Chapter 472. Glomerular Diseases

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 physiological functions of the glomerulus are perturbed.1,2 Some children with glomerulonephritis (GN) are found incidentally to have microscopic hematuria or proteinuria when checked by routine urinalysis but are otherwise asymptomatic. At the other extreme, children may become critically ill with oligoanuric rapidly progressive GN in need of urgent dialysis. A few glomerular diseases are inherited (see Chapter 473), but most forms of GN are acquired and are generally considered to be immunologically mediated. There are three classical clinical syndromes that develop from glomerular injury: acute and chronic glomerulonephritis, defined by the triad of hematuria, hypertension, and azotemia; nephrotic syndrome, defined by proteinuria and hypoalbuminemia; and hemolytic uremic syndrome, defined by microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency.

The pathophysiological sequence of events that lead to the development of the nephritic triad (hematuria, azotemia, and hypertension) are shown in Figure 472-1. In each of the clinical entities with glomerular proliferation, the inflammation process leads to decreased glomerular perfusion, resulting in compromised renal function and retention of salt and water with potential development of hypertension and edema.

Approach to a Patient with Glomerulonephritis

The patient with glomerular disease presents clinically with a constellation of features that may include hematuria, proteinuria, hypertension, edema, and renal insufficiency. 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.1

1. 1. Does this patient have acute or chronic GN? Many patients with chronic GN appear relatively asymptomatic until the disease is advanced. Clues of chronicity include significant anemia, evidence of renal osteodystrophy (abnormal bone radiographs or an elevated PTH level), or small echogenic kidneys on ultrasound examination. Acute onset of severe hypertension often causes neurological symptoms such as headaches and seizures, while long-standing hypertension of insidious onset may be clinically silent, but left ventricular hypertrophy may be present.

   2. Does this patient have isolated renal disease, or are extrarenal organ systems involved? A careful systems review and physical examination will help determine whether the investigation should move in the direction of primary (acquired) GN or toward multisystem disease associated with GN (Table 472-1). Relevant extrarenal involvement may be clinically silent. For example, postinfectious serological studies (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 vasculitis caused by Wegener’s granulomatosis, involvement of the lung parenchyma or sinuses usually requires radiological confirmation.

   3. Does this patient have hypocomplementemic GN? A low serum C3 concentration generally indicates one of four diseases in children: acute postinfectious GN, lupus nephritis, membranoproliferative GN (MPGN), and GN associated with chronic infections (subacute bacterial endocarditis and shunt nephritis), as indicated in Figure 472-1.

   4. Does this patient have recurrent painless macroscopic hematuria? If yes, IgA nephropathy is a likely diagnosis, although this also is a fairly common presentation of Alport syndrome during the first decade of life.

   5. What is the age of the patient? Although most forms of GN can occur in almost any age group, most diseases have a characteristic age range for disease onset (Table 472-2). GN in the newborn period is extremely rare and is often the result of a congenital infection.

   6. Does this patient have clinical evidence of rapidly progressive GN? Such a course is usually caused by crescentic GN and, more rarely, may result from acute GN with superimposed acute tubular necrosis. Rapidly progressive GN is an emergency that needs urgent histological diagnosis. Most of these patients have aggressive diseases that are successfully treated only with immunosuppressive therapy, if treatment is initiated early and in high doses. In patients with anti-GBM nephritis and severe vasculitis, early plasmapheresis may be lifesaving.

   7. Does this patient have nephritic/nephrotic syndrome? Although proteinuria is a hallmark of significant glomerular disease, frank nephrotic syndrome is a less common feature of the acute nephritic syndrome. In a patient presenting clinically with acute GN and a low serum C3 level, the presence of nephrotic syndrome should suggest membranoproliferative GN or lupus nephritis. Nephrotic syndrome can occur in association with acute poststreptococcal GN, but this is rare.

   8.Does this patient need a renal biopsy now? Determining when to perform a renal biopsy is somewhat arbitrary. This procedure is generally not necessary when the diagnosis is obvious and the disease is self-limited without specific therapy (ie, typical acute poststreptococcal GN and mild nephritis secondary to Henoch-Schönlein purpura). For most glomerular diseases, a definitive diagnosis can be made only by renal biopsy. For many of these patients, the only way to design a rational and evidence-based plan of therapy is by histological confirmation of the diagnosis and the pattern and severity of renal damage (Table 472-3).

Acute Poststreptococcal Glomerulonephritis (Apsgn)

APSGN is the most frequent and best-characterized acute postinfectious glomerulonephritis (GN). However, many other bacterial, viral, and parasitic pathogens may also induce postinfectious acute GN. Identifying a specific causative pathogen is often difficult, since the infection usually precedes nephritis by a few weeks. A history of pharyngitis or pyoderma suggests a previous infection by group A, β-hemolytic streptococcal disease that may be confirmed by serological testing. APSGN accounts for 80% to 90% of such cases and is used as the prototype for this group of disorders.

Epidemiology

APSGN is primarily a disease of school-age children (5 to 15 years; younger in epidemic forms) and is more common in boys. Although reported in an 8-month-old child, the disease is rare under 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. This organism has traditionally been characterized by two distinct outer cell wall proteins—M and T—leading to the recognition of more than 80 subtypes. 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.

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 the Republic of Macedonia reported that 23% of sibling contacts had abnormal urinalyses; 9% developed clinical features of nephritis.3 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%. The true incidence is difficult to determine, because 50% to 85% of patients with APSGN are asymptomatic. The incidence of this illness has decreased in the United States and Europe over the past two decades, likely due to earlier recognition and treatment of streptococcal infections. 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.

Pathophysiology

The precise nature of the antigen-antibody complex that causes nephritis remains unclear.4The 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, two proteins are of particular interest, based on currently available evidence. First is the cationic cysteine proteinase exotoxin B (SpeB) that colocalizes 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 plasma receptor (NAPlR), a glyceraldehyde phosphate dehydrogenase (GAPDH) that does not colocalize with glomerular immune deposits but is associated with increased intraglomerular plasmin activity that is thought to facilitate immune complex formation and inflammation.

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 believed that 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.

Clinical Features

Clinical symptoms begin abruptly. Patients are usually afebrile with a latency period of 1 to 2 weeks following pharyngitis and 3 to 6 weeks after a skin infection. The most common presenting features in symptomatic patients are edema (85%) and gross hematuria (30% to 50%). Almost all the patients have microhematuria. The urine often has a unique smoky, cola or tea color. Hypertension is common (60% to 80%) but is usually mild to moderate; rarely, hypertensive encephalopathy and posterior reversible encephalopathy 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 common in children hospitalized with APSGN.5 The degree of renal failure is usually mild. Rapidly progressive GN is unusual, reported in less than 1% of children. 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 nephrotic syndrome. Severe complications, including pulmonary hemorrhage and cerebral vasculitis, have been reported. Occasionally, patients may have significant extrarenal manifestations; features suggestive of Henoch-Schönlein purpura, for example, have occasionally been present.6 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 year, rarely longer (Fig. 472-2 and eFig. 472.1).

Diagnostic Evaluation

The serum C3 level is usually below 50% of normal value in patients with acute poststreptococcal glomerulonephritis (APSGN); this causes acute nephritis. However, up to 10% of APSGN patients have a normal C3 level. In patients with other forms of acute postinfectious GN, the percentage is even higher. Decreased serum C4 levels are unusual but have been reported, usually very early in the clinical course. A significant and persistent decrease in the C3 or C4 level should suggest an alternative diagnosis, such as systemic lupus erythematosus, bacterial endocarditis, shunt nephritis, or idiopathic membranoproliferative GN (Fig. 472-1). 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), but rarely patients may have a normal urinalysis.

Confirmation of a recent streptococcal infection makes 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 serological testing to five 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 is quite reliable to establish a prior streptococcal infection. In the majority of patients, the clinical presentation and laboratory tests make the diagnosis of APSGN quite evident. There is no indication to perform a renal biopsy to confirm the diagnosis in such children. In approximately 10% of cases, acute postinfectious GN follows other antecedent diseases caused by a variety of infectious agents as summarized in eTable 472.1.

Treatment and Complications

APSGN is an acute disease that resolves without specific medical therapy. Close monitoring and supportive care is 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. In the acute phase, patients need to be hospitalized for observation and treatment if hypertension, edema, oliguria, elevated serum creatinine, electrolyte abnormalities, or other less common complications are present (Fig. 472-4). Fluid-overloaded patients often respond to loop diuretics. Fluids need to be balanced to prevent further intravascular volume overload, including appropriate sodium and fluid restriction. Urine output increases spontaneously within 5 to 10 days; severe oliguria beyond 2 weeks is extremely rare and is cause to question the diagnosis. Hypertension is typically not severe and can be managed with short-acting calcium channel blockers.

In patients with more severe renal insufficiency, hyperkalemia, hyperphosphatemia, and acidosis are likely to occur and will require medical management. These patients rarely need dialysis. Despite the old wives’ tale, bed rest is of no proven benefit once patients are well enough to ambulate. Corticosteroids and cytotoxic agents have no substantiated role, although there is limited anecdotal evidence of benefit for the rare patient with rapidly progressive glomerulonephritis associated with crescentic (in > 30% glomeruli) nephritis on biopsy. However, this is such a rare presentation that prospective clinical trials to evaluate the efficacy of therapy are impossible.

