IgA Nephropathy

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Background

Immunoglobulin A (IgA) nephropathy (also known as Berger disease) was first described by Berger and Hinglais in 1968.[1] IgA nephropathy is characterized by predominant IgA deposition in the glomerular mesangium.[2]   Long-term follow-up data illustrated that some patients with IgA nephropathy progress to end-stage renal disease (ESRD).[3] IgA nephropathy is the most common cause of glomerulonephritis in the world.[4, 5]

IgA nephropathy is highly variable, both clinically and pathologically. Clinical features range from asymptomatic hematuria to rapidly progressive glomerulonephritis (RPGN). IgA nephropathy is most often associated with microscopic hematuria or recurrent macroscopic hematuria, and spontaneously resolving acute kidney injury can occur. The condition can sometimes lead to chronic kidney disease as well.

Pathologically, a spectrum of glomerular lesions can be seen, but mesangial proliferation with prominent IgA deposition is observed in almost all biopsies. See the images below.



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Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.



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Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Although IgA nephropathy is a limited nonsystemic renal disease, many systemic diseases are sporadically associated with mesangial IgA deposition. Henoch-Schönlein purpura (HSP), a systemic illness, has been closely linked to IgA nephropathy. Other systemic diseases in which mesangial deposits of IgA are regularly observed include systemic lupus erythematosus, hepatitis, dermatitis herpetiformis, and ankylosing spondylitis.

For discussion of this disorder in children, see Pediatric IgA Nephropathy.

Pathophysiology

IgA nephropathy appears to result from an ordered sequence of events, starting with galactose-deficient IgA1, which contains less than a full complement of galactose residues on the O-glycans in the hinge region of the heavy chains.[6] .These may act as auto-antigens that trigger the production of glycan-specific autoantibodies and the formation of circulating immune complexes that are deposited in renal mesangium. These then induce glomerular injury through pro-inflammatory cytokine release, chemokine secretion, and the resultant migration of macrophages into the kidney.[7]

Deposited IgA is predominantly polymeric IgA1, which is mainly derived from the mucosal immune system. The association of some cases of IgA nephropathy with syndromes that affect the respiratory tract or gastrointestinal tract, such as celiac disease, led to the suggestion that IgA nephropathy is a disease of the mucosal immune system. This concept is also supported by the clinical observation that hematuria worsens during or after upper respiratory tract or gastrointestinal tract infections.

The role of the complement system in the pathogenesis of IgA nephropathy is controversial. While IgA antibodies cannot activate complement through the classic pathway, studies have shown that complement can be activated by the alternate pathway.

Epidemiology

Frequency

United States

IgA nephropathy accounts for about 10% of biopsies performed for glomerular disease in the United States. Prevalence rates are lower in the United States than in Asian countries. These lower rates may be influenced by a conservative approach by nephrologists in the United States, who are reluctant to perform renal biopsies in asymptomatic patients with only mild abnormalities on urinalyses.

International

Distribution of IgA nephropathy varies in different geographic regions throughout the world. IgA nephropathy is observed in up to 40% of all biopsies performed for glomerular disease in Asia, compared with 20% in Europe and 10% in North America. High prevalence rates are observed in Singapore, Japan, Australia, Hong Kong, Finland, and southern Europe, whereas low prevalence rates are the rule in the United Kingdom, Canada, and the United States.

A study from Scotland found a significant twofold increase in the diagnosis of IgA nephropathy in the patients residing in the most compared with the least deprived areas. The variation was not explained by the demographics of the underlying population.[8]

In Asia, routine urinalyses are performed for schoolchildren, and renal biopsies are performed for patients with asymptomatic hematuria, thus raising the reported prevalence of the disease. The estimated annual incidence in Japan is 3.9–4.5 per 100,000 population.[9]

Mortality/Morbidity

This disorder is thought to follow a benign course in most cases. However, many patients are at risk for slow progression to ESRD, which develops in approximately 15% of patients by 10 years and 20% by 20 years, though these percentages depend on how the disease is defined.

Race-, Sex-, and Age-related Demographics

IgA nephropathy is more common in whites and Asians and is rare in blacks, both in the United States and in Africa. The condition is frequently observed in Native Americans of the Zuni and Navajo tribes.

IgA nephropathy is more common in males than in females. Virtually all studies show a male predominance of at least 2:1, with reported ratios of up to 6:1.[10] The higher male predilection is observed in white patients in northern Europe and the United States.

