Antibodies that induce glomerular immune deposits may be directed against normal constituents of the glomeruli (e.g., antiglomerular basement membrane [anti-GBM] antibodies in Goodpasture disease), against nonrenal self-antigens localized in the glomeruli (e.g., DNA-nucleosome complexes in lupus), or against exogenous antigens that are trapped in the glomeruli by charge affinity or local precipitation (e.g., cryoglobulins in hepatitis C virus–associated membranoproliferative GN [MPGN]). The site at which glomerular immune deposits form dictates the degree of injury. Subendothelial deposits on the inner surface of the glomerular capillary walls easily recruit circulating neutrophils and macrophages as effector cells and induce more inflammation than do mesangial or subepithelial deposits, which are less accessible to the circulation. In situ immune complex formation results in local complement activation and is much more nephritogenic than is passive trapping of antibodies from the circulation. The character and quantity of immune deposits also affect the degree of tissue injury. Complement-fixing immunoglobulin G (IgG) subtypes cause more injury than do antibodies that do not activate complement as well. Larger quantities of immune deposits cause more tissue injury.

Immune complexes activate cellular and humoral mediators to induce glomerular injury. Glomerular immune deposits become an inflammatory focus that leads to generation of chemotactic factors that attract neutrophils, T cells, and macrophages to the site. Among the most important chemotactic factors are complement component C5a, interleukin-8, and glomerular endothelial cell adhesion molecules. Neutrophils attracted to the site of the deposits are activated by ingesting the immune complex aggregates and subsequently generate hydrogen peroxide and proteases, which, in turn, damage the locally surrounding tissue. Activated T cells play a less direct role in tissue injury by releasing chemokines to recruit macrophages to the site of injury. Macrophages, either recruited by T cells or attracted by local chemokines or adhesion molecules, release proteolytic enzymes and reactive oxygen species, which digest the immune deposits but also digest and injure the normal GBM. Macrophages also release transforming growth factor, induce fibrin formation, and initiate cellular crescent formation.

A secondary effect of immune mediators occurs in glomerular cells themselves, which respond in several ways, including cell proliferation, overproduction of oxidants and proteases, changes in cell phenotype, and overproduction of extracellular matrix. These changes in glomerular cells may herald a chronic phase of GN that progresses to glomerular sclerosis and permanent loss of renal filtration function.

IgG-containing immune complexes recruit humoral mediators, especially components of complement. The most important of these components is the complement membrane attack complex (C5b-9), which has membranolytic activity to damage glomerular cells directly and to alter glomerular permeability. C5b-9 also mediates an interstitial inflammatory response, especially in association with proteinuric forms of GN, such as membranous GN (MGN). Interstitial inflammation may progress to chronic interstitial fibrosis and may contribute to progressive renal scarring. The importance of C5b-9 as one of the mediators of tissue injury suggests a new avenue for future therapy to prevent chronic GN by altering the pathogenesis of GN at an early stage of the process before injury occurs. The use of molecularly engineered complement regulatory proteins to downregulate the generation of C5b-9 has the potential to ameliorate or completely prevent progression of some forms of GN.

Less is known about the importance of cellular-mediated processes that contribute to the pathogenesis of GN. T cells and macrophages clearly play pathogenic roles in diseases such as MGN, minimal-change nephrotic syndrome (MCNS), and focal segmental glomerulosclerosis (FSGS). In these diseases, no significant antibody deposition, cellular infiltration, or glomerular cell proliferation is apparent by histologic examination of kidney tissue, but clinically dramatic increases occur in glomerular permeability, especially to protein. At least in MCNS and FSGS, a circulating permeability factor derived from T cells has been identified in experimental models as the likely mediator. The probable sites of action of this factor are the GBM and the glomerular epithelial cell (podocyte).

