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Glomerular diseases present clinically in several different ways depending on the nature and severity of the primary disease and the extent to which the normal physiologic functions of the glomerulus are perturbed. Some children with glomerulopathies are found incidentally to have microscopic hematuria or proteinuria but are otherwise asymptomatic. At the other extreme, children may become critically ill with oligoanuric rapidly progressive glomerulopathy in need of urgent dialysis. Whereas numerous glomerular diseases are inherited (see Chapter 469), most forms are acquired and are generally considered to be immunologically mediated. There are 3 classical clinical syndromes that develop from glomerular injury: acute and chronic glomerulonephritis (GN), defined by the triad of hematuria, hypertension, and acute kidney injury (AKI); nephrotic syndrome (NS), defined by proteinuria and hypoalbuminemia; and hemolytic-uremic syndrome (HUS), defined by microangiopathic hemolytic anemia, thrombocytopenia, and AKI.
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The pathophysiologic sequence of events that lead to the development of the nephritic triad (hematuria, hypertension, and AKI) are shown in Figure 468-1. In each of the clinical entities with glomerular proliferation, inflammation leads to decreased glomerular perfusion, resulting in compromised kidney function and retention of salt and water with potential development of hypertension and edema.
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APPROACH TO A CHILD WITH GLOMERULONEPHRITIS
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The patient with glomerular disease presents clinically with a constellation of features that may include hematuria, proteinuria, edema, hypertension, and AKI. The urinary sediment is characterized as active when dysmorphic erythrocytes and cellular casts are present. A series of questions guides the initial diagnostic and management plan.
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Is the process acute or chronic? Many patients with chronic GN appear relatively asymptomatic until the disease is advanced. Clues of chronicity include evidence of chronic kidney disease (CKD): significant anemia, renal osteodystrophy (abnormal bone radiographs or an elevated intact parathyroid hormone level), or small echogenic kidneys on ultrasound examination. Acute onset of severe hypertension often causes neurologic symptoms such as headaches and seizures, whereas long-standing hypertension of insidious onset may be clinically silent, but left ventricular hypertrophy may be present.
Is the kidney disease isolated, or are additional organ systems involved? A careful review of the systems and physical examination will help determine whether the investigation should move in the direction of primary (acquired) GN or toward secondary GN due to multisystem disease (Table 468-1). Relevant extrarenal involvement may be clinically silent. For example, postinfectious serologies (such as a streptozyme or anti–hepatitis B or anti–hepatitis C antibodies) may be indicated if infection-associated GN is a possibility. When patients present with a small-vessel vasculitis, involvement of the lung parenchyma or sinuses usually requires radiologic confirmation.
Is there hypocomplementemia? A low level of complement component C3 in the serum generally indicates 1 of 5 diseases in children: acute postinfectious GN, lupus nephritis (LN), C3 glomerulopathy (C3G), atypical HUS, or GN associated with chronic infections (subacute bacterial endocarditis or shunt nephritis), as indicated in Figure 468-2.
Is there recurrent painless macroscopic hematuria? If yes, immunoglobulin (Ig) A nephropathy is a likely diagnosis, although it also is a fairly common presentation of Alport syndrome during the first decade of life.
What is the age of the patient? Although most glomerular diseases can occur in almost any age group, some have a characteristic age range for onset of disease (Table 468-2). GN in the newborn period is extremely rare and often is the result of a congenital infection.
Is the onset rapidly progressive? Rapidly progressive glomerulonephritis (RPGN) is suggestive of a crescentic GN. More rarely, AKI may result from acute GN with superimposed acute tubular necrosis. RPGN is an emergency that needs urgent histologic diagnosis. Most of these patients have aggressive diseases that are successfully treated only with immunosuppressive therapy initiated early and in high doses. In patients with anti–glomerular basement membrane (GBM) nephritis or severe vasculitis, early plasmapheresis may be lifesaving.
Is NS present? Although proteinuria is a hallmark of many glomerular diseases, NS is suggestive of a more high-risk glomerular histopathology. In a patient presenting clinically with acute GN and hypocomplementemia, the presence of NS increases the concern for membranoproliferative GN, C3 glomerulopathy, or lupus nephritis. NS occurs less commonly in acute poststreptococcal glomerulonephritis (APSGN) and rarely in GN associated with chronic infections.
Is a kidney biopsy needed now? This procedure is generally not necessary when the diagnosis is obvious and the disease is self-limited without specific therapy (ie, typical APSGN and mild nephritis in patients with Henoch-Schönlein purpura), or for isolated steroid-sensitive NS. However, for most glomerular diseases, a definitive diagnosis can be made only by kidney biopsy. Moreover, for many patients, the most rational and evidence-based therapies are based on a histopathologic rather than a clinical diagnosis. Based on the severity and reversibility of the damage to the kidney, a kidney biopsy often predicts response to therapy and prognosis.
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ACUTE POSTSTREPTOCOCCAL GLOMERULONEPHRITIS (APSGN)
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APSGN is the most frequent and best-characterized acute postinfectious glomerulonephritis (PIGN). However, many other bacterial, viral, and parasitic pathogens may also induce acute PIGN. Identifying a specific causative pathogen often is difficult because the infection usually precedes the nephritis by a few weeks. A history of pharyngitis or pyoderma suggests a previous infection by group A β-hemolytic streptococcal species that may be confirmed by serologic testing. APSGN accounts for 80% to 90% of PIGN cases and is used as the prototype for this group of disorders. In approximately 10% of cases, PIGN follows other antecedent diseases caused by a variety of infectious agents as summarized in Table 468-3.
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APSGN is primarily a disease of school-age children and is more common in boys. Although reported in an 8-month-old child, the disease rarely occurs in children younger than 3 years of age and may occur as a sporadic or epidemic disease. APSGN follows infection with specific “nephritogenic” strains of group A β-hemolytic Streptococcus. APSGN has been shown to be nephritogenic following pharyngitis (strains 1, 3, 4, 12, 18, 25, and 49) or impetigo (strains 2, 49, 55, 57, and 60). It is extremely rare for APSGN and acute rheumatic fever (associated with M strains 1, 3, and 12) to occur simultaneously in the same patient.
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Antibiotic treatment of the prodromal disease does not prevent acute GN, but treatment is important as a public health measure to prevent the spread of the nephritogenic bacteria. A study from Macedonia reported that 23% of sibling contacts had abnormal urinalyses and 9% developed clinical features of nephritis. Although difficult to determine with certainty, the overall risk of developing APSGN after infection with a nephritogenic strain is in the range of 10% to 15%. Because 50% to 85% of patients with APSGN are asymptomatic, the true incidence is difficult to determine. Rates of APSGN have decreased in the United States and Europe during the past 2 decades, likely due to earlier recognition and treatment of streptococcal infections, preventing spread of infection. The prevalence of certain nephritogenic stains is decreasing as well. A seasonal pattern exists for APSGN in North America that mirrors that of the pathogenic organisms: pharyngitis in the winter and spring and impetigo in the summer and fall.
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The precise nature of the antigen–antibody complex that causes nephritis remains unclear. The latency period between the acute infection and the onset of nephritis represents the time required to generate sufficient IgG antistreptococcal antibodies to trigger immune complex formation. Although several streptococcal antigens have been identified in the glomerular immune deposits, 2 proteins are of particular interest, based on currently available evidence. First is the cationic cysteine proteinase exotoxin B (SpeB) that co-localizes with complement and IgG within glomerular subepithelial immune deposits. The presence of circulating anti-SpeB antibodies is strong evidence of a recent nephritogenic streptococcal infection. Second is the nephritis-associated plasmin receptor, a protein that does not co-localize with glomerular immune deposits but is associated with increased intraglomerular plasmin activity and is thought to facilitate immune complex formation and inflammation.
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Additional antigens are of interest and suggest that a group of streptococcal proteins may be involved in the initiation and progression of glomerular injury. It is currently thought that the target streptococcal antigen is initially trapped within glomeruli, with subsequent immune complex formation occurring in situ in the kidney. Once glomerular immune deposits are formed, the alternative and lectin complement pathways are activated, followed by neutrophil infiltration and glomerular damage. APSGN is an “exudative” GN characterized by the presence of many intraglomerular neutrophils. Pyuria and even white cell casts may be observed in the urinary sediment.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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Clinical symptoms begin abruptly. Patients usually are afebrile with a latency period of 1 to 2 weeks after having pharyngitis and 3 to 6 weeks after having a skin infection. The most common presenting features in symptomatic patients are edema (85%) and gross hematuria (30–50%). Almost all the patients have microscopic hematuria. The urine often has a unique cola or tea color. Hypertension is common (60–80%) but usually is mild to moderate; rarely, hypertensive encephalopathy and posterior reversible encephalopathy syndrome (PRES) can develop, even without a significant elevation in the serum creatinine concentration. Hypertension is not entirely explained by the degree of intracellular volume expansion. Echocardiographic evidence of left ventricular dysfunction is a common finding in children hospitalized with APSGN. The degree of AKI usually is mild. Rapidly progressive GN can occur, but only rarely. Although many patients have significant proteinuria and a slightly depressed serum albumin level (at least in part due to intravascular volume expansion), fewer than 5% of symptomatic patients develop frank NS. Severe complications, including pulmonary hemorrhage and cerebrovascular accidents, have been reported and can require kidney biopsy to distinguish APSGN from systemic vasculitis or Goodpasture syndrome. Occasionally, patients may have significant extrarenal manifestations suggestive of Henoch-Schönlein purpura. Spontaneous improvement typically begins within 1 week, with resolution of the edema occurring in 5 to 10 days and resolution of hypertension occurring in 2 to 3 weeks; however, the urinalysis may be abnormal for 1 to 2 years or, rarely, longer.
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DIAGNOSTIC EVALUATION
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The serum C3 level usually is below 50% of normal levels in patients with APSGN. However, as many as 10% of APSGN patients have a normal C3 level at the time of assessment. In patients with other forms of acute PIGN, this percentage is even higher. Decreased serum C4 levels are unusual, as consumption of C3 is due primarily to activation of the alternative pathway. A significant and persistent decrease in both C3 and C4 levels should suggest an alternative diagnosis, such as systemic lupus erythematosus, bacterial endocarditis, shunt nephritis, or membranoproliferative GN (see Fig. 468-2). The serum C3 level typically returns to normal within 8 to 12 weeks after APSGN. Urinalysis generally shows hematuria, proteinuria, and cellular casts (both red and white cells); rarely, patients may have a normal urinalysis.
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Confirmation of a recent streptococcal infection renders the diagnosis of APSGN most likely, with a few caveats. A positive throat culture is insufficient to confirm the diagnosis, as 20% of normal schoolchildren are carriers who will have positive throat cultures without disease. An antibody to the streptolysin O enzyme (ASO) is detected in 80% of children with antecedent pharyngitis, but the test is also positive in 16% to 18% of healthy children. After skin infections, a positive ASO is less frequent (50%), possibly because of the ASO enzyme binding to lipids in the skin. The streptozyme assay combines serologic testing to 5 different streptococcal antigens (streptolysin O, streptokinase, hyaluronidase, DNase B, and NADase) and increases the likelihood of a positive test to greater than 95% in patients with pharyngitis and to 80% in patients with skin infections. The DNase B test also is quite reliable to establish a prior streptococcal infection. In the majority of patients, the clinical presentation and laboratory tests render the diagnosis of APSGN quite evident. There is usually no indication to perform a kidney biopsy to confirm the diagnosis in such children. However, for children with persistently low C3 levels or those who fail to recover along the typical timeline (Fig. 468-3), kidney biopsy may reveal a predominance of C3 deposits suggestive of C3 glomerulopathy.
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TREATMENT AND COMPLICATIONS
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APSGN is an acute disease that resolves without specific medical therapy. Close monitoring and supportive care are essential to manage the acute nephritis syndrome until the glomerular injury spontaneously resolves. If not previously administered, antibiotics should be given to prevent the spread of the nephritogenic strain of Streptococcus to other individuals. Prophylactic antibiotics do not prevent future recurrences (an extremely rare event) and are thus not recommended. During the acute phase, patients may need to be hospitalized for observation and treatment of hypertension, edema, oliguria, elevated serum creatinine, or electrolyte abnormalities. Fluid-overloaded patients often respond to loop diuretics. Urine output increases spontaneously within 5 to 10 days; severe oliguria lasting beyond 2 weeks is extremely rare and is cause to question the diagnosis. Hypertension usually is not severe and can be managed with short-acting calcium channel blockers.
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In patients with more severe AKI, hyperkalemia, hyperphosphatemia, and acidosis are likely to occur and will require medical management. These patients rarely need dialysis. Corticosteroids and cytotoxic agents have no substantiated therapeutic role, although there is limited anecdotal evidence of benefit for patients with rapidly progressive GN associated with crescents on biopsy. This is such a rare presentation that performing prospective clinical trials to evaluate the benefit of such therapies is impossible.
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PROGNOSIS AND OUTCOMES
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Spontaneous improvement should begin within 1 week, with the gross hematuria, oliguria, azotemia, and hypertension generally resolving within 4 weeks; low C3 within 2 months; proteinuria by 6 months; and microscopic hematuria by 2 years following diagnosis (see Fig. 468-3). APSGN in children has been considered a completely reversible disease, which is still generally true. In the exceptional patient with crescentic disease, prolonged oliguria, and massive proteinuria, recovery may not be complete. Currently, no data are available on the evaluation of outcomes 2 to 3 decades after uncomplicated childhood APSGN. In the meantime, it seems reasonable to anticipate a good long-term outcome in children with this disease, although those hospitalized with severe acute disease deserve long-term follow-up care, as they may not have a completely benign long-term outcome. Recurrent APSGN is extremely rare but has been reported.
