Chapter 27. Immunoglobulin A Nephropathy & Henoch-Schönlein Purpura

Essentials of Diagnosis

• Immunoglobulin A nephropathy (IgAN) is the most frequent form of primary glomerulonephritis worldwide.
• Hematuria is typical. Younger patients often present with episodes of macroscopic hematuria coincident with mucosal infections or exercise. Adults often have asymptomatic hematuria and proteinuria.
• Abnormal glycosylation of immunoglobulin A (IgA) molecules is believed to be important in disease pathogenesis.
• The diagnosis is established by the presence of dominant or codominant IgA deposition by immunofluorescence microscopy typically in the mesangial region of the glomeruli.
• True IgA nephropathy is not just “benign recurrent hematuria.” End-stage renal disease (ESRD) occurs in 15% of patients by 10 years and 20–40% by 20 years from onset.

General Considerations

IgAN is the most common form of primary glomerulonephritis worldwide. The prevalence of the disease shows geographic variations. In patients who undergo renal biopsy, IgAN accounts for approximately 30–40% of cases in Asia, 15–20% of cases in Europe, and 5–10% of cases in North America. These differences may be attributed to true differences in genetic susceptibility, or just as likely to differences in urinalysis screening practices, indications for renal biopsy, and possibly other factors. The disease is more common in whites, Asians, and American Indians and less common in blacks both in the United States and in Africa. It is most frequently diagnosed in young adults in the second and third decade of life and there is a male predominance.

Although numerous putative specific environmental or infectious agents have been suggested as the underlying stimulus for IgAN, none has been conclusively confirmed in the majority of patients. Familial clustering and a higher risk in identical twins suggest a role for genetic factors in susceptibility. A variety of genetic polymorphisms associated with susceptibility (and/or progression) in IgAN have been reported with conflicting results. Although IgAN is most commonly a primary (or idiopathic) renal disease, there are well-documented associations with a wide variety of conditions in individual patients (Table 27–1). In many of these conditions, IgA deposition in the glomerulus is not associated with inflammation and a progressive course, and thus, it may be clinically insignificant. This suggests that factors beyond the deposition of IgA or IgA-containing immune complexes must be involved in the pathogenesis of progressive disease in patients with idiopathic IgAN.

Pathogenesis

The precise etiology of IgAN is unknown, but much evidence suggests that a basic abnormality in the IgA molecule itself plays a pivotal role in pathogenesis. Humans produce two isotype subclasses of IgA: IgA1 and IgA2. Plasma cells in the bone marrow, lymph nodes, and spleen mainly produce IgA1 (primarily monomeric), whereas both IgA1 and IgA2 are produced by the plasma cells in the respiratory and gastrointestinal tract (primarily polymeric). Analysis of kidney eluates from patients with IgAN reveals that the glomerular deposits are almost exclusively polymeric IgA1. Furthermore, the hinge region of the IgA1 molecule in patients with IgAN is often abnormal with reduced galactose and/or sialic acid content. The mechanisms responsible for this underglycosylation are unclear, but reduced function of the enzyme responsible for performing this glycosylation may be involved. Nevertheless, the altered glycosylation pattern might favor self-aggregation of IgA1, formation of circulating IgA-containing immune complexes, defective clearance of abnormal IgA1 from the circulation, and increased binding of IgA1 to the extracellular matrix components in the kidney. Once deposited in the kidney, IgA1-containing immune complexes trigger cellular proliferation and enhance the production of proinflammatory cytokines, chemokines, and growth factors. Interleukin (IL)-6 may play a prominent role, but other factors including IL-1, platelet-derived growth factor, tumor necrosis factor, free oxygen radicals, and vascular cell adhesion molecule-1 have also been implicated as modulators of disease activity. Complement activation may be mediated by the alternative or lectin pathways since polymeric IgA1 and aberrantly glycosylated IgA1 are efficient at initiation.