Coagulation factors are important contributing factors to the pathogenesis of GN. In patients with rapidly progressive GN (RPGN), deposition of fibrin and its derivatives at sites of glomerular injury and gaps in the GBM is critical to the formation of glomerular crescents. Glomerular crescents are defined histologically by the presence of two or more layers of cells in Bowman’s space that eventually may growth to obliterate that space. Platelet activation also appears to play a role in the pathogenesis of GN through elaboration of substances potentially injurious to the kidney. Platelet cationic proteins may neutralize the GBM-negative charge and allow proteins, which also are negatively charged, to be filtered freely instead of being repelled by the GBM negative-charge barrier. Platelet-activating factor (PAF) produces a decline in renal vascular resistance and mesangial cell contraction, which contributes to reduction of glomerular filtration rate (GFR). PAF also promotes glomerular macrophage accumulation, fibrin deposition, and crescent formation. Platelet-derived growth factor (PDGF), which has properties similar to those of PAF, also promotes glomerulosclerosis. Increased production of PDGF stimulates mesangial and endothelial cell proliferation in some proliferative forms of GN, including experimental nephritis, and the human diseases diffuse proliferative lupus nephritis, IgA nephropathy, mesangial proliferative nephritis, and antineutrophil cytoplasmic antibody-positive crescentic nephritis.

A few exogenous nephrotoxins cause GN. They include the drugs D-penicillamine, trimethadione, probenecid, and captopril and a few of the heavy metals, such as mercury and gold. The mechanism of injury depends on the toxin. D-Penicillamine
induces immune complexes that indirectly injure the glomeruli. Trimethadione and mercury probably cause direct injury to the GBM. MGN is the histopathologic lesion most often induced by glomerular nephrotoxins.

The clinical expression of APSGN is fairly variable and extends from a completely asymptomatic form to the most severe manifestations of acute renal failure, including edema, oliguria, congestive heart failure, hypertension, and encephalopathy. The most common presenting symptoms are hematuria, proteinuria, and edema, often accompanied by rather nonspecific findings of lethargy, anorexia, vomiting, fever, abdominal pain, or headache.

Gross hematuria is present in only 30% to 50% of children with APSGN. Usually, the urine is described as smoky, tea colored, cola colored, or, occasionally, dirty green. At least two-thirds of hospitalized patients have edema, which initially is mild and may be noted only periorbitally but can become fairly marked, especially if normal fluid intake occurs over the course of several days at the height of the disease. Evidence of circulatory congestion, including orthopnea, dyspnea, cough, auscultatory rales, and gallop heart rhythms, is apparent on physical examination in many children with edema. Usually, chest radiography shows cardiomegaly and pulmonary edema of varying degrees. Severe congestive heart failure is a very rare occurrance. Hypertension is seen fairly commonly in inpatients (50% to 90%), but hypertensive encephalopathy, characterized by headache, somnolence, convulsions, coma, confusion, aphasia, transient blindness, agitation, or combativeness, occurs in only a few (5%).

Laboratory investigation should begin with a careful analysis of the urine. The specimen may be yellow, slightly discolored, or grossly bloody and usually has a high specific gravity and a low pH. Microscopic hematuria with predominantly dysmorphic erythrocytes in the centrifuged urinary sediment is present in virtually all cases, and leukocyturia is almost as common. Red blood cell casts are found very often (60% to 85%) in centrifuged specimens in which the resuspended sediment is examined freshly and exhibits an acidic pH. Often, leukocyte casts in addition to hyaline and granular casts are seen. The presence of leukocytes and leukocyte casts should not be considered evidence of superimposed urinary tract infection but rather of glomerular inflammation. Proteinuria occurs in most cases and correlates qualitatively with the amount of blood in the urine, reaching nephrotic proportions in fewer than 5% of patients.

A laboratory evaluation for streptococcal infection is mandatory. Serum ASO and anti-DNase B titers (as described earlier) are most helpful for confirming previous recent infection of the throat or skin. AHT determinations have been discontinued in many laboratories because of difficulties in interpreting the test, which may be positive in other diseases. Throat and skin lesion cultures also may be positive at the time the patient has nephritis and should be treated with appropriate antibiotics. Because asymptomatic family members also may be affected, family screening for subclinical streptococcal disease and nephritis has been recommended.

