IgA Nephropathy: commonest cause of kidney disease seen in young adults.

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?

Figure 1. Pathological Characteristics of 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
DOI: 10.1056/NEJMra1206793)

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.






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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

7 thoughts on “IgA Nephropathy: commonest cause of kidney disease seen in young adults.”

  1. Madam is anticoagulation with prophylactic dose of heparin indicated in pregnancy with nephrotic range proteinuria ? My second question is it’s said that the combination of methyl dopa(which stimulates brain stem alpha2 receptors)and labetolol (a combined alpha and beta blockers) shouldn’t be given in pregnancy as it can lead to sudden acute rise in blood pressure which can be fatal due to untowards alpha effects .What are these untowards alpha effects and what’s the mechanism of lifethreatening rise in BP due to the combination of these 2 drugs.I’ll wait for your reply .Thanks


  2. IgA nephropathy has nothing to do with alpha 1 or alpha 2 receptors.

    Methyldopa is both an alpha-2-agonist and an amino acid decarboxylase enzyme inhibitor that blocks the transformation of DOPA to DA and NE, causing a net decrease in central monoamine neurotransmitter levels.

    α2 agonists: inhibit adenylyl cyclase activity, reduce brainstem vasomotor center-mediated CNS activation. These drugs are used as antihypertensive agents and cause sedation & are used in the treatment of opiate dependence and alcohol withdrawal symptoms.

    The Effect of alpha 2 receptor blockade are: Common effects include: Suppression of release of norepinephrine (noradrenaline) by negative feedback.

    Transient hypertension (increase in blood pressure) caused by transient stimulation of the receptor before blockade cause this, followed by a sustained hypotension (decrease in blood pressure). This effect is seen if labetolol and methyldopa are given together at the start of treatment simultaneously as the blockade of the receptor by labetolol leaves the stimulation by methyldopa unencountered.
    I hope this makes sense.


  3. Thankyou Madam for explaining the interaction between these two drugs in detail.Yes it makes a lot of sense. My first question was regarding nephrotic syndrome diagnosed in early pregnancy. I’ll write the whole scenario tomorrow when I get time in OT. My children are teasing me a lot right now.Thanks again


  4. The risk of thromboembolism is highest in membranous glomerulonephritis. It is high if the proteinuria is higher than 3.5 gm and if the serum albumin is below 3 gm/dl. however the routine use of heparin is not recommended in all pregnancies. you must weigh the risk of bleeding against the risk of embolisation.


  5. Ok Madam. Have you received the scenario regarding pregnancy with nephrotic syndrome I sent you today.It was written on the screen there is some error in posting the comment.I just wanted to ask ,though its a rare condition but if I come across such a situation again should low molecular weight heparin in prophylactic dose be started at diagnosis. In my humble opinion if there is severe hypoalbuminemia and proteinuria of more than 3.5 g per 24 hrs it should be started.Saw one such case a few years back when I was in CMH Lahore. A patient who was a case of nephrotic syndrome had undergone c section at a private clinic and came to CMH in the postpartum period with widespread ileofemoral venous thrombosis.


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