Introduction

IgA nephropathy, also known as Berger disease, is the most common primary glomerulonephritis and the most prevalent chronic glomerular disease in the world. It was first described morphologically by Dr. Jean Berger (nephrologist) and Nicole Hinglais (microscopist) in 1968 by electron microscopy. Later, immunofluorescence microscopy was used to show more specific findings associated with the disease, such as deposits of IgA in the mesangial matrix and its subsequent proliferation, types of immunoglobulins, and complement. The hallmark of the disease is the deposition of IgA in the glomerular mesangium, causing progressive kidney disease in a majority of patients. Because gross hematuria often follows an episode of upper tract respiratory infection, IgA nephropathy is also called synpharyngitic glomerulonephritis. Other names used are IgA nephritis, IgA-IgG nephropathy, nephropathy with mesangial IgA, and IgG deposits. Major clinical risk factors for progression are hypertension, proteinuria, and reduced GFR; whereas, microscopic hematuria is not a significant risk factor for the progressive loss of renal function. The Oxford classification involves scoring based histologic findings, including mesangial hypercellularity, endocapillary proliferation, segmental glomerulosclerosis, tubular atrophy, or interstitial fibrosis.[1][2][3]

Etiology

It is hypothesized that mucosal infection is the culprit of the disease as most patients develop gross hematuria from IgA nephropathy after upper respiratory tract infections, specifically pharyngitis (synpharyngitic). However, most cases of IgA nephropathy are idiopathic. IgA is mainly produced at mucosal surfaces, and its main role is mucosal defense. After the mucosal injury, the IgA1 monomer undergoes a conformational change of its molecule and thus provides the substrate for antigen-antibody formation in susceptible individuals. Galactose-deficient IgA1 is synthesized as a consequence of the mucosal response to various antigens triggered by infections. Circulating immune complexes made from poorly galactosylated IgA1 bind to the mesangial cell plasma membrane, causing proliferation of the mesangial cells with the result of podocyte injury and loss of renal function.[2][4][5]

Epidemiology

IgA nephropathy is the most common glomerulonephritis worldwide and can occur at any age. The peak age of onset is in the second and third decades. Review of cohort studies reports 0.2 to 2.9 per 100,000 annual incidence of IgA nephropathy. The disease is more common in Asia and Australia than in other parts of the world. This may be because some Asian countries enforce routine screening with urinalysis, prompting earlier diagnosis. Among the North American and Western European populations, there is 2:1 male to female ratio. IgA nephropathy is rare in all African populations throughout the world.

Pathophysiology

The main processes leading to the pathogenesis of IgA nephropathy are increased production of IgA1, defective galactosylation of IgA1, binding of antibodies against the galactose-deficient IgA1 with an accumulation of immune complexes in the mesangium, and activation of the mesangial cells. Patients with IgA nephropathy have excess deposits of galactose-deficient IgA1 in their serum and glomerular mesangium. The galactose-deficient immunoglobulin A1 has less galactose in the hinge region of the heavy chains and, subsequently, is recognized as a neo-antigen, triggering the formation of autoantibodies and circulating immune complexes that accumulate in the mesangial cells. This mesangial deposition causes the release of pro-inflammatory and pro-fibrotic mediators and results in mesangial proliferation, extracellular matrix synthesis, and podocyte damage. These mesangial-induced mediators are also filtered in the urine and activate proximal tubular epithelial cells, causing tubulointerstitial scarring.[5]

Histopathology

Light microscopy findings can range from normal to mesangial proliferation, endocapillary proliferation, focal or segmental necrosis, or crescents in Bowman’s space. However, the most common abnormality is mesangial hypercellularity. Because the light microscopy findings are non-specific, electron and immunofluorescent microscopy are required to confirm the diagnosis of IgA nephropathy by identifying the immune deposits, immunoglobulins (IgA, IgG, IgM), and complements (C3 being the most commonly found) associated with the disease. The immune deposits are most commonly located in the mesangial and paramesangial areas, but can also be observed in the subepithelial and subendothelial areas of the glomerular basement membrane.

History and Physical

Most patients present with asymptomatic microscopic hematuria or proteinuria that can be present for many years. Hypertension is initially found in a minority of patients but becomes common as the disease progresses to chronic kidney disease or end-stage renal disease. IgA nephropathy can present with gross hematuria, nephrotic syndrome, and chronic kidney disease and can escalate to rapidly progressive glomerulonephritis. Episodic gross hematuria is commonly seen in children and young adults after upper respiratory tract infection. Synpharingitic macroscopic hematuria is a classic initial presentation of IgA nephropathy.