One of the most important diagnostic laboratory findings in APSGN is a depressed serum concentration of C3. Activation of the alternate pathway of complement occurs in most cases, resulting in reduced serum C3 levels in at least 90% of patients examined in the early phase of nephritis. Occasionally, serum C4 also is depressed. In most cases, serum C3 returns to normal concentrations 10 days to 8 weeks after the onset of the nephritis. If the serum C3 is not measured within the first few days of presentation of the nephritis, the concentration may have returned to normal, and its depression will have been missed. Because prior treatment of the streptococcal infection with antibiotics may attenuate the period of serum C3 depression, the serum C3 may appear normal at the time of presentation of the nephritis. The degree of serum C3 depression bears no relationship to the severity of the disease. A follow-up serum C3 determination must be obtained 8 to 12 weeks after the onset of the acute episode to document the return of a normal concentration, which occurs in more than 90% of patients by this time interval. If the concentration remains low, other kinds of nephritis, such as MPGN or lupus, are more likely, and renal biopsy confirmation of the diagnosis should be sought.

Usually, GFR is depressed in hospitalized patients during the acute stage of moderate to severe nephritis. Serum urea nitrogen may be elevated disproportionately to serum creatinine. Even when GFR is normal or only slightly decreased, severe sodium and fluid retention may occur. Urine volume is reduced, but severe oliguria is uncommon. Urine-concentrating ability is well preserved. The fractional excretion of sodium is less than 1%, even in the presence of reduced GFR. The acutely inflamed kidney of APSGN retains sodium even in acute renal failure, unlike the high fractional excretion of sodium that occurs in acute tubular necrosis. If a child with APSGN is allowed free access to fluids, dilutional hyponatremia may develop. Acidosis and hyperkalemia may result from aldosterone suppression caused by extracellular volume expansion and from severe reduction in GFR.

Although patients with APSGN rarely undergo renal biopsy today, many were assessed by biopsy in previous decades, thus giving us a comprehensive understanding of the histologic spectrum of the disease. By light microscopy, the glomeruli are seen to be enlarged and hypercellular, filling Bowman’s space. The glomeruli are relatively bloodless because of the occlusion of capillary lumina by proliferating mesangial and endothelial cells accompanied by a variable amount of infiltration by neutrophils, macrophages, and eosinophils within the capillary lumina and mesangium. Crescents are uncommon findings but may be extensive and are associated with a poorer prognosis. The renal tubules appear normal. Interstitial edema may be prominent. Usually, the blood vessels are normal. Electron microscopy reveals typical electron-dense “humps” between the glomerular capillary basement membrane and the epithelial cells. The humps are present on immunofluorescence studies, showing up as bright granular deposits containing predominantly IgG and C3. Other immune reactants, such as IgM, IgA, fibrin, and other components of the alternate pathway of complement, may be found along the capillary walls and in the mesangium.

The precise mechanism of pathogenesis remains uncertain, despite widespread acceptance that APSGN is immune-complex mediated and is triggered by constituents of the nephritogenic strains of group A streptococci. Immune complexes containing IgG and C3 have been identified in the serum of affected patients. Attempts to identify streptococcal antigens within these complexes, either in the circulation or fixed in glomeruli, have been negative or inconclusive. Possibly, streptococcal antigens bind to the glomerular capillary wall and form the nidus for in situ immune complex formation. Additionally, direct complement activation by streptococcal antigens deposited in the glomeruli may induce local inflammatory changes that lead to glomerular injury.

At their onset, many types of GN mimic APSGN, but these occur less commonly. The absence of proof of a preceding streptococcal infection or the simultaneous occurrence of infection plus nephritis suggests other types of GN. GN caused by infectious agents other than streptococci (staphylococci, viruses) usually is coincident with the infection and often lacks the telltale sign of hypocomplementemia. Usually, the course of other infection-associated GN depends on the natural history of that infection rather than on the renal manifestations.