IgA nephropathy can affect all ages but is most common in the second and third decades of life. Eighty percent of patients are aged 16-35 years at the time of diagnosis. The condition is uncommon in children younger than 10 years.

History

Two common presentations of patients with IgA nephropathy are episodic gross hematuria and persistent microscopic hematuria. Recurrent macroscopic hematuria, usually associated with an upper respiratory tract infection, or, less often, gastroenteritis is the most frequent clinical presentation and is observed in 40-50% of presenting patients. In 30-40% of patients, the disease is asymptomatic, with erythrocytes (RBCs), RBC casts, and proteinuria discovered on urinalysis. Patients with IgA nephropathy can also present with acute kidney injury or chronic kidney disease.

Gross hematuria

Many patients present with episodes of recurrent macroscopic hematuria, as follows:

Episodes of gross hematuria in IgA nephropathy have been associated with a variety of other infections, as follows:

Gross hematuria has also occurred after the following:

Episodic, grossly visible hematuria is a more common presentation in younger people, whereas that of abnormal urine sediment is more frequent in older individuals. Between episodes of gross hematuria, many patients have persistent microhematuria, proteinuria, or both.

Physical

Physical examination findings in patients with IgA nephropathy are usually unremarkable. A minority of patients have hypertension. More commonly, however, hypertension manifests as the course of the disease lengthens or when patients develop chronic kidney disease and end-stage renal disease (ESRD).

Causes

Most cases of IgA nephropathy are idiopathic, but the onset or exacerbation of the disease is often preceded by a respiratory tract infection. Association with some bacteria, such as Haemophilus parainfluenzae, has been reported. A variety of other disorders have also been linked with IgA nephropathy, as discussed below.

Cirrhosis and other liver diseases

Glomerular IgA deposition is a common finding in cirrhosis, occurring in up to a third of patients. Liver disease is accompanied by impaired removal of IgA-containing complexes by the Kupffer cells, predisposing patients to IgA deposition in the kidney.

Glomerular IgA deposits are common in advanced liver disease, but most adults have no clinical signs of glomerular disease, whereas up to 30% of children may have asymptomatic hematuria or proteinuria. Those abnormalities usually resolve after successful liver transplantation.

Gluten enteropathy (celiac disease)

Glomerular IgA deposition occurs in up to a third of patients with gluten enteropathy. Most of these patients have no clinical manifestations of the disease. However, IgA nephropathy and gluten hypersensitivity are associated, and withdrawal of gluten from the diet of these patients has resulted in clinical and immunological improvement of the renal disease.

HIV disease

IgA nephropathy has been reported in patients with HIV infection, both whites and blacks, despite the rarity of typical IgA nephropathy in the black population.[11] Clinically, patients have hematuria, proteinuria, and, possibly, renal insufficiency.

Histologically, findings range from mesangial proliferative glomerulonephritis to collapsing glomerulosclerosis with mesangial IgA deposits. Several patients have had circulating immune complexes containing IgA antibodies against viral proteins.

Familial IgA nephropathy

Although IgA nephropathy is usually a sporadic disease, data suggest that genetic factors are important in susceptibility to development of mesangial glomerulonephritis. Several cases of familial disease have been reported in Italy and the United States, and an autosomal dominant form has been linked to band 6q22-23.[12] Additionally, increased frequency of specific HLA groups has been reported in some patients.

Ai and colleagues reported increased risk for IgA nephropathy in association with low copy number of the α-defensin gene (DEFA1A3). Low total copy numbers also showed significant association with renal dysfunction in patients with IgA nephropathy.[13] Single-nucleotide polymorphisms (SNPs) of the enabled homolog gene (ENAH) have been associated with increased susceptibility to childhood IgA nephropathy, as well as to the development of proteinuria and gross hematuria, and pathological progression in children with the disease.[14]

Approach Considerations

The first step in confirming the diagnosis is a careful urinalysis of a first-void urine sample performed by an experienced urine analyst. Direct examination of the urine sediment is required to identify red blood cells (RBCs) and RBC casts, both of which indicate glomerular injury.

Proteinuria testing can be accomplished quantitatively by a 24-hour measurement of urinary protein or semiquantitatively by measuring a urine protein/creatinine ratio. A normal ratio should be less than approximately 0.1. Also, adults older than 50 years with proteinuria should have a urine protein electrophoresis performed to exclude monoclonal light chains as a cause of proteinuria.

Assess renal function in patients with proteinuria or hematuria by a 24-hour creatinine clearance test. Alternatively, the glomerular filtration rate (GFR) can be estimated using the Modification of Diet in Renal Disease (MDRD) formula.

