Nephrology

Neoplasia

Infection

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In spite of the extremely varied clinical presentation, the most common feature leading to the diagnosis, by renal biopsy, is recurring episodes of macroscopic hematuria (which is generally the initial complaint). More than 80% of patients are between the ages of 16 to 35 years at the time of diagnosis. However, the disorder may be found at any age, although being uncommon before the age of 10 and after the age of 50. Thus, it should be considered a disease of children and young adults. There is a predilection for males (2:1), which disappears when affecting black persons (this disease is uncommon in blacks).

Episodes of hematuria (gross or microscopic) frequently appear quickly after some nonspecific virus-like syndrome or intercurrent infection such as acute tonsillitis, this latter being called the synpharyngitic nephritis. With the onset of hematuria, mild, nonspecific, constitutional symptoms appear such as: malaise, myalgia, vague back or loin discomfort and low-grade fever. Dysuria may be an important complaint, leading to the erroneous diagnosis of urinary tract infection or, when associated with gross hematuria, to that of hemorragic cystitis. Although usually within the normal range, blood pressure may be elevated in patients with more advanced disease; sometimes it may be the presenting feature. Nephrotic syndrome is usually present in about 10% of patients but despite this relatively high incidence of nephrotic proteinuria, renal vein thrombosis is a rare event. Sometimes recurrent episodes of acute renal failure associated with macroscopic hematuria occur in some patients after acute upper respiratory infection. Renal biopsies in this particular group may show acute tubular necrosis, erythrocyte casts and segmental crescents (usually involving less than half of the glomeruli). In these cases spontaneous recovery is the rule, even though temporary dialysis may be required. Rapidly progressive renal failure, with extensive crescents, is very uncommon.

Differential Diagnosis

On clinical grounds, the two main differential diagnosis of a primary IgA nephropathy are: Post Streptococcal Glomerulonephritis (PSGN) and Schönlein-Henoch purpura. When considering the former the main feature with respect to the history is the latent period between the upper respiratory infection and the symptomatology. In PSGN there is a wider lag period than in Berger disease, in which the infection is quickly followed by the renal manifestations. When considering the laboratory findings PSGN can be distinguished by the low levels of serum C3 and the presence of a variety of specific antibodies to streptococcal antigens as well as by the absence of increased levels of serum IgA. As for Schönlein-Henoch purpura, usually considered a form of secondary nephropathy, the characteristic clinical features (abdominal pain, arthralgias, purpura) leave little doubt about the diagnosis. The laboratory features are of no help since both present a mesangial deposition of IgA, leading most authors to view Berger disease as a monosymptomatic form of Schönlein-Henoch purpura.

Berger disease may occur in siblings and identical twins, and may be sometimes associated with deafness making it difficult to distinguish it from Alport syndrome.

Laboratory Findings

Urinalysis presents dysmorphic erythrocytes, considered characteristic of glomerular injury. Microscopic hematuria occasionally may persist between episodes of macroscopic hematuria. Abnormal proteinuria is characteristically mild and may be absent at times; nephrotic range proteinuria occurs in about 10% of patients. There may be an increased urinary excretion of IgG, which seems to be associated with a poor prognosis. Serum IgA levels are increased in 50% of patients, this consists mainly of the polymeric IgA ( IgA1 subclass). Complement component protein (eg: C3, C4) levels are typically normal or elevated (as opposed to PSGN). Interleukin-6 urinary levels are elevated, but this is not specific since it may also occur in urinary tract infections. IgA-fibronectin aggregates are increased in the serum of 50-95% of patients, and its measurement is extremely useful in differentiating IgA nephropathy from other glomerular diseases. A wide variety of autoantibodies have been found including IgG anti-mesangial cell, antineutrophil cytoplasmic (ANCA), antiendothelial and anti-extracellular matrix antibodies. The role of these findings in the pathogenesis of the disease remains uncertain. The best correlation is the presence of IgA ANCAs and the development of crescentic disease or vasculitis.

