Case 1. A 19 year old college student developed severe sore throat along with fever, dry cough and breathlessness. He saw his doctor three days later. His temperature was 38.6 degrees C, blood pressure was 160/105 mmHg, the throat was congested but there were no pus points in the throat. He had rhonchi in his chest but no crepitations. There was no rash, arthralgia, urticaria. He said that his urine was red in colour. The rest of the examination was unremarkable. His white cell count was raised to 15000/mm squared. The Hb and PCV were normal and there was no eosinophilia. His urine showed ++ proteinuria, macroscopic hematuria which persisted in subsequent samples. His creatinine was 1.6 mg/dl, blood sugars were normal. Creatinine clearance was 28 ml/min. The 24 hour urinary proteins were 1.8 gm/L/1.73 square metre of body surface. Serum proteins were 4.2 gm/dl. His doctor arranged for a renal biopsy.
Case 2. A 34 year old man had been suffering from frequent upper respiratory tract infections in the past year. He developed severe bloody diarrhoea for 4 days and recovered with the administration of a quinolone antibiotic. He decided to see his doctor for a general medical check up. The significant finding was a blood pressure of 180/95 mmHg. He had no evidence of heart failure and neither of his kidneys was palpable. He had no edema, was not anemic, did not have a rash or urticaria, nor arthralgia or Raynaud’s phenomenon. Lymph nodes liver and spleen were not enlarged. He was not diabetic, did not have a history of chest pain on exertion and was still jogging for 2 kilometers daily. His urine showed proteinuria and microscopic hematuria. His serum creatinine was 1.9mg/dl. His 24 hour urinary proteins were 2.1 gm/L/1.73 sq m of body surface. Creatinine clearance was 35 ml/min. Serum proteins were 3 gm/L. The rest of the lab investigations were unremarkable.
What are they both likely to have? IgA nephropathy.
About 75% of children and young adults with IgA nephropathy present with macroscopic hematuria during an upper respiratory or gastrointestinal illness. Evidence of acute kidney injury may be present. Older adults usually present with proteinuria, microscopic hematuria, or hypertension, alone or in combination. Case 1 has the nephropathy with macroscopic hematuria following an upper respiratory infection. Case 2 has a GI infection which seems to be the trigger but the hematuria is microscopic in nature and he does not notice any urinary changes. He could have presented with the hypertension and microscopic hematuria without the GI infection. The nephrotic syndrome is uncommon at presentation, except in patients with the pathological features of minimal-change disease on kidney biopsy.
What is IgA nephropathy?
- Panel A (periodic acid–Schiff stain) shows mesangial hypercellularity, with four or more cells per mesangial area (arrow).
- Panel B (periodic acid–Schiff stain) shows segmental endocapillary proliferation with occlusion of the capillary lumen (arrow).
- Panel C (periodic acid–Schiff stain) shows segmental glomerulosclerosis and adhesion, with focal accumulation of hyaline and obliteration of the capillary lumen (arrow).
- Panel D (trichrome stain) shows tubular atrophy and interstitial fibrosis, with severe interstitial scarring and loss of tubules (arrow).
- Panel E (periodic acid–Schiff stain) shows a glomerular crescent; a circumferential layer of epithelial cells surrounds the glomerular tuft (arrow).
- Panel F (immunofluorescence stain with fluorescein-conjugated anti-IgA antibodies) shows diffuse mesangial staining for IgA (arrow).
- In Panel G, an electron micrograph of a glomerular capillary tuft in a specimen fixed in osmium tetroxide shows electron-dense material in the mesangial area (arrow), a finding that is consistent with the accumulation of immune complexes.
(Taken from June 20, 2013
N Engl J Med 2013; 368:2402-2414
The diagnostic hallmark of IgA nephropathy is the predominance of IgA deposits, either alone or with IgG, IgM, or both, in the glomerular mesangium. The mesangial IgA is exclusively of the IgA1 subclass and is deficient in galactose, a biochemical feature of central importance in the pathogenesis of IgA nephropathy.
Complement C3 and properdin are almost always present. C4 or C4d, mannose-binding lectin,and terminal complement complex (C5b–C9) are frequently detected, whereas C1q is usually absent
The features of IgA nephropathy on light microscopy may vary greatly among patients and within the individual biopsy sample. An increase in mesangial matrix and hypercellularity are common; other glomerular lesions may include focal necrosis (affecting a minority of glomeruli), segmental scarring (affecting only a portion of a glomerulus), and crescents in Bowman’s space.
Electron microscopy usually shows electron-dense material corresponding to immune deposits on immunofluorescence microscopy. These are generally observed in mesangial and paramesangial areas but are occasionally present in subepithelial and subendothelial portions of glomerular basement membranes.
Renal histologic features of Henoch–Schönlein purpura nephritis are strikingly similar to those of IgA nephropathy. The diagnosis of Henoch–Schönlein purpura nephritis rests on the concurrent presence of palpable purpura due to leukocytoclastic vasculitis with IgA in the walls of dermal capillaries.