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GLOMERULONEPHRITIS WITH CHRONIC INFECTIONS
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Immune responses may also induce GN in the face of certain chronic persistent infections. In pediatric patients, the most important examples are infective endocarditis, shunt nephritis, hepatitis B and C, and human immunodeficiency virus (HIV), as well as congenital infections with cytomegalovirus or toxoplasmosis that may present clinically as infantile NS. In endemic tropical areas of the world, chronic infection with Plasmodium malariae, Schistosoma mansoni, and filariasis may cause more chronic forms of GN.
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INFECTIVE ENDOCARDITIS
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Subacute bacterial endocarditis (usually caused by Streptococcus viridans) is less common with the decline in rheumatic fever, but acute bacterial endocarditis is now more common, especially among intravenous drug abusers. Staphylococcus aureus is the most common pathogen, but several other organisms are occasionally implicated. Both serum C3 and C4 levels are depressed in 90% of patients. A subset of patients may develop circulating anti-neutrophil cytoplasmic antibodies (ANCA). Histologically, the disease resembles APSGN, even in the small ANCA-positive subset. With appropriate antibiotic therapy, the glomerulopathy improves, but chronic kidney injury may persist. Normalization of the serum complement levels is a good prognostic indicator. The possibility of other kidney lesions being present, especially drug-induced interstitial nephritis and septic emboli, needs to be considered in this population.
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Shunt nephritis was first recognized in children with ventriculoatrial shunts for hydrocephalus. The risk of development of nephritis is reportedly 4% among patients with infected shunts. This complication is extremely rare in patients with infected ventriculoperitoneal shunts. A similar form of nephritis occurs with infected vascular access grafts. Coagulase-negative Staphylococcus is the most common organism. Blood cultures may be negative, but the organism often is cultured from the graft itself. The kidney disease frequently has an indolent presentation: gross hematuria occurs frequently, and 25% to 30% of patients may develop NS. Serum C3 and C4 levels usually are depressed (90%). Histologically, the lesion is a diffuse proliferative GN that resembles membranoproliferative GN (MPGN). Treatment includes antibiotic therapy and removal of the infected shunt. The glomerular disease slowly resolves, but residual CKD is a frequent occurrence.
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An association exists between chronic hepatitis B (HBV) and membranous nephropathy. Less common kidney manifestations associated with chronic HBV infection are MPGN, crescentic GN, and kidney disease related to polyarteritis nodosa (PAN). Introducing the hepatitis B vaccination during infancy has decreased the incidence of HBV-associated kidney disease. Children present clinically with NS or with nonnephrotic proteinuria during the chronic carrier stage. Depressed serum C3 and C4 levels are not characteristic but may occur. In children, most kidney complications remit spontaneously within 5 to 7 years, concomitant with the disappearance of HBe antigenemia and the appearance of HBe antibodies. The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommend antiviral therapy for HBV infection and membranous nephropathy with interferon alpha or nucleoside analogs for persistent kidney disease. Because these agents are nephrotoxic, kidney function must be followed closely during therapy. Immunosuppressive therapy is contraindicated due to an increased risk of developing chronic active hepatitis, although corticosteroids have been used in a select subset of patients with severe vasculitis or crescentic GN.
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In adults, chronic active infection with hepatitis C virus also can cause MPGN, especially in association with cryoglobulinemia, membranous nephropathy, and IgA nephropathy. Unlike in adults, MPGN has been associated with viral infections in only a very limited number of children. KDIGO guidelines suggest combined antiviral treatment for hepatitis C virus–associated MPGN using PEGylated interferon and ribavirin, titrated according to the patient’s tolerance and level of kidney function.
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HIV-ASSOCIATED NEPHROPATHY
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Prior to the development of highly active anti-retroviral therapy (HAART), approximately 2% to 10% of patients infected with HIV developed nephropathy. Most patients present with proteinuria, usually with NS. It may be the first manifestation of HIV infection, or it may occur in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. A unique variant of focal segmental glomerulosclerosis (FSGS) is found in 60% of patients, the vast majority of whom are of African descent with advanced HIV disease. In addition to the typical FSGS lesion, “collapsed” glomeruli (also seen in a small subset of patients with idiopathic FSGS), degenerated and microcystic tubules, interstitial edema and inflammation, and glomerular endothelial tubuloreticular inclusions (reminiscent of those associated with lupus nephritis) are common features. Carrying the risk allele for the apolipoprotein L1 (APOL1) gene increases the chance for developing HIV-associated nephropathy among African Americans. HAART slows the rate of progression and may even prevent the development of nephropathy. Anecdotal case reports suggest a beneficial outcome in patients treated with steroids or cyclosporine. Because opportunistic infections are common occurrences, the relative risks and merits of these more aggressive treatments need to be carefully considered. Nephrotoxicity due to urinary crystal formation or tubular damage may occur with the use of certain antiretroviral drugs. In addition to the “collapsing” variant of FSGS, HIV-infected patients have an increased risk of developing other glomerulopathies, including IgA nephropathy, thrombotic microangiopathy, PIGN, MPGN, and immune complex GN. HAART has been less effective for treating these forms of kidney diseases in HIV-infected individuals. Hepatitis C co-infection and drug-induced nephrotoxicity are also common occurrences. Kidney transplantation, once contraindicated in patients with HIV, is now the most effective renal replacement therapy, provided rigorous criteria are met.
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MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS (MPGN)
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MPGN, less commonly called mesangiocapillary GN, is not a distinct disease. It is a biopsy diagnosis characterized morphologically by (1) thickening of the GBM caused by immune complex deposition or interposition of mesangial cell cytoplasm in the GBM and (2) hypercellularity caused by proliferation of mesangial cells and the influx of leukocytes, which produces a typical lobular appearance of the glomerular tuft. MPGN is frequently idiopathic in children but may be secondary to a variety of other entities, as shown in Figure 468-4.
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The idiopathic varieties are classified as 2 distinct and unrelated diseases based on kidney biopsy findings. Immunoglobulin-mediated MPGN (Ig-MPGN, formerly MPGN type I) is an immune complex disease characterized by a predominance of IgG deposition along the subendothelial space of the GBM. In contrast, C3 glomerulopathy (C3G) is a disease of dysregulated complement activation characterized by predominantly C3 deposits in the glomerulus. C3G can be further subdivided into dense deposit disease (DDD, formerly type II MPGN) and GN with dominant C3 (C3GN) based on abnormalities on electron microscopy.
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MPGN usually presents between the ages of 8 and 30 years; it rarely occurs in patients younger than the age of 5 years (although cases as young as 15 months have been reported) and mainly affects Caucasians. Although uncommon, familial clusters are increasingly recognized and associated with inherited complement gene variants. Overall, male and female patients are equally affected, but the condition is slightly more common in female adolescents. The incidence of idiopathic Ig-MPGN appears to have decreased during the past 2 decades. In adults, this may be explained by the recognition that many patients previously classified as having Ig-MPGN actually are chronically infected with hepatitis C. The reason for the declining pediatric incidence of idiopathic MPGN is unclear.
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Ig-MPGN is an immune complex–mediated glomerular disease. The close association with hepatitis C infection in some adult populations and the declining overall incidence of this disease suggest that exogenous antigens trigger the disease. C3G is caused by abnormalities in the regulation of the alternate pathway of complement activation, resulting in predominant deposition of complement C3 fragments within the glomerulus and subsequent injury. Complement factor H (CFH) and CFH-related gene variants associate with disease, as CFH is the major regulator of the alternative pathway of complement. In C3G, the abnormal CFH-related proteins interfere with CFH regulation of complement activation predominantly along the GBM, which results in abnormal glomerular C3 deposition in glomeruli with little to no effect on plasma C3 regulation.
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DDD is characterized by the presence of dense ribbon-like deposits within the GBM, as seen by electron microscopy. The nature of this dense material remains unknown, but it appears to be biochemically similar to GBM itself. This material appears to activate the alternative complement cascade, with C3 characteristically lining the outer aspect of these deposits. Immunoglobulins usually are absent. C3 nephritic factor (C3NeF) is an autoantibody that causes unregulated activation of the alternative complement pathway. C3NeF may be present in all types of MPGN but is most common in DDD.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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Twenty to 30% of children with MPGN/C3G present with an acute nephritic syndrome that initially mimics APSGN. In fact, many patients have had a preceding upper respiratory illness, and as many as 40% have evidence of having had a recent streptococcal infection. The presence of NS and a depressed serum C4 level are early clues that differentiate MPGN from APSGN. Another 20% to 40% of children are diagnosed following an incidental finding of proteinuria and hematuria. NS is a presenting feature in 30% to 50% of children, and even more children will develop the syndrome during the course of the disease. Much rarer presentations include recurrent episodes of gross hematuria that mimic IgA nephropathy and rapidly progressive GN. Subtle, but not substantial, differences exist between the clinical features at presentation of Ig-MPGN, C3GN, and DDD. Some patients with DDD have partial lipodystrophy (Barraquer-Simons disease).
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DIAGNOSTIC EVALUATION
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Although a kidney biopsy is required to establish the diagnosis of MPGN/C3G, persistent hypocomplementemia is highly suggestive of the diagnosis. Patients with Ig-MPGN have evidence of activation of the classical complement cascade with low serum C3 levels and borderline or low C4 levels. The complement profile in patients with C3G suggests activation of the alternative pathway with low C3 and normal C4 levels. The presence of C3NeF is most characteristic of DDD. However, the serum C3 level is normal in 25% of all patients with MPGN/C3G at the time of initial presentation. The levels are variable over time and appear not to have prognostic significance.
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TREATMENT AND COMPLICATIONS
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Optimal therapy remains uncertain. Clinical trials have shown no clear benefit of any treatment, but the duration of many trials has been relatively short, which is significant because MPGN/C3G usually is a chronic, slowly progressive disease process, so the benefit of treatment may not be evident unless given for years. For many children without NS, kidney function may remain stable for many years without specific therapy. The consensus in North America is that children with Ig-MPGN and significant proteinuria will do better if treated with alternate-day steroids, based on data from a cohort of children in Cincinnati and the International Study of Kidney Disease in Children (ISKDC). A variety of different protocols have been tried, but most involve a dose of 2 mg/kg every other day (maximum 60 mg) for at least 1 year, with various tapering schedules thereafter. Hypertension is a frequent complication that requires treatment. The role of antiplatelet therapy with aspirin or dipyridamole has been evaluated and is generally not recommended. Limited and conflicting data on the use of cytotoxic drugs and complement inhibition preclude recommendation.
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There is limited but emerging evidence to support the use of immunosuppression or complement inhibition for C3GN or DDD. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are recommended for proteinuria and hypertension control. Plasma exchange therapy may have a role in the patient subgroups with inherited CFH deficiency and possibly those with significant glomerulopathy associated with C3NeF. In an uncontrolled trial of pediatric patients, treatment with the anti-C5 antibody eculizumab was associated with reduction in proteinuria and increase in kidney function, but many children at other centers were nonresponders. The increasing number of small case series reporting beneficial outcomes in patients with severe C3G treated with rituximab highlights the need for a well-designed clinical trial.
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PROGNOSIS AND OUTCOMES
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Limited data are available on the long-term outcome of children with MPGN/C3G. For many patients, the disease carries a poor prognosis, particularly if associated with NS. Overall, 50% to 60% of untreated patients develop end-stage renal disease within 10 to 15 years; fewer than 10% undergo spontaneous remission. The prognosis is worse in patients with persistent NS and significant crescent formation and interstitial fibrosis on kidney biopsy. The outcome may have improved in recent years, but because of the indolent course of this disease, long-term follow-up will be necessary to confirm this impression. Following kidney transplantation, recurrent disease is common and can lead to graft failure.
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Treatment response and prognosis of patients with C3GN appear to be worse than those of patients with Ig-MPGN.
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Systemic lupus erythematosus (SLE) is considered the prototype of multisystem diseases that cause immune complex–mediated tissue injury to the kidney. At diagnosis, a finding of a completely normal kidney without IgG and C3 deposits is extremely rare, although kidney biopsies are performed generally only in patients with clinical or laboratory evidence of nephropathy, which includes 40% to 60% of children at the time of diagnosis and another 10% to 20% within 5 years of diagnosis.
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The mechanism of tissue injury is the glomerular deposition or in situ formation of immune complexes. Most tissue deposits contain IgG and C3, but the presence of IgM or IgA is also common. The presence of circulating autoantibodies has been shown to predate (by an average of 3 years) the onset of clinical symptoms. Autoantibodies to double-stranded DNA, nucleosomes, and α-actinin are most closely associated with GN in patients with SLE. Nucleosomes (chromatin fragments with a histone core) that are released from apoptotic cells have been of particular interest as antigenic triggers. Through the activation of complement, the glomerular immune deposits are thought to trigger an inflammatory response that causes kidney damage.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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Symptoms of lupus nephritis span the spectrum of glomerular injury, ranging from asymptomatic microscopic hematuria or proteinuria to rapidly progressive GN. AKI is a rare but recognized presentation. Usually other systemic manifestations of SLE are apparent, and a kidney biopsy is almost never required to establish the diagnosis of this disorder. The presence of 4 of 11 American College of Rheumatology classification criteria for SLE confers a 96% sensitivity and specificity for the diagnosis of SLE and has been validated in children. Although the diagnosis of SLE usually is established by clinical criteria, a kidney biopsy is needed to determine the histologic pattern of renal injury, which guides initial therapy.
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Several distinct patterns of histopathology occur at comparable rates in both childhood and adult-onset SLE. The revised classification of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) defines 6 classes of lupus nephritis that are further subdivided based on the degree of disease activity (indicating the potential for therapeutic responsiveness) and chronicity (nonreversible damage). Class I is characterized by mesangial immune deposits with normal-appearing glomeruli. Class II lesions include mild mesangial matrix expansion and/or mesangial hypercellularity and predominantly mesangial immune complex deposits. The proliferative forms of lupus nephritis are the most common and most severe. Class III is focal proliferative nephritis (15–24% of the cases), with involvement in fewer than 50% of the glomeruli. Class IV, also called diffuse proliferative lupus nephritis (DPLN), has involvement of greater than 50% of the glomeruli and unfortunately accounts for 40% to 50% of the patients with lupus nephritis. In class III or IV nephritis, immune deposits occur in the mesangium and along the capillary wall, mainly in a subendothelial location. Class V is also called membranous lupus nephritis (10–20% of cases) and involves immune complex deposition in a subepithelial location. Combinations of proliferative and membranous lesions are possible (mixed class). Class VI is an irreversible advanced disease in which more than 90% of the glomeruli are destroyed by sclerosis.
