eMedicine Specialties > Nephrology > Glomerular Diseases

IgA Nephropathy

Author: Mona Brake, MD, Assistant Professor, Department of Internal Medicine, Kansas University School of Medicine
Coauthor(s): Douglas Somers, MD, Assistant Professor, Department of Internal Medicine, Division of Nephrology, University of Iowa Medical Center
Contributor Information and Disclosures

Updated: Aug 6, 2009

Introduction

Background

Immunoglobulin A (IgA) nephropathy (also known as Berger disease) was first described by Berger and Hinglais in 1968. IgA nephropathy is characterized by predominant IgA deposition in the glomerular mesangium. Long-term follow-up data illustrated that some patients with IgA nephropathy progress to end-stage renal disease (ESRD).¹ IgA nephropathy is the most common cause of glomerulonephritis in the world.²

IgA nephropathy is highly variable, both clinically and pathologically. Clinical features range from asymptomatic hematuria to rapidly progressive glomerulonephritis (RPGN). IgA nephropathy is most often associated with microscopic hematuria or recurrent macroscopic hematuria, and spontaneously resolving acute renal failure can occur. The condition can sometimes lead to chronic kidney disease as well. Pathologically, a spectrum of glomerular lesions can be seen, but mesangial proliferation with prominent IgA deposition (as seen in the images below) is observed in almost all biopsies.

Pathophysiology

The pathogenesis of IgA nephropathy remains incompletely understood.³ The characteristic pathologic findings by immunofluorescence microscopy of granular deposits of IgA and complement 3 (C3) in the glomerular mesangium suggest that this disease is the result of the deposition of circulating immune complexes leading to the activation of the complement cascade.

Deposited IgA is predominantly polymeric IgA1, which is mainly derived from the mucosal immune system. The association of some cases of IgA nephropathy with syndromes that affect the respiratory tract or gastrointestinal tract, such as celiac disease, led to the suggestion that IgA nephropathy is a disease of the mucosal immune system. This concept is also supported by the clinical observation that hematuria worsens during or after upper respiratory tract or gastrointestinal tract infections.

The role of the complement system in the pathogenesis of IgA nephropathy is controversial. While IgA antibodies cannot activate complement through the classic pathway, studies have shown that complement can be activated by the alternate pathway.

IgA in the mesangium is likely to be deposited from the circulation as IgA-containing immune complexes. This hypothesis is supported by the high recurrence rate of IgA nephropathy in renal transplant recipients who have IgA nephropathy and, conversely, by the disappearance of the deposits from donor kidneys with IgA nephropathy when transplanted into donors without the disease. Furthermore, the mesangial pattern of IgA deposits suggests that circulating IgA complexes are responsible for the disease.

Serum IgA levels are elevated in approximately half of patients with IgA nephropathy, but that increase is unlikely to play a role in the pathogenesis of the disease, as markedly elevated IgA levels are observed in patients with AIDS who do not have IgA nephropathy. However, IgA is probably accumulated and deposited because of a systemic abnormality rather than a defect intrinsic to the kidney.

Frequency

United States

Distribution of IgA nephropathy varies in different geographic regions throughout the world. The condition accounts for about 10% of biopsies performed for glomerular disease in the United States. Prevalence rates are lower in the United States compared to Asian countries. These lower rates may be influenced by a conservative approach by nephrologists in the United States who are reluctant to perform renal biopsies in asymptomatic patients with only mild abnormalities on urinalyses.

International

IgA nephropathy is observed in up to 40% of all biopsies performed for glomerular disease in Asia, compared to 20% in Europe and 10% in North America. High prevalence rates are observed in Singapore, Japan, Australia, Hong Kong, Finland, and southern Europe, whereas low prevalence rates are the rule in the United Kingdom, Canada, and the United States.

In Asia, routine urinalyses are performed for schoolchildren, and renal biopsies are performed for patients with asymptomatic hematuria, thus raising the reported prevalence of the disease.

Mortality/Morbidity

This disorder is thought to follow a benign course in most cases. However, many patients are at risk for slow progression to ESRD, which develops in approximately 15% of patients by 10 years and 20% by 20 years, though these percentages depend on how the disease is defined.

Race

IgA nephropathy is more common in whites and Asians and is rare in blacks, both in the United States and in Africa. The condition is frequently observed in American Indians of the Zuni and Navajo tribes.

Sex

IgA nephropathy is more common in males than in females. Virtually all studies show a male predominance of at least 2:1, with reported ratios of up to 6:1. The higher male predilection is observed in white patients in northern Europe and the United States.

Age

IgA nephropathy can affect all ages but is most common in the second and third decades of life. Eighty percent of patients are aged 16-35 years at the time of diagnosis. The condition is uncommon in children younger than 10 years.