Pathology

Upon light microscopy, the major abnormality, involving virtually all glomeruli, is expansion of the mesangium, usually affecting all lobules. There is an increase in mesangial cellularity as well as in the mesangial matrix. Other patterns of glomerular injury may be superimposed on the basic alteration of the mesangium. When there is formation of crescents, acute renal failure may take place, but this may be temporary; this being determined basically by the involvement of more or less than 50% of all glomeruli. If more than 50% of glomeruli are affected, rapidly progressive glomerulonephritis (RPGN) ensues (once again, this is not the rule). When acute renal failure develops, the decline in renal function is usually due to tubular swelling, erythrocyte casts and hemoglobin nephrotoxicity than to the crescent itself. There is a subgroup of patients who present with nothing but a slight IgA mesangial deposition (the glomeruli are usually close to normality on light microscopy) and have the nephrotic syndrome. It is extremely important to identify this particular group since they are the ones with the best response to glucocorticoid therapy.

When considering electron microscopy, in almost all cases, finely granular to homogeneous electron dense deposits are identified in the mesangium of all lobules of all glomeruli. On immunofluorescence IgA is localized in all biopsy specimens; IgG may also be detected and the frequency of such occurrence may reach up to 90% of examined materials. C3 is usually observed in about the same proportion of specimens as IgG, whereas C1q and C4 are almost never found (this is consistent with the fact that polymeric IgA is a potent activator of the complement alternate pathway).

It is also of great importance that many studies have found that IgA-specific helper T cells are increased in number in patients with Berger disease, while IgA-specific supressor T cells are decreased. Other patients have been shown to have a decreased clearence of IgA complexes instead of its overproduction. A genetic predisposition has been found in some patients (which is linked to HLA). Many apparently healthy individuals, relatives of patients with IgA nephropathy, show some abnormality in the IgA system.

Course and Prognosis

Most patients continue to have episodes of gross or microscopic hematuria, although symptom-free intervals may occur. Spontaneous complete remissions occur in less than 4% of adults (usually more than four years after the clinical presentation). On the other hand, pediatric patients tend to have a higher frequency of spontaneous complete remissions. The development of chronic renal failure is poorly predictable solely on clinical grounds; despite that, some clinical features may indicate a poor prognosis such as: - male sex

The serum IgA level, severity and frequency of episodes of hematuria seem to have no consistent relantionship to prognosis.

Pathologic findings that indicate a poor outcome include:

Treatment

The majority of patients does not require specific therapy; this is usually saved for those who have features indicative of a poor prognosis such as: proteinuria greater than 1g/day, impaired GFR, persistent hypertension, sclerosing or crescentic glomerular lesions, or tubulointerstitial fibrosis.

Glucocorticoid therapy showed to be effective only in the cases of modest proteinuria and well-preserved renal function. The use of cytotoxic agents, although not extensively evaluated,does not seem to yield promising results specially because of the indolent and unpredictable course of the disease (this is still in the realm of experimenttal approaches). Many regimens have been tried such as the use of prophylatic antibiotics, cyclosporine, plasmapheresis,danazol and phenytoin (this latter aiming the reduction of serum IgA), but none has consistently showed promising results.

ACE inhibitors have been associated with a lower protein excretion and better preservation of renal function, probably due to its intrarenal effects. NSAIDs may also retard the progression of IgA nephropathy. Patients with severe disease (crescentic glomerulonephritis),can be treated either with plasma exchange and immunosupression, or with high dose immunoglobulins. Patients with acute renal failure during intercurrent infections, if having few crescents, can be managed conservatively while awaiting spontaneous recovery (dialysis may be necessary during this period). If hypertension is part of the clinical picture, ACE inhibitors should be the drug of choice because of its beneficial effects in the disease (as mentioned above). The overall prognosis is generally good, with a 10-year survival exceeding 80% in well managed cases.

References

The Kidney 5th Edition - Barry M. Brenner

Hall RP, Stachura I, Cason J, et al : IgA containing circulating immune complexes in patients with IgA nephropathy. Am J Med 74:56,1983

Ballardie FW, Brenchley PEC, Williams S, O’Donoghue D: Autoimmunity in IgA nephropathy. Lancet 2:588, 1988

Rostoker G, Desvaux-Belghiti D, Pilatte Y, et al : High-dose immunoglobulin therapy for severe IgA nephropathy and Henoch-Schonlein purpura. Ann Int Med 120:476-484, 1994

Robbin’s Pathologic Basis of Disease - 5th Edition

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