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Clinically, patients with class I or II usually have mild hematuria with or without low-grade proteinuria. Patients with class V usually present with proteinuria, often in the nephrotic range. As many as half the patients have microscopic hematuria, but cellular casts are not seen in the urine sediment. Although typically patients with the most severe clinical disease will have DPLN, the same histologic pattern may be observed in patients with relatively mild clinical features. The presence of isolated NS is most likely to be associated with class V disease, whereas nephritis and NS together is most commonly caused by DPLN. However, either can be seen in patients with class III or even class II nephritis.
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DIAGNOSTIC EVALUATION
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Almost all patients have positive antinuclear antibodies (ANA), although these autoantibodies can be detected in individuals who do not have SLE (especially in a speckled pattern). True ANA-negative SLE is a rare occurrence in children. Hypocomplementemia is another important finding in patients with SLE and active disease. Anti–double-stranded DNA titers and serum C3 levels are useful parameters for monitoring the activity of the kidney disease and response to therapy. No combination of these serologic studies will effectively predict the histologic type or severity of kidney involvement.
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TREATMENT AND COMPLICATIONS
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SLE nephritis may be controlled with medical therapy, but currently there is no known cure. The treatment of patients with classes I and II should be determined by the extrarenal manifestations. This is a mild glomerular lesion that has an excellent prognosis. However, for many patients, the class and severity of the nephritis guide the approach to immunosuppression.
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DPLN is an aggressive disease that will ultimately destroy the kidney if left untreated. Consensus treatment recommendations developed for children, supported by several studies, indicate that the combined use of corticosteroids with immunosuppressive drugs results in a better long-term outcome than does treatment with corticosteroids alone. DPLN treatment is now divided into 2 phases: induction therapy to achieve remission and maintenance therapy to prevent relapses. If focal necrotizing lesions or crescents are present, patients with class III should be treated similarly. Induction includes corticosteroids initiated at high doses and tapered to low doses (often in the range of 0.1–0.5 mg/kg/d) over several months. Intravenous pulse therapy (30 mg/kg; maximum 1000 mg/dose) may be included, especially if the initial kidney disease is severe, as there is a delayed onset of action of the cytotoxic drugs. Six doses of intravenous cyclophosphamide (0.5–1.0 g/m2) administered monthly or twice-daily oral mycophenolate mofetil (MMF) is used in addition to corticosteroids.
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The maintenance phase of therapy includes low-dose corticosteroids, discontinuation of cyclophosphamide (if used for induction therapy), and addition/continuation of MMF or azathioprine. Hydroxychloroquine is first-line therapy for any patient with SLE unless there is a contraindication, as its use is proven to prevent disease flares and to prolong survival. The optimal duration of maintenance therapy is uncertain, but 2 years after achieving remission without evidence of a relapse appears to be the minimum. During this period, serologic studies are monitored. Rising anti-dsDNA titers and falling serum complement levels are warning signs of an impending flare. Even with current treatment plans, only 80% of patients achieve remission, and 35% to 50% will experience at least 1 relapse.
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Evidence is lacking regarding the best treatment approach for class V nephritis. Patients with a pure membranous lesion have a fairly good renal prognosis and often are managed like idiopathic membranous nephropathy with low-dose prednisone and MMF or cyclosporine A. In patients with superimposed proliferative lesions (mixed class), treatment depends on the severity of the proliferative lesions because they infer a higher risk for developing progressive CKD.
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Other therapy has been used in patients with severe lupus nephritis, especially in the group that does not achieve an initial remission and in those who relapse early. There is insufficient evidence to recommend their use at this time. Although large clinical trials have failed to show efficacy of rituximab as an add-on therapy, there is evidence from large case series in adults and children that B-cell–depleting agents should be a first consideration for refractory lupus nephritis. Monoclonal antibody therapy targeting B-cell activating factor (belimumab) is approved for only adults with nonrenal SLE, but is now being studied in adults with lupus nephritis and children with nonrenal SLE. Intravenous immunoglobulin (IVIg) is beneficial for severe disease associated with hypogammaglobinemia. Plasmapheresis has not been shown to alter kidney outcomes, and its use in SLE should be limited to the rare subset of patients with thrombotic microangiopathy associated with antiphospholipid antibodies.
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PROGNOSIS AND OUTCOMES
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End-stage renal disease (ESRD) remains a problem in patients with DPLN, especially in those with advanced kidney scarring at the time of initial diagnosis and in noncompliant individuals. A small minority of patients have aggressive disease that is difficult to control with current treatment strategies. The incidence of ESRD in patients with SLE and DPLN has decreased from 50% in the 1950s to 5% to 10% today. Following kidney transplantation, deposits occasionally recur in the allograft, but they do not lead to graft failure. Overall patient survival is now in the range of 80% at 15-year follow-up. Several factors predict a worse prognosis and include ethnicity (African American, Hispanic), gender (male), failure to achieve disease remission, kidney disease severity (elevated creatinine, hypertension, or NS at diagnosis), and kidney histology (class VI disease, DPLN with crescents, significant interstitial fibrosis). Death within the first 5 years is usually due to active disease, infection, or thrombosis, whereas late mortality usually is caused by accelerated cardiovascular disease and malignancy.
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IgA nephropathy is the most common primary cause of GN throughout the world. Even though the course of the disease is indolent in most patients, a significant number of patients are at risk of ultimately developing ESRD.
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The true incidence of IgA nephropathy is uncertain, as there are no reliable serologic markers; a kidney biopsy is the only way to establish the diagnosis. The disease appears to be more prevalent in Asians and Caucasians and is relatively rare in blacks, with the male-to-female ratio ranging from 2:1 to 6:1. Although it may occur at any age, it most commonly presents in the second and third decades of life and rarely in the first decade. However, it has been reported in children as young as 3 years of age. Although IgA nephropathy is generally considered to be a sporadic disease, familial clustering has been observed in a pattern suggesting an autosomal dominant inheritance with incomplete penetrance. Specific disease-causing gene mutations have yet to be identified.
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Most cases of IgA nephropathy are idiopathic, but numerous secondary causes are described and include severe liver disease (with regression following liver transplant); portosystemic shunts; enteropathies such as celiac disease and Crohn disease; chronic lung diseases, including obstructive bronchitis, cystic fibrosis, and idiopathic interstitial pneumonia; neoplasias such as small cell carcinomas and lymphoma; infections such as HIV, Mycoplasma, toxoplasmosis, and leprosy; dermatitis herpetiformis; and seronegative arthropathies. Lupus nephritis may also be characterized by significant IgA deposits. Many children with Henoch-Schönlein purpura have evidence of GN that histopathologically resembles IgA nephropathy. Some consider these 2 entities to be different manifestations of the same disease. An overlapping pathogenesis is suggested by the fact that both diseases share similar geographic and racial distribution; the 2 disorders have been reported to coexist in different individuals in the same family (including monozygotic twins), and rare patients with the idiopathic form of IgA nephropathy have been reported to develop Henoch-Schönlein purpura several years later.
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IgA nephropathy is a systemic autoimmune disease that manifests exclusively in the kidney. Glomerular IgA deposits are polymeric IgA1 derived from systemic rather than mucosal immune responses. It is proposed that 4 processes must come together to induce IgA nephropathy. First, compared to IgA from normal individuals, the IgA molecule itself is different, with a unique glycosylation pattern in the hinge region of the antibody characterized by reduced galactose residues. The serum level of galactose-deficient IgA1 is a heritable trait in diverse racial or ethnic groups. Second, loss of tolerance to galactose-deficient IgA1 results in production of antibodies specific for the aberrant IgA1. A dysregulated mucosal immune system with defective responses to commonly encountered alimentary pathogens or dietary substances is hypothesized to be the key trigger. The third and fourth processes occur when galactose-deficient IgA1 forms immune complexes and deposit in the mesangium, where they may interact with mesangial cells, activate complement via the mannose-binding lectin pathway, and trigger glomerular injury. These complexes may react with naturally occurring IgG antibodies. Indeed, IgG glomerular deposits often are present together with IgA. Glomerular IgA deposits are present in 3% to 16% of healthy individuals, suggesting that an abnormality of immune complex responsiveness or clearance by glomerular cells is required for disease.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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There are 3 classic clinical presentations of IgA nephropathy. Most frequently, 40% to 50% of patients present with recurrent episodes of painless macroscopic hematuria. The onset of macrohematuria often is preceded 24 to 48 hours earlier by an upper respiratory tract infection; associations with gastroenteritis, sinusitis, and strenuous exercise also have been reported but are less common. The latency period between the onset of prodromal symptoms and macrohematuria is considerably shorter than that observed in patients with APSGN. The gross hematuria episodes typically resolve within a few days, but microscopic hematuria and variable degrees of proteinuria typically persist. Some patients complain of flank or loin pain, presumably because of swelling of the kidney capsule. The first episode of macrohematuria may mimic APSGN. Recurrent episodes of macroscopic hematuria may occur in patients with Alport syndrome during the first decade of life, mimicking the clinical presentation of IgA nephropathy. Painless gross hematuria also may be the initial presentation of children with MPGN/C3G. The interval between episodes in IgA nephropathy is highly variable, ranging from a few months to many years. The frequency of the episodes decreases with age.
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Almost as frequently, between 20% and 40% of patients present with an incidental finding of microscopic hematuria and mild proteinuria. A subset of this group will develop future episodes of gross hematuria, which occurs more frequently in children. Less commonly, fewer than 10% of patient will present with NS, occasionally mimicking minimal change NS clinically, but with IgA deposits on kidney biopsy. Finally, rare patients will present with an acute nephritic episode or RPGN. Most of the acute nephritic episodes resolve without specific therapy, and the long-term prognosis remains relatively good. If a kidney biopsy is performed during the acute phase, the degree of glomerular disease usually fails to explain the degree of kidney dysfunction. Superimposed acute tubular necrosis often is evident, with tubular toxicity from erythrocyte products such as hemoglobin and iron being possible contributory factors. The very small number of patients who develop RPGN caused by a severe crescentic form of IgA nephropathy have a poor outcome.
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DIAGNOSTIC EVALUATION
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There are currently no diagnostic serologic tests for IgA nephropathy. With the first episode of gross hematuria, serologic studies usually are performed to rule out other causes of acute GN. Serum IgA levels may be elevated in 8% to 16% of children with IgA nephropathy; the percentage is higher in adults, but this test is not sufficiently specific to establish a diagnosis. Although IgA and C3 have been found in the dermal capillaries of forearm skin biopsies in 30% to 50% of patients with IgA nephropathy, this test is not currently recommended. Testing for galactose-deficient IgA1 or urinary IgA1-IgG immune complexes remains investigational. Many pediatric nephrologists would recommend a biopsy for suspected patients with IgA nephropathy who have impaired kidney function, hypertension, or significant proteinuria, as these individuals are at increased risk of ultimately developing ESRD. The Oxford classification is an evidence-based schema devised by the International IgA Nephropathy Network and the Renal Pathology Society to predict potential progression of the disease that scores 4 histologic features of kidney injury: mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis.
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TREATMENT AND COMPLICATIONS
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Optimal therapy for IgA nephropathy is controversial, but there is emerging evidence to guide treatment decisions (Fig. 468-5). The disease usually follows a benign course so that no therapeutic intervention is necessary. However, a subset of patients can develop progressive CKD. Risk factors include male sex, older age, elevated serum creatinine, hypertension, persistent proteinuria greater than 1.0 g/24 h, and the severity of the proliferative and sclerotic lesions on kidney biopsy. Current management recommendations include the following:
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Patients with isolated microscopic hematuria and urinary protein-to-creatinine ratios less than 0.6 to 0.8 mg/mg (males and females, respectively) require no treatment except monitoring.
Tonsillectomy has been proposed as a therapeutic option, but there is a lack of evidence of long-term benefit when performed in patients without evidence of tonsil-associated clinical symptoms.
Hypertensive patients should be treated with an ACEi or ARB, as these drugs control the blood pressure and may slow the rate of decline in glomerular filtration rate. Normotensive patients with proteinuria greater than 0.5 to 1.0 g/24 h may also benefit from such treatment with a decrease in proteinuria.
The benefit of treatment with omega-3 fatty acids in the form of fish oil has not been firmly established due to conflicting clinical trial outcomes. It is thought to act as an anti-inflammatory agent. Compliance is poor due to fishy aftertaste; otherwise, it is well tolerated and may add some benefit, especially when combined with an ACEi or ARB in proteinuric patients with well-preserved kidney function.
Alternate-day steroids appear to benefit patients with progressive CKD. The optimal treatment duration is unclear; 6 months has been used in several clinical trials. Addition of cytotoxic agents, azathioprine, or MMF has yet to prove beneficial in preventing progression of CKD, but several clinical trials are under way to evaluate the efficacy of alternative protocols and new agents.
Patients with aggressive crescentic GN usually are treated with corticosteroids and an immunosuppressive agent, as the prognosis is otherwise poor. One approach is cyclophosphamide for 3 months followed by azathioprine or MMF for 1 to 2 years; the latter is based on results in small case series.