Evaluation

Evaluation involves urinalysis and renal biopsy. The urinalysis demonstrates hematuria, dysmorphic red blood cells, and proteinuria. Renal biopsy and immunohistologic examination confirm the diagnosis. Light microscopy can show focal or diffuse mesangial proliferation and increased mesangial matrix and cellularity. In advanced disease, interstitial fibrosis with tubular atrophy can be found. Electron microscopy shows the electron-dense deposits of IgA in the mesangium. Immunofluorescence microscopy shows the types of immunoglobulins deposits (mainly IgA, but also IgG and IgM) in the mesangium and capillary walls. C3  and C4 are commonly detected with C4d, indicating a poor prognosis with progression to end-stage renal disease. The Serum IgA level is of no clinical utility.[6][7][8]

Treatment / Management

Treatment options are patient-dependent based on clinical findings and disease evolution. Conservative therapy with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to slow proteinuria is recommended in all patients. If no response, a trial of corticosteroids can be started for 3 to 6 months. Immunosuppressants (mycophenolate, azathioprine, cyclophosphamide) are reserved for patients with progressive crescentic IgA nephropathy and avoided if the biopsy shows advanced interstitial fibrosis or tubular atrophy. Aggressive treatment of blood pressure with the goal of blood pressure of less than 130/80 mm Hg is highly encouraged. Although rituximab is used in many other glomerular diseases, it did not show beneficial effects on renal function or proteinuria of patients with IgA nephropathy. Tonsillectomy is not supported by current Kidney Disease Improvement Global Outcomes guidelines. Diet should consist of adequate protein and avoidance of increased salt intake. Fish oil therapy did not show a delay in disease progression and is not supported by current treatment guidelines. Renal transplantation is the preferred treatment for patients who require renal replacement therapy, but the IgA nephropathy recurrence rate is high after transplantation.[9][10][2]

The role of tonsillectomy to remove the production of degalactosylated IgA remains controversial. Some studies do show that tonsillectomy slows down the progression of IgA nephropathy. However, the current consensus is that the procedure should be reserved for patients with tonsillar infections.

Differential Diagnosis

• Henoch-Schonlein purpura
• Thin glomerular basement membrane disease
• Alport syndrome
• Lupus nephritis
• Membranoproliferative glomerulonephritis
• Benign familial hematuria
• Acute postinfectious glomerulonephritis

Pertinent Studies and Ongoing Trials

KIDGO recommendations

1. Long term therapy with ACE inhibitors or ARBs is recommended in patients with proteinuria (more than 0.5-1g per day)
2. Manage blood pressure
3. Corticosteroids for 6 months in patients with persistent proteinuria (more than 1 g/day) despite optimal blood pressure control
4. Fish oil may be an option for patients with proteinuria who have not responded to blood pressure control

Prognosis

Risk factors for disease progression include clinical factors such as hypertension, reduced glomerular filtration rate at the time of renal biopsy, or persistent proteinuria on follow-up) and pathological risk factors as based on the Oxford classification. According to Oxford classification, the following parameters provide prognostic information: mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, and tubular atrophy. Poor prognosis is associated with a glomerular filtration rate of less than 60 mL per minute, proteinuria greater than 0.5 g per day, hypertension greater than 140/90 mm Hg, more than 50% glomeruli affected by mesangial hypercellularity. Other prognostic histologic factors indicative of progression to end-stage renal disease are the presence of segmental glomerulosclerosis, interstitial fibrosis, and endocapillary proliferation. It is estimated that about half of all patients eventually develop end-stage renal disease within 20 years after diagnosis. IgA nephropathy is the main cause of end-stage renal disease secondary to primary glomerular disease.

Complications

• Progressive glomerulonephritis
• Nephrotic syndrome
• Chronic renal failure
• End-stage renal disease

Consultations

Nephrologist

Pediatrician

Pearls and Other Issues

Many diseases have IgA glomerular deposition but do not have the clinical findings of the IgA nephropathy. Some of the conditions that have secondary causes of mesangial IgA deposition include liver diseases (alcoholic, cryptogenic or primary biliary cirrhosis), inflammatory bowel disease (ulcerative colitis, Crohn disease), infections (HIV, leprosy, tuberculosis), skin disorders (psoriasis, dermatitis herpetiformis), malignancy (lung, pancreas, larynx), sarcoidosis, cystic fibrosis, among others.

Enhancing Healthcare Team Outcomes

Even though IgA nephropathy is a benign disorder, it does worsen in about 20% of patients leading to end-stage renal failure, which may require dialysis or renal transplant. Today, the goal is to prevent the condition from worsening because end-stage renal disease is not only associated with its serious complications but leads to a significant increase in healthcare costs.

Thus, an interprofessional team approach is being used to manage and monitor IgA nephropathy from progressing. Besides the nephrologist and pediatrician, the nurse and pharmacist play a critical role in patient education. The patient must be educated about the importance of blood pressure control and compliance with antihypertensive medications. Patients must be taught how to monitor their blood pressure regularly and see a clinician if it is uncontrolled. At all times, the nephrologist must be informed of any decision making so that the goals of the treatment remain unchanged.

A dietitian should educate the patient on a low salt diet and eating foods that are low in fat and carbohydrates. The patient should be encouraged to join a rehab program and maintain a healthy body weight. Finally, smoking cessation is vital to prevent the progression of the disease. Those patients managed with corticosteroids must be monitored for side effects. Only through such an approach can be morbidity of the disease be lowered.[11] [Level 5]

Outcomes

In the majority of patients, Berger disease has a benign course, but about 10-20% will develop end-stage renal failure within ten years. Predictors of poor outcomes include hypertension, ongoing proteinuria, high serum creatinine, and CD4 staining on biopsy.[5] [Level 5]