IgA nephropathy appears to be a systemic disease in which the kidneys are damaged as innocent bystanders, because IgA nephropathy frequently recurs after transplantation. Conversely, IgA glomerular deposits in a kidney from a donor with subclinical IgA nephropathy were reported to clear within weeks after engraftment in a patient with a different kidney disease. Of primary importance is the glycosylation pattern of IgA1. In IgA nephropathy, an increased fraction of circulatory IgA1 has a galactose deficiency in some carbohydrate side chains (O-glycans) that are attached to the hinge-region segment of the heavy chain. As a consequence of the galactose deficiency, N-acetylgalactosamine in truncated IgA1 hinge-region glycans is exposed. Recognition of this IgA1 hinge-region neoepitope by naturally occurring IgG or IgA1 antibodies leads to the formation of immune complexes in the circulation or perhaps in situ after glomerular deposition of galactose-deficient IgA1
Do genes affect IgA nephropathy?
Genetic factors undoubtedly influence the pathogenesis of IgA nephropathy. About 5% of patients with IgA nephropathy have a relative with biopsy-confirmed IgA nephropathy, microscopic hematuria, or proteinuria. The mode of inheritance is usually autosomal dominant with incomplete penetrance, suggesting a major gene with a large effect.
The serum level of galactose-deficient IgA1 is a heritable trait in diverse racial or ethnic groups. About 75% of patients with IgA nephropathy have a serum galactose-deficient IgA1 level above the 90th percentile for healthy controls; moreover, about 30 to 40% of first-degree relatives have similarly high levels. A study involving Han Chinese and Europeans identified five susceptibility loci: three on chromosome 6p21 in the MHC, one on chromosome 1q32 in the cluster of genes encoding complement factor H (CFH), and one on chromosome 22q12.
Common genetic variants influence the risk of IgA nephropathy across ethnically diverse populations and implicate adaptive immunity in the pathogenesis.
Biomarkers for IgA nephropathy.
Although the serum level of galactose-deficient IgA1 is frequently elevated in patients with IgA nephropathy, the sensitivity and specificity of this laboratory finding are insufficient for the test to replace kidney biopsy as the diagnostic standard. The serum level of glycan-specific IgG antibodies is correlated with the level of urinary protein excretion and the risk of progression to end-stage renal disease (ESRD) or death. This biomarker may prove useful for monitoring disease progression or the response to therapy.
Many urinary markers like epidermal growth factors, podocytes, mannose binding lectins, are available for differentiating this disease from other kidney diseases and for prognosis but are not sufficiently specific for generalized clinical use in making a definite diagnosis.
How prevalent is IgA nephropathy?
The prevalence of IgA nephropathy relative to other glomerular diseases is generally inferred from the proportion of cases in biopsy series, but the true prevalence of IgA nephropathy is unknown because diagnosis requires kidney biopsy. The prevalence of clinically silent IgA nephropathy may be surprisingly high; in a Japanese study, 16% of donor kidneys had glomerular IgA deposits and nearly 2% exhibited mesangioproliferative changes with C3 deposits characteristic of IgA nephropathy.
What is going to be the clinical outcome?
The likelihood of dialysis or death was recently estimated with the use of three risk factors that are documented at biopsy:
- urinary protein excretion of more than 1 g per day,
- hypertension (>140/90 mm Hg), and
- severe histologic lesions on the basis of glomerular, vascular, tubular, and interstitial features.
The 20-year predicted survival without the need for dialysis was 96% among patients with no risk factors versus 36% among those with three factors. The 10-year renal survival rate is about 90% among adults and children with normal renal function at diagnosis.
An impaired GFR, sustained hypertension, and substantial proteinuria independently predict a poor clinical course. In the Oxford classification three histologic features showed an independent value for predicting the outcome of renal function, even after clinical indicators at the time of biopsy and during follow-up observation were taken into account:
- mesangial hypercellularity
- segmental glomerulosclerosis or adhesion
- tubular atrophy and interstitial fibrosis
- A fourth histologic feature, endocapillary proliferation, showed an interaction with glucocorticoid or immunosuppressive therapy that suggested benefit from treatment
How should IgA nephropathy be treated?
Despite a better understanding of pathogenic mechanisms, there is no disease-targeted treatment for IgA nephropathy.
Control proteinuria and blood pressure by suppression of angiotensin II with an ACE inhibitor or angiotensin II–receptor blocker (ARB). The target systolic blood pressure is less than 130 mm with urinary protein excretion of less than 1 g per day but less than 125 mm Hg when the initial urinary protein excretion is more than 1 g per day.
Intensive immunosuppression (glucocorticoids with cyclophosphamide or azathioprine) is reserved for patients with crescents in more than half the glomeruli and a rapid decline in renal function.
The KDIGO guidelines do not support the use of mycophenolate mofetil or antiplatelet drugs.
Tonsillectomy has been recommended by some centers, particularly in Japan, but this approach was not included in the KDIGO guidelines because of the lack of data from randomized, controlled trials.
Patients presenting with mild disease (normal blood pressure, normal estimated GFR, and a urinary protein-to-creatinine ratio consistently <0.20) do not require treatment.
IgA nephropathy is a common glomerular disease and an important cause of kidney failure. Because of the critical interaction between an intrinsic antigen (galactose-deficient IgA1) and circulating anti-glycan antibodies, IgA nephropathy can be considered an autoimmune disease.