Prognosis and Outcomes

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 1 year following diagnosis. Intermittent or orthostatic proteinuria may persist for up to 2 years (see eFig. 472.1). Prolonged hematuria up to 5 years has been observed but is rare. Traditionally, APSGN in children has been considered a completely reversible disease, and this 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 two to three 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. Recently, cases of APSGN with superimposed histological lesions of thrombotic microangiopathy have been reported. Outcome may be poorer in this unique patient cohort, but insufficient data are available at this time. Recurrent APSGN is extremely rare but has been reported.7

Glomerulonephritis with Chronic Infections

Immune responses may also induce glomerulonephritis (GN) in the face of certain chronic persistent infections. In pediatric patients, the most important examples of this are infective endocarditis, shunt nephritis, hepatitis B and C, and AIDS,8 as well as congenital infections with cytomegalovirus or toxoplasmosis that may present clinically as infantile nephrotic syndrome. In endemic tropical areas of the world, chronic infection with Plasmodium malariae, Schistosoma mansoni, and filariasis may cause more chronic forms of GN.

Infective Endocarditis

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 antineutrophil cytoplasmic antibodies (ANCA). Histologically, the disease resembles APSGN, even in the small subset with (ANCA). With appropriate antibiotic therapy, the glomerulopathy improves, but chronic renal failure may persist. Normalization of the serum complement levels is a good prognostic indicator. The possibility of other renal lesions needs to be considered in this population, especially drug-induced interstitial nephritis and septic emboli.9

Shunt Nephritis

Shunt nephritis was first recognized in children with ventriculoatrial shunts used for hydrocephalus. The risk of nephritis is reportedly 4% among patients with infected shunts. This complication is distinctly 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 is often cultured from the graft itself. The renal disease frequently has an indolent presentation: gross hematuria is common, and 25% to 30% may develop nephrotic syndrome. Serum C3 and C4 levels are usually depressed (90%). Histologically, the lesion is a diffuse proliferative GN that resembles idiopathic MPGN. Treatment includes antibiotic therapy and removal of the infected shunt. The glomerular disease slowly resolves, but residual renal damage is common. In patients with end-stage renal disease managed with hemodialysis, complications of infected vascular grafts and fistulae remote infectious complications such as endophthalmitis have been reported.

Chronic Hepatitis

An association exists between chronic hepatitis B (HBV) and membranous nephropathy. Less common renal manifestations associated with chronic HBV infection are membranoproliferative glomerulonephritis (MPGN), crescentic GN, and kidney disease related to polyarteritis nodosa. Introducing the hepatitis B vaccination during infancy has decreased the incidence of HBV-associated kidney disease.10 Children present clinically with nephrotic syndrome or with non-nephrotic proteinuria during the chronic carrier stage. Depressed serum C3 and C4 levels are not characteristic but may occur. In children, most renal complications remit spontaneously within 5 to 7 years, concomitant with the disappearance of HBe antigenemia and the appearance of HBe antibodies. Specific treatment guidelines for renal disease are not available, but antiviral drugs or interferon alpha is often recommended for persistent renal disease (see Chapter 308).11-13 Since these agents are nephrotoxic, renal function must be followed closely during therapy. Immunosuppressive therapy is contraindicated due to an increased risk of chronic active hepatitis, although corticosteroids have been used in a select subset of patients with severe vasculitis or crescentic GN.

Hepatitis C also can cause MPGN in adults, especially when it occurs in association with cryoglobulinemia. It has also been reported as a cause of MPGN in renal allografts and as a cause of membranous nephropathy and IgA nephropathy. Only isolated cases of hepatitis C–related renal disease have been reported in children.

HIV-Associated Nephropathy

About 2% to 10% of patients infected with HIV have nephropathy. Most patients present with proteinuria, usually with nephrotic syndrome. This may be the first manifestation of HIV infection or may occur in patients with 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 systemic lupus erythematosus [SLE] nephritis) are commonly observed features. Highly active anti-retroviral therapy (HAART) therapy appears to slow the rate of progression and may even prevent the development of nephropathy.14,15 Anecdotal case reports suggest a beneficial outcome in patients treated with steroids or cyclosporine (CSA). Because opportunistic infections are common, 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, a glomerular microangiopathy that resembles hemolytic uremic syndrome; postinfectious glomerulonephritis (GN); membranoproliferative GN; and a lupuslike immune complex GN. Hepatitis C coinfection and drug-induced nephrotoxicity are also common in HIV-infected patients.

IgA Nephropathy

IgA nephropathy is the most common primary cause of GN throughout the world. Although it may occur at any age, it is most common in the second and third decades of life and is rare in the first decade. However, it has been reported in children as young as 3 years of age. Even though the course of the disease is indolent in most patients, a significant number are at risk of ultimately developing end-stage renal disease (ESRD).

Epidemiology

The true incidence of IgA nephropathy is uncertain, as there are no reliable serological markers; a renal 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 IgA nephropathy is generally considered a sporadic disease, familial clustering has been observed in a pattern suggesting an autosomal dominant inheritance with incomplete penetrance. Specific genes have yet to be identified.

Most cases of IgA nephropathy are idiopathic, but multiple secondary causes are described, including 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 nephrologists consider these two 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 two 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.

Pathophysiology

The pathophysiology and genetics of IgA nephropathy remain unclear. The glomerular IgA deposits are polymeric IgA1 derived from systemic rather than mucosal immune responses. IgA nephropathy has resolved when an IgA nephropathy kidney was transplanted into a patient with a different cause of ESRD, or following stem cell transplantation in a patient with IgA nephropathy. 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. These modified IgA complexes may deposit in the mesangium, may interact with mesangial cells, and may activate C3 via the mannose-binding lectin pathway. They may react with naturally occurring IgG antibodies. Indeed, IgG glomerular deposits are often present together with IgA.

Clinical Features and Differential Diagnosis

There are three classic clinical presentations of IgA nephropathy. Forty to 50% present with recurrent episodes of painless macroscopic hematuria. The onset of macrohematuria is often preceded 24 to 48 hours earlier by an upper respiratory tract infection; associations with gastroenteritis, sinusitis, and strenuous exercise have also 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 acute poststreptococcal glomerulonephritis (APSGN). The gross hematuria typically resolves within a few days, but microscopic hematuria and variable degrees of proteinuria typically persist. Some complain of flank or loin pain, presumably because of swelling of the renal capsule.

The first episode of macrohematuria may mimic APSGN. Recurrent episodes of macroscopic hematuria may occur in Alport syndrome during the first decade of life. Painless gross hematuria may be the initial presentation of children with MPGN. About 40% of patients present with an incidental finding of microhematuria and mild proteinuria (20% to 40%). A subset of this group will develop future episodes of gross hematuria, which occurs more frequently in children. For reasons that remain unclear, patients with recurrent gross hematuria have a better long-term prognosis. The interval between episodes is highly variable, ranging from a few months to many years. The frequency of the episodes decreases with age. Less than 10% present with nephrotic syndrome, an acute reversible nephritic episode, or rapidly progressive GN. Most of the acute nephritic episodes resolve without specific therapy, and the long-term prognosis remains relatively good. If a renal biopsy is performed during the acute phase, the degree of glomerular disease usually fails to explain the degree of renal dysfunction. Superimposed acute tubular necrosis is often evident, with tubular toxicity from erythrocyte products such as hemoglobin and iron being possible contributory factors. A very small number of patients develop rapidly progressive GN caused by a severe crescentic form of IgA nephropathy and have a poor outcome. Another unique presentation mimics minimal change nephrotic syndrome clinically and histologically, but IgA deposits are detected in the kidney biopsy. This disease typically responds to steroids, and it is possible that the IgA deposits occur by chance. Indeed, it has been reported that glomerular IgA deposits are present in 3% to 16% of healthy individuals.

Diagnostic Evaluation

There are currently no reliable serological markers for IgA nephropathy. With the first episode of gross hematuria, serological studies are usually 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 reported in the dermal capillaries of forearm skin biopsies in 30% to 50% of IgA nephropathy patients, this test is not currently recommended. Most pediatric nephrologists would recommend a biopsy for IgA nephropathy patients who have impaired renal function, hypertension, or significant proteinuria (greater than 0.5 to 1.0 g/24 h), as these individuals are at increased risk of ultimately developing end-stage renal disease. Future urinary proteomic studies may lead to the discovery of a specific IgA nephropathy biomarker. Its presence on urinary IgA-IgG immune complexes has been suggested as a candidate.

Treatment

Optimal therapy for IgA nephropathy is controversial, but guidelines are beginning to emerge (Fig. 472-2 and Fig. 472-4).16-20 The disease usually follows a benign course so that no therapeutic intervention is necessary. However, a subset of patients can develop progressive renal insufficiency. 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 renal biopsy. Current management recommendations include the following:

1. 1. Hypertensive patients should be treated with an ACE inhibitor (ACEi) plus/minus angiotensin receptor blockers (ARB), as these drugs control the blood pressure and may slow the rate of decline of 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.

   2. The benefit of treatment with omega-3 fatty acids in the form of fish oil (eicosapentaenoic acid and docosahexanoic acid) 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 ACEi and ARB in proteinuric patients with well-preserved GFR.

   3. Alternate-day steroids appear to benefit patients with slowly declining renal function. The optimal treatment duration is unclear; 6 months has been used in several clinical trials. Addition of cytotoxic agents appears to offer little benefit, although the efficacy of mycophenolate mofetil (MMF) is still under investigation.

   4. Patients with aggressive crescentic GN are typically 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. Since the outcome is poor and the relative incidence of this form of IgA nephropathy is rare, evidence-based treatment guidelines are nearly impossible to generate.

   5. 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. 6) Patients with isolated microscopic hematuria and urinary protein-to-creatinine ratios less than 0.6–0.8 mg/mg (males and females respectively) require no treatment except monitoring.

Prognosis

IgA nephropathy is a disease with a highly variable outcome. Complete remission occurs in less 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.21 In the high-risk patient group, renal function slowly deteriorates. After 20 to 25 years of follow-up, 20% to 30% develop end-stage kidney disease while 20% have reduced renal function. Following kidney transplantation, IgA deposits commonly recur in the allograft (20% to 75%), but recurrent disease is not a common cause of graft failure (eTable 472.2).

