Continuing Education Activity
IgA nephropathy is a common form of glomerulonephritis caused by the deposition of IgA immunoglobulins in the glomerular basement membrane. Immune-mediated damage to the basement membrane results in hematuria and renal insufficiency. This activity reviews the etiology, pathogenesis, evaluation, and management of IgA nephropathy and explains the role of the interprofessional team in evaluating and treating patients with this condition.
- Identify the epidemiology of IgA nephropathy.
- Describe the evaluation of IgA nephropathy.
- Summarize the treatment and management options available for IgA nephropathy.
- Explain interprofessional team strategies for improving care coordination and communication to improve outcomes for patients affected by IgA nephropathy.
IgA nephropathy is one of the common forms of glomerulonephritis caused by the deposition of IgA immunoglobulin in the glomerular basement membrane. Immune-mediated damage to the basement membrane results in hematuria and renal insufficiency. Berger was the first to describe the disease, so it also carries the name Berger disease.
The key feature of IgA nephropathy is mesangial proliferation with significant IgG deposition in the kidney. While primary IgA nephropathy is a limited disorder, it can also be associated with Henoch Schönlein purpura, lupus, dermatitis herpetiformis, and hepatitis.
IgA nephropathy is an autoimmune disease, causing antibody-mediated destruction of the glomerular basement membrane. 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.
IgA nephropathy may also be seen in the following conditions:
- Celiac disease
- Hepatitis, cirrhosis
Although IgA nephropathy is a 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. The high prevalence 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.
The current understanding is that IgA nephropathy occurs as a result of a multi-hit mechanism. The first ‘hit’ is a genetically susceptible host who is predisposed to developing a dysregulated immune response. The next ‘hit’ is a precipitating factor producing the immunological attack. Infections are potential precipitants of IgA nephropathy. 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. The damage to the basement membrane results in the ultrafiltration of larger molecules and produces hematuria. The pathophysiology of how some develop asymptomatic hematuria while some develop rapidly progressive glomerulonephritis, culminating in renal failure, is poorly understood.
Histologically, IgA nephropathy is characterized by:
- The diffuse proliferation of mesangial cells and matrix
- Hypercellular or normal glomeruli with diffuse necrotizing crescentic glomerulonephritis
- Mesangial involvement resembling focal and segmental glomerulosclerosis
- Immunofluorescence will reveal a diffuse granular pattern of IgA deposits in the mesangium. Staining with C4d indicates a poor prognosis.
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 infections such as pharyngitis may be present just before hematuria. 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 should start by establishing the diagnosis. The first investigation is urine analysis to look for microscopic hematuria. The presence of red cells and red cell casts indicate a 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:
- Mesangial cellularity
- Endocapillary proliferation
- Segmental glomerulosclerosis
- Tubular atrophy
- Crescents assessed by a renal biopsy
Treatment / Management
The management of IgA nephropathy involves first confirming the diagnosis, followed by a renal biopsy. Secondary causes of IgA nephropathy should be ruled out. The 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.
Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are used to manage proteinuria and lower blood pressure. Salt intake is restricted to control blood pressure. The blood pressure target is 130/80 mmHg.
Immunosuppression with steroids or steroid-sparing agents is used to reduce the rate of progression. Steroids have the most benefit if there is heavy proteinuria. Various regimens of oral prednisolone and methylprednisolone are available. If there are contraindications for steroids or if the risks of therapy outweigh the anticipated benefits of steroid therapy, steroid-sparing agents may be an option. Cyclophosphamide, azathioprine, and cyclosporine are potential steroid-sparing agents.
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.
The most important component of any management plan is regular follow-up monitoring of blood pressure, proteinuria, hematuria, eGFR, and drug compliance. Corticosteroids should not be used for more than six months because of serious adverse effects.
The diagnosis is usually apparent clinically and can be easily confirmed by investigations. Lupus nephritis, nephrotic syndrome, membranoproliferative glomerulonephritis, and Henoch-Schönlein 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.
Frequently IgA nephropathy has a benign course. Others gradually progress to end-stage renal disease (ESRD), with the frequency of ESRD increasing with age. 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.
About 20% of patients will progress to end-stage renal failure within ten years. Currently, the MEST-C score is often used to predict the outcome. The score includes the following features:
- M: Mesangial cellularity defined as greater than 4 mesangial cells in any mesangial segment of the glomerulus
- E: Endocapillary proliferation is the degree of hypercellularity
- S: Segmental glomerulosclerosis is defined as sclerosis or adhesions in the glomerular tuft
- T: Tubular atrophy or interstitial fibrosis
- C: Presence or absence of crescents
In general, if any of the above features are seen, then the prognosis is poor. Other factors that determine outcomes include elevated creatinine, hypertension, or need for antihypertensive treatment, presence of proteinuria, significant interstitial fibrosis, and CD4 staining.
Although only a small percentage of patients diagnosed with IgA glomerulonephritis progress to ESRD, IgA glomerulonephritis remains a frequent cause of ESRD.. 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. Immunosuppression, anaphylaxis, renal, and hepatotoxicity are complications of steroid-sparing agents.
Postoperative and Rehabilitation Care
A low antigen diet with limitations in gluten, meat, and dairy products is recommended. Some studies indicate that low protein diets may slow down the deterioration of renal function. The role of tonsillectomy remains controversial. Some experts believe that removing the tonsils may restrict the production of IgA. In the USA, tonsillectomy is only recommended for patients with tonsillar infections.
Deterrence and Patient Education
A minor upper respiratory tract infection can trigger the disease in genetically susceptible patients. Routine screening to identify the persons at risk is not feasible. Prophylactic tonsillectomy has no proven benefit, nor does early antibiotic therapy. 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 has 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. The primary care team should be continuously updated about 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 with communication as necessary to the clinical team. Laboratory staff should ensure the correct sample collection to avoid false positives for proteinuria. A dietitian should plan a low salt, low protein, and low-fat diet for the patient.
Fluid intake must be adjusted considering the fluid balance and renal function. If progression to ESRD is anticipated, the patient should be informed early in the course and be prepared for renal replacement therapy. A social worker would be a helpful member of the team at this stage. Due to the complexity of this disease, an interprofessional team of clinicians, pharmacists, nurses, and allied health professionals educating and assisting the patient and family will result in the best outcomes. [Level V]