Other disorders frequently confused with APSGN include IgA nephropathy, hereditary nephritis (Alport syndrome), MPGN, HSP nephritis, idiopathic hypercalciuria, benign hematuria, and resolving episodes of previously undiagnosed postinfectious GN. Unlike in ASPGN, the episodic hematuria of IgA nephropathy occurs coincident with and not after an upper respiratory tract infection, and serum complement levels are normal. Previously unrecognized hereditary nephritis with microscopic or gross hematuria but no associated hypocomplementemia may first come to attention because of an abnormal urinalysis found during evaluation for ASPGN. In contrast, MPGN may present as an acute nephritic syndrome during or after a streptococcal infection but with hypocomplementemia that, when reassessed at a later date, does not resolve. The nephritis of HSP may mimic clinical APSGN precisely if it is associated with mild extrarenal manifestations and an evanescent rash. A careful history and physical examination may uncover the true diagnosis in such cases, and serum complement levels are normal. Idiopathic hypercalciuria may present as isolated hematuria but without proteinuria or hypocomplementemia. Benign hematuria is a diagnosis of exclusion after all other causes of hematuria have been eliminated and, like hypercalciuria, has no associated proteinuria or hypocomplementemia.

The exacerbation of chronic previously unrecognized GN also must be excluded. Patients with chronic GN may exhibit episodic gross hematuria, hypertension, or azotemia at the time of an intercurrent infection. A prior history of renal symptoms or features of chronic renal failure, such as growth retardation or renal osteodystrophy, should be sought carefully to help to distinguish forms of chronic GN from APSGN.

No specific or general therapy is effective in ameliorating the inflammatory lesion of APSGN. All therapy is supportive and is directed toward treating the clinical manifestations of acute nephritis. Hypertension may be severe and require emergency treatment. Severe hypertension with encephalopathy demands immediate treatment. Fast-acting antihypertensive medication such as sublingual nifedipine or intravenous labetalol may be a suitable choice for initial therapy. If multiple doses are required, maintenance antihypertensive therapy should be started. Loop diuretics and fluid restriction are important adjunct therapies and usually suffice alone for mild hypertension and for relieving edema and circulatory congestion. Restricting fluid intake to an amount equal to insensible water loss may obviate the need for diuretic therapy. Conversely, the use of diuretics may allow affected patients to have a more palatable diet and to avoid the psychological tension associated with severe fluid restriction. Patients with oligoanuria may respond poorly to diuretics and may require strict fluid restriction for control of edema and hypervolemia. In such patients, hyperkalemia should be anticipated and treated with dietary potassium restriction, binding resins, or dialysis as needed.

Patients with evidence of ongoing throat or skin infection should receive a course of appropriate antistreptococcal antibiotics. This therapy in no way influences the course or prognosis of the nephritis. Bed rest has no therapeutic advantage but should be allowed as needed by the child. Dietary limitations of sodium, potassium, and fluid usually are necessary for the hospitalized child but are liberalized for the patient at discharge, when the peak of the disease has passed. Those who require maintenance antihypertensive therapy should continue dietary sodium restriction at home.

Overall, the prognosis of APSGN is excellent, with full recovery expected in more than 98% of affected children. The resolution must be documented at follow-up office visits over time. Most children spend no more than 5 days in the hospital, but the disease resolves fairly slowly over the course of many months. Few children develop chronic renal failure. Usually, hypertension and gross hematuria resolve within 3 weeks. Gross hematuria may recur at the time of future intercurrent infections during the recovery phase, but the reappearance holds no prognostic significance. Microscopic hematuria persists for many months and has been documented for as long as 3 years in a few patients. Proteinuria resolves within a few months; its persistence after 6 months should raise concern regarding the possibility of an incorrect diagnosis. The serum C3 concentration must be measured again 8 to 12 weeks after the acute episode occurs. Failure of C3 to increase into the normal range during this period, especially with persistent symptoms of hypertension, gross hematuria, or heavy proteinuria, strongly suggests the diagnosis of MPGN, and a renal biopsy should be performed for the appropriate diagnosis.

