IgA Nephropathy

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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, 3]

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 is observed in almost all biopsies.


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Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.


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Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Although IgA nephropathy is a limited nonsystemic renal disease, many systemic diseases are sporadically associated with mesangial IgA deposition. Henoch-Schönlein purpura (HSP), a systemic illness, has been closely linked to IgA nephropathy. Other systemic diseases in which mesangial deposits of IgA are regularly observed include systemic lupus erythematosus, hepatitis, dermatitis herpetiformis, and ankylosing spondylitis.

Recent studies

In a retrospective study of 146 patients with IgA nephropathy, Walsh et al investigated the efficacy of using the histopathologic features of this condition as prognostic indicators for primary outcome (defined in the study as a composite of doubling of serum creatinine levels, end-stage renal disease, or death). Employing a median follow-up period of 5.8 years and using multivariable models adjusted for clinical characteristics, the authors determined that interstitial fibrosis, glomerular sclerosis, and crescent formation independently predicted adverse outcomes in the study's patients. They also noted that an increased risk for progressive IgA nephropathy arose from even a relatively small amount of interstitial fibrosis.[4]

Pathophysiology

The pathogenesis of IgA nephropathy remains incompletely understood.[5] 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.

Epidemiology

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.

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.

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.

Laboratory Studies

Procedures

Histologic Findings

Light microscopy

The most common light microscopy findings are focal or, more often, diffuse mesangial proliferation and extracellular matrix expansion (as seen in the image below). Morphology can range from normal to moderate or severe intracapillary or extracapillary proliferative lesions. While some patients have IgA deposits on immunofluorescence and little or no change by light microscopy, a few patients have segmental necrotizing lesions with crescent formation due to extensive disruption of the capillaries. Occasionally, patients have focal glomerular sclerosis indistinguishable from focal segmental glomerulosclerosis on light microscopy. A number of other findings can be observed in advanced disease, including interstitial fibrosis, tubular atrophy, and vascular sclerosis. These findings can be helpful prognostic tools in patients with IgA nephropathy.


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Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

Electron microscopy

Electron microscopy shows mesangial hypercellularity and increased mesangial matrix. The important finding is electron-dense deposits in the mesangium, such as those in the image below, but deposits in the subendothelial and subepithelial region of the glomerular capillary wall are found in a minority of patients, especially those with more severe disease.


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Electron microscopy showing large dark mesangial deposits.

Immunofluorescence

Immunofluorescence findings are the pathologic hallmark of this disease. IgA is deposited in a diffuse granular pattern in the mesangium (as seen in the image below) and occasionally in the capillary wall. Immunoglobulin G (IgG)4 may accompany IgA, and C3 is often present.


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Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Medical Care

IgA nephropathy is a common cause of glomerulonephritis. Although it is a benign disease in most patients, chronic renal failure and ESRD occur in about 20-40% of patients within 20 years of presentation. Currently, no cure exists for IgA nephropathy, but therapies that can delay the onset of need for dialysis and transplantation are available. Current recommendations include the following:

Surgical Care

Consultations

Patients should be seen by a nephrologist.

Diet

Medication Summary

Currently, no cure exists for IgA nephropathy. However, therapies that can delay the onset of need for dialysis and transplantation are available. Hypertension should be treated early and aggressively. ACE inhibitors are the antihypertensives of choice.

Benazepril (Lotensin)

Clinical Context:  Prevents conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. Also causes lower aldosterone secretion, thus reducing systemic and glomerular capillary pressure.

Class Summary

Comparative studies show ACE inhibitors are more effective than other antihypertensives (ie, beta blockers, calcium channel blockers) in reducing blood pressure and proteinuria, protecting renal function, and delaying onset of ESRD.

Losartan (Cozaar)

Clinical Context:  Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, do not affect the response to bradykinin, and are less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.

Class Summary

Reduce blood pressure and proteinuria, protect renal function, and delay onset of ESRD.

Prednisone (Sterapred)

Clinical Context:  Immunosuppressant for treating autoimmune disorders. Decreases inflammation by reducing capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Class Summary

Prednisone should be used in patients with nephrotic syndrome and minimal histologic findings. When treated with corticosteroids, patients with proteinuria and preserved renal function (ie, CrCl >70 mL/min) have shown significant delay of disease progression compared to patients not receiving corticosteroids.

Omega-3 polyunsaturated fatty acid (Fish oil)

Clinical Context:  May be of benefit by decreasing mediators of glomerular injury and decreasing platelet aggregation.

Class Summary

Orphan drug indicated for treatment of IgA nephropathy. Used in patients with proteinuria and decreased renal function.

Cyclophosphamide (Neosar, Cytoxan)

Clinical Context:  Cyclic polypeptide that suppresses some humoral activity. Chemically related to nitrogen mustards. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. Interaction of phosphoramide mustard with DNA considered cytotoxic.

When used in autoimmune diseases, mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.

In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T cell functions.

Class Summary

Cyclophosphamide is used in nonmalignant renal diseases for its immunosuppressive effects.

Prognosis

Author

Mona Brake, MD, Assistant Professor, Department of Internal Medicine, Kansas University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Douglas Somers, MD, Assistant Professor, Department of Internal Medicine, Division of Nephrology, University of Iowa Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

James H Sondheimer, MD, FACP, Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director of Hemodialysis, Harper University Hospital at Detroit Medical Center; Medical Director, DaVita Greenview Dialysis (Southfield)

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Christie P Thomas, MBBS, FRCP, FASN, FAHA, Professor, Department of Internal Medicine, Division of Nephrology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Disclosure: Nothing to disclose.

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine

Disclosure: Renal Ventures Ownership interest Other

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System

Disclosure: Nothing to disclose.

Additional Contributors

The authors thank Dr. Tim Timmerman, pathologist, for his invaluable help with the pathology slides.

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Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

Electron microscopy showing large dark mesangial deposits.

Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

Electron microscopy showing large dark mesangial deposits.

Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.