IgA Nephropathy


Article Author:
Prashanth Rawla


Article Editor:
Faten Limaiem


Editors In Chief:
Linda Lindsay


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
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Radia Jamil
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Patrick Le
Anoosh Zafar Gondal
Saad Nazir
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Hussain Sajjad
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Heba Mahdy
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Daniyal Ameen
Altif Muneeb
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
6/26/2019 1:05:05 PM

Introduction

IgA nephropathy is one of the common forms of glomerulonephritis caused by the deposition of IgA type immunoglobulins in the glomerular basement membrane. Immune-mediated damage to the basement membrane results in hematuria and renal insufficiency.[1] Berger was the first to describe the disease, so it also carries the name Berger disease.

Etiology

IgA nephropathy is an autoimmune disease, causing antibody-mediated destruction of the glomerular basement membrane.[2] Usually, there is an infectious disease preceding the nephropathy which leads to the dysregulated immune response, but IgA nephropathy per se is not of an infectious etiology.

Epidemiology

Although IgA nephropathy is a very common disease, the data on prevalence is not very accurate because a renal biopsy is necessary to establish the diagnosis. Not all patients undergo a biopsy to confirm the diagnosis and instead receive conservative management. About 10% of the renal biopsies in the United States show IgA nephropathy. Forty percent of renal biopsies in Asia and 20% of renal biopsies in Europe show IgA nephropathy.[3] The high prevalence of is thought to be due to the early detection of hematuria during screening and aggressive treatment plans. The disease is common in children and young adults with a male predominance.[4]

Pathophysiology

Current understanding is that IgA nephropathy occurs as a result of a multi-hit mechanism.[5] First ‘hit’ is a genetically susceptible host who is predisposed to developing a dysregulated immune response. Next ‘hit’ is a precipitating factor producing the immunological attack. Infections are potential precipitants of IgA nephropathy.[2] Trivial mucosal infections, chronic exposure to pathogens and abnormal handling of commensals in the gut have all been hypothesized to trigger the abnormal immune response in IgA nephropathy.[2] The damage to basement membranes results in the ultrafiltration of larger molecules and produces hematuria. Pathophysiology of how some develop asymptomatic hematuria while some develop rapidly progressive glomerulonephritis culminating in renal failure is poorly understood.[6]

Histopathology

Histologically, IgA nephropathy is characterized by: 

  • Diffuse proliferation of mesangial cells and matrix 
  • Hypercellular or normal glomeruli with diffuse necrotizing crescentic glomerulonephritis
  • Mesangial involvement resembling focal and segmental glomerulosclerosis

History and Physical

In most patients with IgA nephropathy history and examination would be unremarkable. The most common complaint is gross hematuria. Acute renal failure may cause ankle edema, facial puffiness, and hypertension. Frothy urine may be present. History of upper respiratory tract infection such as pharyngitis may be present just before hematuria.[7] History of previous episodes of hematuria and proteinuria should be verified.

Physical examination should include checking for blood pressure and looking for signs of reduced renal function such as edema, ascites, and lung basal crepitations. IgA nephropathy may coexist with cirrhosis, liver diseases, and celiac disease. Relevant general examination and examination of the abdomen should be done to exclude these clinically.

Evaluation

Evaluation should start by establishing the diagnosis. The first investigation is urine analysis to look for microscopic hematuria. Presence of red cells and red cell casts indicate glomerular injury. Protein to creatinine ratio in urine or 24-hour urinary protein excretion is done to look for proteinuria. Serum creatinine and eGFR is done to quantify renal function. Confirmation of the diagnosis relies on renal biopsy. Light microscopy, electron microscopy, and immunofluorescence are used to study renal histology. Immunofluorescence demonstrating the deposit of IgA in the glomerular basement membrane is the gold standard for diagnosis. IgA nephropathy should be classified using the Oxford classification which can predict prognosis. The Oxford classification has its basis in a combination of histological, clinical and biomarker criteria. 