Clinical Findings

Symptoms and Signs

Patients with IgAN present in a variety of ways. Recurrent episodes of painless macroscopic hematuria (brown- or tea-colored urine) are more common in younger patients. These episodes often coincide with, or occur within, 1–2 days of an upper respiratory infection and are referred to as “synpharyngitic.” Macroscopic hematuria may also be temporally related to other acute infections (gastroenteritis or urinary tract infection) and occasionally to strenuous exercise. Dull loin pain may accompany the hematuria, presumably due to renal capsular swelling.

In 30–40% of patients, IgAN is indolent with microscopic hematuria and proteinuria incidentally discovered on urinalysis. This asymptomatic presentation is more common in adults who are diagnosed with the urinary abnormalities at insurance physicals, pregnancy screening, and routine annual checkups. Other less common presentations include the nephrotic syndrome, acute renal failure (which may be the result of crescentic glomerulonephritis, renal tubular obstruction by red blood cells, or acute tubular necrosis), or chronic kidney disease representing long-standing disease that has gone undetected.

Laboratory Findings

There are no specific laboratory tests that distinguish IgAN from other glomerular diseases. The serum creatinine may be normal or elevated at presentation. Hematuria usually dominates the urinalysis. Proteinuria is often present, but the nephrotic syndrome is uncommon (˜10–15% of patients). Urine microscopy typically reveals dysmorphic red blood cells and red blood cell casts indicating bleeding of glomerular origin. Complement levels are normal. Some, but not all IgAN patients have elevated levels of serum IgA (IgA1). Nevertheless, measurement of IgA levels has no diagnostic or prognostic value. Increased IgA levels alone are insufficient to cause disease. This conclusion is supported by observations that other diseases associated with increased serum IgA (ie, HIV, hepatobiliary disease, and IgA myeloma) infrequently result in IgAN.

A kidney biopsy is required for definitive diagnosis of IgAN. Immunofluorescence microscopy demonstrates the pathognomonic finding of dominant or codominant deposits of IgA in a diffuse granular pattern predominantly within the mesangium often with focal paramesangial and subendothelial extension (Figure 27–1). Other immunoglobulins and complement may be codeposited (with less intensity) including IgG, IgM, C3, and λ and κ light chains. Electron microscopy confirms the presence of electron-dense deposits in the mesangium. Light microscopic findings are variable and can reveal mesangial cell proliferation, mesangial expansion, focal or diffuse proliferative glomerulonephritis, crescentic glomerulonephritis, chronic sclerosing glomerulonephritis, and a membranoproliferative glomerulonephritis type I pattern. A subset of nephrotic patients with normal appearing glomeruli by light microscopy may have only prominent visceral epithelial cell foot process effacement on electron microscopy and appear indistinguishable from patients with minimal change disease.

Differential Diagnosis

Macroscopic hematuria due to IgAN is a much less common presentation in middle aged or elderly patients and thus its presence should raise suspicion of a nonglomerular etiology such as urinary tract malignancy or stones, and appropriate imaging should be performed to exclude these. Examination of the urine sediment is helpful in distinguishing glomerular from nonglomerular causes of hematuria. In children, postinfectious (streptococcal) glomerulonephritis may present with dark or smoky urine that may be confused with IgAN. However, the timing of the hematuria relative to the pharyngitis provides clues. Hematuria occurs consistently between 7 and 14 days after streptococcal infection as opposed to the synpharyngitic hematuria characteristic of IgAN. Episodic gross hematuria, often in association with upper respiratory infections, may also be seen in familial glomerular diseases such as thin basement membrane disease or Alport's syndrome.

Lupus nephritis is another glomerular disease associated with prominent mesangial IgA deposition. Lupus can be distinguished from IgA nephropathy by the more intense deposition of IgG compared to IgA, as well as the typical deposition of C1q, the characteristic “full house” immunofluorescent staining for IgA, IgG, IgM, C1q, and C3, and the serologic and clinical signs of lupus.

Treatment

A diagnosis of IgAN does not necessarily warrant immunosuppressive therapy since many patients will have a good outcome without treatment. The decision to treat depends on identification of those patients likely to progress based on adverse prognostic features. Patients with mild proteinuria (<500 mg/day), normal renal function, and normal blood pressure may be treated conservatively with close monitoring (every 6 months). Patients with normal renal function (creatinine <1.5 mg/dL) and greater degrees of proteinuria (500–1000 mg/day) may or may not benefit from other therapies. All certainly need optimal blood pressure control (goal <130/80). Many believe that use of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) alone or in combination should be used to optimize blood pressure and decrease proteinuria in most patients with IgAN.