Membranoproliferative Glomerulonephritis (Mpgn)

MPGN, less commonly called mesangiocapillary GN, is not a distinct disease. It is a specific form of glomerulonephritis (GN) characterized morphologically by (1) thickening of the glomerular basement membrane (GBM) caused by immune complex deposition or interposition of mesangial cell cytoplasm in the GBM, and (2) by 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 472-5.

The idiopathic varieties are classified as two distinct and unrelated diseases. Type I is an immune complex disease characterized by immune deposits containing C3 and immunoglobulins (IgG > IgM) deposited along the subendothelial space of the GBM. Type III appears to be a histological variant of type I, with codeposition of prominent subepithelial deposits. Splitting this latter group of patients into a subgroup distinct from type I is not universally accepted. Although subtle clinical and laboratory differences between patients with type I and type III exist, overall they are quite similar and are considered together here. In contrast, type II MPGN, also known as dense intramembranous deposit disease, is clearly a distinct entity characterized ultrastructurally by the presence of dense ribbonlike deposits within the GBM. Similar deposits may be found in other kidney basement membranes and within the mesangium. 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 are typically absent.

Epidemiology

Idiopathic membranoproliferative glomerulonephritis (MPGN) usually presents between the ages of 8 and 30 years; it is rare under the age of 5 years (although cases as young as 15 months have been reported) and mainly affects Caucasians. Although uncommon, familial clusters are reported. Overall, male and female patients are equally affected, but the condition is slightly more common in female adolescents. The incidence of idiopathic MPGN, particularly type II, appears to have decreased over the past decade. In adults, this may be explained by the recognition that many patients previously classified as idiopathic MPGN actually are chronically infected with hepatitis C. The reason for the declining pediatric incidence of idiopathic MPGN is unclear.

Pathophysiology

The pathophysiology of idiopathic MPGN remains enigmatic. Type I/III is considered 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. A small subset of patients who have inherited complement deficiencies are predisposed to develop MPGN, especially those with factor H deficiency. In type II MPGN, the nature of the renal electron-dense deposits remains unclear despite numerous attempts to isolate and characterize them. The only plausible explanation at present is that these deposits are biochemically modified renal basement membranes. C3 nephritic factor (C3NeF) is an autoantibody that reacts with and stabilizes the convertase activity of C3bBb, leading to ongoing C3 activation. C3NeF may be present in all types of MPGN but is most common in type II. Whether it plays a pathogenic role, is a disease marker, or is a secondary epiphenomenon remains unclear.

Clinical Features and Differential Diagnosis

Twenty to 30% of children with MPGN present with an acute nephritic syndrome that initially mimics acute poststreptococcal glomerulonephritis (APSGN). In fact, many patients have had a preceding upper respiratory illness, and up to 40% have evidence of a recent streptococcal infection. The presence of nephrotic syndrome 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. Nephrotic syndrome 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 glomerulonephritis. Subtle, but not substantial, differences exist between the clinical features at presentation of types I and II. Some patients with MPGN II have partial lipodystrophy (Barraquer-Simons disease).

Diagnostic Evaluation

A renal biopsy is required to establish the diagnosis of membranoproliferative glomerulonephritis (MPGN), although a characteristic clinical presentation with persistent hypocomplementemia is highly suggestive. Type I patients have evidence of activation of the classical complement cascade with low serum C3 levels and borderline or low C4 levels. The complement profile in type II patients suggests alternative pathway activation with low C3 and normal C4 levels. The presence of C3 nephritic factor is most characteristic of type II disease. Serum C3 levels are depressed in 50% of patients with MPGN III; C4 may be normal or low. Overall, the serum C3 level is decreased in 75% of all patients at the time of initial presentation. The levels are variable over time and do not have prognostic significance. Normalized C3 levels 6 to 8 weeks after the onset of acute nephritis will help differentiate APSGN from MPGN (Fig. 472-1).

Treatment and Complications

Optimal therapy remains uncertain. Randomized clinical trials have shown no benefit of any treatment, but the duration of trials has been relatively short; this is significant because MPGN is typically a chronic, slowly progressive disease process, so the benefit of treatment may not be evident unless given for years.22 For many children without nephrotic syndrome, renal function may remain stable for many years without specific therapy. The consensus in North America is that children with idiopathic MPGN type I and significant proteinuria will do better if treated with alternate-day steroids for 3 to 10 years. 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 remains unclear and is generally not recommended. Limited and conflicting data on the use of cytotoxic drugs preclude recommendation.

There are few data to support the use of immunosuppression for dense deposit disease.16,23 ACEi and angiotensin receptor blockers (ARB) are recommended for proteinuria and hypertension control. Plasma exchange therapy may have a role in the patient subgroups with inherited complement factor H and deficiency and possibly those with significant renal disease associated with C3NeF.

Prognosis and Outcomes

Limited data are available on the long-term outcome of children with idiopathic MPGN. For many patients, the disease carries a poor prognosis, particularly if associated with nephrotic syndrome. Overall, 50% to 60% of untreated patients develop ESRD within 10 to 15 years; less than 10% undergo spontaneous remission. The prognosis is worse in patients with persistent nephrotic syndrome and significant crescent formation and interstitial fibrosis on renal 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.

Rapidly Progressive (Crescentic) Glomerulonephritis (Rpgn)

RPGN is a clinical syndrome characterized by sudden onset and rapid decline in renal function.24 Renal 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.

Epidemiology

RPGN is a rare disorder in childhood that is classified into three groups based upon the immunopathologic features (Fig. 472-6): (1) anti-GBM nephritis (12%), (2) immune complex nephritis (45%), and (3) pauci-immune disease associated with ANCA (42%). Less commonly, other forms of proliferative glomerulonephritis may present as severe crescentic disease.

Clinical Features and Differential Diagnosis

Children with RPGN either present with gross hematuria (50% to 85%), edema (13% to 80%), anemia (70%), and hypertension (63% to 85%), or in a more insidious manner, they may present with symptoms due to chronic renal failure. Nephrotic syndrome is uncommon, likely because of the rapid onset of renal insufficiency. The urinalysis typically reveals an active urine sediment with hematuria, proteinuria, and cellular casts. Depending on the etiology, extrarenal manifestations may also be present. Pulmonary hemorrhage suggests a diagnosis of anti-GBM nephritis or Wegener’s granulomatosis and may be fatal if treatment is delayed.

Diagnosis

Serological studies can be very helpful in establishing a tentative diagnosis, but biopsy confirmation is mandatory. Initial tests should include a C3, C4, antinuclear factor (ANA), anti-GBM antibody, and ANCA antibodies. Biopsy establishes the diagnosis in most patients and provides valuable information about the relative degree of acute (potentially treatable) and chronic histological changes (Fig. 472-6). If the kidney is damaged beyond the point of repair, immunosuppressive therapy is futile, at least for the renal component of the disease.

Treatment

Therapy is directed to the specific disease entity, but a few general principles apply in all cases. Spontaneous resolution of RPGN is extremely unlikely. The prognosis is poor unless aggressive therapy is started early in the course of the disease. Since 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 methylprednisolone, followed by daily oral prednisone and cytotoxic therapy (usually cyclophosphamide). The one exception is crescentic acute poststreptococcal glomerulonephritis (APSGN), which often spontaneously resolves. Plasmapheresis is indicated for patients with anti-GBM disease and severe ANCA-associated glomerulonephritis (serum creatinine greater than 5.7 mg/dl in adults studies) or associated pulmonary hemorrhage; its efficacy in other crescentic diseases in unclear. In general, the severity of renal failure at diagnosis predicts long-term outcome, but this is uncertain.

Antiglomerular Basement Membrane (GBM) Disease

A rare and most aggressive form of crescentic glomerulonephritis is mediated by anti-glomerular basement membrane (anti-GBM) antibodies.25 Pulmonary involvement typically causing pulmonary hemorrhage occurs in 40% to 70% of the patients. This pulmonary-renal syndrome is called Goodpasture syndrome.

Epidemiology

Anti-GBM disease typically occurs in Caucasian adults with two peak incidences, one in the third and one 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 -DR4 associated) has been noted in some patients. Anti-GBM nephritis may occur as a rare complication of other renal 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 is reported. Why some, but not all, patients develop pulmonary disease is unclear, because the target antigen is present in all alveolar basement membranes. Experience with experimental models suggests that a second factor in addition to the anti-GBM antibodies may be required before the lung becomes involved. 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. Another unique situation in which anti-GBM nephritis may occur is in the small subset (5% to 10%) of patients with Alport syndrome who receive a normal kidney allograft. The antibody produced recognizes an antigen on the α5 NC1 domain of collagen IV, distinct from the Goodpasture target antigen.

Pathophysiology

The Goodpasture target antigen is a normal structural component of renal 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 six distinct polypeptide chains (α1 to α6), three of which combine to form triple helices. The relative abundance of the 3 chain in glomeruli and alveoli likely explains the restriction of antibody-mediated disease to these organs. Most anti-GBM antibodies are of the IgG isotype, although a few patients with IgA antibodies have been reported. Antigen-sensitized T cells also appear to contribute to disease pathogenesis.

Clinical Features and Differential Diagnosis

Patients present with acute nephritis or with symptoms caused by chronic renal insufficiency. Progression to irrevers+ible renal failure 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 glomerulonephritis. The episodes of hemoptysis may be life-threatening. A pulmonary-renal syndrome may also occur in patients with systemic lupus erythematosus, systemic vasculitis, Wegener’s granulomatosis, Henoch-Schönlein purpura, cardiovascular disease, and various infections.