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PROGNOSIS AND OUTCOMES
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IgA nephropathy is a disease with a highly variable outcome. Complete sustained remission occurs in fewer than 10% of patients. For patients with self-limited episodes of recurrent gross hematuria who do not develop significant proteinuria, the long-term outcome is quite good. Risk factors for progressive disease include persistent and significant degrees of proteinuria, hypertension, and an elevated serum creatinine. In the high-risk patient group, kidney function slowly deteriorates. After 20 to 25 years of follow-up, 20% to 30% develop ESRD and another 20% have progressive CKD. Following kidney transplantation, IgA deposits commonly recur in the allograft (20–75%), but recurrent disease is not a common cause of graft failure.
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HENOCH-SCHÖNLEIN PURPURA (HSP) NEPHRITIS
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Henoch-Schönlein purpura (HSP) or anaphylactoid purpura is the most common vasculitis in children. It is a self-limited systemic vasculitis syndrome characterized clinically by a tetrad of clinical features that occur in any order and at any time over the course of several days to weeks: a purpuric rash (may initially look urticarial), arthralgias, abdominal pain, and GN. Unlike arthritis and gastrointestinal involvement, nephritis rarely, if ever, precedes the onset of purpura. Histologically, the GN is indistinguishable from idiopathic IgA nephropathy. Depending on the diagnostic criteria, the incidence of GN ranges from 20% to 40%. The kidney complications of HSP are discussed here, whereas the diagnosis and management of HSP are discussed elsewhere (see Chapter 200).
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Although HSP nephritis and IgA nephropathy are related diseases, they display pathophysiologic differences with important therapeutic implications. Whereas IgA nephropathy manifests exclusively in the kidney, HSP leads to many extrarenal manifestations. The pathophysiology is similar in its involvement of glomerular deposition of polymeric IgA1 immune complexes. The serum IgA1 in patients with HSP is also galactose-deficient. Circulating immune complexes containing galactose-deficient IgA1 also are detectable in HSP. The role of galactose-deficient IgA1 molecules in kidney lesions is suggested by the observation that they are found only in the serum of patients with HSP when they are having an episode of nephritis. The mucosal immune system is dysregulated, at least in part due to increased intestinal permeability to gut contents. Familial clustering of individuals with HSP nephritis and IgA nephropathy has been described in those who have similar circulating IgA abnormalities.
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The variability of disease course between patients with HSP nephritis and IgA nephropathy might be explained by differences in the duration of production, amount, composition, and localization of the galactose-deficient IgA immune complexes and/or different predispositions to parenchymal cell injury within and beyond the kidney.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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Whereas most patients with HSP nephritis have asymptomatic hematuria and mild proteinuria, some (∼20%) develop gross hematuria. Approximately 10% of the children with kidney disease present with an acute nephritic syndrome. NS and RPGN with AKI are much less common. Many patients develop nephritis after the appearance of the rash; glomerulopathy usually is evident within 1 month of disease onset in the remainder. Rare clinical presentations include hypertension with a normal urinalysis and microscopic hematuria due to urethritis. Occasionally, patients with ANCA-positive vasculitis, SLE, and even APSGN may present clinically with a syndrome that mimics HSP, which should be ruled out by serologic studies in atypical patients. Seventy percent of children with HSP are clinically well within 4 weeks, but recurrent episodes occur fairly commonly for the first 4 months (∼33%) and have been reported after an interval as long as 5 years. GN is often more severe in those with recurrent disease.
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DIAGNOSTIC EVALUATION
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The diagnosis depends on the presence of palpable purpura with a normal platelet count and coagulation studies, plus 1 or more of the following: diffuse abdominal pain, arthritis/arthralgia, or a biopsy with prominent IgA deposition. There are no specific diagnostic laboratory tests for HSP. Testing for galactose-deficient IgA1 or urinary IgA1-IgG immune complexes remains investigational. Elevated serum IgA levels and IgA rheumatoid factor are detected in approximately 50% of patients. Serum complement levels usually are normal or elevated. Although not routinely performed, a skin biopsy shows small vessel leukocytoclastic vasculitis with IgA deposition. Kidney biopsy is not necessary for diagnosis but can be helpful in making treatment decisions when patients develop NS or RPGN. The histologic lesions of HSP nephritis can be categorized as defined by the ISKDC. Grade I has minimal histologic alterations; grade II, pure mesangial proliferation without crescents; grade III, mesangial proliferation with < 50% crescentic glomeruli; grade IV, 50% to 75% crescentic glomeruli, grade V,> 75% crescentic glomeruli; and grade VI, membranoproliferative-like GN.
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TREATMENT AND COMPLICATIONS
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There is no curative treatment for HSP nephritis. Most patients recover spontaneously with supportive care. However, a small subset present with severe GN are at risk of developing CKD and even ESRD. Current management recommendations are based on KDIGO guidelines (KDIGO Glomerulonephritis Work Group 2012). If proteinuria is > 0.5g/1.73 m2/d (including those with NS), ACEis or ARBs should be prescribed. Patients with ISKDC grades IV to VI have a less favorable prognosis and usually are treated with steroids with or without an immunosuppressive agent (cyclophosphamide and/or plasma exchange), depending on the severity of AKI. Long-term follow-up of a pediatric cohort failed to show a benefit for steroids in grade III HSP nephritis in which there were fewer than 50% crescents. If abnormal proteinuria persists for longer than 3 to 6 months in patients with grade I, II, or III nephritis, corticosteroids also should be considered.
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Steroid treatment appears to decrease the severity of abdominal pain and may decrease recurrence rates. Nonsteroidal anti-inflammatory drugs (NSAIDs) may help relieve joint pain, but careful monitoring to detect nephrotoxicity is important. Studies in children have shown that early treatment with a short course (2–4 weeks) of prednisone does not reduce the risk of developing nephropathy within the first 12 months.
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PROGNOSIS AND OUTCOMES
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HSP is a self-limited disease that usually lasts 1 to 2 weeks. Typically, the prognosis is excellent. HSP morbidity is determined in most cases by gastrointestinal complications during the acute phase and by nephritis in the long term. Although the urinalysis remains abnormal in 50% of the children at 3 months and in 10% to 20% after 2 years, more than 90% of patients eventually achieve full clinical remission. A few children (3–4%) have a catastrophic acute illness and develop a rapidly progressive clinical course with ESRD within months. Another group (∼5%) has evidence of CKD, usually persistent proteinuria, with progression over a period of several years. Poor prognostic features include an acute nephritic presentation, heavy proteinuria, and the presence of glomerular crescents (> 50%) on biopsy. All patients with severe nephritis need monitoring for many years. In an outcomes study of 78 patients with HSP (after mean follow-up of a remarkable 23 years), 44% of individuals with NS or acute nephritis at presentation had developed hypertension or a progressive CKD, whereas 82% with isolated hematuria at presentation had normal renal function.
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ANCA-ASSOCIATED VASCULITIS (AAV)–ASSOCIATED NEPHROPATHY
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Systemic vasculitis with ANCA is associated with pauci-immune (minimal evidence of immune complex deposition) focal necrotizing GN. Two target ANCA antigens, both present in neutrophil granules, have been identified: proteinase-3 (PR3) produces a diffuse cytoplasmic staining pattern (cANCA), and myeloperoxidase provides a perinuclear staining pattern (pANCA). There are 2 small vessel vasculitic syndromes associated with ANCA and focal necrotizing GN: microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA; formerly Wegener granulomatosis). Eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg-Strauss) is a third type of small vessel vasculitis defined by a triad of asthma, eosinophilia, and eosinophilic inflammation; it has not been reported to cause glomerulopathy.
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Whereas ANCA-associated vasculitis (AAV) occurs mainly in middle-aged adults, it can present in adolescents and has been reported in children as young as 4 years of age. Nephritis is seen in 70% to 80% of children with both GPA and MPA, and in some cases, disease is renal-limited.
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These disorders are all associated with the formation of autoantibodies that react with antigens normally “hidden” from immune surveillance within neutrophil and monocyte cytosolic primary granules and lysosomes. The most common targets for ANCAs are thought to be myeloperoxidase (MPO) and PR3. The PR3 antigen also has been detected on renal tubular epithelia. The critical cryptic epitopes become expressed and are visible on the cell membrane in response to neutrophil “priming.” Infections (eg, S aureus), drugs (eg, antithyroid drugs, hydralazine, minocycline, and several others), environmental factors (eg, silica dust and heavy metals), and genetic risk factors all have been implicated as priming events. The ensuing immune response results in the formation of ANCA and sensitized mononuclear cells, both implicated in the pathogenesis of vascular inflammation and subsequent kidney damage. Neutrophil extracellular traps (NETs), Fc-receptors, microparticles, and localized complement activation also play roles in the ensuing nephritis.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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The Chapel Hill Consensus Conference Nomenclature of Systemic Vasculitis provides a framework for diagnosis and classification but has not been validated in children with vasculitis. The Paediatric Rheumatology European Society (PRES) has developed classification criteria for GPA but not MPA, and it has been endorsed by both the European Society of Paediatric Nephrology and the European League Against Rheumatism. The features of GPA and MPA overlap, except for necrotizing granulomatous lesions of the upper and lower airway in GPA but absent in patients with MPA. Both diseases may represent a clinical spectrum of the same primary pathologic process. They both typically present with a flu-like prodrome and systemic symptoms such as fever, anorexia, malaise, weight loss, and myalgias. Skin involvement (purpura or urticaria) and arthritis/arthralgia are common occurrences. Lung disease occurs in both syndromes, ranging from clinically silent involvement to life-threatening pulmonary hemorrhage. In MPA, the lung disease results from alveolar capillaritis, whereas in GPA, necrotizing granulomas form pulmonary nodules or even cavitating lesions. Granulomatous involvement of the upper airway, sinuses, nasal passages, and ears also is present in many patients with GPA. Frequently associated symptoms include nasal discharge, pain due to local ulcers, sinus pain, hoarseness, stridor, earache, and sensorineural hearing loss. Kidney involvement is very common in both, with rates of approximately 90% in MPA and 80% in GPA. There is a small subset of patients who present with renal-limited vasculitis. Histologically, the pauci-immune focal necrotizing GN is similar and often severe. All patients with nephritis have hematuria, most have proteinuria, and more than 70% have a reduced glomerular filtration rate at diagnosis. Some patients present with RPGN due to severe glomerular damage caused by fibrinoid necrosis and crescent formation. Even though GPA is classified as a granulomatous disease, granulomas are only rarely detected in perhaps 5% of kidney biopsies. Immune deposits are sparse or completely absent (justifying the name pauci-immune GN).
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DIAGNOSTIC EVALUATION
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ANCAs are detected in 85% to 95% of patients with active GPA (80–90% PR3-ANCA) and 70% with MPA (60% MPO-ANCA). Most patients (75–80%) with renal-limited vasculitis are MPO-ANCA positive. A small subset of patients with GN caused by anti-GBM antibodies and with autoimmune connective tissue disorders may also be ANCA positive. Although there is some overlap, the type of ANCA may predict the nature of the disease. ANCA may be present in other disorders, including inflammatory bowel disease, cystic fibrosis, and autoimmune hepatitis, for which the target antigen is typically neither PR3 nor MPO.
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TREATMENT AND COMPLICATIONS
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ANCA-associated systemic vasculitis is an aggressive disease. Without treatment, the 2-year mortality rate is 90%. The introduction of cyclophosphamide therapy has resulted in a dramatic improvement in outcomes, but significant morbidity and mortality are still encountered. Treatment plans are completely based on evidence from adult studies and small pediatric cohort studies. There is little role for corticosteroid therapy alone except to control the extrarenal localized disease. The first goal of therapy is to induce remission of the disease; it generally involves 3 to 6 months of corticosteroids and either cyclophosphamide or rituximab. Intravenous pulse steroids (30 mg/kg; maximum 1000 mg/dose) may be included, especially if the initial kidney disease is severe. Plasmapheresis is beneficial in patients with severe acute nephritis or severe pulmonary hemorrhage. Once the disease is in remission, maintenance immunosuppression with azathioprine, methotrexate, or rituximab is administered for at least 18 months to prevent relapse. Prophylactic therapy to prevent Pneumocystis pneumonia, cystitis, candidiasis, gastritis, osteopenia, and amenorrhea usually is prescribed. Trimethoprim-sulfamethoxazole appears to be beneficial for patients with GPA to prevent airway disease relapses. Relapse rates of 50% within 5 years (the risk is higher in the PR3-ANCA group) are typical.
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Monitoring the ANCA titer can be useful in evaluating disease activity. Relapses are unusual when the titer is persistently negative, whereas disease relapses often are accompanied by the reappearance of ANCA or a significant titer increase. The Birmingham Vasculitis Activity Score (BVAS) is a validated tool for clinical treatment trials.
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PROGNOSIS AND OUTCOMES
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Patient and kidney survival have improved dramatically with intensive immunosuppressive therapy. There are few long-term follow-up studies of children. Five-year survival rates in adults are now in the range of 75% to 85%. The published pediatric series are small, but they often report 5-year survival rates greater than 90%. CKD persists in as many as half of the patients, with 20% to 25% eventually developing ESRD. Following kidney transplantation, recurrence in the allograft has been reported, but too few cases have been reported to know the effect on graft survival. Early deaths are commonly due to active disease, infectious complications, and thromboembolism; late deaths are often due to treatment sequelae. Long-term complications include an increased risk of infertility and malignancy.
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ANTI–GLOMERULAR BASEMENT MEMBRANE DISEASE
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A rare and most aggressive form of crescentic GN is mediated by anti-GBM antibodies. Pulmonary involvement, typically causing pulmonary hemorrhage, occurs in 40% to 70% of patients. This pulmonary-renal syndrome is called Goodpasture syndrome.
