IMMUNOGLOBULIN A NEPHROPATHY

Etiology and Epidemiology

I gA nephropathy, also known as Berger disease, was first described in France in 1968. It now is the
most common primary glomerulonephritis in the world and accounts for 10% of patients with ESRD in
many countries. The prevalence among patients with glomerulonephritis or patients who had kidney
biopsy varies from as high as 50% in Japan and East Asia to 10% to 30% in Europe. In the United States,
the overall prevalence is approximately 10% to 15% but is as high as 35% among Native Americans
living in New Mexico.

These differences in prevalence may reflect variations in genetic predisposition, as well as the criteria
used for urinary screening and kidney biopsy. I gA nephropathy is more frequently seen in younger adults
and is two to six times more common in males than in females. It is uncommon in blacks, both in the
United States and in Africa.

IgA nephropathy was once thought to be a benign disease presenting with asymptomatic hematuria;
however, its ability to present with any clinical syndrome associated with glomerular disease is now
recognized. Some patients will develop ESRD over variable periods of time.

Pathophysiology

Primary IgA nephropathy is an immune-complex–mediated disease in which IgA deposits and other
pathologic lesions are found in kidney tissues. In contrast, Henoch-Schönlein purpura, a systemic disease
that is believed to be closely linked to IgA nephropathy, shares similar immunohistologic findings in the
kidneys. Both typically have vasculitis affecting the joints, skin, and gastrointestinal tract, which may
result from the same pathologic process of IgA nephropathy. The diagnosis of IgA nephropathy is
established by the presence of mesangial IgA deposits upon immunofluorescence examination of the
kidney biopsy. The IgA immune complex, composed of IgA antibody bound with an environmental
antigen, such as a virus, bacteria, or food substances, is presumed deposited from the systemic circulation.
Alternately, the complex may be formed in situ, with the IgA antibody bound with an endogenous antigen
in the mesangium. In the mesangium, IgA can bind with receptors on the mesangial cells to induce
proliferation and cytokine production. In addition, IgA can activate complement through the alternate
pathway to induce glomerular damage.

The extent of the injury depends on the characteristics of the IgA that favor mesangial deposition, the
susceptibility of the mesangium toward deposition, the ability of the patient to mount an inflammatory
response to the deposits, and the response of the kidney to the injury in a way that favors progressive
renal damage.

Clinical Presentation

IgA nephropathy commonly presents in the second and third decades of life, but it can occur at any age.
Many patients have microscopic hematuria and proteinuria for years, persistently or intermittently, during
the early stages of the disease. About half of the patients present with gross hematuria concurrent with an
infection, commonly in the upper respiratory tract.
 68 The hematuria may occur 1 to 2 days after the onset of infection symptoms, which is different from
the 10- to 14-day delay seen after the pharyngitis in poststreptococcal glomerulonephritis. Proteinuria is
common, and nephrotic range often indicates advanced disease. Hypertension and edema are infrequent
but are common in poststreptococcal glomerulonephritis. R enal dysfunction is uncommon at the initial p
resentation; however, approximately 10% to 20% of the patients develop ESRD within 10 years, and 30%
develop it after 20 years. Hypertension, severe proteinuria, renal function impairment, old age, and the
severity of histologic lesions are all predictive factors for poor longterm outcome.

TREATMENT

Immunoglobulin A Nephropathy

Spontaneous remission is seen in only 10% to 25% of children and 5% to 7.5% of adults. Unfortunately,
no therapy is known to be consistently effective for the treatment of IgA nephropathy. Because of the
slow progression of the disease to ESRD, it is very difficult to conduct trials to evaluate the long-term
effectiveness of specific treatments. The lack of understanding of the pathogenetic mechanisms and the
unavailability of appropriate animal models severely limit the development of rational treatment
regimens.