Diagnosis

More than 90% of patients have an anti-GBM antibody detected in the plasma at the time of clinical presentation, but the titer of the antibody does not correlate with disease severity. A subset of patients (10% to 40%) may also have a positive ANCA due to antimyeloperoxidase antibodies. Some of these overlap patients have evidence of extrarenal disease caused by vasculitis, and this group seems to have a slightly better prognosis. Carbon monoxide diffusion capacity may be increased due to the presence of hemoglobin in the alveoli. Iron-deficiency anemia may occur as a complication of pulmonary hemorrhages. Short-lived acute pulmonary hemorrhage can manifest as the presence of hemosiderin-laden macrophages in bronchoalveolar lavage fluid. The diagnosis is confirmed by a renal biopsy showing crescentic nephritis with linear deposits of IgG and C3 along the glomerular basement membrane (Table 472-3).

Treatment

If the patient has pulmonary disease or evidence of reversible (typically acute dialysis-independent) renal disease, the mainstay of therapy is plasmapheresis to remove the circulating antibody. Immunosuppressive therapy (prednisone plus cyclophosphamide) is added to reduce new antibody production. For reversible disease, the duration of therapy may be as guided by anti-GBM antibody titers.

Prognosis

The renal disease is unlikely to be reversible unless treatment is started early. In most patients, anti-GBM antibody production 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 renal 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 renal biopsy. Patients who recover from the acute disease generally do well. Relapses are extremely rare, in the range of 2%.

Lupus Nephritis

Systemic lupus erythematosus (SLE) is considered the prototype of multisystem diseases that cause immune complex–mediated tissue injury to the kidney.26,27 Details of the classification, diagnosis, management, and prognosis for SLE nephritis are provided in Chapter 204. At diagnosis, a finding of a completely normal kidney without IgG and C3 deposits is extremely rare, although renal biopsies are performed generally only in patients with clinical or laboratory evidence of renal involvement, which includes 40% to 60% of children at the time of diagnosis28 and another 10% to 20% within 5 years of diagnosis. The diagnosis and management of kidney disease in SLE is discussed in detail in Chapter 204.

Renal Pathophysiology

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.29 Autoantibodies to double-stranded DNA, nucleosomes, and α-actinin are most closely associated with glomerulonephritis (GN) in SLE patients. 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 believed to trigger an inflammatory response that causes kidney damage.

Clinical Features and Diagnosis

Lupus nephritis symptoms span the spectrum of glomerular diseases, ranging from asymptomatic microscopic hematuria or proteinuria to rapidly progressive GN. Acute renal failure is a rare but recognized presentation. Usually other systemic manifestations of SLE are apparent, and a renal biopsy is almost never required to establish the diagnosis of this disorder. The presence of 4 out of 11 American Rheumatism Association criteria for SLE confers a 96% sensitivity and specificity for the diagnosis of SLE, as discussed in Chapter 204. Although the diagnosis of SLE is typically established by other criteria, a renal biopsy is needed to determine the histological pattern, which guides initial therapy (Table 472-3, eFig. 472.2).

The modified World Health Organization (WHO) describes six patterns with a distribution among forms of lupus nephritis that do not differ between childhood and adult-onset systemic lupus erythematosus (SLE) (Table 472-3).30 Class I is characterized by mesangial immune deposits but normal cellularity. Class II is characterized by mild mesangial matrix expansion, sometimes with mild mesangial hypercellularity and immune complexes limited to the mesangium. Clinically, these patients usually have mild hematuria with or without low-grade proteinuria. The proliferative forms of lupus nephritis are the most common and most severe. Class III is focal proliferative nephritis (15% to 24% of the cases), with involvement in less than 50% of the glomeruli. Class IV, also called diffuse proliferative lupus nephritis (DPLN), is defined as greater than 50% glomerular involvement and unfortunately accounts for 40% to 50% of the patients with lupus nephritis. IV may represent a spectrum of quantitative differences in a similar pattern of glomerular injury. The proliferative diseases are characterized by immune deposits in the mesangium and along the capillary wall, mainly in a subendothelial position. There is considerable overlap of the clinical features of patients with class III and class IV nephritis.

Class V is membranous lupus nephritis (10% to 20% of cases), which is characterized by immune complexes in the subepithelial position. These patients typically present with proteinuria, often in the nephrotic range. Hematuria may be absent or microscopic, and cellular casts are typically absent in the urine sediment. Class VI is an irreversible advanced disease in which more than 90% of the glomeruli are destroyed by sclerosis.

Even though it may be easy to predict that a patient with severe clinical disease will have DPLN, the same histological pattern may be observed in patients with relatively mild clinical features. The presence of nephrotic syndrome is most likely to be associated with DPLN, but the syndrome is also present in more than 50% of patients with membranous lupus nephritis and, occasionally, in patients with focal proliferative and even mesangial lupus nephritis. The biopsy also provides important information about the acuity of the disease (indicating the potential for therapeutic responsiveness) and its chronicity, features that are considered for therapeutic planning.

Diagnosis

Almost all patients have a positive antinuclear antibody (ANA), although this antibody can be detected in individuals who do not have SLE (especially in a speckled pattern). True ANA-negative SLE is rare in childhood. Hypocomplementemia is another important finding in SLE patients 7with active disease. Anti-dsDNA titers and serum C3 levels are useful parameters for monitoring renal disease activity and response to therapy. No combination of these serological studies will effectively predict the histological type or severity of renal involvement.

Treatment

SLE nephritis may be controlled with medical therapy, but currently there is no known cure.31,32 For some patients, the optimal therapy will be determined by the severity of extrarenal disease. However, for many patients, the class and severity of the renal disease guides the approach to immunosuppression (eFig. 472.2). The treatment of patients with glomerular deposits limited to the mesangium (classes I and II) should be determined by the extrarenal manifestations. This is a mild renal lesion that has an excellent prognosis. Patients with focal proliferative disease (class III) can generally be managed with prednisone alone. If focal necrotizing lesions or crescents are present, patients with class III should be treated as DPLN even if more than 50% of the glomeruli lack proliferative changes.

Diffuse proliferative lupus nephritis (DPLN) is an aggressive disease that will ultimately destroy the kidney if left untreated. Several studies now indicate that the combined use of corticosteroids with immunosuppressive drugs results in a better long-term outcome than treatment with corticosteroids alone. Current treatment guidelines are based on a series of recent clinical trials that have evaluated both efficacy and adverse side effects. DPLN treatment is now divided into two phases: induction therapy to achieve remission and maintenance therapy to prevent relapses. Even with current treatment protocols, only 80% of patients achieve remission and 35% to 50% will experience at least one relapse. All protocols include corticosteroids initiated at high doses and tapered to low doses (often in the range of 0.1 to 0.2 mg/kg per day) over several months. Intravenous pulse therapy (15 to 30 mg/kg; maximum 1000 mg) may be included, especially if the initial kidney disease is severe.as there is a delayed onset of action of the cytotoxic drugs. Intravenous cyclophosphamide (0.5 to 1.0 g/m2) administered monthly for 4 to 7 months is the standard induction protocol; MMF is can also be used for patients with well-preserved glomerular filtrate rates at the time of diagnosis. The maintenance phase of therapy includes low-dose corticosteroids, discontinuation of cyclophosphamide, and addition of MMF or azathioprine. The optimal duration of maintenance therapy is uncertain, but 2 years without evidence of a relapse appears to be the minimum. During this period, serological studies are monitored. Rising anti-dsDNA titers and falling serum complement levels are warning signs of an impending flare, but alone they are insufficient criteria to change therapy.

Evidence is lacking regarding the best treatment approach for membranous lupus nephritis. Patients with a pure membranous lesion (class V) have a fairly good renal prognosis and are often managed like idiopathic membranous nephropathy with low-dose prednisone and CSA. In patients with superimposed proliferative lesions, treatment depends upon the severity of the proliferative lesions, which infers a higher risk for developing renal insufficiency.

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. Rituximab is of current interest, and more data to guide its use should be available soon. Plasmapheresis has not been shown to alter renal outcomes, and its use should be limited to the rare subset of patients with thrombotic microangiopathy associated with antiphospholipid antibodies.

Prognosis

End-stage renal disease (ESRD) remains a problem in patients with DPLN, especially in those with advanced renal 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 protocols. The incidence of ESRD in systemic lupus erythematosus (SLE) patients with DPLN has decreased from 50% in the 1950s to 5% to 10% today. Overall patient survival is now in the range of 80% at 15-year follow-up. Several factors predict a worse prognosis, including ethnicity (African American, Hispanic), gender (male), failure to achieve disease remission, renal disease severity (elevated creatinine, hypertension, or nephrotic syndrome at diagnosis), and renal histology (class VI disease, DPLN with crescents, significant interstitial fibrosis). Death within the first 5 years is usually due to active disease, infection, and thrombosis, whereas late mortality is usually due to accelerated cardiovascular disease and malignancy.

Henoch-Schönlein Purpura (Hsp) Nephritis

HSP or anaphylactoid purpura 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 several days to weeks: a purpuric rash (may initially look urticarial), arthralgias, abdominal pain, and GN.33 Unlike arthritis and gastrointestinal involvement, nephritis rarely, if ever, precedes the onset of purpura. Histologically, the renal disease is indistinguishable from idiopathic IgA nephropathy. The incidence of renal disease is between 20% to 60%, depending on the diagnostic criteria used. The renal complications of HSP are discussed here, whereas the diagnosis and management of HSP is discussed in more detail in Chapter 203.

Clinical Features and Differential Diagnosis

Most patients with HSP nephritis have asymptomatic hematuria and mild proteinuria. Some (~20%) develop gross hematuria. Approximately 10% of the children with renal disease present with an acute nephritic syndrome. Nephrotic syndrome and renal insufficiency are much less common. Many patients develop nephritis after the appearance of the rash; renal involvement is evident within 1 month of disease onset for the others. Rare clinical presentations include hypertension with a normal urinalysis and microscopic hematuria due to urethritis. Rarely patients with ANCA-positive vasculitis, SLE, and even acute poststreptococcal glomerulonephritis (APSGN) may present clinically with a syndrome that mimics HSP, and these should be ruled out by serological 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. Renal disease is often more severe in those with recurrent attacks.