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Anti-GBM disease typically occurs in Caucasian adults with 2 peak incidences, 1 in the third and 1 in the seventh decade of life. It is rare in the first decade of life but has been reported in children as young as 2 years. Although most cases are sporadic, mini-epidemics have occurred. A genetic predisposition (HLA-DR15 and HLA-DR4 associated) has been noted in some patients. Anti-GBM nephritis may occur as a rare complication of other kidney diseases (after extracorporeal shock wave lithotripsy or in association with staghorn calculi, membranous nephropathy, or minimal change disease). Many patients had an antecedent flulike illness, and an association with influenza A2 has been reported. Another unique situation in which anti-GBM nephritis may occur is in the small subset (5–10%) of patients with Alport syndrome who receive a kidney transplant.
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The Goodpasture target antigen is a normal structural component of glomerular and pulmonary basement membranes. It consists of the last 36 amino acid residues of the carboxy-terminal region (NC1 domain) of the α3 chain of type IV collagen. Basement membrane type IV collagen consists of 6 distinct polypeptide chains (α1 to α6), 3 of which combine to form triple helices. The relative abundance of the α3 chain in glomeruli and alveoli likely explains the restriction of antibody-mediated disease to these organs. The antibodies produced after transplantation in patients with Alport syndrome recognize an antigen on the α5 NC1 domain of collagen IV, distinct from the Goodpasture target antigen. Most anti-GBM antibodies are of the IgG isotype, although a few patients with IgA antibodies have been reported. Antigen-sensitized T cells also contribute to the disease’s pathogenesis.
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Why some, but not all, patients develop pulmonary disease is unclear, because the target antigen (α3 chain of type IV collagen) is present in all alveolar basement membranes. Experimental models suggest that a second factor in addition to the anti-GBM antibodies may be required before the lung tissue becomes affected. Exposure to tobacco, hydrocarbons, cocaine, and viral pneumonitis, all of which may cause lung injury, has been associated with an enhanced likelihood of pulmonary hemorrhage.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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Patients present with acute nephritis or with symptoms caused by CKD. Progression to irreversible kidney injury can occur within weeks. Pulmonary hemorrhage presenting as hemoptysis often precedes or accompanies the onset of nephritis. In 30% of patients, the pulmonary involvement may be clinically silent or may follow the onset of GN. The episodes of hemoptysis may be life-threatening. Pulmonary-renal syndrome may also occur in patients with SLE, systemic vasculitis, GPA, HSP, cardiovascular disease, and various infectious diseases.
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DIAGNOSTIC EVALUATION
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More than 90% of patients have an anti-GBM antibody detected in the plasma at the time of clinical presentation; however, the titer of the antibody does not correlate with the severity of the disease. A subset of patients (10–40%) may also have a positive ANCA due to anti-myeloperoxidase antibodies. Some of these overlap patients have evidence of extrarenal disease caused by vasculitis, and this group seems to have a slightly better prognosis. Iron deficiency anemia may occur as a complication of pulmonary hemorrhages. Short-lived acute pulmonary hemorrhage can be detected by the presence of hemosiderin-laden macrophages in bronchoalveolar lavage fluid. The diagnosis is confirmed by a kidney biopsy showing crescentic nephritis with linear deposits of IgG and C3 along the GBM.
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TREATMENT AND COMPLICATIONS
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If the patient has pulmonary disease or evidence of reversible (typically acute dialysis-independent) kidney disease, the mainstay of therapy is plasmapheresis to remove the circulating antibody. Immunosuppressive therapy (prednisone plus cyclophosphamide) is added to reduce new production of antibodies. For reversible disease, the duration of therapy may be guided by anti-GBM antibody titers.
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PROGNOSIS AND OUTCOMES
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The kidney disease is unlikely to be reversible unless treatment is started early. In most patients, production of anti-GBM antibody is of limited duration, with the antibody disappearing from the circulation within 8 to 14 weeks; it is rarely detected after 6 months. Nonetheless, the ability of this antibody to cause irreversible kidney injury is remarkable. ESRD in adults is almost inevitable if the initial creatinine is greater than 5 mg/dL or if more than 75% of the glomeruli have crescents on kidney biopsy. Patients who recover from the acute disease generally do well. Disease relapses are extremely rare, in the range of 2%.
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RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS (RPGN)
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RPGN is a clinical syndrome characterized by sudden onset and rapid decline in kidney function. Kidney histology shows extensive crescent formation, typically in more than 50% of the glomeruli. Without specific therapy, most patients progress to ESRD within a period of weeks to months. Early treatment offers the best chance for renal recovery, so in suspected cases, early diagnosis is a nephrologic emergency.
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RPGN is a rare disorder in childhood that is classified into 3 groups based on the immunopathologic features (Fig. 468-6): (1) anti-GBM nephritis (5–10%), (2) immune complex nephritis (45–75%), and (3) pauci-immune disease associated with ANCA (10–40%). Less commonly, other forms of proliferative GN may present as severe crescentic disease.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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Children with RPGN may present with gross hematuria (50–85%), edema (13–80%), anemia (70%), and hypertension (63–85%). NS is uncommon, likely because of the rapid reduction in glomerular filtration leading to AKI. The urinalysis usually reveals an “active” urine sediment with hematuria, proteinuria, and cellular casts. Depending on the etiology, extrarenal manifestations also may be present. Pulmonary hemorrhage suggests a diagnosis of anti-GBM nephritis or ANCA vasculitis and may be fatal if treatment is delayed.
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DIAGNOSTIC EVALUATION
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Serologic studies can be very helpful in establishing a tentative diagnosis, but biopsy confirmation is essential. Initial tests should include C3, C4, ANA, ANCA, and anti-GBM antibodies. Kidney biopsy establishes the diagnosis in most patients and provides valuable information about the relative degree of acute (potentially treatable) and chronic histologic changes. If the kidney is damaged beyond the point of repair, immunosuppressive therapy is futile, at least for the glomerulopathy.
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TREATMENT AND COMPLICATIONS
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Therapy is directed to the specific disease entity, but a few general principles apply in all cases. Spontaneous resolution of RPGN is extremely unlikely to occur. The prognosis is poor unless aggressive therapy is started early in the course of the disease. The one exception is crescentic APSGN, which often spontaneously resolves. Because the diseases that cause crescentic nephritis are immunologically mediated, the mainstay of therapy is immunosuppression. Because RPGN is so rare, especially in the pediatric population, evidence-based treatment guidelines are not available. If immunosuppressive therapy is warranted, most nephrologists begin with high-dose intravenous corticosteroids, followed by daily oral prednisone and cytotoxic therapy (usually cyclophosphamide). Plasmapheresis is indicated for patients with anti-GBM disease (before AKI progresses to dialysis dependence) and severe ANCA-associated GN or associated pulmonary hemorrhage; its efficacy in other crescentic diseases is unclear. In general, the degree of kidney failure at diagnosis predicts long-term outcome.
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Nephrotic syndrome (NS) is not a disease but a constellation of clinical findings common to several glomerular disorders. By definition, it comprises proteinuria greater than 50 mg/kg per 24 hours (> 40 mg/m2 per hour or a urinary protein-to-creatinine ratio > 2.0 mg/mg), hypoalbuminemia (serum albumin < 3.0 g/dL), and hyperlipidemia (elevated very-low-density lipoprotein, intermediate-density lipoprotein, low-density lipoprotein, and triglycerides). The reason for the increased hepatic production of lipoproteins during the nephrotic state is not entirely understood, but it appears to be associated with low plasma oncotic pressure or defects in lipoprotein catabolism. NS may be a manifestation of any of the proliferative glomerular diseases, but in children, it more commonly occurs as an isolated entity without clinical evidence of nephritis or significant glomerular hypercellularity on kidney biopsy. The pathophysiologic sequence of events that lead to the classical clinical features in NS, proteinuria, and hypoalbuminemia are depicted in Figure 468-7.
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APPROACH TO A CHILD WITH ISOLATED NEPHROTIC SYNDROME
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The NS of childhood has been divided into 3 broad groups: congenital/infantile, primary (inherited or idiopathic), and secondary. Only 10% to 15% of children have an identifiable secondary cause for their NS. The histologic lesions that are associated with secondary causes of NS are frequently indistinguishable from the idiopathic lesions, but the treatment is targeted to the primary underlying cause. During the past 2 decades, mutations in at least 28 genes have been identified in either inherited or sporadic primary NS (Table 468-4).
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Primary NS is the occurrence of the constellation of clinical findings that define NS in the absence of an identifiable causative agent or disease. Primary NS is classified into 4 categories based on biopsy findings: minimal change nephrotic syndrome (MCNS), MCNS with proliferative changes, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN). Although it is still debated, one theory is that MCNS and FSGS represent different ends in the spectrum of the same disease rather than distinct disorders. From a prognostic perspective, the histologic pattern is less important than is the responsiveness to corticosteroids. Most children with steroid-sensitive disease have MCNS, so patients with new-onset NS do not undergo routine kidney biopsy at the time of diagnosis.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS OF STEROID-SENSITIVE NEPHROTIC SYNDROME (SSNS)
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Most patients (95%) initially present with dependent edema that is most obvious in the eyelids, scrotum, and labia. Early morning swelling of the eyelids (periorbital edema) is a common occurrence, and frequently new patients are misdiagnosed as having allergic conjunctivitis. Increasing abdominal girth from ascites also frequently occurs. Most episodes of NS are triggered by an antecedent upper respiratory tract infection, as are most relapses. Less commonly, patients with NS present with symptoms secondary to complications of the NS, such as infections (peritonitis, cellulitis) or thromboembolic events. Hypertension is not typical, but a mild elevation in blood pressure occurs in 10% of patients. Microscopic hematuria is seen in approximately 20% of patients. Macroscopic hematuria is a distinctly uncommon manifestation and suggests another diagnosis.
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DIAGNOSTIC EVALUATION
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In addition to proteinuria, the urinalysis may show oval fat bodies (lipid-containing tubular cells) and waxy or hyaline casts. Granular casts are seen frequently when the patients are volume-contracted. Cellular casts are absent in idiopathic NS. When patients first present, the serum creatinine level is sometimes elevated, especially in the presence of intravascular volume contraction (frequently associated with an elevated hematocrit). Hyponatremia suggests dehydration with an appropriate increase in antidiuretic hormone level. The serum C3 level usually is normal or elevated. Urinary protein losses may result in low serum levels of IgG, thyroxine-binding globulin (nephrotic infants in particular are at risk of clinical hypothyroidism), vitamin D–binding globulin, alternative complement pathway factor B, and antithrombin III. Serum fibrinogen levels often are elevated and can be used as a surrogate marker for the risk of thrombosis.
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Corticosteroids will induce a remission in the vast majority of children with NS. Therefore, for those with a typical clinical presentation, a kidney biopsy is not indicated prior to initiating steroid therapy. Atypical features that may require a kidney biopsy prior to treatment include age younger than 1 year, macroscopic hematuria, hypertension, hypocomplementemia, extrarenal symptoms such as a rash of arthritis, or AKI not caused by volume concentration.
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Edema is mild in most patients and can be managed with dietary salt restriction. Fluid intake is not usually restricted except in the face of severe hyponatremia. Diuretics are effective but rarely are needed and must be used cautiously to avoid intravascular volume contraction. Intravenous albumin infusions may be hazardous but can be lifesaving in patients with clinical signs and symptoms caused by severe hypovolemia or generalized anasarca. A low serum albumin level alone is never sufficient reason to administer intravenous albumin. Hypertension seldom is present, even during corticosteroid therapy, but when present, it requires treatment with antihypertensive medications. In these situations, the hypertension usually is transient, and medications often can be discontinued once the disease is in remission.
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A major aspect of the initial management is education for the parents. The majority of patients will follow a chronic relapsing course, and the families need to be prepared in advance. All families should be taught how to use a dipstick to check the urine for protein. The family should keep a diary of the urinary-dipstick results, along with drug doses and significant clinical events. The importance of testing the urine during concurrent illness must be emphasized. Whereas relapses are frequently triggered by an upper respiratory tract infection, transient low-grade proteinuria may also occur and resolve spontaneously. Using nonsteroidal anti-inflammation drugs as antipyretics is best avoided in these patients due to the potential nephrotoxicity of these drugs.
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PHARMACOLOGIC THERAPY
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Although spontaneous remissions may occur, the current standard of care is to treat these children with corticosteroids. Screening for tuberculosis and ascertainment of varicella immune status are recommended before high-dose corticosteroids are given. The optimal dose, schedule of administration, and total duration of steroid therapy are unknown. Most children receive initial treatment with prednisone (60 mg/m2/d or 2 mg/kg/d; maximal dose 80 mg/d) based on the ISKDC. Prednisone can be given in a single daily dose or can be divided into 2 or 3 daily doses. Ninety percent of children who will respond do so within 4 weeks and 98% by 8 weeks. The current definition of steroid-responsiveness is response within 8 weeks. Once the urine becomes negative for protein, the prednisone is switched to alternate days and tapered over the course of 6 weeks or longer. The total duration of daily and alternate-day steroid therapy used to treat the initial episode influences the subsequent relapse rate. However, 3 recent well-designed clinical trials showed no significant reduction in the risk of having a relapse when extending the therapy past 3 months. Alternate-day dosing of prednisone during the taper has been shown in pediatrics to cause less growth suppression.
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Almost 50% of children with steroid-sensitive nephrotic syndrome (SSNS) experience several relapses. There is no agreement on a standard protocol for treating relapses. A commonly used protocol is prednisone 60 mg/m2/d until the urine is free of protein for 5 to 7 days; this is followed by alternate-day therapy that is tapered over several weeks.
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FREQUENTLY RELAPSING NEPHROTIC SYNDROME (FRNS)
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If a child with NS experiences frequent relapses (2 or more relapses within 6 months of initial response or 4 or more relapses within any 12-month period), then the potential adverse effects of cumulative steroid doses required to achieve remission begin to exceed the presumed benefits of maintaining remission of the NS.
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The possibility of medication noncompliance, including use of lower than recommended prednisone doses, and the presence of occult infections (dental infections or sinusitis) should always be considered in patients with frequent relapses. Although some nephrologists perform kidney biopsy on children after diagnosis of frequently relapsing nephrotic syndrome (FRNS), nearly all have proven to be minimal change disease.