Clinical

History

Two common presentations of patients with IgA nephropathy are episodic gross hematuria and persistent microscopic hematuria. Recurrent macroscopic hematuria, usually associated with an upper respiratory tract infection, or, less often, gastroenteritis is the most frequent clinical presentation and is observed in 40-50% of presenting patients. In 30-40% of patients, the disease is asymptomatic, with erythrocytes (RBCs), RBC casts, and proteinuria discovered on urinalysis. Patients with IgA nephropathy can also present with acute or chronic renal failure.

• Hematuria: Many patients present with episodes of recurrent macroscopic hematuria.
  • Eighty percent of these episodes are associated with upper respiratory tract infections, mainly acute pharyngotonsillitis. This synchronous association of pharyngitis and macroscopic hematuria has been dubbed synpharyngitic nephritis.
  • Gross hematuria usually appears simultaneously or within the first 48-72 hours after the infection begins; persists less than 3 days; and, in about a third of patients, is accompanied by loin pain, presumably due to renal capsular swelling.
  • Urine is usually brown rather than red, and clots are unusual.
  • The presenting illness of episodic, grossly visible hematuria is more common in younger people, whereas that of abnormal urine sediment is more frequent in older individuals.
  • Episodes of gross hematuria in IgA nephropathy have been associated with a variety of other infections.
    • Urinary tract infections
    • Pneumonia
    • Staphylococcal sepsis
    • Staphylococcal osteomyelitis
    • Acute gastroenteritis
    • Influenza
    • Infectious mononucleosis
  • Gross hematuria has also followed tonsillectomy, vaccinations, strenuous physical exercise, and trauma.
  • Between episodes of gross hematuria, many patients have persistent microhematuria, proteinuria, or both.
• It is rare for proteinuria to occur without microscopic hematuria in IgA nephropathy.
  • Mild proteinuria is common.
  • Nephrotic range proteinuria is uncommon, occurring in only 5% of patients with IgA nephropathy, and is more commonly seen in children and adolescents. Nephrotic range proteinuria can be seen at different stages of the disease, both in patients early in the disease course and in patients with advanced disease.
  • Patients with heavy proteinuria and nephrotic syndrome are likely to have IgA deposition with diffuse proliferative glomerular lesions or minimal-change light microscopic findings.
• Acute renal failure: Acute renal failure, with edema, hypertension, and oliguria, occurs in fewer than 5% of patients. It can develop from either of 2 distinct mechanisms.
  • Acute severe immune injury can manifest as necrotizing glomerulonephritis and crescent formation.
  • Alternatively, only mild glomerular injury is observed with gross hematuria, and renal failure is presumably due to tubular occlusion by RBCs. This is reversible, and renal function recovers with supportive measures.
• Hypertension: Hypertension seldom occurs at the time of initial presentation but more commonly manifests as the course of the disease lengthens or when patients develop chronic kidney disease and ESRD.
• Chronic renal failure: Chronic kidney disease (stage II and higher) seldom develops but is usually slowly progressive. Approximately 1-2% of all patients with IgA nephropathy develop ESRD each year.

Physical

A minority of patients have hypertension; otherwise, physical examination findings in patients with IgA nephropathy are usually unremarkable.

Causes

Most cases of IgA nephropathy are idiopathic, but the onset or exacerbation of the disease is often preceded by a respiratory tract infection. Association with some bacteria, such as Haemophilus parainfluenzae, has been reported. A variety of other disorders have also been linked with IgA nephropathy, as discussed below.

• Cirrhosis and other liver diseases
  • Glomerular IgA deposition is a common finding in cirrhosis, occurring in up to a third of patients. Liver disease is accompanied by impaired removal of IgA-containing complexes by the Kupffer cells, predisposing patients to IgA deposition in the kidney.
  • Glomerular IgA deposits are common in advanced liver disease, but most adults have no clinical signs of glomerular disease, whereas up to 30% of children may have asymptomatic hematuria or proteinuria. Those abnormalities usually resolve after successful liver transplantation.
• Gluten enteropathy (celiac disease)
  • Glomerular IgA deposition occurs in up to a third of patients with gluten enteropathy.
  • Most of these patients have no clinical manifestations of the disease. However, IgA nephropathy and gluten hypersensitivity are associated, and withdrawal of gluten from the diet of these patients has resulted in clinical and immunological improvement of the renal disease.
• HIV disease
  • IgA nephropathy has been reported in patients with HIV infection, both whites and blacks, despite the rarity of typical IgA nephropathy in the black population.
  • Clinically, patients have hematuria, proteinuria, and, possibly, renal insufficiency.
  • Histologically, findings range from mesangial proliferative glomerulonephritis to collapsing glomerulosclerosis with mesangial IgA deposits.
  • Several patients have circulating immune complexes containing IgA antibodies against viral proteins.
• Familial IgA nephropathy
  • While IgA nephropathy is usually a sporadic disease, data suggest that genetic factors are important in susceptibility to development of mesangial glomerulonephritis. Several cases of familial disease have been reported in Italy and the United States, and an autosomal dominant form has been linked to band 6q22-23.
  • Additionally, increased frequency of specific HLA groups has been reported in some patients.

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