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IgA NEPHROPATHY

IgA nephropathy is the commonest primary glomerular disease. It is seen in about 10 percent of all renal biopsies performed for primary glomerular disease in North America, 20% in Europe, and as high as 30 to 40% in the Asian Pacific area. This may reflect regional differences in the indications for renal biopsy rather than a true difference in geographic incidence. Genetic influence as well as environmental factors may also contribute.

It is most common in the second and third decade, However all ages may be affected. Males are more commonly affected (2:1).

Can be viewed as a monosymptomatic form of Henoch Schonlein purpura

CLINICAL PICTURE:

Microscopic or macroscopic hematuria is the commonest manifestation. May follow quickly upon some nonspecific virus-like syndrome or intercurrent infection (e.g. synpharyngitic nephritis)

It may be precipitated by upper respiratory tract infection. Proteinuria (usually less than 1 gm per 24 hour).

Blood pressure is usually normal.

Dysuria may be a prominent complaint

Progressive renal failure may occur. Renal function is usually normal. Slowly progressive fall in GFR usually occurs  Renal biopsies are of value in estimating prognosis in individual patients.

The disease recurs in 50% of transplanted kidney but is an unusual cause for graft loss.

Pathogenesis:

Uncertain

Abnormality of IgA regulation may be present.

Disease associated with IgA nephropathy

Skin Diseases

Dermatitis herpetiformis

Psoriasis

Intestinal Diseases

Crohn’s disease

Celiac disease

Connective Tissue disease

Seronegative arthropathy

Rheumatoid arthritis

Ankylosing spondylitis

Reiter’s syndrome

Sicca syndrome

Episclerttis

Neoplasia

IgA monoclonal  Gammopathy

Mucin secreting carcinoma

Carcinoma of lung , larynx, pharynx, pancreas

Mycosis fungoides

Sezary syndrome

Hematological

Mixed cryoglobulinemia

Immune thrombocytopenia

Polycythemia

Miscellaneous

HIV infection

Toxoplasmosis

Leprosy

Alcoholic liver disease

Portal systemic shunts

Familial immunothrombocytopenia

Pulmonary hemosiderosis

Various pulmonary diseases

Buerger’s disease

Laboratory findings

Urinalysis

Microscopic or macroscopic hematuria

RBCs are dysmorphic

Protein excretion less than one gm in 60% of the cases.

Nephrotic range proteinuria may occur in 10%

Plasma IgA

Serum IgA levels is increased in about 50% of cases. Polymeric IgA is increased

Elevated plasma IgA level is seen in up to o one half of cases. Circulating IgA containing immune complexes that roughly parallel the activity of the disease may be seen. Oral antigens that lead to activation of intestinal IgA production may be important in certain patients. After deposition in the kidney the membrane attack complex may mediate the damage.

Complement levels

Complement levels are usually normal

Skin biopsy

Biopsies from the volar surface of the forearm reveal dermal capillary deposits of IgA, C3, properdin, and fibrin but not C1q, C4, or IgA secretory piece in 20 to 50% of cases. This pattern is similar to that found in kidney biopsies.

Kidney biopsy

Light Microscopy

The most frequent abnormality is mesangial enlargement and hypercellularity. Other pictures seen include, circumscribed foci of epithelial proliferation, segmental areas of capillary collapse and hyalinosis, global sclerosis of some scattered glomeruli, interstitial changes, arteriolar hyalinosis.

Virtually all of biopsies performed during episodes of gross hematuria have disclosed crescents. This lesion may be associated with a better prognosis as opposed to a chronic sclerosing lesion. It is the presence of segmental sclerosis , often with hyalinosis, which might allow for confusion of IgA nephropathy with focal and segmental glomerulosclerosis if only light microscopy is used in studying renal biopsies.