IgA nephropathy may present at any age, but it most commonly occurs clinically in patients between the ages of 10 through 30 years. The prevalence is higher in boys, especially in North America and Europe. The disease occurs more frequently in Asians, whites, Native Americans in the southwestern United States, and Australian aborigines than in blacks in the United States and South Africa. Hematuria is the most common initial sign. Hematuria is microscopic in 100% and macroscopic in 85% of the children with biopsy-proven IgA nephropathy. Hematuria may occur for years without progression of disease. Gross hematuria often is episodic, usually in association with a febrile illness, most commonly of the upper respiratory tract. Proteinuria unrelated to gross hematuria occurs in approximately 40% to 50% of affected children, and it reaches the nephrotic range in some. Patients with moderate to severe proteinuria are at greater risk of developing renal insufficiency. Isolated proteinuria is not a sign of IgA nephropathy in children. Hypertension occurs in only approximately 10%; usually, its occurrence coincides with the development of chronic renal failure. Approximately 20% of patients experience a mild decrease in GFR during episodic gross hematuria. Complaints of fever, malaise, and loin or abdominal pain also are common findings at that time. Usually, renal function returns to normal after an acute episode.

A renal biopsy is necessary to confirm the diagnosis of IgA nephropathy. No other laboratory studies are specific. Serum
IgA levels are elevated in 50% to 70% of affected patients but appear to bear no relation to the severity or the activity of the disease. Serum IgG, IgM, and C3 concentrations seldom are abnormal.

Immunofluorescence microscopy of a renal biopsy of a patient with IgA nephropathy characteristically shows dominant IgA or IgA codominant with IgG deposition in the mesangium. Light microscopy shows focal or diffuse mesangial cell proliferation and expansion of mesangial matrix. The renal lesion in HSP nephritis looks exactly the same and is distinguished from IgA nephropathy only by clinical symptoms. IgA may be found in the glomeruli in several other nephropathies, including systemic lupus erythematosus (SLE) or chronic liver disease, but it may be neither the dominant immune reactant nor confined to the mesangium. Often, IgM, C3, and properdin accompany IgA in the same pattern as the IgA distribution but with much less intensity. Electron microscopy confirms the presence of electron-dense deposits in the mesangium and rarely in adjacent subepithelial or intramembranous spaces of the GBM.

Although immunofluorescence defines the glomerulopathy, light microscopy predicts the prognosis. Biopsies have been classified into three groups according to the severity of glomerular proliferative changes. Approximately one-fourth of the biopsies show histologically normal glomeruli, with little or no interstitial disease. The other three-fourths are divided approximately evenly between those showing mesangial hypercellularity and those showing mesangial hypercellularity plus focal and segmental areas of necrosis, synechiae, crescent formation, or collapse of the glomerular capillary wall and sclerosis.

The pathogenesis of IgA nephropathy remains uncertain after 3 decades of investigation. The serum IgA immune response of patients with IgA nephropathy is increased in both antigen-specific and nonspecific assays. Systemic IgA may play a role in the pathogenesis of the disease. Lines of evidence to support this supposition include the presence of IgA in the mesangium, the recurrence of IgA nephropathy in renal allografts, and the observations that serum IgA concentrations are increased in some patients and that IgA-containing circulating immune complexes are found in nearly one-half the patients. The predominant form of IgA found in renal biopsies from affected patients is polymeric IgA1, reflecting the increased serum concentration of polymeric IgA1. Serum IgA1 has been found to have abnormal O-glycosylation in patients with IgA nephropathy and HSP nephritis but not in patients with other glomerulonephritides. A combination of polyclonal stimulation of IgA plus structural abnormalities of IgA may lead to mesangial deposition of IgA1 and glomerular injury, but has never been proven. Secretory IgA (IgA2) does not appear to play a major role in the immunogenesis of IgA nephropathy.

A genetic predisposition of some patients to IgA nephropathy is suggested by the association of human leukocyte antigen (HLA) types BW35, B27, DR1, and DR4 with IgA nephropathy and by the occurrence of the disease in multiple members of the same family and in HLA-identical twins.