Because of the observed association of upper respiratory tract infections and macroscopic hematuria in IgAN, tonsillectomy has been proposed as a means of preventing progression of the disease. The results are at best conflicting with a lack of compelling evidence demonstrating long-term preservation of renal function. Nevertheless, in patients with recurrent episodes of severe tonsillitis associated with gross hematuria, tonsillectomy is reasonable.

The use of fish oils rich in omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) in large doses (12 g/day) may be beneficial. They may provide anti-inflammatory effects and retard renal injury by decreasing platelet aggregation and by competing with arachidonic acid to produce biologically less inflammatory prostaglandins and leukotrienes. Clinical trials with fish oils in IgAN have led to conflicting results. Some randomized controlled trials have shown significant preservation of renal function over time compared to placebo-treated patients, while others have failed to show a benefit. Given the potential efficacy and lack of toxicity, high doses of fish oil are often used in combination with ACEI/ARB therapy in patients with proteinuria (>1 g/day) and/or mildly impaired renal function. In some countries, combinations of dipyridamole and warfarin are used (with or without concomitant immunosuppressive agents) for their antiproliferative and antithrombotic effects. Dipyridamole has been shown to inhibit mesangial proliferation in vitro.

A trial of corticosteroids (6 months) may be warranted in IgAN patients with significant proteinuria (despite angiotensin inhibition) and normal renal function. In one randomized controlled trial, long-term follow-up of patients treated with 6 months of corticosteroids(1.0 g pulse of methylprednisolone at the beginning of months 1, 3, and 5 with continuous oral prednisone 0.5 mg/kg every other day) demonstrated improved renal survival and a decrease in proteinuria in treated patients compared to controls. However, patients with impaired renal function and more severe pathologic changes on renal biopsy appear to respond less favorably to steroids alone. Nevertheless, there are two forms of IgAN in which the use of prednisone is clearly indicated as initial treatment. Patients with the nephrotic syndrome and histologic findings characteristic of minimal change disease (minimal glomerular changes on light microscopy and diffuse foot process fusion on electron microscopy) typically go into remission with corticosteroids. Additionally, patients with clinical or pathologic features of rapidly progressive glomerulonephritis (RPGN) may also benefit from steroid therapy in conjunction with other agents.

Cytotoxic agents [short-term cyclophosphamide followed by maintenance with prednisone plus either azathioprine or mycophenolate mofetil (MMF)] may be indicated for patients with progressive disease but with creatinine less than 3 mg/dL. Improvement with such regimens is less likely when the plasma creatinine is greater than 2.5–3 mg/dL, which is considered past the “point of no return.”

MMF has been used in at least five trials some of which were double blind and randomized. The results are conflicting with either favorable outcomes with treatment or no benefit. This may depend upon the population studied.

For patients who progress to ESRD, renal transplantation is suitable therapy. Histologic evidence of IgA deposition is reported in 30–60% of allografts by 10 years and 5–10% of affected allografts are lost to progressive disease. Contemporary immunosuppression regimens, which include cyclosporine, tacrolimus, and MMF, have not altered the recurrence rate.

Prognosis

The course of IgAN is highly variable. Certain features may confer a poor renal prognosis including male gender, absence of gross hematuria, elevated serum creatinine at time of biopsy, and greater severity of hypertension and proteinuria (except when the proteinuria is associated with a minimal-change-like lesion). Likewise, elevations of serum creatinine and proteinuria at the point of 1-year post-renal biopsy are predictive of a poor outcome.

It has been estimated that ESRD occurs in 15% of cases at 10 years and 20–40% of cases at 20 years, although this likely reflects a selection bias with follow-up of patients with more severe disease. Many patients have a very slow progressive decline in renal function over 10–20 years.