Diagnosis

The diagnosis depends on the presence of palpable purpura with a normal platelet count and coagulation studies, plus one or more of the following: diffuse abdominal pain, arthritis/arthralgia, or a biopsy with prominent IgA deposition. There are no diagnostic laboratory tests. Elevated serum IgA levels and IgA rheumatoid factor are detected in approximately 50% of patients. Serum complement levels are typically normal or elevated. Although not routinely performed, a skin biopsy shows small vessel leukocytoclastic vasculitis with IgA deposition.

Treatment and Complications

HSP is a self-limited disease that usually lasts 1 to 2 weeks. The disease has a tendency to recur within an initial 6-week period, but exacerbations may occur as late as 2 years after onset. The prognosis of the disease is excellent. HSP morbidity is determined in most cases by GI complications during the acute phase and by renal involvement in the long term. There is no curative treatment for HSP nephritis. Most patients recover spontaneously with supportive care. However, a small subset present with severe renal disease and are at risk of developing chronic and even end-stage renal disease.34 These severely affected children should undergo renal biopsy to establish the extent of the glomerular injury, as clinical and pathological findings do not always correlate.

The histological severity of HSP nephritis has been graded on a scale of 1 to 6, based on criteria established by the International Study of Kidney Disease in Children. This grading system is weighted to the number of crescents, which is felt to be highly predictable of a poorer outcome: grade I, minor abnormalities; grade II, pure mesangial proliferation; grade III, focal or diffuse mesangial proliferation with crescents in fewer than 50% of glomeruli; grade IV, same as grade III except crescents in 50% to 75% of glomeruli; grade V, same as grade III but more than 75% of glomeruli have crescents; and grade VI is a rare variant resembling membranoproliferative glomerulonephritis (MPGN). Patients with grades III to VI have a less favorable prognosis and are generally treated with steroids with or without an immunosuppressive agent (cyclophosphamide or azathioprine), depending on the degree of renal dysfunction.35,36 However, evidence-based treatment guidelines are not available.

Steroid treatment appears to decrease the severity of abdominal pain and may decrease recurrence rates.37 Nonsteroidal anti-inflammatory drugs (NSAIDs) may help joint pain but in patients with renal insufficiency, careful monitoring to detect nephrotoxicity is important if NSAIDs are used to treat extrarenal manifestations. A still debated question is whether early treatment with a short course (2 to 4 weeks) of corticosteroids improves renal injury. Recent studies suggest that “prophylactic” steroids do not alter the incidence but may reduce the severity of nephritis. A systematic review published in 2007 found that such therapy significantly reduced the odds ratio of developing persistent renal disease.37 A randomized prospective study of 353 HSP patients published in abstract form by Dudley and colleagues in the same year showed no difference in the risk of developing nephropathy within the first 12 months, which is consistent with the findings of the prospective study of 171 children by Ronkainen and others, published in 2006.38

Prognosis

Short-term follow-up studies indicate an excellent prognosis. More than 90% of patients recover completely, although the urinalysis is still abnormal in 50% of the children at 3 months and in 10% to 20% two years after symptoms have resolved. A few children (3% to 4%) have a catastrophic acute illness and develop a rapidly progressive clinical course with ESRD within months. Another group (~5%) has evidence of chronic renal damage, 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. There are emerging data that all patients with severe acute renal involvement need monitoring for many years. In a long-term follow-up study (averaging 23 years) of 78 patients with HSP, 44% of individuals with nephrotic syndrome or acute nephritis at presentation had hypertension or a progressive decline in renal function, whereas 82% with hematuria alone were normal.

ANCA-Associated Vasculitis

Vasculitides are discussed in Chapter 203. Systemic vasculitis with antineutrophil cytoplasmic antibodies (ANCA) is associated with pauci-immune (minimal evidence of immune complex deposition) focal necrotizing glomerulonephritis (GN). Two target ANCA antigens, both present in neutrophil granules, have been identified: proteinase-3 produces a diffuse cytoplasmic staining pattern (cANCA), and myeloperoxidase provides a perinuclear staining pattern (pANCA). There are three small-vessel vasculitic syndromes associated with ANCA and focal necrotizing GN: Churg-Strauss syndrome, microscopic polyangiitis, and Wegener’s granulomatosis. Churg-Strauss syndrome is very uncommon in children. It is characterized by an initial phase of allergic asthma, followed by vasculitis associated with eosinophilic infiltrates and peripheral blood eosinophilia. GN occurs in 30% to 40% of Churg-Strauss patients, but the degree of involvement is usually mild. The other disorders that are more frequently associated with renal disease in childhood include microscopic polyangiitis and Wegener’s granulomatosis.

Epidemiology

Detailed pediatric epidemiological studies are just beginning to appear in the literature, because these diseases are uncommon in the pediatric population and the diagnosis was often unclear before a serological marker became available in the mid-1980s.39 Wegener’s granulomatosis and microscopic polyangiitis are more prevalent in middle-aged adults. In the pediatric population, they are mainly diseases of adolescents but have been reported in a 4-year-old.

Pathophysiology

These disorders are all associated with the formation of antibodies that react with antigens normally “hidden” from immune surveillance within neutrophil and monocyte cytosolic primary granules and lysosomes. The PR3 antigen has also been detected on renal tubular epithelia. The critical cryptic epitopes become expressed and are visible on the cell membrane in response to an initial “priming” event. The nature of this event is unclear and likely multiple. Infections (eg, Staphylococcus aureus), drugs (eg, antithyroid drugs, hydralazine, minocycline, and several others), environmental factors (eg, silica dust and heavy metals), and genetic risk factors have all been implicated.40 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. Interactions with neutrophil IgG receptors are also involved.41

Clinical Features and Differential Diagnosis

The features of Wegener’s granulomatosis and microscopic polyangiitis overlap, except for necrotizing granulomatous lesions of the upper and lower airway in Wegener’s that are absent in patients with microscopic polyangiitis.42 Both diseases may represent a clinical spectrum of the same primary pathological process. They both typically present with a flulike prodrome and systemic symptoms such as fever, anorexia, malaise, weight loss, and myalgias. Skin involvement (purpura or urticaria) and arthritis/arthralgia are common. Lung disease occurs in both syndromes, ranging from clinically silent involvement to life-threatening pulmonary hemorrhage. In microscopic polyangiitis, the lung disease results from alveolar capillaritis, whereas in Wegener’s disease, necrotizing granulomas form pulmonary nodules or even cavitating lesions. Granulomatous involvement of the upper airway, sinuses, nasal passages, and ears is also present in many patients with Wegener’s. Common associated symptoms include nasal discharge, pain due to local ulcers, sinus pain, hoarseness, stridor, earache, and sensorineural hearing loss. Renal involvement is very common in both, approximately 90% in microscopic polyangiitis and 80% in Wegener’s granulomatosis. 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 rapidly progressive GN due to severe glomerular damage caused by fibrinoid necrosis and crescent formation. Even though Wegener’s is classified as a granulomatous disease, granulomatous renal vasculitis is rare, detected in perhaps 5% of biopsied patients. Immune deposits are sparse or completely absent.

Diagnosis

ANCA are detected in 85% to 95% of patients with active Wegener’s (80% to 90% PR3-ANCA) and 70% with microscopic polyangiitis (most MPO-ANCA). Most patients (75% to 80%) with renal-limited vasculitis are MPO-ANCA positive. A small subset of patients with GN caused by anti-GBM antibodies (10% to 40%) 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, where the target antigen is typically neither PR3 nor MPO.

Treatment

ANCA-associated systemic vasculitis is an aggressive disease. Without treatment, mortality rates are 90% within 2 years. The introduction of cyclophosphamide therapy has resulted in a dramatic improvement in outcomes, but significant morbidity and mortality are still encountered. There is little role for corticosteroid therapy alone except to control the extrarenal localized disease. The first goal of therapy is to induce disease remission; this generally involves 3 to 6 months of corticosteroids and cyclophosphamide.43 Traditionally, oral cyclophosphamide is recommended; intravenous therapy is also effective, although the subsequent relapse rate may be higher. Trimethoprim-sulfamethoxazole appears beneficial for the patients with Wegener’s granulomatosis to prevent airway disease relapses. The role of plasmapheresis is unclear, but it appears to be helpful in patients with severe dialysis-dependent acute glomerulonephritisor severe pulmonary hemorrhage. Once the disease is in remission, low-dose maintenance immunosuppression is administered to prevent relapse. Relapse rates of 50% within 5 years (the risk is higher in the PR3-ANCA group) are typical.

Monitoring the ANCA titer can be useful in evaluating disease activity. Relapses are unusual when the titer is persistently negative, whereas disease relapses are often accompanied by the reappearance of ANCA or a significant titer increase. The ideal maintenance regimen has not been determined for patients with glomerulonephritis, but it often includes low-dose prednisone and azathioprine or MMF for another 12 to 18 months, sometimes longer if the patient is still ANCA-positive. Weekly methotrexate appears effective in patients without renal involvement. Prophylactic therapy to prevent Pneumocystis pneumonia, cystitis, candidiasis, gastritis, osteopenia, and amenorrhea are usually prescribed. Newer biological agents may eventually find their place in the therapeutic armamentarium. Infliximab (tumor necrosis factor-alpha antagonist) and rituximab (anti-CD20-positive B cells) as rescue therapy for refractory or relapsing disease appear promising based on published case series, but results of randomized clinical trials are not yet available.44 The Birmingham Vasculitis Activity Score has been developed and validated as a useful tool for clinical treatment trials.45

Prognosis

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 is now in the range of 75% to 85%. The published pediatric series are small, but they often report 5-year survival rates over 90%. Chronic kidney failure persists in as many as half of the patients, with 20% to 25% eventually developing end-stage kidney disease. Early deaths are 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.