Microscopic hematuria with or without mild proteinuria between episodes of gross hematuria also occurs in hereditary nephritis (Alport syndrome), in benign hematuria, in idiopathic hypercalciuria, occasionally in MPGN, and rarely in MGN. Hereditary nephritis can be distinguished from IgA nephropathy clinically by discovery of a positive family history or associated deafness. Usually, MPGN is associated with a decreased serum C3 level and heavier proteinuria, whereas MGN presents as NS with normal complement levels and microscopic or less often gross hematuria. Benign hematuria occurs without proteinuria or other signs or symptoms of renal disease. Proteinuria is absent in idiopathic hypercalciuria, which can be diagnosed by the presence of abnormally high calcium excretion in a 24-hour urine collection.

IgA nephropathy is easy to confuse with APSGN, especially if the initial presentation consists of an episode of gross hematuria and mild systemic complaints. Unlike patients with APSGN, patients with IgA nephropathy have no latent period between the development of infection and the onset of hematuria, and the serum C3 concentration is normal. Gross hematuria persists for only a few days in patients with IgA nephropathy and usually resolves when the fever remits.

Distinguishing the nephritis of HSP from IgA nephropathy is even more difficult. If the HSP rash is transient and is not obviously purpuric, and if the extrarenal manifestations of HSP are mild, the clinical syndrome is identical to IgA nephropathy. Furthermore, the renal biopsy findings of HSP nephritis are virtually identical to those of IgA nephropathy. These similarities have led some investigators to speculate that IgA nephropathy is a monosymptomatic form of HSP.

No specific therapy is available for IgA nephropathy. The potential for progression to chronic renal failure and end-stage renal disease led to many uncontrolled trials of prednisone, cytotoxic drugs, platelet inhibitors, angiotensin-converting enzyme inhibitors, antioxidants, plasma exchange, and combination therapies. These studies were conducted mostly with patients who exhibited severe symptoms and signs of progressive disease, which may have been too late in the course of the disease to prove these therapies efficacious. Prednisone therapy has been shown to improve urinary findings and histopathologic lesions in subsequent renal biopsies in some children but not in others. In adult patients, daily fish oil supplementation for 2 years retarded the progression of renal failure in one controlled trial but not in others. No children were studied. A few multicenter randomized, controlled therapeutic trials for prednisone, fish oil, vitamin E, mycophenolate mofetil, and other therapeutic agents have been completed or are in progress, but they have shown no efficacy of any specific agent to date. More well-designed trials are needed before any guidelines for therapy of IgA nephropathy can be developed. In the meantime, attention should be paid to controlling hypertension and proteinuria to prevent progression of the disease. Angiotensin-converting enzyme inhibitors are the drugs of choice because of their antihypertensive and additional antiproteinuric effects.

Most children with IgA nephropathy have either a very slowly progressive or a completely benign course until adulthood; however, 5% to 10% of children develop end-stage renal disease in childhood or adolescence. IgA nephropathy recurs in a renal transplant at least 35% of the time but is slowly progressive and has not changed the 10-year renal transplant survival in these patients compared with other patients with end-stage renal disease. Predictors of poor prognosis in children are heavy proteinuria and the NS, hypertension, and the presence in the renal biopsy of glomerular proliferative lesions with crescents, sclerosis, or GBM alterations.

Most affected children are boys between ages 3 and 10 years. Two-thirds of patients report the onset of an upper respiratory tract infection 1 to 3 weeks before the onset of purpura. The incidence of HSP is seasonal, with its peak in winter.

Usually, the disease begins with an acute erythematous macular rash, most often on the ankles and spreading to the dorsum of the legs, the buttocks, and occasionally the ulnar surfaces of the arms. The trunk is spared. Within a day, the lesions become purpuric and may coalesce. The skin lesions disappear in approximately 2 weeks, although in some children, the rash comes and goes over a period of days to weeks. Many patients with the rash experience edema of the scalp, face, and dorsum of the hands and feet. Joint pain with or without edema occurs in 60% to 75% of cases. Colicky abdominal pain with melena or bloody diarrhea occurs in one-half of affected children and mimics other gastrointestinal diseases. The incidence of abdominal pain is highest (90%) in children with HSP nephritis. Severe vasculitis of the bowel may result in gastrointestinal hemorrhage, perforation, or intussusception.

