followed carefully as an outpatient.

2.If the child has widespread edema, scrotal or labial edema, hypotension, or symptomatic pleural effusions, IV infusions of 25% albumin should be given initially to achieve a diuresis and to maintain the intravascular volume.

3.The diet should consist of meals with no added salt.

4.Most patients with MCD respond to therapy with corticosteroids. Steroid-dependent and frequently relapsing children may achieve a prolonged remission during treatment with cyclophosphamide, mycophenolate mofetil, tacrolimus, or cyclosporine. For the steroid-resistant patient a prolonged course of tacrolimus plus steroids may induce a remission.

5.Because of the risk of pneumococcal infection, if the child is febrile, evaluation should include blood culture, urine culture, and chest radiograph. If peritonitis is suspected, paracentesis for Gram stain, culture, and cell count of the ascites fluid is indicated. Empiric broad-spectrum IV antibiotic coverage should be initiated.

H.Prognosis varies according to the underlying cause. Mortality approaches 5%, almost exclusively in children who are steroid-resistant and almost always from overwhelming infection or thrombosis.

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VII. Hemolytic Uremic Syndrome (HUS)

See Chapter 13, section I.F.2.b.(3) and Chapter 7, Table 7-6.

A.Definition. HUS is a condition characterized by acute kidney injury (AKI) in the presence of microangiopathic hemolytic anemia and thrombocytopenia.

B.Subtypes. There are three different subtypes of HUS, which differ in their known etiology, treatments, and prognoses: Shiga-like toxin HUS, pneumococcal HUS, and atypical HUS.

C.Shiga-like toxin–associated HUS (STEC-HUS)

1.Epidemiology. STEC-HUS is the most common subtype seen in childhood.

2.Etiology

a.STEC-HUS occurs as a result of an intestinal infection with a toxin-producing bacterial strain. In North America, the most common pathogen is Escherichia coli 0157:H7. Other pathogens include other strains of E. coli and Shigella dysenteriae type 1. Testing the stool with cultures for enteropathogenic E. coli and for Shiga toxin is informative.

b.Known sources of bacterial contamination include undercooked beef, unpasteurized milk, produce, and contaminated fruit juices. Human-to-human transmission has been described.

3.Pathogenesis

a.Vascular endothelial injury by the Shiga-like toxin is the key to the pathogenesis of injury in STEC-HUS.

b.The toxin binds to endothelial cells, causing endothelial cell injury, most especially in the renal vasculature. This leads to platelet thrombi formation and renal ischemia from the microthrombi.

4.Clinical features. The clinical presentation includes a diarrheal prodrome (often bloody and may be severe) followed by the sudden onset of hemolytic anemia, thrombocytopenia, and AKI.

5.Management. Treatment is supportive.

a.Transfusions as needed for severe anemia and thrombocytopenia.

b.AKI is managed as described in section X.E.

c.The use of antibiotics is controversial in treating diarrhea due to HUS-associated bacteria. Although antibiotic treatment of E. coli hemorrhagic colitis with certain antibiotics may increase the likelihood that the patient will eventually develop HUS, there is some preliminary evidence that fosfomycin may be protective and could be considered during outbreaks of E. coli–associated diarrhea.

6.Prognosis. The prognosis is generally favorable and depends on the severity of the presentation.

a.Poor prognostic signs for renal recovery include a high white blood cell (WBC) count on admission and prolonged oliguria.

b.A minority of patients die during the acute phase from the complications of colitis, such as toxic megacolon, or from central nervous system complications, such as cerebral infarctions.

D.Pneumococcal HUS

1.Pneumococcal HUS is triggered by infection with pneumococcus and accounts for about 5% of the cases of HUS.

2.It is mediated by neuraminidase, which functions as a toxin in the presence of a S. pneumoniae infection. Plasma infusions may worsen the symptoms in this type of HUS, and if plasma exchange is considered, albumin should be used instead of plasma.

3.It often carries a worse prognosis than STEC-HUS because of necrotizing pneumonia.

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E.Atypical HUS (aHUS)

1.Epidemiology. aHUS is much less common than STEC-HUS.

2.Etiology

a.Drugs (e.g., oral contraceptives, cyclosporine, tacrolimus) or pregnancy may cause aHUS.

b.Inherited aHUS occurs with both autosomal dominant and autosomal recessive inheritance patterns, although not all patients have identifiable mutations. These genetic mutations cause chronic, excessive activation of complement, which also leads to platelet activation, endothelial cell damage, and systemic thrombotic microangiopathy.

3.Clinical features. Clinical findings are similar to those of STEC-HUS. Diarrhea may also be present, and severe proteinuria and hypertension are more consistently found. The clinical course is generally more severe with multiorgan damage.

4.Management. Treatment is supportive. Inciting medications, if any, must be stopped immediately.

5.Prognosis. Some patients have a chronic relapsing course (recurrent HUS). All patients with aHUS have a higher risk of progression to ESRD than patients with STEC-HUS.

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