NONPHARMACOLOGIC THERAPY: LOW-GLUTEN DIET AND TONSILLECTOMY

Restriction of dietary gluten is effective for patients with celiac disease but not for patients with no
identifiable nephritogenic antigens. Removal of the tonsils, which produce IgA 1 and may contribute to
IgA nephropathy, may reduce proteinuria and hematuria. This is especially helpful for patients who
developed recurrent macroscopic hematuria as provoked by bacterial tonsillitis. There are limited studies
to show the long-term renoprotective effects of tonsillectomy; however, larger studies with longer follow-
up are needed to affirm such beneficial effect.

PHENYTOIN

Phenytoin was evaluated because of its ability to reduce the amount of polymeric IgA in the circulation.
Although it reduced serum IgA concentrations and frequency of macroscopic hematuria, the glomerular
lesions deteriorated in some of the patients and the drug is not generally used nowadays.

CORTICOSTEROIDS

Corticosteroids with or without immunosuppressive agents have been used to t reat IgA nephropathy for
many years. A recent metaanalysis of available trials showed that steroid therapy is associated with
reduction in proteinuria, risk for progression to ESRD, as well as the rate of renal function deterioration.
Low-dose, shortterm (<3 months) steroid therapy is not expected to yield favorable results. In contrast,
larger doses of steroids (IV methylprednisolone 1g/day for 3 days at months 1, 3, and 5 and oral
prednisone 0.5 mg/kg every other day for 6 months) were able to reduce proteinuria and renal function
deterioration. However, the dose of the steroids and the risk for toxicity might be considered high by
many. Patients with nephrotic range proteinuria and impaired renal function are likely candidates for
steroid therapy; however, the responses to such treatment are not favorable.
 CYTOTOXIC AGENTS

Several studies have evaluated the efficacy of azathioprine and cyclophosphamide. In some of the studies,
cyclophosphamide was used in conjunction with dipyridamole, heparin and warfarin. It is difficult to
assess which of these agents contributed to the limited favorable effects observed. In addition, in many of
these studies, blood pressure control and ACE inhibition were not always optimal. At present, there is no
clear evidence to support the use of these cytotoxic agents for IgA nephropathy, except perhaps for those
patients with advanced rapidly progressive disease.

CLINICAL CONTROVERSY

Is fish oil effective for IgA nephropathy?

FISH OIL

The third approach is to reduce glomerular inflammation and glomerulosclerosis induced by IgA
deposits. Antiinflammatory agents, antiplatelet drugs, and anticoagulants have been tried without success
to decrease the production or action of mediators responsible for IgA immune-complex–induced
glomerular damage. However, the n- 3 fatty acids in fish oil reduce the production or action of
prostaglandins and leukotrienes, thus limiting the renal damage caused by inflammation, platelet
aggregation, and vasoconstriction.

In a controlled trial on patients with heavy proteinuria and mildly impaired renal function, daily use of
fish oil delayed the progression of renal failure with modest reduction in proteinuria. A metaanalysis of
five controlled studies indicated that a minor, but not statistically significant, beneficial effect on renal
function may be observed. Results from several recent studies failed to confirm the beneficial effects
reported earlier, and further studies are needed to confirm the role as well as the optimal dose. In many of
the studies, 4 to 12 g/day were given for 2 or more years. Some of the fish oil preparations are rich in
cholesterol; thus, it is appropriate to monitor the LDL cholesterol levels for patients receiving therapy.

ANGIOTENSIN-CONVERTING ENZYME INHIBITION

Because hypertension is a negative prognostic indicator of IgA nephropathy and many of these patients
already have left ventricular diastolic malfunction despite being normotensive, early antihypertensive
intervention with ACEIs or ARBs is important.

If a single agent is insufficient to reduce proteinuria and maintain blood pressure at 125/75 mm Hg,
combined use of ACEI and ARB should be instituted.

