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. 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 Schonlein 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 sen in the following conditions:
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. 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.
The current understanding is that IgA nephropathy occurs as a result of a multi-hit mechanism. 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. 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 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.
Histologically, IgA nephropathy is characterized by:
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. 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:
Management is 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 the 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 started 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 are 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 blood pressure, proteinuria, hematuria, eGFR and ensure drug compliance. Corticosteroids should not be used for more than 6 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-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.
Frequently IgA nephropathy takes 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 ESRF within 10 years. Today the Mest score is often used to predict the outcome. The score includes the following features:
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.
A low antigenic 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 infection.
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.
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 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 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. 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]
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