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In cases of FRNS, the alternate-day dose can be tapered to a “threshold dose” (a dose below which relapses occur) to reduce the number of relapses and the total cumulative dose of steroid therapy. This dose is often in the range of 15 to 20 mg/m2 and is continued for 12 to 18 months. There is evidence that taking this dose every day during upper respiratory tract infections may reduce relapse rates. Regular assessment of growth (both height and weight) and monitoring for cataracts are imperative in children receiving chronic or recurrent corticosteroid therapy.
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Steroid-sparing strategies have also been developed to treat FRNS. One strategy involves alkylating agents such as oral cyclophosphamide for 8 to 12 weeks, which is generally well tolerated with minimal risk of gonadal toxicity (total cumulative dose < 200 mg/kg). Chlorambucil also is effective but is used less widely because of the risk of seizures. The alkylating agent is ideally started after induction of remission (to minimize the risks of developing infections and hemorrhagic cystitis) and is used in combination with low-dose prednisone. After undergoing treatment, the majority of patients experience a prolonged remission (35–65% still in remission at 5 years), but relapses do recur in a sizeable subset.
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Other steroid-sparing strategies used for treatment include a 6-month course of oral MMF, B-cell depletion with rituximab, and calcineurin inhibitors.
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STEROID-DEPENDENT NEPHROTIC SYNDROME (SDNS)
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When a child with NS develops 2 consecutive relapses during steroid therapy or when the ability to achieve and/or remain in remission from NS requires administration of corticosteroids (relapse within 14 days of its cessation), then the child is considered to be steroid-dependent. Patients with steroid-dependent nephrotic syndrome (SDNS) may also fit the definition for having FRNS, and similarly to FRNS, the potential adverse effects of the cumulative steroid doses required to maintain remission exceed presumed benefits of achieving remission of NS. MCNS is the most common cause of SDNS. Before initiating steroid-sparing therapies, a biopsy may be performed.
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As in FRNS, the alternate-day oral corticosteroid can be tapered to the threshold dose. Other steroid-sparing strategies used for treatment include a 6-month course of oral MMF, B-cell depletion with rituximab, calcineurin inhibitors, and vincristine. Children with SDNS do not respond as well to alkylating agents as does the FRNS subgroup. Patients with SDNS tend to also be medication-dependent to maintain a sustained remission.
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STEROID-RESISTANT NEPHROTIC SYNDROME (SRNS)
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Steroid-resistant nephrotic syndrome (SRNS) is defined as a failure to achieve remission after 6 to 8 weeks of full-dose daily prednisone. Approximately 15% to 20% of children with idiopathic NS will develop disease that is resistant to steroids. In addition, a small subset of patients who initially are responsive to steroids do evolve into having SRNS. Because MCNS is less common and FSGS is more common in this population, a biopsy is recommended for steroid-resistant patients prior to initiating alternative therapies. Genetic testing also is performed by many nephrologists for patients with SRNS, especially those who present at younger than 2 years of age or when there is a positive family history of NS.
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The French Pediatric Nephrology Society recommends 3 doses of intravenous pulse steroids (1000 mg/m2) every other day for children with NS who are unresponsive to 4 weeks of steroids. Lack of response within 7 days is used as the indication for biopsy. If tolerated, a further 4 weeks of therapy will then increase the rate of SSNS by 10% to 20%.
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The role of alkylating agents in treating SRNS is unclear, but a subset of patients will respond, especially those who had at least a partial response to prednisone therapy. Combined treatment with high-dose corticosteroids (oral prednisone with or without intravenous pulse steroids) and alkylating agents has reportedly induced a partial or complete remission in 30% to 60% of patients in some case series, but these protocols are associated with significant morbidity and should be limited to patients with well-preserved kidney function. Even a partial response is associated with a better outcome.
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Cyclosporine A (CsA) is effective in inducing and sustaining remission in 75% to 80% of patients with SRNS and has had a major impact in a small group of patients debilitated by the disease and by steroid toxicity and in some patients who have had a poor response to cyclophosphamide. A common starting dosage is 5 to 6 mg/kg divided into 2 doses, with target predose blood levels of 50 to 100 ng/mL. Higher blood levels (100–200 ng/mL) are sometimes necessary in the more challenging patients, but the potential benefit of higher levels needs to be weighed against the risk of developing nephrotoxicity, which increases with the dose and duration of use. CsA levels must be carefully monitored, and some recommend repeat kidney biopsy to evaluate the degree of interstitial fibrosis if therapy is continued for longer than 18 months. Unfortunately, relapses commonly occur once CsA is discontinued. Mild side effects frequently occur and include hypertension, gingival hypertrophy, and hirsutism. Tacrolimus appears to be equally effective, avoids the development of the hirsutism and gingival hypertrophy associated with CsA treatment, and is now more commonly used in many programs. Starting doses of 0.05 to 0.1 mg/kg/dose twice daily are usually adjusted to achieve goal predose blood levels of 4 to 10 ng/mL. Steroid- and calcineurin inhibitor–resistant patients rarely respond to the other known immunosuppressant medications, including cytotoxic agents, rituximab, and MMF.
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All hypertensive patients should be treated with ACEis or ARBs; these agents may also be recommended in normotensive patients for their antiproteinuric effects as long as serum potassium levels remain normal and the patient is not pregnant or at risk of becoming pregnant.
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CONGENITAL NEPHROTIC SYNDROME
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Congenital NS is defined as heavy proteinuria, hypoproteinemia, and edema starting within 3 months after birth. It is rare. Cases are caused either by genetic defects, especially nephrin and podocin (see Table 468-4), or by a perinatal infection. The Finnish type of congenital NS is caused by a nephrin gene mutation and is not accompanied by extrarenal malformations. Most of these children are born prematurely, with a birth weight ranging between 1.5 and 3.5 kg. The placental weight is more than 25% of the newborn weight in practically all cases. Proteinuria begins in utero and is detectable in the first urine sample after birth. Microscopic hematuria and normal creatinine values during the first months are typical. Heavy protein loss (up to 100 g/L) results in oliguria and severe edema if not treated. Hyperlipidemia, hypothyroidism, and hypogammaglobulinemia are present, due to urinary losses of lipoproteins, thyroid-binding globulins, and immunoglobulin. By ultrasound, the NPHS1 kidneys are large with increased cortical echogenicity and indistinct corticomedullary borders. The glomerular histopathology can vary and include minimal change, mesangial expansion, focal segmental glomerulosclerosis, or diffuse mesangial sclerosis, and the findings overlap in different entities. If congenital infections are ruled out, genetic analysis is the preferred method for establishing a definitive diagnosis.
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For congenital NS, immunosuppression is not recommended. Conservative management of edema with sodium and fluid restriction and intermittent IV albumin and loop diuretics can usually keep these patients out of the hospital. The management of these patients also includes a hypercaloric diet, thyroid hormone replacement, monitoring for thrombotic episodes, and prompt management of infectious complications. The outcome of these patients without major extrarenal manifestations is comparable with those of other patient groups after kidney transplantation. Judicious use of ACEis and indomethacin to limit glomerular filtration and subsequent protein losses can allow for adequate growth until the children are large enough to get a kidney transplant. However, other patients require unilateral or bilateral nephrectomy and chronic dialysis as a bridge to kidney transplant.
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MINIMAL CHANGE NEPHROTIC SYNDROME (MCNS)
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MCNS, also known historically as nil disease or lipoid nephrosis, is the most common cause of NS in children, accounting for 90% of patients presenting at younger than 10 years of age and 70% to 80% of all pediatric patients with NS. MCNS is characterized by response to corticosteroids (> 90%), a chronic relapsing course (60–80%), and an excellent long-term prognosis. As long as future relapses remain steroid responsive, the long-term prognosis is good.
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The incidence of MCNS is 2 to 7 per 100,000 children under the age of 16, per year. The peak incidence is in preschool children, with a median age of 2.5 years; 80% of patients present before reaching their sixth birthday. Boys are more commonly affected. Familial cases have been reported (3% in some series), but the responsible genes have not yet been identified. There appears to be a higher incidence in the Asian population; however, a recent study suggests that they have less complicated clinical outcomes. A history of atopy is reported in 30% to 60% of these children, and occasional associations with food allergies have been made.
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In children, MCNS usually is idiopathic, although several secondary causes are known (Table 468-5). Isolated NS is considered to be a primary disease of the glomerular epithelial cell (podocyte) that is either injured by an unknown systemic factor or defective due to a cell-specific genetic defect (sometimes referred to as podocytopathy). See Table 468-4 for a list of podocyte genes known to cause podocytopathy and steroid-resistant NS. Thus far, the nature of the soluble “nephrotic factor” remains elusive. Evidence for the existence of a circulating “nephrotic factor” in idiopathic NS is supported by the observation that on the rare occasion when an MCNS kidney in relapse was transplanted, proteinuria rapidly resolved in the recipient. Conversely, MCNS has been reported to recur in kidney transplant recipients with a history of MCNS.
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Corticosteroids will induce a remission in approximately 90% of children with MCNS. Of those, approximately 60% relapse. The therapy for children with MCNS and FRNS, SDNS, or SRNS does not differ from that for patients with FSGS.
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PROGNOSIS AND OUTCOMES
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Before the introduction of antibiotics and corticosteroids, 40% of nephrotic children died within 5 years of being diagnosed. Deaths were most commonly due to infectious complications. Although today more than 95% of these children are alive at 25 years, deaths secondary to infections or thrombotic complications still occur (∼3% overall mortality rate). Late-onset kidney injury is very unusual, but a small number of patients develop acute tubular necrosis if a relapse is accompanied by sepsis or hypovolemia. NSAIDs increase the risk of developing AKI during a relapse.
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Eight to 10 years after being diagnosed, 85% of patients achieve a long-lasting remission. Younger age at diagnosis and frequent relapses within the first 6 months predict longer duration of the disease. A number of patients (14–42%) continue to experience relapses into adulthood; the frequency may be more common than previously known and may even occur after a 20- to 25-year remission. Some patients who are initially steroid-responsive later become steroid-resistant. Many of these patients have FSGS, which may have been missed on an early biopsy or may have evolved from MCNS.
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FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
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The majority of children with SRNS (∼75%) have primary FSGS. FSGS is a more serious form of idiopathic NS, because only 20% to 25% of patients respond to steroids. It is the most frequent glomerular disease to cause ESRD in children and is second only to congenital anomalies of the kidney and urinary tract (CAKUT) as a cause of pediatric ESRD. FSGS is diagnosed histologically by the complete collapse of a segment of the glomerulus associated with mesangial sclerosis. Only some of the glomeruli are affected initially (ie, a focal rather than diffuse lesion), and the deep juxtamedullary glomeruli are involved first. FSGS may be primary, or it may develop as a secondary consequence of prior glomerular injury or hypertension (Table 468-6). The majority of children with hereditary or idiopathic FSGS present with SRNS (75–80%). The secondary forms of FSGS more typically present as asymptomatic proteinuria without the NS.
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In children, primary FSGS typically begins when they are between 2 and 7 years of age and occurs with an incidence of 0.3 cases per 100,000 patient years. There is a slight predominance in boys, especially when it develops at a young age. There is also a higher incidence among African Americans, Hispanics, and South Asians. The incidence of FSGS has been increasing in many pediatric and adult populations.
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Primary idiopathic FSGS recurs in kidney allografts, often within hours of the surgery, suggesting that a systemic factor(s) leads to the disorder. The nature and source of this factor and the reason for its production remain elusive. Pregnant women with FSGS gave birth to infants with NS that disappeared spontaneously a few weeks after birth. A bioassay based on the ability of plasma from patients with FSGS to increase albumin permeability in isolated rat glomeruli has been developed, but this factor has also been detected in genetic forms of FSGS, suggesting that it may not be a primary etiologic agent.
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In a growing percentage of patients, steroid-resistant FSGS has been identified as an inherited disease (one that typically presents before 6 years of age). Mutations in the slit diaphragm protein nephrin (NPHS1) are the most common cause of congenital NS, followed by mutations in the Wilms tumor suppressor gene 1 (WT1) and podocin (NPHS2). Less common genetic causes of congenital NS have also been reported, although many (including WT1 and NPHS2) can present clinically later than 3 months of age. Across all pediatric age groups, mutations in podocin are the most common cause of FSGS. Inheritance is autosomal recessive; both homozygous mutations and compound heterozygous mutations have been reported. Importantly, 10% to 30% of children with no family history of SRNS harbor sporadic podocin mutations. An ever-growing number of genes have been linked to inherited forms of SRNS, and additional genes remain to be identified (see Table 468-4).
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Genetic factors also enhance FSGS susceptibility. Variants of APOL1 have been linked to FSGS in African Americans with HIV or hypertension. The risk alleles are common in sub-Saharan Africa due to evolutionary pressure to maximize resistance to trypanosomiasis. Homozygosity for the risk alleles confers an estimated 4% lifetime risk for developing FSGS. Moreover, APOL1-associated FSGS occurs earlier and progresses to ESRD more rapidly.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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Most children (90%) with idiopathic FSGS present with NS that initially may be indistinguishable from SSNS. At the time of disease presentation, approximately 30% of children have mild hypertension, 55% have microscopic hematuria, and 20% have an elevated serum creatinine level. Less commonly, patients may present with asymptomatic proteinuria with or without microscopic hematuria. Macroscopic hematuria is rare.
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DIAGNOSTIC EVALUATION
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Definitive diagnosis requires a kidney biopsy, as is recommended for all patients with SRNS. Patients with FSGS also have tubulointerstitial damage that may impair proximal tubular function, causing features of Fanconi syndrome such as glycosuria, phosphaturia, renal tubular acidosis, and low-molecular-weight proteinuria. Genetic testing for podocin mutations is recommended for autosomal recessive, familial FSGS and for patients who fail to respond to calcineurin therapy.