Although the serum IgA level is elevated in up to half of patients, this finding is insensitive, nonspecific, and of no clinical utility

Diagnosis of IgA nephropathy is confirmed by renal biopsy.

Proteinuria

In IgA nephropathy, proteinuria rarely occurs without microscopic hematuria. Mild proteinuria is common.

Nephrotic-range proteinuria is uncommon, occurring in only 5% of patients with IgA nephropathy, and is more commonly seen in children and adolescents. Nephrotic-range proteinuria can be seen early in the disease course as well as in patients with advanced disease

Patients with heavy proteinuria and nephrotic syndrome are likely to have IgA deposition with diffuse proliferative glomerular lesions or minimal-change light microscopic findings

Acute kidney injury

Acute kidney injury, with edema, hypertension, and oliguria, occurs in fewer than 5% of patients. It can develop from either of the following two distinct mechanisms:

Histologic Findings

Light microscopy

The most common light microscopy findings are focal or, more often, diffuse mesangial proliferation and extracellular matrix expansion (as seen in the image below). Morphology can range from normal to moderate or severe intracapillary or extracapillary proliferative lesions. While some patients have IgA deposits on immunofluorescence and little or no change by light microscopy, a few patients have segmental necrotizing lesions with crescent formation due to extensive disruption of the capillaries. Occasionally, patients have focal glomerular sclerosis indistinguishable from focal segmental glomerulosclerosis on light microscopy. A number of other findings can be observed in advanced disease, including interstitial fibrosis, tubular atrophy, and vascular sclerosis. These findings can be helpful prognostic tools in patients with IgA nephropathy.



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Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

Electron microscopy

Electron microscopy shows mesangial hypercellularity and increased mesangial matrix. The important finding is electron-dense deposits in the mesangium, such as those in the image below, but deposits in the subendothelial and subepithelial region of the glomerular capillary wall are found in a minority of patients, especially those with more severe disease.



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Electron microscopy showing large dark mesangial deposits.

Immunofluorescence

Immunofluorescence findings are the pathologic hallmark of this disease. IgA is deposited in a diffuse granular pattern in the mesangium (as seen in the image below) and occasionally in the capillary wall. Immunoglobulin G (IgG)4 may accompany IgA, and C3 is often present.



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Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Medical Care

IgA nephropathy is a common cause of glomerulonephritis. Although it is a benign disease in most patients, chronic kidney disease and end-stage renal disease (ESRD) occur in about 20-40% of patients within 20 years of presentation. Currently, no cure exists for IgA nephropathy, but therapies that can delay the onset of need for dialysis and transplantation are available. Current recommendations include the following:

Angiotensin-converting enzyme inhibitors (ACEIs) are the preferred agents for lowering blood pressure. They are also beneficial in decreasing proteinuria and should be strongly considered even in normotensive patients with proteinuria. The decrease in proteinuria with ACEIs may be an effect of decreasing the intraglomerular pressure and of changing the glomerular size selectivity.

Reports have demonstrated that ACEIs are more effective than other antihypertensive drugs in slowing the progression of proteinuric renal disease. In a randomized, controlled trial that followed patients for a mean of approximately 6 years, the group that received ACEIs had an improved renal survival rate compared with the group receiving other antihypertensive agents.

Angiotensin II receptor blockers (ARBs) should be used for patients who cannot tolerate ACEIs. ACEIs and ARBs may have an additive effect in decreasing proteinuria. Whether high-dose ACEIs better preserve renal function than combination therapy with ACEIs and ARBs is unknown.

The combination of an ACEI and the ARB losartan has shown an additive urinary protein–lowering effect compared with doubling the dose of monotherapy.[17]   However, patients on combination therapy should be monitored closely for the development of hyperkalemia, and combination therapy should be avoided in patients with advanced kidney disease.

Administer prednisone for 4-6 months to patients who have IgA nephropathy with preserved renal function, nephrotic syndrome, and minimal-change findings on light microscopy. Early treatment with prednisone in patients with proliferative IgA nephropathy has been shown to be effective in reducing proteinuria and improving histologic findings, such as proliferation and cellular crescents. Additionally, corticosteroids given for 6 months have been seen to be beneficial against deterioration in renal function in patients with moderate proteinuria (1.5-3.5 g/d).