Electron Microscopy

Finely granular to homogenous electron dense deposits are identified in the mesangium of all lobules of all glomeruli. in advanced lesions distortion, layering and splitting of the basement membranes may be noted. There may also be lysis of basement membrane

Prominent mesangial deposition of IgA is seen in only two other disorders: henoch-Schonlein purpura, which is histologically indistinguishable from IgA nephropathy and lupus nephritis in which IgG is the primary immunoglobulin that is deposited.

Immunofluorescence

IgA is the predominant or sole immunoglobulin that is found. Some patients may have IgG deposits as well. IgM, may also be seen with the same frequency as IgG. C3 may be seen

C1q and C4 are almost never found. This suggests prominent involvement of the alternative pathway of complement activation.

Prognosis

Most patients continue to have episodes of gross and or microscopic hematuria

Occasionally long symptom free intervals may occur

Spontaneous complete remissions occur in less than 4% of patients

In long term studies 20 to 30% developed progressive renal insufficiency 20 years or more after initial discovery of disease

It can be estimated that 1 to 2% of patients will enter end stage renal failure each year from time of diagnosis

Rapid progression may occur in some patients

Clinical features indicating a poor prognosis include

Clinical

Male sex

Late age onset

Decreased GFR at diagnosis

Persistent nephrotic range proteinuria and moderate hypertension

Peripheral capillary IgA

Persistent microscopic hematuria combined with proteinuria

Renal biopsy findings of

Diffuse proliferative glomerular lesions especially if accompanied by segmental or diffuse crescents

Focal and segmental glomerular sclerosis

Tubule atrophy

Arteriolar sclerosis

Interstitial fibrosis

C3 deposits may confer a worse prognosis

Effect of pregnancy

Unexpected deterioration of renal function in a small number of patients

Pregnancy was successful and safe in patients without hypertension and with a serum creatinine less than 2.3 mg/dl

Hypertension developed in one quarter of patients

The presence of HLA Bw35 or DR 4 conferred a worse prognosis

Treatment

no therapeutic intervention were found to be consistently successful

Control of blood pressure

Corticosteroids

May reduce severity of hematuria but does not influence long term course of disease

May helpful in the uncommon patients with nephrotic syndrome and mild glomerular lesions. Also patients with rapidly progressive disease may benefit

Fish oil:

A recent study showed that treatment with fish oil for two years retards the rate at which renal function is lost in patients with Ig A nephropathy and proteinuria [i],[ii]. The n-3 polyunsaturated fatty acids (Eicosapentaenoic acid and docosahexaenoic acid)  may limit the production or action of cytokines and eicosanoids evoked by the initial immunologic renal injury. Fish oil in this study was given to patients likely to develop progression of the disease. The treatment did not affect the degree of proteinuria. The drug was administered for 2 years. Blood pressure was controlled as needed with various agents including enalapril. The results of this study should be interpreted  with caution as the observation period is rather short, and the rate of development of renal failure in the placebo group was high

ACE Inhibition:

A recent study showed benefit in terms of decrease in proteinuria in patients with Ig A nephropathy without hypertension[iii]

Plasmapheresis

May be of value in the rare patient with rapidly progressive glomerulonephritis and crescentic involvement

Avoidance of food antigens e.g. gluten and alcohol

may be beneficial

Non-steroidal anti-inflammatory agents

might retard progression

Aspirin and dipyridamole

similar to placebo

Eicosapentaenoic acid

no benefit

Tonsillectomy

May reduce frequency of episodes of hematuria in patients with recurrent tonsillitis

Danazol

No clear cut beneficial effect

Phenytoin

can lower IgA levels

No consistent effect on the progression of disease

Prophylactic penicillin, sulfonamide or broad spectrum antibiotics

No success

cyclosporine

Transiently decreases the proteinuria but is usually associated with further decline in GFR

Cytotoxic agents

Have not been rigorously examined

May be of benefit in patients with a demonstrably progressive course.

May be combined with anticoagulant and antithrombotic drugs

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Last updated Monday, November 26, 2001