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FSGS is a challenging disease to treat. With a poor overall response rate to immunosuppressive therapy and a high rate of recurrence in kidney allografts, this disease can be devastating. The current KDIGO guidelines recommend initial treatment of primary FSGS with high-dose prednisone given for between 4 and 16 weeks or until complete remission. At best, 25% of patients achieve a remission after treatment with a prolonged course of corticosteroids alone. Often the steroid therapy must be continued for several months.
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Calcineurin inhibitors are recommended for patients who are resistant or intolerant to corticosteroids. Considerable evidence-based literature supports the use of CsA as the second-line agent together with low-dose prednisone. Initial plasma trough levels may need to be higher than those for SSNS, often in the range of 125 to 225 ng/mL. Tacrolimus is sometimes effective in CsA nonresponsive patients and is increasingly replacing CsA due to a better side effect profile. Rituximab can be effective in steroid-responsive patients but has been disappointing in patients with SRNS. MMF may have a role in the treatment of steroid- and calcineurin-resistant FSGS, but data in children are limited. Triple therapy (steroids, CsA, and MMF), plasmapheresis, protein adsorption columns, and low-density lipoprotein apheresis are all reportedly effective in selected individuals, but data are insufficient to recommend their use at this time.
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Although controversial, patients with monogenic secondary forms of FSGS should still receive at least a trial of immunosuppressive drugs, although responsiveness is exceptional. Until genetic testing becomes standard of care, most patients with steroid-resistant FSGS have already tried and failed a variety of immunosuppressive agents by the time the genetic testing is considered.
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For recurrent FSGS after kidney transplantation, plasmapheresis and escalation of the dose of calcineurin inhibitors have occasionally been effective. However, many patients will lose their graft and return to dialysis.
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PROGNOSIS AND OUTCOMES
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The single best prognostic indicator in patients with idiopathic NS is responsiveness to steroid therapy. Approximately 50% of the patients who do not achieve remission of NS develop ESRD within 10 years. The risks of developing progressive CKD are higher among patients of Hispanic and African descent, children with disease onset when younger than 1 year of age, and patients with the collapsing variant of FSGS. The severity of the proteinuria and the degree of interstitial fibrosis on kidney biopsy also correlate with the rate of progression to ESRD. Recurrence of proteinuria and NS after transplantation occurs in 20% to 30% of patients. Patients with podocin mutations have rarely achieved remission with immunosuppressive therapy, so progression to ESRD is predicted.
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MEMBRANOUS NEPHROPATHY (MN)
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Membranous nephropathy (MN) is a noninflammatory proteinuric glomerular disease characterized by the presence of hallmark subepithelial immune deposits (usually containing IgG and C3). NS secondary to MN does not usually respond to an 8-week course of prednisone; therefore, diagnosis is made on biopsy.
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MN is a rare cause of NS in children, accounting for approximately 1% of all NS cases in North America. Although slightly more common in adolescents, it can present at any age, including in infants. Cases affecting identical twins and siblings have been reported, suggesting a genetic factor. Detailed epidemiologic studies in children have not been conducted.
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Unlike the disease in adults, the majority of childhood cases are secondary to an underlying disorder (Table 468-7). Idiopathic MN appears to be an antibody-mediated disease. Immune complexes are thought to form locally within the subepithelial space, where the target antigen is located. In a rat model of MN (Heymann nephritis), the target antigen is megalin, a normal constituent of rat but not human podocytes. Compared to 70% to 80% of adult patients with MN, autoantibodies to M-type phospholipase A2 receptor (aPLA2R) are seen in 45% to 75% of children and adolescents with primary MN. Noncoding genetic sequence variants in the gene locus encoding PLA2R also are associated with the development of MN. In a small number of pediatric patients, immune complexes involving cationic bovine serum albumin (BSA) and anti-BSA antibodies have been implicated, raising the possibility of a role for certain food antigens in MN pathogenesis. Other targets for autoantibodies in adult idiopathic MN, such as aldose reductase, manganese superoxide dismutase, alpha-enolase, and thrombospondin type 1 domain–containing 7A, have been described. An unusual antenatal form of MN has been reported and is associated with transplacental passage of antibodies to the podocyte antigen neutral endopeptidase. MN has also been reported rarely in patients with insulin-dependent diabetes mellitus, Crohn disease, and primary biliary cirrhosis, suggesting that other candidate autoantigens will eventually be unveiled. Glomerular inflammation does not explain the proteinuria; rather, the terminal membrane attack complex of the complement cascade C5b-9 appears to be the critical mediator.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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Proteinuria is the hallmark of MN. At presentation, 70% have NS, 70% have microscopic hematuria, and 20% are hypertensive. The disease usually is insidious in its onset and progression. When a kidney biopsy establishes a diagnosis of MN (usually after the patient’s failure to respond to corticosteroid therapy for NS), an exhaustive investigation is warranted to look for an underlying cause. Only 3% of children have kidney failure at presentation. A rapid deterioration in kidney function mandates a search for an additional cause. For example, a small subset of these patients develops a superimposed crescentic GN, sometimes due to the formation of anti-GBM antibodies. Although renal vein thrombosis is a common complication among adult patients with MN, this complication is rare in children.
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DIAGNOSTIC EVALUATION
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A kidney biopsy is required to establish a definitive diagnosis. Serologic tests, including serum complement levels, usually are normal. Laboratory investigations are particularly helpful during the search for a secondary cause (see Table 468-7). Hepatitis serology, serum complement levels, and an ANA test should be obtained in all patients. The kidney biopsy suggests a secondary cause if immune deposits are also found in the mesangium (SLE), if significant deposits of IgA are present (IgA nephropathy), or if inflammatory cells are present (APSGN); all these features are atypical of the idiopathic MN.
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Established treatment guidelines for children with idiopathic MN do not currently exist. Children who present with nonnephrotic proteinuria, normal blood pressure, and normal kidney function appear to have a good prognosis without specific therapy, but close follow-up is warranted. Spontaneous remissions have been reported in 3% to 30% of adult patients. Use of ACEi or ARB therapy and a low-sodium diet are recommended for hypertension and as antiproteinuric therapy.
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Treatment guidelines for patients at risk of developing CKD (NS, scarring on kidney biopsy, rising serum creatinine level during follow-up) have been developed for adults and often are applied to children for whom there are no evidence-based data, although the long-term prognosis appears to be better in children. In general, corticosteroids alone decrease proteinuria, but effects on long-term kidney function are less clear. For this reason, they are usually combined with an alkylating agent, either at the beginning of therapy or within 6 months, depending on the initial response. Therapy is required for several months. Calcineurin inhibitors are an alternative, especially for patients in whom alkylating agents are contraindicated. Data are emerging to suggest that MMF and rituximab may be useful in MN and that PLA2R-Ab levels are predictive of rituximab effect.
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PROGNOSIS AND OUTCOMES
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MN usually is an indolent, slowly progressive disease with fewer than 5% of children developing ESRD 5 years after being diagnosed. Good, long-term follow-up studies are not yet available for patients who develop MN in childhood.
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MEDICAL COMPLICATIONS OF NEPHROTIC SYNDROME
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Persistence of NS is associated with significant morbidity and even mortality. Short-term mortality rates of 3% are most frequently due to infectious complications and less commonly to thromboembolic events. Because NS frequently follows a chronic relapsing course, children are at risk for developing several recognized long-term complications (Table 468-8). Not to be overlooked is the tremendous psychological stress that the patients and their families endure. The side effects of corticosteroids and cytotoxic drugs are also significant for many children.
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Even in the current medical era, acute bacterial infections are relatively common and potentially fatal complications of NS. The acute onset of fever in a child during a relapse of NS needs urgent evaluation. Primary peritonitis still occurs in 2% to 6% of these children. Patients with serum albumin levels less than 1.5 g/dL have a greater risk of developing peritonitis. Fever associated with abdominal pain must be considered peritonitis until proven otherwise. Prior to the advent of routine immunization against pneumococcal organisms, 50% of peritonitis cases were caused by Streptococcus pneumoniae, whereas other encapsulated or gram-negative organisms were occasionally isolated (especially Escherichia coli). Patients with presumed peritonitis should be treated with antibiotics to cover both gram-positive and gram-negative organisms while culture results are pending. Unfortunately, the peritoneal culture is negative in 15% to 50% of patients with a presumptive diagnosis of peritonitis. Prophylactic penicillin has not proven to be effective for preventing pneumococcal peritonitis. Once a nephrotic patient is in remission and off steroids for a few months, inoculation with the 23-valent pneumococcal polysaccharide vaccine (Pneumovax) and the pneumococcal conjugate vaccine (Prevnar 13) should be done, if not given in infancy as is currently recommended.
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Several abnormalities associated with the nephrotic state predispose patients to development of bacterial infections: abnormalities of cellular immunity; low total serum IgG and specific antibody levels (only partly explained by urinary losses); and decreased serum levels of complement proteins B and D, which impair plasma bacterial opsonic activity and may explain the predisposition to infections caused by encapsulated bacteria. Local factors related to tissue edema, breakdown of the skin barrier, and the presence of peritoneal fluid, which is a rich culture medium, may also facilitate infections. The use of immunosuppressive drugs is another contributing factor.
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Varicella-zoster infections occurring during a relapse may be severe. The live-attenuated vaccine should be given only after immunosuppressive drugs have been discontinued for a few months. In the interim, significant exposures should be treated with zoster immune globulin if available or antiviral drugs such as valacyclovir. Varicella antibody levels may decline in patients with numerous relapses or with NS that is refractory to treatment. Annual immunization with killed influenza vaccine is recommended.
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Thromboembolism is one of the most serious complications of NS. Virtually all nephrotic patients are in a hypercoagulable state, and as many as 20% experience thrombotic events that are often clinically silent (only 2–4% have symptoms). The cause of the NS may affect the absolute risk. Thrombosis is a relatively common occurrence in adults with MN but infrequent in children with MCNS, but it is still recommended that children with documented thrombotic complications undergo an evaluation for known genetic causes of thromboembolic disorders. Which abnormalities of the clotting process best correlate with the risk of thrombosis remains unclear. Plasma fibrinogen levels appear to be the best surrogate measure of hypercoagulability. Virtually every component of the hemostatic pathway is perturbed in some way, including increased serum levels of clotting factors (especially factors VIII and V and fibrinogen), urinary loss of anticoagulants (antithrombin III and protein S), and increased platelet number and adhesiveness. Other contributing factors include hyperlipidemia and hyperviscosity. The risk of developing thrombotic disease is significantly enhanced in the presence of hypovolemia and during prolonged periods of immobilization. Hospitalized young adult nephrotic patients have a 7-fold increased risk of experiencing thromboemboli. Indwelling venous catheters impose a major risk and should be avoided if at all possible.
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The clinical presentation is highly variable and dependent on the site of the clot. In children, both arterial and venous clots occur. The renal vein and sagittal sinus may be targets, as are the pulmonary and femoral arteries. Aspirin therapy may be recommended for patients with significant thrombocytosis. Prophylactic anticoagulation is not recommended in the pediatric age group due to the risks of bleeding. In those with a documented clot or very high risk factors (such as an indwelling catheter), warfarin or low-molecular-weight heparin is used; the latter requires adequate factor VIII activity levels.
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ACUTE KIDNEY INJURY (AKI)
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AKI is a common occurrence in children hospitalized with complications of NS (50% in a recent study). Predisposing factors are numerous and may include infection, nephrotoxic medication, and hemodynamic consequences of the nephrotic state.
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CARDIOVASCULAR DISEASE
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An unresolved issue of significant concern is whether children with chronic relapsing NS are at risk of developing premature atherosclerotic disease. Autopsies done on children as young as 5 years who died from NS have found atheromatous lesions. In adults with NS, the relative risk of myocardial infarction is 5.5 compared with a control population after adjustment for other known risk factors.
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Several factors may contribute to the increased risk of having cardiovascular disease and stroke; they include hypertension, the use of steroids, systemic inflammation, and the atherogenic plasma lipid profile. In particular, plasma cholesterol and lipoprotein levels are high. Whether hypercholesterolemia should be treated with 3-hydroxyl-3-methylglutaryl-CoA reductase inhibitor (statin) therapy in children aged 8 to 18 years with hypercholesterolemia is controversial. Use of statins may reduce cardiovascular risks, but there is no strong evidence that it slows the progression of kidney disease. The potential benefits of using statins must be weighed against the concerns about its effects on myelination and the risk of developing statin-induced rhabdomyolysis, which appears to be higher with concurrent use of a calcineurin inhibitor. Although no consensus statement exists to guide decisions in NS, there are expert panel integrated guidelines published on pediatric cardiovascular risk reduction by the National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov/health-pro/guidelines/).
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Although reduced bone formation rates, osteoporosis, and avascular necrosis are known complications of long-term use of corticosteroids, these complications appear to be rare in patients with SSNS based on an evaluation of bone density by dual energy x-ray absorptiometry. One proposed explanation is that the steroid-associated increase in the body mass index is protective as a consequence of increased biomechanical loading. Children with numerous steroid-treated relapses may not reach their final adult-height potential. A recent study reported that more than 5% of children with NS had radiographic evidence of vertebral fractures at 1 year, indicating that bone health needs ongoing surveillance in patients with frequent relapses.
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HEMOLYTIC-UREMIC SYNDROME (HUS)
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Historically, HUS is the most common glomerular disease to cause severe AKI in a previously healthy young child. Most children with HUS (90%) have an antecedent diarrheal illness caused by a strain of E coli that produces a Shiga-like toxin. This group of patients had been formerly classified as having “diarrhea-associated” HUS (D+HUS), and this disorder is now known as Shiga toxin–producing E coli–associated (STEC+) HUS.
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Approximately 10% of patients develop HUS for other reasons, which are summarized in Table 468-9; these cases are referred to as atypical HUS.