The Oxford classification relies on[8]:

  • Mesangial cellularity
  • Endocapillary proliferation
  • Segmental glomerulosclerosis
  • Tubular atrophy
  • Crescents assessed by a renal biopsy

Treatment / Management

Management is first confirming the diagnosis followed by a renal biopsy. Secondary causes of IgA nephropathy should be ruled out. Amount of proteinuria, eGFR, blood pressure, and histological appearance is important in formulating the management plan. Treatment aims to induce remission and prevent the development of complications.[9]

Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are used to manage proteinuria and lower the blood pressure. Salt intake is restricted to control blood pressure. Blood pressure target is 130/80 mmHg.[7]

Immunosuppression with steroids or steroid-sparing agents is started to reduce the rate of progression.[10] Steroids have the most benefit if there is heavy proteinuria. Various regimens of oral prednisolone and methylprednisolone are available.[11] If there are contraindications for steroids or if the risks of therapy outweigh the anticipated benefits of steroid therapy, steroid-sparing agents may are an option. Cyclophosphamide, azathioprine, and cyclosporine are potential steroid-sparing agents.[12][13]

For the few who progress to develop ESRD, renal transplantation is an option. There is still the risk of IgA nephropathy in the transplanted kidney. Treatment with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker may delay the progression of recurrent disease in allografts.[14]

The most important component of any management plan is regular follow-up monitoring blood pressure, proteinuria, hematuria, eGFR and ensure drug compliance.

Differential Diagnosis

The diagnosis is usually apparent clinically and can be easily confirmed by investigations. Lupus nephritis, nephrotic syndrome, membranoproliferative glomerulonephritis, and Henoch-Schonlein purpura are also possibilities for the differential diagnosis. Malignancies anywhere from the kidneys to the urethra, local trauma, urolithiasis, and even urinary tract infections can cause hematuria. The presentation of these conditions is very different; thus they rarely pose diagnostic difficulty.

Prognosis

Frequently IgA nephropathy takes a benign course.[8] Others gradually progress to end-stage renal disease (ESRD) with the frequency of ESRD increasing with age.[1] Prognosis is predictable to some extent based on the Oxford classification. Additionally, nephrotic range proteinuria, hypertension, high serum creatinine level, and widespread intestinal fibrosis of the kidneys on presentation indicates a poor prognosis.[4]

Complications

Although only a small percentage of patients diagnosed with IgA glomerulonephritis progress to ESRD, IgA glomerulonephritis remains a frequent cause of ESRD.[15]. Complications of renal failure such as hypertension, edema, anemia, heart failure, and pulmonary edema may arise as the disease worsens. Side effects and complications of steroid and steroid-sparing therapy are common. Increased risk of infections, hypertension, fluid retention, weight gain, diabetes mellitus, osteoporosis, and iatrogenic Cushing’s syndrome are the most frequent side effects of steroid therapy.[11] Immunosuppression, anaphylaxis, renal, and hepatotoxicity are complications of steroid-sparing agents.

Consultations

Nephrology

Pediatric Nephrology

Deterrence and Patient Education

A minor upper respiratory tract infection can trigger the disease in genetically susceptible patients.[2] Routine screening to identify the persons at risk is not feasible. Prophylactic tonsillectomy has no proven benefit, nor does early antibiotic therapy.[7] Therefore, there are virtually no preventive measures. Patients with other autoimmune diseases and a strong family history of IgA nephropathy are more likely to have the disease. Screening for hematuria can detect patients early in the disease progression while asymptomatic.

Patients should receive instruction about the disease, the possibility of ESRD needing renal transplantation, the side effects of steroid therapy, and the importance of follow up. Salt, protein, and saturated fat restriction is advised.

Enhancing Healthcare Team Outcomes

IgA nephropathy usually takes a protracted course during which the patient may undergo management by a diverse team of healthcare providers. Ideally, a nephrologist (or pediatric nephrologist) plays a vital role in the management of the patient. Coexisting autoimmune diseases may require management by a nurse practitioner, physician assistant, physician, endocrinologist, or gastroenterologist appropriately. The primary care team should in the loop about the diagnosis and steroid therapy. A “steroid card” should be given to the patients. The pharmacist should educate the patient regarding steroid therapy and promote compliance. Laboratory staff should ensure the correct sample collection to avoid false positives for proteinuria. A dietitian should plan on a low salt, low protein, low-fat diet. Fluid intake must be adjusted considering the fluid balance and renal function. If progression to ESRD is anticipated, this should be informed to the patient early in the course and planned for renal replacement therapy. A social worker would be a helpful member of the team at this stage. [Level V]


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IgA Nephropathy - Questions

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A 17-year-old otherwise healthy male presents complaining of pink urine while he was ill with a "chest cold" that resolved. He is found to have a blood pressure of 110/72 mmHg and a urinalysis with the following findings: 2+ protein, 15-20 RBC/HPF, and dysmorphic RBCs. What is his most likely diagnosis?



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What is the likely diagnosis in a 26-year-old otherwise healthy male who presents with pink urine while he was ill with a "chest cold" that resolved? His blood pressure is 115/78 and a urinalysis reveals 3+ protein, 12-20 RBC/HPF, and dysmorphic RBCs.