The renal manifestations of HSP are clinically mild and often silent. If the urine is examined over the duration of the disease, abnormalities will be found in almost every case. The spectrum of renal disease in HSP is broad, ranging from asymptomatic hematuria and proteinuria to full-blown acute nephritic syndrome with the NS. Hypertension is an uncommon finding.

No laboratory test is diagnostic of HSP. Leukocytosis occurs early in the course. Hemoglobin, hematocrit, and the peripheral blood smear are normal, as are the platelet count, bleeding time, and coagulation studies. The erythrocyte sedimentation rate may be elevated. Microscopic hematuria, red blood cell casts, and proteinuria are present in the urinalysis. Gross hematuria may be seen in 20% to 30% of cases. Azotemia occurs in as many as 20% of cases but usually is transient. Uremia requiring acute dialysis for a short time is very rare.

Serum IgA concentration is elevated in 50% of children with HSP. Often, the elevation occurs during the acute phase only, with levels returning to normal as symptoms resolve. Serum C3 concentration is normal, but breakdown products of complement are increased in the serum, a finding indicating complement activation, presumably by circulating immune complexes or cryoglobulins, which have been identified in many patients.

If the clinical signs and symptoms of HSP are atypical, the diagnosis can be confirmed by microscopic examination of skin and renal biopsy specimens. Typically, skin lesions show leukocytoclastic vasculitis, characterized by transmural and perivascular infiltration with polymorphonuclear leukocytes, histiocytes, and sometimes eosinophils. The renal lesion is identical to that seen in IgA nephropathy (see foregoing) and ranges from no identifiable abnormalities by light microscopy to mesangial proliferation, focal and segmental proliferative lesions, and diffuse proliferative lesions with or without crescents. Brightly staining deposits of IgA always are found in the mesangium by immunofluorescence. Electron microscopic examination shows dense deposits in the same location.

The pathogenesis of HSP may involve a primary immune defect of IgA activity. The systemic nature of HSP, the appearance of IgA in extrarenal blood vessels, and the presence of IgA-containing circulating immune complexes in the serum of most patients suggest this possibility. An immune response has been assumed to be triggered by the presentation of offending antigen to the surface of either the respiratory or the gastrointestinal tract, which then leads to the production of IgA antibodies that may form immune complexes in the blood. Then the complexes make their way to various sites, including the kidney, where an inflammatory response ensues. For years, antigenic stimuli for the IgA response have been sought intensively, but specific relationships never have been substantiated, although many allergens have been implicated.

The purpuric nature and distribution of the skin lesions of HSP can be fairly characteristic. If the rash is atypical in distribution, other causes of purpura, such as leukemia, septicemia, hemolytic-uremic syndrome, SLE, and idiopathic thrombocytopenic purpura, must be considered. The abdominal symptoms mimic those of many infectious and inflammatory bowel diseases. HSP may cause an acute surgical emergency secondary to bowel perforation or intussusception. Pancreatitis is an uncommon development. Vasculitis of the testis may resemble torsion of the testis, orchitis, or incarcerated hernia. Distinguishing joint symptoms from those seen in rheumatoid arthritis, SLE, and acute rheumatic fever is difficult. The renal manifestations of HSP may appear identical to those seen in APSGN, bacterial endocarditis, SLE, polyarteritis, and MPGN.

The clinical course varies from very mild to severe. Most patients have several bouts of rash and abdominal pain during the first month of disease. Recurrences over the course of a longer period may be associated with a poorer prognosis. The main determinant of the overall prognosis is the persistence and severity of the renal disease. Children with minor urinary abnormalities have an excellent prognosis for complete recovery, whereas those who present with severe crescentic nephritis with acute renal failure or the NS are most likely to develop chronic renal failure and even end-stage renal disease. Patients who have renal disease should have long-term follow-up until the urinalysis is normal for several years. Those showing persistent urinary abnormalities or evidence of progressive renal failure should be seen by a pediatric nephrologist.