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The possibility of a genetic form of the disease should be considered in any child with an atypical presentation. Although both HUS and thrombotic thrombocytopenic purpura (TTP) are characterized by thrombotic microangiopathy, the triggers, primary target organs, response to specific treatments, and clinical outcomes are distinct. These disorders are currently considered as separate entities. A syndrome resembling HUS can also be seen in patients with malignant hypertension.
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HUS occurs worldwide with sporadic and epidemic patterns. More than 70% of children in the United States and Western Europe with STEC+ HUS, which is mainly a disease of infants and young children (9 months to 5 years of age), have been infected with E coli 0157:H7. The incidence is estimated to be 2 to 3 new cases per year per 100,000 children younger than the age of 5 years. In children younger than the age of 15 years, the risk of developing HUS following an E coli 0157:H7 colitis is in the range of 8% to 10%. Other strains of Shiga toxin–producing E coli (0103:H2, associated with HUS after causing a urinary tract infection) and Shigella dysenteriae serotype 1 may also trigger HUS. There is often a seasonal disease pattern, with the greatest incidence in the summer and fall in North America. HUS is an uncommon occurrence in African Americans and occurs more frequently in rural populations. The primary reservoir for E coli 0157:H7 is farm animals, especially cattle; in the United States, approximately 1% of cattle harbor this bacterium. The bacteria can be killed by exposure to adequate heat; undercooked beef and nonpasteurized milk or milk products are frequent sources of exposure. Consumption of fruits, juices, or vegetables that have been exposed to contaminated manure and contaminated lakes and swimming pools all have caused disease outbreaks. Although it is unusual, person-to-person spread has been documented.
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The sequence of events that result in the clinical features and differential diagnosis of HUS are depicted in Figure 468-8. HUS is initiated by damage to the endothelium with formation of microthrombi, leading to the diagnostic triad of microangiopathic hemolytic anemia, thrombocytopenia, and AKI. The enteropathogenic E coli are characterized by the production a Shiga-like toxin (first reported in stool of patients with S dysenteriae). These toxins are also referred to as verotoxins because of their cytopathic effects on Vero cells, a cell line that is derived from African green monkey kidney cells. The toxins can bind to a glycosphingolipid receptor (Gb3) that is expressed on human glomerular endothelial and mesangial cells and on tubular epithelial cells. During the enteric prodrome, plasma samples show evidence of a prothrombotic state. Once the toxin damages glomerular endothelial cells, a thrombotic microangiopathic reaction ensues that is characterized by depositions of fibrin and damage to erythrocytes and platelets. A similar cascade of events may cause injury in other vascular tissues as well.
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The most common cause of atypical HUS is a dysregulation of the alternative complement activation pathway. Loss-of-function mutations in CFH, factor I, and membrane cofactor protein (MCP), complement regulatory proteins, as well as gain-of-function mutations in C3 and complement factor B have all been identified in patients with atypical HUS. In a small subset of patients, autoantibodies against CFH (and less commonly factor I) prevent normal regulation of the alternative pathway. More than 90% of patients with anti-CFH antibodies have a complete deficiency of CFH-related proteins 1 (CFHR1) and 3 (CFHR3) due to a homozygous deletion of CFHR1-R3. It is not yet entirely clear how complement dysregulation is manifest differently in atypical HUS compared to C3 glomerulopathy. It is likely that the initial kidney injury triggers are distinct. Common antecedents of atypical HUS include upper respiratory infections, other febrile episodes, non–E coli diarrhea, and drug exposure.
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Another important cause (15–30% cases) of atypical HUS occurs as a complication of S pneumoniae infections in young children. Many of the offending strains are not included in the multivalent pneumococcal conjugate vaccine that is now routinely given in infants. This organism produces neuraminidase, an enzyme that cleaves cell membrane sialic acid residues on erythrocytes, platelets, and glomeruli to expose the cryptic Thomsen-Friedenreich (T) antigen. It is hypothesized that naturally occurring IgM antibodies react with the T-antigen to induce hemolysis, thrombocytopenia, and glomerular capillary damage. These patients have a positive Coombs test, and difficulties are encountered with ABO cross-matching. Use of fresh-frozen plasma, an additional source of the pathogenic antibody, is contraindicated. The outcome has improved in this patient group, but mortality rates remain high, in the range of 12%.
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CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS
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Following ingestion of E coli–contaminated food or liquid, most affected children develop abdominal pain and diarrhea that is usually bloody (90%). Half of the patients have nausea and vomiting. Fever is typically low-grade or absent. The colitis usually is self-limited, but complications may occur and include rectal prolapse, toxic megacolon, bowel wall necrosis, and perforation. Strictures may develop later. HUS occurs in approximately 15% of infected children. The onset of HUS usually is abrupt, occurring 5 to 10 days (median 1 week) after the onset of the diarrhea, as the colitis is resolving. The presenting symptoms often are due to AKI and relate to the patient’s intravascular volume status. The severity of the AKI is highly variable, but 50% to 60% develop oligoanuria and require dialysis. Hypertension is variable but may be severe. It is caused by fluid overload and by activation of the renin–angiotensin system within the ischemic kidneys. The mean duration of AKI is 2 weeks. In atypical HUS, the antecedent illness is more nonspecific, often associated with fever, upper respiratory symptoms, and vomiting. Sometimes a prodromal illness is not apparent at all. The clinical onset of HUS can be insidious.
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The microangiopathic hemolytic anemia causes pallor, mild icterus, and symptoms secondary to acute anemia. The degree of thrombocytopenia is variable; patients may present with petechiae. Hemolysis may continue for several weeks. There is no correlation between the severity of the hemolysis and thrombocytopenia and the degree of AKI.
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Neurologic involvement is a common occurrence and can mimic TTP. Most patients are very irritable and somnolent. However, more serious involvement leading to seizures and coma occurs in 10% of children. The neurologic manifestations may be the presenting feature and may impact acute mortality rates and long-term morbidity.
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Although the bowel and the kidneys are always involved, virtually any organ can become damaged by microvascular thrombosis. Approximately 40% of patients have hepatomegaly with elevated serum transaminases, and 20% have pancreatic involvement with elevations of serum amylase and lipase levels. Less commonly, patients develop hyperglycemia and may require insulin therapy. Most of these patients are able to discontinue insulin when the acute illness resolves, but some develop chronic insulin-dependent diabetes. Although primary cardiac involvement not related to volume overload rarely occurs, myocarditis and myocardial ischemia are serious complications. Pericardial effusions may also occur.
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DIAGNOSTIC EVALUATION
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Biochemical evidence of AKI associated with microangiopathic hemolytic anemia and thrombocytopenia are the hallmark features of HUS. Urinalysis typically shows hematuria and proteinuria. Anemia is characterized by the presence of schistocytes and helmet cells on the smear, negative Coombs test (except in pneumococcus-associated HUS), elevated reticulocytes and lactose dehydrogenase (LDH) level, and low serum haptoglobin concentrations. The prothrombin (PT) and partial thromboplastin time (PTT) are usually normal unless antibiotic therapy has caused vitamin K deficiency. Serum levels of many prothrombotic molecules are increased (tissue factor, platelet-activating factor, plasminogen activator inhibitor, von Willebrand factor, thromboxane A2), whereas decreased levels have been reported for some antithrombotic systems (prostacyclin, thrombomodulin, plasminogen activator). Hypoalbuminemia a frequent occurrence at presentation, primarily due to gastrointestinal losses. Leukocytosis is a common occurrence, and peripheral white blood cell counts greater than 20,000/μL correlate with a poorer prognosis. Serum C3 level and CH50 (total hemolytic complement, the dilution of serum that lyses 50% of red blood cells in a reaction mixture) may be depressed, but only in those 30% to 40% of patients with atypical HUS associated with genetic mutations in complement regulatory genes. However, a normal serum C3 level does not rule out the possibility of a genetic complement deficiency.
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When a patient presents with clinical features suggestive of STEC+ HUS, documentation of a Shiga toxin–producing E coli is in order to identify the source of exposure and minimize the spread of the disease. Stool cultures should be obtained as soon as possible with special sorbitol-MacConkey agar plates used to identify colorless colonies of E coli 0157:H7. The organism is difficult to culture after the first few days of diarrhea. Many laboratories can also test for the presence of the Shiga toxin in the stool.
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When atypical HUS is a possibility, it is important to obtain a critical serum sample before initiating transfusion or plasma exchange. ADAMT13 activity and inhibitor testing is important to rule out a diagnosis of TTP (while not common in children but for which urgent plasmapheresis therapy is indicated) as well as to evaluate the complement system: serum C3, C4, CH50, CFH, and complement factor I levels and antibodies to CFH and complement factor I (or activity levels if antibody testing will be delayed), and MCP staining on leukocytes if available. Low serum C3 levels are an early clue to a genetic complement regulatory abnormality, but normal levels do not preclude such a diagnosis. Other clues might include diarrhea-negative HUS, patients with an HUS relapse, a positive family history of nonsynchronous HUS, postpartum HUS, and HUS after bone marrow transplant.
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A definitive genetic etiology will require specific gene testing and is important as it has long-term therapeutic and prognostic implications.
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TREATMENT AND COMPLICATIONS
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For STEC+ HUS, supportive medical care is by far the most important aspect of treatment and is responsible for the drastic decline in mortality rates, down from greater than 50% in the predialysis era. Meticulous attention must be paid to management of fluids and electrolytes. Volume loss from diarrhea and vomiting must be replaced, but care must be taken to avoid intravascular volume overload. Severe oligoanuric AKI requiring dialysis still develops in 40% to 50% of the patients. Packed red blood cell transfusions should be reserved for patients with clinical indications of severe anemia (hematocrit < 18%) but are eventually required in approximately 80% of patients. Packed red blood cells must be infused slowly or during dialysis, with careful monitoring of the patient’s blood pressure. Platelet transfusions should be avoided unless the patients are actively bleeding or the transfusions are needed in preparation for an invasive procedure. Many patients require antihypertensive drugs; angiotensin pathway inhibitors are best avoided during the acute phase due to their effects on kidney perfusion that may aggravate AKI. Nutritional support is important, as many patients with HUS are already catabolic due to several days of poor caloric intake before presentation.
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No specific therapeutic interventions have proven beneficial for treating patients with STEC+ HUS. Plasma infusion or plasma exchange therapies do not decrease mortality rates or improve long-term outcome. However, these therapies are still considered in patients with severe central nervous system involvement based on their proven efficacy in adults with TTP. Antiplatelet drugs and fibrinolytic therapy are of no proven benefit but increase the risk of having hemorrhagic complications and should be avoided. During the prodromal phase of colitis, antimotility drugs are contraindicated, and antibiotics should be avoided as they have been reported to increase the probability of developing HUS.
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There is a consensus treatment approach for optimal treatment of atypical HUS. Eculizumab, a monoclonal anticomplement component C5 antibody, prevents many of the proinflammatory and prothrombotic effector functions of the complement cascade. Prospective clinical trials in children with atypical HUS show that eculizumab is highly effective in patients with identifiable complement mutations. Prior to the availability of eculizumab, the prognosis of atypical HUS was poor and the recurrence rate was high. Plasma therapy could achieve complete or partial remission in 75% of HUS episodes, but 50% of affected children either died or reached ESRD at 3-year follow-up. If atypical HUS is due to an anti-CFH autoantibody, immunosuppressive agents with or without plasmapheresis must be used in addition to eculizumab in order to eliminate autoantibody-producing cells.
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During the recovery phase, the hemolytic process resolves more slowly than do the other manifestations, and patients often are discharged with a persistent anemia from an inappropriately low reticulocyte count that cannot be explained by deficiency of folate, vitamin B12, or iron. A low serum erythropoietin level may be a factor. The hemoglobin level eventually normalizes in most patients without specific intervention. Cholelithiasis has been reported as a late sequel to the hemolytic process.
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PROGNOSIS AND OUTCOMES
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Acute mortality rates for STEC+ HUS are in the range of 3% to 5%, often related to severe complications such as neurologic disease and cardiac failure or multiorgan involvement. Kidney function spontaneously improves, and almost all patients are able to discontinue dialysis. Approximately 5% of survivors suffer long-term damage to the kidney or brain. However, several recent long-term follow-up studies suggest 5% to 25% of patients will follow a course of slowly progressive CKD with or without hypertension. Patients with proteinuria, hypertension, or kidney dysfunction need long-term follow-up. Poor prognostic indicators include oliguria or anuria for longer than 2 weeks, an initial neutrophil count greater than 20,000, coma on admission, and atypical forms of the disease. Although kidney biopsies are not generally performed, when these data are available, CKD has been predicted by the presence of cortical necrosis or thrombi in more than 60% of the glomeruli and by involvement of extraglomerular renal vessels. Atypical HUS generally follows a more severe clinical course, is more likely to relapse, and may be associated with genetic deficiency of 1 of the key complement cascade regulatory proteins (see Table 468-8).
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Recurrent disease in either native or transplant kidney is extremely rare in STEC+ HUS (< 10%) but occurs quite commonly in atypical HUS. Prophylactic eculizumab treatment in patients with atypical HUS and ESRD is recommended at the time of kidney transplantation, and ongoing treatment may be necessary for long-term allograft survival.
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Children actively infected with Shiga toxin–producing E coli should not be treated with antibiotics or antimotility agents, as they may increase the risk of developing HUS. Maintaining a normal intravascular volume during the diarrheal phase (often necessitating hospitalization for intravenous fluids) may decrease the severity of AKI when HUS ensues. Treatment during the diarrheal stage with Synsorb-Pk in an attempt to trap Shiga toxin in the gut failed to improve outcomes. The best way to prevent infection with Shiga toxin–producing E coli is by eating well-cooked meat (especially ground beef) and washed fruits and vegetables. Good hand-washing practices will decrease the (low) risk of person-to-person spread. Routine irradiation of meat and vaccine development offer the best hope for disease control but are currently not available options.
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