Nephrotic syndrome (NS) is not a disease but a constellation of clinical findings common to several renal disorders.46 By definition, it comprises proteinuria greater than 50 mg/kg per 24 hr (> 40 mg/m2 per hour or a urinary protein-to-creatinine ratio greater than 2.0 mg/mg) and hypoalbuminemia (serum albumin less than 3.0 g/dl), edema, and hypercholesterolemia. The reason for the increased hepatic production of lipoproteins during the nephrotic state is not entirely understood, as 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 nephritic features or evidence of significant glomerular hypercellularity on renal biopsy. The pathophysiological sequence of events that lead to the classical clinical features in nephrotic syndrome, proteinuria, and hypoalbuminemia are depicted in Figure 472-7.

The NS of childhood has been divided into three broad groups: congenital/infantile, primary or idiopathic, and secondary. Only 10% to 15% of children have an identifiable secondary cause for their NS. The histological lesions that are associated with secondary causes of NS are frequently indistinguishable from the idiopathic lesions, but the treatment is targeted to the specific underlying cause. Over the past decade, several genetic mutations have been identified that define a fourth nephrotic syndrome category: inherited nephrotic syndrome, which is associated with clinical symptoms that begin after infancy.

Primary (idiopathic) 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 four categories based on biopsy findings: minimal change nephrotic syndrome (MCNS), MCNS with proliferative changes, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN). From a prognostic perspective, the histological pattern is less important than the responsiveness to corticosteroids. Most children with steroid-responsive disease no longer undergo renal biopsy. For these reasons, the terms corticosteroid-sensitive (SSNS) and steroid-resistant (SRNS) are generally preferred in clinical practice. Complications of nephrotic syndrome are discussed at the end of this section.

Steroid-Responsive Nephrotic Syndrome (Srns)

Minimal-change nephrotic syndrome (MCNS), also known historically as nil disease or lipoid nephrosis, is the most common cause of NS in childhood, accounting for 90% of patients presenting under 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% to 80%), and an excellent long-term prognosis. Idiopathic FSGS is a more serious form of idiopathic NS, because only 20% to 25% of patients respond to steroids. As long as future relapses remain steroid-responsive, the long-term prognosis is good in this subset of FSGS patients. Although this is still debated, many believe that MCNS and FSGS represent different ends in the spectrum of the same disease rather than distinct disorders.

Epidemiology

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 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. A history of atopy is reported in 30% to 60% of these children, and occasional associations with food allergies have been made.

Pathophysiology

In children, MCNS is usually idiopathic, although several secondary causes are known (Table 472-4). Steroid-sensitive nephritic syndrome (SSNS) is considered to be a primary disease of the glomerular epithelial cell (podocyte) that is injured by an unknown systemic factor. T-cell-derived cytokines such as interleukin-13 have been suggested as candidates, but thus far, the nature of the “nephrotic factor” remains elusive. Several subtle differences in the phenotype and in vitro function of lymphocytes (comparing cells harvested from nephrotic and non-nephrotic patients) have been ascribed to the nephrotic plasma milieu rather than to some intrinsic T-cell alteration. Evidence of a circulating “nephrotic factor” is supported by the observation that when a renal transplant patient received a kidney from a deceased donor who had active MCNS, proteinuria decreased rapidly in the transplant recipient and remained persistently negative after 6 weeks. Conversely, MCNS was reported to recur in a renal allograft transplanted into a patient with a history of MCNS.

Another potentially pathogenic mechanism in MCNS is the loss of charge-selective barrier function of the glomerular capillary wall, caused by a decrease in the heparan sulfate proteoglycan content. However, the mechanisms responsible for this change remain unknown, and loss of charge selectivity is a feature in many other diseases associated with the nephrotic syndrome; this suggests that this is a non-specific change. Recent observations in genetically engineered mice challenge the charge-selectivity hypothesis.

Clinical Features and Differential Diagnosis

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 common, and frequently new patients are misdiagnosed as having allergic conjunctivitis. Increasing abdominal girth from ascites is also common. Most episodes of NS are triggered by an antecedent upper respiratory tract infection, as are most relapses. Less commonly, patients with MCNS present with symptoms secondary to complications of the nephrotic syndrome, 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 distinctly uncommon and suggests another diagnosis.

Diagnosis

In addition to proteinuria, the urinalysis may show oval fat bodies (lipid-containing tubular cells) and waxy or hyaline casts. Granular casts are common 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 is typically 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 are often elevated and can be used as a surrogate marker for a risk of thrombosis.

Supportive Treatment

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 are rarely 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 is relatively uncommon, even during corticosteroid therapy, but when present, it requires treatment with antihypertensive medications. In these situations, hypertension is usually transient and medications can often be discontinued once the disease is in remission.

A major aspect of the initial management is parent education. The majority of patients will follow a chronic relapsing course, and the families need to be prepared in advance. All families should be taught to check the urine for protein using a dipstick. 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 intercurrent 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 these drugs’ potential nephrotoxicity.

Pharmacological Therapy

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 is recommended before high-dose corticosteroids are given. Corticosteroids will induce a remission in approximately 90% of children with MCNS. Therefore, for those with a clinical presentation typical of steroid-sensitive nephrotic syndrome (SSNS), a renal biopsy is not indicated prior to initiating steroid therapy. Atypical features that may require a renal biopsy prior to treatment include age less than 1 year, macrohematuria, hypertension, hypocomplementemia, extrarenal symptoms such as a rash of arthritis, or renal failure not caused by volume concentration.

The optimal dose, schedule of administration, and total duration of steroid therapy is unknown. Most children receive initial treatment with prednisone (60 mg/m2 per day or 2 mg/kg per day, maximal dose 80 mg/d). Prednisone can be given in a single daily dose or can be divided into daily doses. Ninety percent of children who will respond do so within 4 weeks and 98% by 8 weeks (eFig. 472.3). The current definition of steroid-responsiveness is response within 8 weeks. Once the urine become negative for protein, the subsequent duration of daily prednisone is debated. Many centers use 6 weeks total daily therapy; one group has suggested an additional 30 days. Thereafter, prednisone is switched to alternate days and tapered over 6 weeks or longer. The total duration of steroid therapy used to treat the initial episode influences the subsequent relapse rate. A meta-analysis47 found that for every additional month of therapy beyond 2 months and up to 7 months, the relative relapse risk was reduced by 11%. Due to concerns of steroid toxicity, additional clinical trials are needed before therapy longer than 3 months (6 weeks daily; 6 weeks alternate day) becomes a new practice standard. Failure to achieve remission after 6 to 8 weeks of full-dose daily prednisone is an indication for renal biopsy. Niaudet and colleagues suggest a modified approach. Patients without a steroid response after 4 weeks are given three intravenous doses of methylprednisone (1000 mg/m2) every other day. Lack of response within 7 days is used as the indication for biopsy.48 Some of these unresponsive children will prove to have MCNS, which will ultimately respond to a more prolonged course of steroids or to an alkylating agent or cyclosporin.

Almost 50% of children with SSNS experience multiple relapses. There is no agreement on a standard protocol for treating relapses. A commonly used protocol is prednisone 60 mg/m2 per day 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. If the child is experiencing frequent relapses (two or more relapses within 6 months of initial response or 4 or more relapses within any 12-month period) or has become steroid-dependent (two consecutive relapses occurring during steroid therapy or within 14 days of its cessation), the alternate-days dose is typically tapered to a “threshold dose” (the 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. A recent study suggests that taking this dose every day during upper respiratory tract infections may reduce relapse rates.49 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. Regular assessment of growth (both height and weight) and monitoring for cataracts are imperative in children receiving chronic or recurrent corticosteroid therapy.

Risks of steroid toxicity (especially reduced height velocity and overweight) with frequent relapses have led to the use of other immunosuppressive agents. Before initiating cytotoxic therapy, a biopsy is recommended for steroid-resistant patients, but most nephrologists agree that a biopsy is unnecessary in those with steroid-dependent or frequently relapsing disease.50 Although there is not a complete consensus on this topic, alkylating agents are often the next drug used. Cyclophosphamide for 8 to 12 weeks is generally well tolerated, with minimal risk of gonadal toxicity (total cumulative dose < 200 mg/kg). Monthly intravenous doses may also be effective. Chlorambucil is also effective but is less widely used due to the risk of seizures. The alkylating agent is ideally started after induction of remission (to minimize the risks of infections and hemorrhagic cystitis) and is used in combination with low-dose prednisone. Following treatment, the majority of the patients experience a prolonged remission (35% to 65% still in remission at 5 years), but relapses do recur in a sizeable subset. Children with frequent relapses have a better response to alkylating agents than does the steroid-dependent subgroup.

Cyclosporine (CSA) is effective in inducing and sustaining remission in 85% to 90% of steroid-responsive nephrotics and has had a major impact in a small group of patients debilitated by the disease, by steroid toxicity, and some who have had a poor response to cyclophosphamide.51 Unfortunately, relapses commonly occur once CSA is discontinued. Due to nephrotoxic side effects, CSA levels must be carefully monitored, and renal biopsies are recommended to evaluate the degree of interstitial fibrosis if therapy is continued for longer than 18 months. A common starting dosage is 5 to 6 mg/kg divided into two doses, with target predose blood levels of 50 to 100 ng/ml. Higher blood levels (100 to 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 nephrotoxicity, which increases with the dose and duration of use. Mild side effects are common and include hypertension, gingival hypertrophy, and hirsutism. To avoid the hirsutism and gingival hypertrophy associated with CSA treatment, tacrolimus is gaining popularity but clinical trials are lacking.