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What is the most common cause of acute glomerulonephritis in the United States?



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Which of the following investigations would be repeated routinely in a 14-year-old boy who is diagnosed with Henoch-Schonlein purpura (HSP)?



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A 27-year-old otherwise healthy male presents with pink colored urine while he was ill with a "chest cold" that resolved. His blood pressure is 110/68 mmHg, and urinalysis reveals 3+ protein, 12 to 20 RBC/HPF, and dysmorphic RBCs. The diagnosis of IgA nephropathy is being considered in this patient. Which of the following best predicts the prognosis of IgA nephropathy?



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A 35-year-old mother of 2 children aged two years and five years was diagnosed with renal failure due to IgA nephritis. She is worried about the risk of her daughters facing the same plight as her. What advice should be given to her regarding the risk for her daughters developing IgA nephritis?



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A 35-year-old male presents with a history of recurrent sinopulmonary infection since childhood. He also has a history of recurrent allergies. His family history is significant for his elder brother with similar complaints and he eventually was diagnosed with lymphoma. The patient is supposed to undergo an appendicectomy. The on-call surgeon wants to keep 2 units of blood products on hold for the surgery in case if he needs them. Which of the following is the most appropriate blood product to arrange for this patient?



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IgA Nephropathy - References

References

Shen PC,He LQ,Tang Y,Wang Q,Wang W,Li J, Clinicopathological characteristics and prognostic factors of asymptomatic IgA nephropathy. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2010 Mar;     [PubMed]
Rollino C,Vischini G,Coppo R, IgA nephropathy and infections. Journal of nephrology. 2016 Aug;     [PubMed]
Rodrigues JC,Haas M,Reich HN, IgA Nephropathy. Clinical journal of the American Society of Nephrology : CJASN. 2017 Apr 3;     [PubMed]
Soares MF,Roberts IS, IgA nephropathy: an update. Current opinion in nephrology and hypertension. 2017 May;     [PubMed]
Magistroni R,D'Agati VD,Appel GB,Kiryluk K, New developments in the genetics, pathogenesis, and therapy of IgA nephropathy. Kidney international. 2015 Nov;     [PubMed]
Appel GB,Waldman M, The IgA nephropathy treatment dilemma. Kidney international. 2006 Jun;     [PubMed]
Walsh M,Sar A,Lee D,Yilmaz S,Benediktsson H,Manns B,Hemmelgarn B, Histopathologic features aid in predicting risk for progression of IgA nephropathy. Clinical journal of the American Society of Nephrology : CJASN. 2010 Mar;     [PubMed]
Pozzi C, Treatment of IgA nephropathy. Journal of nephrology. 2016 Feb;     [PubMed]
Gharavi AG,Yan Y,Scolari F,Schena FP,Frasca GM,Ghiggeri GM,Cooper K,Amoroso A,Viola BF,Battini G,Caridi G,Canova C,Farhi A,Subramanian V,Nelson-Williams C,Woodford S,Julian BA,Wyatt RJ,Lifton RP, IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23. Nature genetics. 2000 Nov;     [PubMed]
Lv J,Xu D,Perkovic V,Ma X,Johnson DW,Woodward M,Levin A,Zhang H,Wang H, Corticosteroid therapy in IgA nephropathy. Journal of the American Society of Nephrology : JASN. 2012 Jun;     [PubMed]
Herlitz LC,Bomback AS,Stokes MB,Radhakrishnan J,D'Agati VD,Markowitz GS, IgA nephropathy with minimal change disease. Clinical journal of the American Society of Nephrology : CJASN. 2014 Jun 6;     [PubMed]
Suzuki H,Kiryluk K,Novak J,Moldoveanu Z,Herr AB,Renfrow MB,Wyatt RJ,Scolari F,Mestecky J,Gharavi AG,Julian BA, The pathophysiology of IgA nephropathy. Journal of the American Society of Nephrology : JASN. 2011 Oct;     [PubMed]
Coppo R, Treatment of IgA nephropathy: Recent advances and prospects. Nephrologie     [PubMed]
Lai KN,Leung JC,Tang SC, The Treatment of IgA Nephropathy. Kidney diseases (Basel, Switzerland). 2015 May;     [PubMed]
Courtney AE,McNamee PT,Nelson WE,Maxwell AP, Does angiotensin blockade influence graft outcome in renal transplant recipients with IgA nephropathy? Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2006 Dec;     [PubMed]

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