Essentials of Diagnosis

• Henoch–Schönlein purpura (HSP) is the multisystem form of primary IgA nephropathy.
• It is a form of leukocytoclastic vasculitis with IgA-dominant immune deposits affecting small vessels of the skin, joints, gastrointestinal system, and kidney.
• It is most common in children.
• The classic tetrad of signs and symptoms includes rash, arthralgias, abdominal pain, and renal disease.

General Considerations

Henoch-Schönlein purpura, as defined by the International Consensus Conference on Nomenclature of Systemic Vasculitides, is “a vasculitis with IgA dominant immune deposits affecting small vessels and typically involving the skin, gut and glomeruli and associated with arthralgias or arthritis.” There is much evidence to suggest that HSP and IgAN represent a spectrum of clinical presentations of similar disorders with HSP being the systemic form of IgAN. Both HSP and IgAN can occur consecutively in the same patient and each has been described in identical twins. Both diseases bear similar immunologic abnormalities and renal histologic findings. Furthermore, a history of recent or simultaneous infection (upper respiratory, gastrointestinal, or urinary tract) is common in children with both HSP and IgAN.

HSP can occur at any age, but preferentially affects children between the ages of 5 and 15 years. It is the most common cause of acute systemic vasculitis in children, with an incidence estimated at 10–20 cases per 100,000 children per year. In adults, the annual incidence is much lower (1.3–1.4/100,000), with a mean age of presentation of about 50 years.

Renal involvement varies depending on the diagnostic criteria used and method of detection of renal disease. In children, nephritis (HSPN) is manifested in 20–40% of cases but occurs more frequently in adults (50–85%).

Pathogenesis

There are significant gaps in our understanding of the pathogenesis of HSP, although abnormalities in IgA play a central role. Increases in both serum polymeric IgA1 and IgA1-containing immune complexes are present. Deposition of IgA1-containing immune complexes is associated with a systemic small vessel vasculitis and capillary damage. Complement activation, platelet activation, and release of cytokines and growth factors may all contribute to the pathogenesis. Why this leads to systemic vasculitis and extrarenal manifestations in HSP and not in isolated IgAN is unknown. Diminished galactosylation of IgA1 appears to correlate with the presence of nephritis as patients with HSP, but without nephritis, have normal IgA1 glycosylation.

Numerous infectious agents (ie, varicella, HIV, parvovirus B19, hepatitis A and B, mycoplasma, group A streptococci, Epstein-Barr virus, and Campylobacter enteritis) as well as other factors (medications, vaccinations, insect bites) have been linked to the development of HSP, but a causative relationship is unproven. IgA ANCA has also been found in some patients with HSP, but its pathogenetic role and clinical significance are unclear.

Clinical Findings

Symptoms and Signs

The classical clinical presentation includes palpable purpura (present in most cases), polyarthralgias (75–80% of cases), and abdominal pain (50–75% of cases). Symptoms and signs can occur in any order and at any time over a course of several days to weeks, and reflect the systemic leukocytoclastic vasculitis. The skin lesions usually appear as crops of palpable purpura on the lower limbs and buttocks. Gastrointestinal involvement is characterized by colicky abdominal pain sometimes associated with gastrointestinal bleeding (melena, hematochezia, or occult). Joint involvement, consisting of arthralgias or frank arthritis, is typically limited to the knees and ankles, and does not lead to permanent deformity. Pulmonary, neurologic, genitourinary, and cardiac manifestations may also occur.

Renal manifestations may occur within days or up to several weeks after onset of the clinical presentation of HSP, but rarely precedes the other major components of the disease. Renal findings include hematuria (microscopic or gross), proteinuria, and abnormal renal function tests.

Laboratory Findings

Laboratory tests are nonspecific. Coagulation tests and platelet counts are normal despite the presence of dramatic purpuric lesions. Plasma creatinine may be normal or elevated. Serum complement levels are normal and cryoglobulins are absent. Serum IgA levels may be elevated, but measurement of IgA levels is not diagnostic and they do not correlate with disease severity. Urinalysis in affected individuals reveals blood and protein, which is often mild (<500 mg/day), but can be in the nephrotic range. The urine sediment typically has red cells and cellular casts consistent with nephritis.