Other medications used for treatment include levamisole, which has been shown to reduce the number of relapses; however, this drug is no longer available. MMF (900 to 1200 mg/m2 per day divided into two doses) appears promising as a steroid-sparing agent, although efficacy data from randomized clinical trials are not yet available.52 Mizoribine has been used in Japan and vincristine in Australia with some success reported in small case series.

Prognosis

Before the introduction of antibiotics and corticosteroids, 40% of nephrotic children died within 5 years of diagnosis. 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. Late-onset renal failure is very unusual, but a small number of patients develop acute tubular necrosis if a relapse is accompanied by sepsis or hypovolemia. Nonsteroidal anti-inflammatory drugs increase the risk of acute renal failure during a relapse.

Eight to 10 years after diagnosis, 80% of patients achieve a long-lasting remission (eFig. 472.4). Younger age at diagnosis and frequent relapses within the first 6 months predict longer disease duration. A small number (14% to 42%) continue to experience relapses into adulthood; the frequency may be more common than previously known.53 Reported rates vary widely, from 14% to 42%, 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.

Steroid-Resistant Nephrotic Syndrome (Srns)

Approximately 15% to 20% of children with idiopathic NS have SRNS; the majority (~75%) have focal segmental glomerulosclerosis (FSGS). It is the most frequent glomerular disease to cause ESRD in childhood and is second only to congenital anomalies as a cause of pediatric ESRD. FSGS is diagnosed histologically by the complete collapse of a segment of the glomerulus associated with mesangial sclerosis (Table 472-3). 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 idiopathic, or it may develop as a secondary consequence of prior glomerular injury or hypertension (Table 472-5). The majority of children with idiopathic FSGS present with SRNS (75% to 80%). The secondary forms of FSGS more typically present as asymptomatic non-nephrotic proteinuria.

Epidemiology

In children, idiopathic FSGS typically begins 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, an observation that is not simply explained by disease resulting from HIV nephropathy.54

Pathophysiology

FSGS recurs in renal 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 nephrotic syndrome that disappeared spontaneously a few weeks after birth. A bioassay based on the ability of plasma from FSGS patients 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 etiological agent.

FSGS occasionally is an inherited disease that typically presents before 6 years of age. Mutations in the slit diaphragm protein podocin (NPHS2) are most common. Inheritance is autosomal recessive (AR); both homozygous mutations and compound heterozygous mutations have been reported. In Israeli-Arab children, the podocin mutation is also associated with cardiac anomalies. Importantly, 10% to 30% of children with apparent idiopathic SRNS harbor podocin mutations; no podocin mutations have been reported in individuals with SSNS. No patients with podocin mutations have achieved remission with immunosuppressive therapy, so progression to end-stage kidney disease is predicted.55 Other genes have been linked to inherited forms of SRNS, and additional genes remain to be identified (Table 472-1).

Clinical Features and Differential Diagnosis

Most children (90%) with idiopathic focal segmental glomerulosclerosis (FSGS) present with nephrotic syndrome that initially may be indistinguishable from SSNS. Less commonly, patients may present with asymptomatic proteinuria with or without microhematuria. 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. Macroscopic hematuria is rare.

Diagnosis

Definitive diagnosis requires a renal 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 AR familial FSGS and for patients who fail to respond to calcineurin therapy.

Treatment

Patients with genetic SRNS or secondary forms of FSGS are not treated with immunosuppressive drugs.55 Idiopathic SRNS is a challenging disease to treat; optimal therapy is still unclear.47 With a poor overall response rate to immunosuppressive therapy and a high rate of recurrence in renal allografts, this disease can be devastating. At best, 20% to 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. 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 or who have minimal change disease on renal biopsy. Combined treatment with high-dose corticosteroids (oral prednisone with or without pulse doses of methylprednisone) and alkylating agents has reportedly induced a partial or complete remission in 30% to 60% in some case series, but these protocols are associated with significant morbidity and should be limited to patients with well-preserved renal function. Even a partial response is associated with a better outcome.

There is considerable evidence-based literature to support the use of CSA as the second-line agent for idiopathic SRNS, 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. Efficacy of tacrolimus (trough levels in the 4-to-7 ng/ml range) is based only on case series. An unresolved question is how long a calcineurin drug should be continued before a patient is declared unresponsive; 3 to 6 months is often suggested. CSA needs to be continued for long periods of time, because the NS frequently relapses once CSA is discontinued. Drug levels, blood pressure, and renal function must be closely monitored.

MMF may have a role in the treatment of steroid and calcineurin-resistant SRNS, although data in children are limited. Triple therapy (steroids, CSA, and MMF), rituximab (anti-CD20), plasmapheresis, protein adsorption columns, low-density lipoprotein apheresis, and even bone marrow transplantation are all reportedly effective in selected individuals, but there are insufficient data to recommend their use at this time.

All hypertensive patients should be treated with ACEi and or angiotensin receptor blockers (ARB) drugs; 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. Hydroxymethylglutaryl CoA reductase inhibitors (statin) therapy is recommended in older children and adolescents with hypercholesterolemia to reduce cardiovascular risks and to possibly slow the progression of renal disease.

Prognosis

The single best prognostic indicator in patients with idiopathic NS is responsiveness to steroid therapy. Approximately 50% of the patients who do not achieve an NS remission develop ESRD within 10 years. The risks of progressive renal failure are higher among patients of Hispanic and African descent, children with disease onset under 1 year of age, and patients with the collapsing variant of FSGS. The severity of the proteinuria and the degree of interstitial fibrosis on renal biopsy also correlate with the rate of progression to ESRD. Recurrence of proteinuria and NS after transplantation occurs in 20% to 30% of patients.

Membranous Nephropathy

Membranous nephropathy is a noninflammatory proteinuric glomerular disease characterized by the presence of hallmark subepithelial immune deposits (usually containing IgG and C3). Membranous nephropathy is a rare cause of nephrotic syndrome in childhood, accounting for approximately 1% of cases in North America. Nephrotic syndrome secondary to membranous nephropathy does not usually respond to an 8-week course of prednisone; it is therefore necessary to do a biopsy for diagnosis.

Epidemiology

Although this disease is rare in childhood, it can present at any age, including in infants. Cases affecting identical twins and siblings have been reported, suggesting a genetic factor. Detailed epidemiological studies in childhood have not been conducted.

Pathophysiology

Unlike the disease in adults, the majority of childhood cases are secondary to an underlying disorder (Table 472-6). Idiopathic membranous nephropathy appears to be an antibody-mediated disease even though the target antigen remains unknown. Immune complexes are thought to form locally within the subepithelial space, where the target antigen is located. In a rat model of membranous nephropathy (Heymann nephritis), the target antigen is megalin, a normal constituent of rat but not human podocytes. An unusual antenatal form of membranous nephropathy has been reported and is associated with transplacental passage of antibodies to the podocyte antigen neutral endopeptidase (NEP).56 However, the target antigen in most forms of idiopathic human membranous nephropathy remains unknown. In addition to the more common associations with autoimmune diseases listed in Table 472-6, membranous nephropathy 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.

Clinical Features and Differential Diagnosis

Proteinuria is the hallmark of membranous nephropathy. At presentation, 70% have nephrotic syndrome, 70% have microhematuria, and 20% are hypertensive. The disease is typically insidious in its onset and progression. When a renal biopsy establishes a diagnosis of membranous nephropathy (usually after failure to respond to corticosteroid therapy for nephritic syndrome), an exhaustive investigation is warranted to look for an underlying cause. Only 3% of children have renal failure at presentation. A rapid deterioration in renal function mandates a search for an additional cause. For example, a small subset of these patients develops a superimposed crescentic glomerulonephritis, sometimes due to the formation of anti-GBM antibodies. Although renal vein thrombosis is a common complication among adult patients with membranous nephropathy, this complication is rare in children.

Diagnosis

A renal biopsy is required to establish a definitive diagnosis. Serological tests, including serum complement levels, are typically normal. Laboratory investigations are particularly helpful during the search for a secondary cause (Table 472-6). Hepatitis serology, serum complement levels, and an ANA test should be obtained in all patients. The renal 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 (postinfectious GM); all these features are atypical of the idiopathic disease.

Treatment

Established treatment guidelines for children with idiopathic membranous nephropathy do not currently exist. Children who present with non-nephrotic proteinuria, normal blood pressure, and normal renal 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 angiotensin receptor blocker therapy and a low-sodium diet are recommended for hypertension and as antiproteinuric therapy; older children with hypercholesterolemia should be treated with a statin drug.

Treatment guidelines for patients at risk of chronic kidney disease (> 4 g proteinuria/1.73m2/day, nephrotic syndrome, renal scarring on biopsy, rising serum creatinine level during follow-up) have been developed for adults and are often applied to children for whom there are no evidence-based data, although the long-term prognosis appears to be better in children.57,58 In general, corticosteroids alone decrease proteinuria, but effects on long-term renal function are less clear. For this reason, they are usually combined with an alkylating agent or a calcineurin inhibitor, either at the beginning of therapy or within 6 months, depending on the initial response. Therapy is required for several months. Patients on tacrolimus are more likely to develop glucose intolerance, but troublesome side effects such as hirsutism and gingival hypertrophy with CSA are avoided. The risk of statin-induced rhabdomyolysis appears to be higher with concurrent use of a calcineurin inhibitor. Data are emerging to suggest that MMF and rituximab may be useful in membranous nephropathy.

Prognosis

Membranous nephropathy is typically an indolent, slowly progressive disease with fewer than 5% of children developing ESRD 5 years after diagnosis. Good, long-term follow-up studies are not yet available for patients who develop membranous nephropathy in childhood.