No drug therapy has been shown to be effective for severe HSP nephritis. Therapy usually is limited to supportive measures, when nephritis is mild or moderate. Careful monitoring to detect serious abdominal complications is of paramount importance in patients with abdominal pain. When abdominal pain is severe and incapacitating even after administration of analgesics, corticosteroids may provide relief. The use of analgesics and steroids is not without risk because they may
mask symptoms of gastrointestinal perforation. No evidence corroborates that corticosteroids have any beneficial effect on the clinical course of the renal disease.

Like the extrarenal manifestations of SLE, lupus nephritis presents in various ways with varying levels of intensity. Rarely, patients with known SLE may have no symptoms of renal disease and a completely normal urinalysis but show an active renal lesion by renal biopsy. Some patients have only renal disease without extrarenal signs of SLE initially but later fulfill the diagnostic criteria for SLE.

Although SLE is more often a disease of young women (8:1 female-to-male ratio), 20% to 25% of cases are diagnosed in the first 2 decades of life, rarely even in infants. Nephritis occurs more commonly in childhood lupus and affects as many as 80% of patients. All World Health Organization (WHO) classes of nephritis occur in childhood (Table 325.1).

The laboratory diagnosis of SLE is reviewed in detail in Chapter 434. Usually, the serum C3 and C4 concentrations are severely decreased. Antinuclear antibody and antidouble-stranded DNA antibody titers are elevated at the time of diagnosis in 95% of patients with nephritis. Urinary abnormalities include hematuria, proteinuria, and casts (red cell, white cell, hyaline, or broad-waxy). Proteinuria may be mild or moderate or in the nephrotic range. Heavy proteinuria is associated with more severe disease. One-half of children with SLE nephritis have reduced renal function as noted by either an elevated serum creatinine level or decreased creatinine clearance.

Renal tubular disorders (e.g., type IV renal tubular acidosis or glucosuria) may occur, especially in patients with evidence of tubulointerstitial disease by renal biopsy. Ureteral vasculitis and noninfectious cystitis have been described and may be responsible for obstructive uropathy and lower urinary tract symptoms, respectively.

Over the years, several classifications of lupus nephritis have been proposed, but the most widely accepted today is that of the WHO (see Table 325.1). This classification is a useful investigational tool, but because not every biopsy fits neatly into one of the classes, the use of the WHO classification for predicting the prognosis for an individual patient is not as helpful. Serial biopsies often show transformation between classes during therapy and are useful to guide further therapy.

Biopsies from only approximately 5% of the patients show normal kidneys (class I). Minimal amounts of electron-dense deposits and immunofluorescent IgG and complement found exclusively in the mesangium are allowed in this class. Urinary abnormalities and renal failure hardly ever occur in this group of patients.

Mesangial proliferative lupus GN (class II) accounts for 20% of biopsies. Varying degrees of mesangial hypercellularity and mesangial deposition of IgG or IgM and C1q, C4, C3, and properdin are found in these biopsies. Clinically, urinalysis shows only mild asymptomatic hematuria or proteinuria in patients with class II disease.

Renal biopsies from patients with focal and segmental proliferative lupus GN (class III) are characterized by the finding
of additional deposits of C1q, C4, C3, and properdin in the capillary walls but have fewer than 50% of glomeruli involved by the disease process. This lesion is similar to that found in severe IgA nephropathy and HSP nephritis. Hematuria and proteinuria are present in most patients, but the NS and renal failure are uncommon. Approximately 25% of biopsies are class III.

Diffuse proliferative GN (class IV) is found in 40% of biopsies. The pathologic features are similar to those of class III, but more than 50% of glomeruli are affected, rendering the lesion more severe and diffuse. Electron microscopic and immunofluorescence studies show heavy deposits of all immunoglobulins and complement, especially in the subendothelial space of the capillary wall. When these deposits are circumferential, the capillary loop has a “wire loop” appearance. Mesangial and epimembranous deposits are numerous. Crescent formation varies but may be severe, and it correlates clinically with the presence of RPGN. In class IV nephritis, hematuria and proteinuria almost always are present. Most patients who have the NS and/or renal failure also fall into this category. Class IV lupus nephritis is associated with progressive uremia and high mortality, if it is not aggressively treated with cytotoxic drugs such as cyclophosphamide as well as prednisone.