Confirmation of the diagnosis requires the identification of tissue deposition of IgA in the skin or kidney. Renal biopsy, the more invasive of the two options, is generally reserved for those with an unclear diagnosis or with evidence of more severe renal involvement. Biopsy of skin lesions reveals leukocytoclastic vasculitis with vessel wall necrosis and perivascular accumulation of inflammatory cells, mostly polymorphonuclear leukocytes and mononuclear cells, surrounding the capillaries and postcapillary venules of the dermis. Immunofluorescence reveals the presence of IgA. In some cases, these findings can be seen in areas of skin that appear uninvolved.

In renal biopsies, histologic findings resemble those of IgAN. A mesangioproliferative glomerulonephritis is typical, although some will have a membranoproliferative pattern. Necrotizing glomerular lesions, diffuse endocapillary proliferation, crescents, and fibrin deposits are more frequent in HSPN than in IgAN. Immunofluorescence microscopy demonstrates the characteristic granular deposition of IgA in the mesangium indistinguishable from that seen in IgAN. On electron microscopy, electron-dense deposits are scattered throughout the mesangium. In some patients, prominent capillary wall deposits of IgA and occasionally subepithelial deposits are present.

Differential Diagnosis

In children, the characteristic tetrad of rash, joint, gastrointestinal, and renal involvement usually makes the syndrome of HSP clearly identifiable. Clotting disorders, septic emboli, and infections (ie, meningococcemia, gonococcemia, rickettsial) may mimic the findings of HSP. Any of the four major symptoms or signs may be present before the other, which may lead to misdirected evaluations (ie, abdominal pains alone may be mistaken for cholecystitis, appendicitis, and bowel infarction).

The differential diagnosis is much broader in adults and it must be distinguished from other forms of vasculitis including pauci-immune small vessel vasculitis, polyarteritis nodosa, systemic lupus erythematosis (SLE), cryoglobulinemia, and hypersensitivity vasculitis. Clinical and histologic characteristics in combination with serologic testing for ANCA, anti-GBM, cryoglobulins, hepatitis B and C, antinuclear antibody (ANA), and complement levels narrow the diagnosis.

Treatment

In patients with normal kidney function, treatment is generally supportive. There are limited data available that define the optimal treatment for patients with renal involvement. Most patients require no specific therapy, as spontaneous remission is common. However, in patients with rapidly progressive renal failure caused by crescentic nephritis, aggressive therapy using high-dose pulse methylprednisolone in combination with cyclophosphamide followed by oral prednisone to decrease the inflammatory process may be beneficial. Uncertainty remains as to the optimal duration of therapy. Other regimens used with variable results include azathioprine, dipyridamole, urokinase, immune globulin, and plasma exchange. There are anecdotal reports of abatement of persistent HSP (purpuric rash, hematuria, and proteinuria) with fish oil in combination with ACEI, as well as cyclosporine A/steroid combinations. Prospective randomized clinical trials are needed to truly evaluate the efficacy of any of these agents.

Prognosis

In the majority of patients, HSP is a self-limiting illness characterized by spontaneous resolution of manifestations and a good prognosis. One-third to one-half of patients will have one or more recurrences of symptoms, usually within 6 weeks, but they may recur as late as 3–7 years later.

Transient hematuria and proteinuria typically resolve within several months. Spontaneous recovery may also occur in patients with severe renal involvement including acute renal failure and nephrotic-range proteinuria. The incidence of long-term renal impairment varies among the different series in the literature. In children, renal survival is generally over 95% at 15 years. The prognosis of HSPN in adults may be worse than that of children with up to 30% of adults showing chronic decline in glomerular filtration rate with progression to ESRD. Nephrotic syndrome, persistent proteinuria, elevated serum creatinine at onset, extensive crescents (>50%), and advanced tubulointerstitial disease on renal biopsy are associated with a worse renal prognosis.

Recurrent renal disease can occur in renal transplants. Histologic recurrences of HSPN may occur in up to 50% of renal transplants and are associated with clinical disease in 20% and graft loss in 9% of cases. Graft loss may be more likely in patients who had aggressive initial disease with rapid progression to ESRD, or who undergo transplant either with living related donors or while still clinically active.