Results of a prospective, open-label, multicenter, centrally randomized, controlled trial in 97 patients suggested that the combination of the ACEI ramipril and prednisone was more effective than ramipril alone in discouraging progression of renal disease associated with IgA nephropathy.[18]

A randomized, controlled, long-term study on the effectiveness of steroids in IgA nephropathy showed improved 10-year renal survival in the steroid-treated group compared with the control group. Patients had a proteinuria of 1.9 g/d on average in the treatment group and 1.7 g/d in the control group. Steroids were given for 6 months.

Mycophenolate mofetil has been used in patients with IgA nephropathy associated with proteinuria, even though some reports have shown some benefit and others have not. The studies are of small size, and longer-term studies are required for more information. At this time, the evidence for the use of mycophenolate in IgA nephropathy is inconclusive.[15, 19]

Patients with crescentic rapidly progressive glomerulonephritis (RPGN) can be treated similarly to patients with idiopathic RPGN by using intravenous pulse prednisone followed by oral prednisone and cyclophosphamide.

Fish oil (omega-3 fatty acids) at a dose of 12 g/d has been used with controversial and conflicting results, but it is frequently used in patients with declining renal function.[20, 9] Deficiencies of essential fatty acids have been detected in IgA nephropathy, and fish oil is rich in long-chain omega-3 polyunsaturated fatty acids. These produce altered and less biologically effective prostaglandins and leukotrienes, as well as reduced platelet aggregation.

A study by Liu examined the effect of calcitriol on urinary protein excretion among patients with IgA nephropathy. The study found that adding calcitriol to a renin-angiotensin system inhibitor resulted in a safe decrease in proteinuria.[21]

Diet

A low-antigen diet, which consists of restricting dietary gluten and avoiding meats and dairy products, has been recommended to decrease mucosal antigen exposure. However, it has not been shown to preserve renal function.

Low-protein diets have been recommended to slow the rate of progression of many nephropathies. No large trial explicitly addresses the role of low-protein diets in slowing the decline in renal function in IgA nephropathy. The MDRD Study Group trial is the largest trial of low-protein diets to date, but it included patients with a variety of renal diseases. This trial was unable to determine whether a low-protein diet was beneficial. Although the meta-analysis of studies of low-protein diets suggests some benefits, the effects are subtle and difficult to apply to a given patient.[22, 23]

Tonsillectomy

Tonsillectomy is a controversial treatment for IgA nephropathy. Tonsillectomy may limit the production of degalactosylated IgA1 by reducing mucosal-associated lymphoid tissue (MALT). However, an Italian study found that other markers of innate immunity activation (eg, toll-like receptors) were not affected by tonsillectomy, possibly because of extra-tonsillar MALT.[24]

A study in Caucasian patients in which 98 of 264 patients underwent tonsillectomy found that tonsillectomy may slow the progression of IgA nephropathy, but mainly in patients with macroscopic hematuria.[25] A Japanese study in which 70 of 200 patients underwent tonsillectomy concluded that the procedure was associated with a favorable renal outcome of IgA nephropathy in terms of clinical remission and delayed renal deterioration, even in non-steroid-treated patients.[26]

Especially in Japan, tonsillectomy has been combined with steroid pulse administration for clinical remission.[27] Japanese guidelines from 2014 note that evidence supporting the benefit of tonsillectomy is weak, but recommend that tonsillectomy, by itself or combined with steroid pulse therapy, may be considered a treatment option.[9]

Renal Transplantation

Renal transplantation is effective in patients with IgA nephropathy. Survival of cadaveric kidney transplants in patients with IgA nephropathy is among the highest observed in patients undergoing transplantation for common causes of end-stage renal disease (ESRD).

However, IgA nephropathy frequently recurs after transplantation (20-60%). The higher recurrence rates in transplantation from living related donors suggest genetic susceptibility to the disease.[28] Some patients present with microscopic hematuria and proteinuria; others have only positive histologic findings. The disease usually progresses slowly, similarly to the disease in the native kidneys, and graft loss due to recurrent disease occurs in fewer than 10% of patients.

Baek et al have reported reasonably good long-term results in patients receiving a second kidney transplant for IgA nephropathy. Recurrent disease was identified in only 2 of 28 patients during follow-up of 61.61 ± 47.23 months.[29]

Medication Summary

Currently, no cure exists for IgA nephropathy. However, therapies that can delay the onset of need for dialysis and transplantation are available. Hypertension should be treated early and aggressively. ACE inhibitors are the antihypertensives of choice.

Benazepril (Lotensin)

Clinical Context:  Prevents conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. Also causes lower aldosterone secretion, thus reducing systemic and glomerular capillary pressure.

