Berger Disease


Article Author:
Naimeh Tashakkorinia


Article Editor:
Maria Tudor


Editors In Chief:
Mohamed Alhajjaj
Fatima Anjum
Pramil Cheriyath


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
11/14/2018 7:20:02 AM

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 the IgA in the mesangial matrix and its subsequent proliferation, types of immunoglobulins, and complement. The hallmark of the disease is 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 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 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 auto-antibodies 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 seen commonly 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 IgA1, but also IgG and IgM) in mesangium and capillary walls. C3  and C4 are commonly detected with C4d indicating a poor prognosis with progression to end-stage renal disease. 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 IgA nephropathy recurrence rate is high after transplantation.[9][10][2]

Differential Diagnosis

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

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 the end-stage renal disease within 20 years after diagnosis. In fact, 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's 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. Today, the focus on management is to prevent the kidney disease 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. 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 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 V)

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 V)


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Berger Disease - Questions

Take a quiz of the questions on this article.

Take Quiz
Which antibody is involved in Berger disease?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
How do the majority of individual who have Berger disease present?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is used to decrease proteinuria in a patient with Berger disease?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A young otherwise healthy male presents complaining of pink urine that recently occurred while he was ill with a "chest cold" and has since resolved. His blood pressure is 110/72 mmHg and a urinalysis demonstrated the following: 2+ protein, 15-20 RBC/HPF, and dysmorphic RBCs. What is the most likely diagnosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What statement is correct regarding renal biopsy in IgA nephropathy



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 23-year-old male presents with recurrent gross hematuria after upper respiratory infection, persistent proteinuria, and hypertension. What finding on light microscopy of his renal biopsy is consistent with the diagnosis of IgA nephropathy on light microscopy?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the most common clinical course in IgA nephropathy?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 53-year-old male with history of IgA nephropathy diagnosed at age 22 presents for follow up. He has been previously treated with methylprednisolone, azathioprine, and mycophenolate mofetil. His creatinine in 2.6 mg/dl and 24-hour urine protein 1.8 grams. He undergoes a new renal biopsy for evaluation of disease progression which shows diffuse glomerulosclerosis and tubulointerstitial atrophy. What is the best treatment option?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 27-year-old male presents with recurrent gross hematuria after an upper respiratory infection. His BMI is 29, blood pressure 165/97 mmHg, heart rate 72 bpm, and oxygen saturation 98% on room air. Physical exam is unremarkable. Laboratory data shows normal electrolytes, serum protein 6.1 g/dL, albumin 3 g/dL, liver enzymes in normal ranges, serum creatinine 1.4 mg/dl, 24-hour urine protein 1.3 g. His renal biopsy demonstrated increased mesangial matrix and hypercellularity on light microscopy and large mesangial IgA deposits on immunofluorescence microscopy consistent with diagnosis of IgA nephropathy. What finding at the time of diagnosis is not considered a risk factor for poor prognosis?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which is true about IgA nephropathy?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Berger Disease - References

References

Sethi S,Fervenza FC, Standardized classification and reporting of glomerulonephritis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2018 Aug 13     [PubMed]
Bollin R,Haller H, [Pathophysiology and treatment of IgA nephropathy]. Der Internist. 2018 Jul     [PubMed]
Lafayette RA,Kelepouris E, Immunoglobulin A Nephropathy: Advances in Understanding of Pathogenesis and Treatment. American journal of nephrology. 2018     [PubMed]
Saha MK,Julian BA,Novak J,Rizk DV, Secondary IgA nephropathy. Kidney international. 2018 May 24     [PubMed]
Penfold RS,Prendecki M,McAdoo S,Tam FW, Primary IgA nephropathy: current challenges and future prospects. International journal of nephrology and renovascular disease. 2018     [PubMed]
Agrawal V,Singh A,Kaul A,Verma R,Jain M,Pandey R, Utility of Oxford Classification in Post-Transplant Immunoglobulin A Nephropathy. Transplantation proceedings. 2017 Dec     [PubMed]
Lin J,Cheng Z,Qian Q, Elderly patients with glomerular diseases and IgA nephropathy. Nephrology (Carlton, Vic.). 2017 Dec     [PubMed]
Barbour S,Feehally J, An update on the treatment of IgA nephropathy. Current opinion in nephrology and hypertension. 2017 Jul     [PubMed]
Di Genova L,Ceppi S,Stefanelli M,Esposito S, IgA Deficiency and Nephrotic Syndrome in Children. International journal of environmental research and public health. 2018 Aug 9     [PubMed]
Locatelli F,Del Vecchio L,Ponticelli C, Should we really STOP treating patients with IgA nephropathy with steroids? Physiology international. 2018 Jun 1     [PubMed]
Salvadori M,Rosso G, Update on immunoglobulin a nephropathy. Part II: Clinical, diagnostic and therapeutical aspects. World journal of nephrology. 2016 Jan 6     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Pulmonary. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Pulmonary, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Pulmonary, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Pulmonary. When it is time for the Pulmonary board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Pulmonary.