Medical Complications of Nephrotic Syndrome

Persistence of nephrotic syndrome 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 nephrotic syndrome frequently follows a chronic relapsing course, children are at risk for several recognized long-term complications (eTable 472.3). 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.

Infections

Even in the current medical era, acute bacterial infections are relatively common and potentially fatal complications of nephritic syndrome. The acute onset of fever in a child during 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 peritonitis. Fever associated with abdominal pain must be considered peritonitis until proven otherwise. Approximately 50% of cases are caused by Streptococcus pneumoniae while other encapsulated or gram-negative organisms are 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.59 Once a nephrotic patient is in remission and off steroids for a few months, inoculation with the 23-valent pneumococcal vaccine (Pneumovax) and the heptavalent vaccine (Prevnar) is recommended.

Several abnormalities associated with the nephrotic state predispose patients to 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, might also facilitate infections. The use of immunosuppressive drugs is another contributing factor.

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 multiple relapses or with NS that is refractory to treatment. Annual immunization with killed influenza vaccine is recommended.

Thrombotic Disease

Thromboembolism is one of the most serious complications of nephrotic syndrome. Virtually all nephrotic patients are in a hypercoagulable state, and as many as 20% experience thrombotic events that are often clinically silent (2% to 4% have symptoms). However, it is still recommended that children with documented thrombotic complications undergo an evaluation for known genetic causes of thromboembolic disorders. The cause of the nephrotic syndrome may affect the absolute risk; thrombosis is relatively common in adults with membranous nephropathy and is infrequent in children with MCNS. Which abnormalities of the clotting process best correlate with the risk of thrombosis is still unclear. 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 VIII, V, and fibrinogen), urinary loss of anticoagulants (antithrombin III, protein S), and increased platelet number and adhesiveness. Other contributing factors include hyperlipidemia and hyperviscosity. The risk of thrombotic disease is significantly enhanced in the presence of hypovolemia and during prolonged periods of immobilization. Hospitalized young adult nephrotic patients have a sevenfold increased chance of experiencing thromboemboli. Indwelling venous catheters impose a major risk and should be avoided if at all possible.

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 bleeding risks. 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.60 Guidelines for the duration of therapy once remission of the nephrotic syndrome has been achieved are not established.

Cardiovascular Disease

An unresolved issue of significant concern is whether children with chronic relapsing nephrotic syndrome are at risk of premature atherosclerotic disease. Studies using sensitive imaging techniques such as electron beam CT or B-mode ultrasonographic imaging of carotid intima-media thickness have not yet been reported. Autopsies done on children as young as 5 years who died from nephrotic syndrome have found atheromatous lesions. In adults with nephrotic syndrome, the relative risk of myocardial infarction is 5.5 compared with a control population after adjustment for other known risk factors. Several factors may contribute to the increased risk of cardiovascular disease and stroke, including hypertension, the use of steroids and systemic inflammation, and the atherogenic plasma lipid profile. In particular, plasma cholesterol and lipoprotein levels are high. Whether hypercholesterolemia should be treated with statin drugs remains unclear.

Bones

Although reduced bone formation rates, osteoporosis, and avascular necrosis are known complications of long-term corticosteroid use in several patient populations, these complications appear to be rare in patients with SSNS based on an evaluation of bone density by dual energy x-ray absorptiometry.61 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 multiple steroid-treated relapses may not reach their final adult height potential.

HUS is the most common cause of severe acute renal failure in a previously healthy young child. Most children with HUS (90%) have an antecedent diarrheal illness caused by a strain of Escherichia coli that produces a Shiga-like toxin.62,63 This group of patients has been classified as having “typical” or “diarrhea-associated” (D+HUS) or Shiga toxin–associated HUS. Approximately 10% of patients develop HUS for other reasons, which are summarized in Table 472-7; these cases are referred to as atypical or non-diarrheal-associated HUS.

The possibility of a genetic form of the disease should be considered in a 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.

Epidemiology

HUS occurs worldwide with sporadic and epidemic patterns. More than 70% of children in the United States and western Europe with diarrhea-associated 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 two to three new cases per year per 100,000 children under the age of 5 years. In children below the age of 15 years, the risk of HUS following an E. coli 0157:H7 colitis is in the range of 8% to 10%. Other strains of Shiga-toxin (Stx) producing E. coli as well as 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 uncommon in African Americans and is more common 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 or nonpasteurized milk or milk products are frequent exposure sources. Consumption fruits, juices, or vegetables that have been exposed to contaminated manure; and contaminated lakes and swimming pools have all caused disease outbreaks. Although unusual, person-to-person spread has been documented.

Pathophysiology

The sequence of events that result in the clinical features and differential diagnosis of HUS are depicted in Figure 472-8. HUS is initiated by damage to the endothelium with microthrombi formation, leading to the diagnostic triad of microangiopathic hemolytic anemia, thrombocytopenia, and renal insufficiency. The enteropathogenic E. coli are characterized by the production a Shiga-like toxin (Stx1 or Stx2), toxins that were first reported in association with Shigella 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. A few other bacterial strains have been shown to produce SLT, including E. coli 0103:H2, which was associated with HUS after causing a urinary tract infection, including E. coli 0103:H2, which was associated with HUS after causing a urinary tract infection. 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 fibrin deposition and damage to erythrocytes and platelets. A similar cascade of events may cause tissue injury in other vascular tissues as well.

An important cause (15% to 30% cases) of atypical HUS occurs as a complication of Streptococcus pneumoniae infections in young children.64 Many of the offending strains are not included in the conjugate heptavalent pneumococcal vaccine given in infancy. 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). 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 crossmatching. Use of fresh-frozen plasma, an additional source of the pathogenic antibody, is contraindicated. The outcome has improved in this patient group, but mortality remains high, in the range of 12%.

Clinical Features and Differential Diagnosis

Following ingestion of E. coli–contaminated food or liquid, most children typically 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 is usually self-limited, but complications may occur, including rectal prolapse, toxic megacolon, bowel wall necrosis, and perforation. Strictures may develop later. HUS occurs in about 15% of infected children. The onset of HUS is usually abrupt, occurring 5 to 10 days (median 1 week) after the onset of the diarrhea, as the colitis is resolving. The presenting symptoms are often due to renal failure and relate to the patient’s intravascular volume status. The severity of the renal failure 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 the renal failure 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 features is more insidious.

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 renal failure.

Neurological involvement is common. Most patients are very irritable and somnolent. However, more serious involvement leading to seizures and coma occur in 10% of children. The neurological manifestations may be the presenting feature and may impact acute mortality rates and long-term morbidity.

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. As many as 20% of patients have pancreatic involvement, indicated by an elevation 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 is rare, myocarditis and myocardial ischemia are serious complications. Pericardial effusions may also occur.

Diagnosis

Biochemical evidence of renal insufficiency 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, elevated reticulocytes and LDH level, and low serum haptoglobin concentrations. The PT and 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 is common at presentation, primarily due to gastrointestinal losses. Leukocytosis is common, and peripheral WBC counts greater than 20,000 correlate with a poorer prognosis. Serum C3 and CH50 levels may be depressed, especially in 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.

When a patient presents with diarrhea-associated HUS, documentation of a Stx–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. Some laboratories can also test for the presence of the Stx in the stool.

Treatment

For typical diarrhea or Stx-associated 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 fluid and electrolyte management. Volume loss from diarrhea and vomiting must be replaced, but care must be taken to avoid intravascular volume overload. Severe oligoanuric renal failure requiring renal replacement therapy 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 RBCs must be infused slowly or during dialysis, with careful blood pressure monitoring. Platelet transfusions should be avoided unless the patients are actively bleeding or if they 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 renal perfusion that may aggravate renal injury. Nutritional support is important, as many HUS patients are already catabolic due to several days of poor caloric intake before presentation.

No specific therapeutic interventions have proven beneficial for treating patients with HUS. Plasma infusion or exchange therapies do not decrease mortality 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 thrombotic thrombocytopenic purpura. Antiplatelet drugs and fibrinolytic therapy are of no proven benefit but increase the risk of hemorrhagic complications and should be avoided. During the prodromal phase of colitis, antimotility drugs are contraindicated, and antibiotics have been reported to increase the probability of developing HUS.

The optimal treatment of atypical familial and recurrent forms of HUS is less clear. Because of the poor overall prognosis of this group of patients and the high recurrence rates, most centers recommend treatment with daily plasma exchange until the patient’s condition stabilizes (to remove a possible pathogenic factor or to replace a missing protective factor).

Complications

During the recovery phase, the hemolytic process resolves more slowly than the other manifestations, and patients are often discharged with a persistent anemia from an inappropriately low reticulocyte count that cannot be explained by deficiency of folate, 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.

Prognosis

Acute mortality rates for diarrhea-associated HUS are in the range of 3% to 5%, often related to severe complications such as neurological disease and cardiac failure or multiorgan involvement. Renal 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 chronic kidney disease with or without hypertension. Patients with proteinuria, hypertension, or a low GFR 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 renal biopsies are not generally performed, when these data are available, chronic kidney disease 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 one of the key complement cascade regulatory proteins (Table 472-7).

Recurrent disease in both native and transplant kidneys is extremely rare in diarrhea-associated HUS (< 10%) but occurs quite commonly in atypical genetic forms of the disease. Combined liver and kidney transplantation appears to offer the best chance for long-term survival in the atypical severe disease associated with factor H deficiency.

Prevention

Children actively infected with Shiga-toxin-producing E. coli should not be treated with antibiotics or antimotility agents, since they may increase the risk of HUS. Maintaining a normal intravascular volume during the diarrheal phase (often necessitating hospitalization for intravenous fluids) may decrease the severity of renal injury when HUS ensues. Treatment during the diarrheal stage with Synsorb-Pk in an attempt to trap Stx in the gut failed to improve outcomes. The best way to prevent infection with Stx-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.