Class Summary

Comparative studies show ACE inhibitors are more effective than other antihypertensives (ie, beta blockers, calcium channel blockers) in reducing blood pressure and proteinuria, protecting renal function, and delaying onset of ESRD.

Losartan (Cozaar)

Clinical Context:  Nonpeptide angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, do not affect the response to bradykinin, and are less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.

Class Summary

Reduce blood pressure and proteinuria, protect renal function, and delay onset of ESRD.

Prednisone (Sterapred)

Clinical Context:  Immunosuppressant for treating autoimmune disorders. Decreases inflammation by reducing capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.

Class Summary

Prednisone should be used in patients with nephrotic syndrome and minimal histologic findings. When treated with corticosteroids, patients with proteinuria and preserved renal function (ie, CrCl >70 mL/min) have shown significant delay of disease progression compared to patients not receiving corticosteroids.

Omega-3 polyunsaturated fatty acid (Fish oil)

Clinical Context:  May be of benefit by decreasing mediators of glomerular injury and decreasing platelet aggregation.

Class Summary

Orphan drug indicated for treatment of IgA nephropathy. Used in patients with proteinuria and decreased renal function.

Cyclophosphamide (Neosar, Cytoxan)

Clinical Context:  Cyclic polypeptide that suppresses some humoral activity. Chemically related to nitrogen mustards. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. Interaction of phosphoramide mustard with DNA considered cytotoxic.

When used in autoimmune diseases, mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.

In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T cell functions.

Class Summary

Cyclophosphamide is used in nonmalignant renal diseases for its immunosuppressive effects.

Prognosis

Although IgA nephropathy usually follows a benign course, end-stage renal disease (ESRD) develops in 15-20% of patients within 10 years of onset and in about 25-30% of patients by 20 years. However, these observations are obtained from biopsy-proven disease and do not include patients with isolated hematuria, who typically do not have a biopsy performed and have a good prognosis.

In a 2012 study in 141 Caucasian patients with biopsy-proven IgA nephropathy who presented with normal renal function, microscopic hematuria, and minimal or no proteinuria, the long-term prognosis was excellent. Such patients are not often biopsied, so the study served to validate the Oxford classification criteria at the benign end of the spectrum. The study was conducted in a European population, suggesting that genetic factors play a role in IgA prognosis, as studies of similar "benign" presenting Asian groups had a worse prognosis.[30]

In a study of 1155 Chinese patients with IgA nephropathy, the long-term prognosis was significantly better in patients presenting with recurrent macroscopic hematuria than in those with isolated macroscopic hematuria or no history of macroscopic hematuria. The 20-year cumulative renal survival after biopsy for the three groups was 91%, 64%, and 57%, respectively.[31]

Predictors of disease progression

IgA nephropathy is characterized by a highly variable clinical course. Many efforts have been made to determine clinical and histological features associated with progression to ESRD, as follows[32, 33] :

Patient Education

See the list below:

Author

Mona Brake, MD, Assistant Professor, Department of Internal Medicine, Kansas University School of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Christie P Thomas, MBBS, FRCP, FASN, FAHA, Professor, Department of Internal Medicine, Division of Nephrology, Departments of Pediatrics and Obstetrics and Gynecology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Disclosure: Nothing to disclose.

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Huberwald Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Renal Section, Southeast Louisiana Veterans Health Care System

Disclosure: Nothing to disclose.

Additional Contributors

James H Sondheimer, MD, FACP, FASN, Associate Professor of Medicine, Wayne State University School of Medicine; Medical Director of Hemodialysis, Harper University Hospital at Detroit Medical Center; Medical Director, DaVita Greenview Dialysis (Southfield)

Disclosure: Receive dialysis unit medical director fee (as independ ent contractor) for: DaVita .

Acknowledgements

Douglas Somers, MD Assistant Professor, Department of Internal Medicine, Division of Nephrology, University of Iowa Medical Center

Douglas Somers, MD is a member of the following medical societies: American Society of Nephrology

Disclosure: Nothing to disclose.

Acknowledgments

The authors thank Dr. Tim Timmerman, pathologist, for his invaluable help with the pathology slides.

References

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Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

Electron microscopy showing large dark mesangial deposits.

Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.

Light microscopy of a glomerulus from a patient with immunoglobulin A nephropathy showing increased mesangial matrix and cellularity.

Electron microscopy showing large dark mesangial deposits.

Immunofluorescence microscopy demonstrating large mesangial immunoglobulin A (IgA) deposits diagnostic of IgA nephropathy.