ALTERNATIVE THERAPEUTIC APPROACHES

Patients with IgA nephropathy have abnormal production of IgA and several different immunoglobulins.
Immunoglobulins, administered intravenously initially and then i ntramuscularly, may have beneficial
effects through immunomodulation, increased catabolism of autoantibodies, and blockade of receptors.
The doses in this experimental t rial, which has not been independently replicated, were very high: 1 g
/kg/day for 2 days IV for the first three months, then 0.35 mL/kg IM every 15 days for the next six
months. Plasmapheresis with albumin replacement was performed before the 2- to 12-hour IV infusions
to avoid serum sickness. Reduction in proteinuria, hematuria, GFR decline, and histologic activity index
were observed for 11 patients with a progressive course of the disease. Renal survival was prolonged for
eight of these patients who were followed for 3 to 10 years. Larger, randomized, controlled trials are
needed before one can recommend this regimen with confidence. Urokinase, danazol, dapsone, sodium
cromoglycate, and plasma exchange have also been evaluated, but none is consistently effective nor
shown to affect renal function. Cyclosporine treatment was found in a limited number of studies to reduce
proteinuria; however, renal function decreased during treatment. Consequently, its use is limited by the
potential for nephrotoxicity.

The HMG-CoA reductase inhibitor fluvastatin was reported to reduce urinary protein excretion in
moderately proteinuric (0.6 to 1.6 g /day) patients who had IgA nephropathy with normal renal function.
Creatinine clearance remained stable during the 6-month study. Although evaluation for a longer term in a
larger patient population is needed to confirm this beneficial effect, statin use is an obvious choice for
hyperlipidemic patients with IgA. Antiplatelet agents are commonly used in Japan and rarely outside of
Asia for IgA nephropathy. A recent metaanalysis of seven trials (four in Japan and three in Hong Kong)
revealed that these agents reduced proteinuria and stabilized renal function. Mycophenolate mofetil and
several new strategies are being evaluated as experimental treatments for IgA nephropathy on the premise
that they may reduce IgA synthesis and mesangial uptake and/or suppress the effects of proinflammatory
or profibrogenic mediators. Normotensive patients with normal renal function, isolated microhematuria,
and proteinuria less than 1 g /day should be observed closely without specific treatment.

Patients with minimal proteinuria of 0.5 to 1 g/day receive fish oil and an ACEI or ARB ( Fig. 56–6) to
attain BP of <103/80 mmHg and urinary protein excretion of <500 mg/day.

Combined ACEI and ARB seems to be more effective than monotherapy. Because corticosteroids reduce
proteinuria, a course of alternate-day prednisone (1 mg/kg/day) with subsequent tapering is indicated for
patients with proteinuria greater than 3 g/day who have good renal function [>70 mL/ min (>1.17 mL/s)].
A more aggressive IV or oral steroid regimen may be considered, even though its efficacy has not been
definitively established. For patients with a slow progressive decline in creatinine clearance [<70 mL/min
(<1.17 mL/s)], fish oil should be given. Azathioprine, cyclophosphamide, mycophenolate mofetil, or
dipyridamole/warfarin therapy may also be used, althoug the efficacy of these agents has not been firmly
established. If the patient experiences rapid GFR decline of more than 2 mL/min (0.033 mL/s) per month,
immunoglobulin therapy may be considered despite the fact that only limited data are available. Other
therapies that may be considered for these patients include pulse steroids, a cyclophosphamide–steroid
combination, mycophenolate mofetil, and plasmapheresis.

THERAPEUTIC OUTCOMES

Urinary protein excretion and the mean arterial blood pressure at follow-up correlate well with the
progression of disease. The risk of developing ESRD is proportional to the amount of proteinuria, under
the influence of ACEI and ARB therapy, after 1 year of follow-up. For those patients who develop end-
stage renal failure, transplantation is appropriate, especially for young adults. Recurrence of IgA
mesangial deposits in the renal allograft may occur in up to 50% of patients in 5 years and be universally
present at 10 years or more posttransplant, but the recurrence of clinical disease is only approximately
10% to 15%. There is also no correlation between the aggressiveness of the primary disease and the rate
of recurrence.

Use of ACEI may improve graft survival while immunosuppression with corticosteroids, azathioprine,
and/or cyclosporine is not expected to prevent the recurrent nephropathy.