Pediatric IgA Nephropathy 

Updated: Mar 20, 2017
Author: Mohammad Ilyas, MD, FAAP; Chief Editor: Craig B Langman, MD 

Overview

Background

Idiopathic immunoglobulin A (IgA) nephropathy, or Berger disease, is a worldwide primary glomerulonephritis first described by Berger and Hinglais in 1968, based on the finding of predominant IgA deposition in the mesangium with a mesangial proliferation. The clinical spectrum varies from asymptomatic microhematuria to rapidly progressive glomerulonephritis. The vast majority of patients are characterized by recurrent episodes of gross hematuria, which usually occurs in concomitance with mucosal infections of the upper respiratory tract or other infections, or by asymptomatic microscopic hematuria with or without proteinuria.[1]

Although it can present at any time, the peak incidence of disease is in the second and third decades of life. A male-to-female ratio of 2:1 is observed in North American and Western European populations, although this difference is not observed among populations in the Pacific.

IgA nephropathy occurs with greatest frequency in Asians and whites and is relatively rare in blacks. In a Chinese study, IgA nephropathy constituted 45% of all cases of primary glomerulonephritis.[2] However, IgA deposits may also be seen on kidney biopsy findings in individuals with no evidence of renal disease. The reported incidence rate of mesangial IgA deposition in apparently healthy individuals is 3-16%. These cases had no clinical features of nephritis, but their renal biopsy findings were consistent with IgA nephropathy.

Spontaneous remission has been reported in children and adults. Secondary IgA nephropathy is also associated with various underlying disease processes. It was initially considered a benign condition, but extended follow-up indicates that IgA nephropathy does lead to significant kidney damage, and progressive disease develops in 20-30% of children 15-20 years after disease onset. Advanced age, hypertension, proteinuria, and impaired renal function at presentation are poor prognostic indicators.

Pathophysiology

IgA nephropathy, the most common form of primary glomerulonephritis worldwide, is defined by predominant IgA1 deposits in the glomerular mesangium (see the image below). Over the last decade, the understanding of the pathogenesis of IgA nephropathy has improved. It is believed that IgA nephropathy represents abnormal polyclonal IgA production, specifically a post-translational glycosylation defect. This abnormal glycosylation impairs the normal clearance from the bloodstream of the circulating IgA molecules, as well as predisposing their deposition within the kidneys.[3]

Mesangial deposits of immunoglobulin A (IgA). Fluo Mesangial deposits of immunoglobulin A (IgA). Fluoresceinated Anti-IgA Antibody, Immunofluorescence microscopy, original magnification 400x. Image courtesy of Patrick D Walker, MD.

Immunoglobulin antibody A is a major serum immunoglobulin and the predominant antibody class in the external secretions that bathe mucosal surfaces. This plays a key role in immune protection. Indeed, the body expends considerable energy in producing IgA, such that the daily production of IgA exceeds that of all the other antibody classes combined.

IgA, at concentrations of about 2-3 mg/mL, is the second most prevalent antibody in serum after IgG, which is normally present at about 12 mg/mL. Because serum IgA is metabolized 5 times faster than IgG, the production rates of serum IgA and IgG must be similar. Serum IgA is predominantly monomeric in nature; the secretory IgA (S-IgA) is chiefly polymeric, comprising mainly dimeric forms of IgA containing the J (joining) chain. S-IgA serves various functions to protect the vast surface area (approximately 400 m2) occupied by mucosal surfaces, such as the linings of the respiratory, GI, and genitourinary tracts. As the major class of antibody present at these sites, S-IgA can be considered an important first line of defense against many invading pathogens.

Among abnormalities of the IgA immune system reported so far in IgA nephropathy, aberrant O-linked glycosylation in the hinge region of IgA1 is the most consistent finding. IgA1 molecules bearing abnormal glycosylation have been found in serum, tonsillar lymphocytes, and elute from mesangial deposits, and they are characterized by decreased O-linked N -acetylgalactosamine residues with or without alteration in the terminal sialylation of the O-linked sugars.[4]

Increasing evidence supports the underglycosylated IgA-containing immune complex including IgG antibodies against the glycans of the hinge region of IgA1 are key factors for mesangial deposition and then trigger inflammation and glomerular injury. The polymeric IgA is produced after an aberrant mucosal IgA response. The displacement of mucosal B cells to systemic lymphoid organs and bone marrow may arise from abnormal trafficking of lymphocytes along the mucosa–bone marrow axis, involving changes of chemokines and adhesion molecules.[5]

Galactose-deficient IgA1 is recognized by unique autoantibodies, resulting in the formation of pathogenic immune complexes that ultimately induce glomerular injury. Thus, formation of the galactose-deficient IgA1-containing immune complexes is a critical factor in the pathogenesis of IgA nephropathy.[3]

Current data indicate that at least 4 processes contribute to development of IgA nephropathy. Patients with IgA nephropathy often have a genetically determined increase in circulating levels of IgA1, with galactose-deficient O-glycans in the hinge-region (Hit 1). This glycosylation aberrancy is, however, not sufficient to induce renal injury. Synthesis and binding of antibodies directed against galactose-deficient IgA1 are required for the formation of immune complexes that accumulate in the glomerular mesangium (Hits 2 and 3). These immune complexes activate mesangial cells, inducing proliferation and secretion of extracellular matrix, cytokines, and chemokines, which results in renal injury (Hit 4).[6]

The galactose-deficient IgA, through interaction with RR Fc alpha/gamma, may activate circulating lymphocytes and monocytes and enhance their response to chemoattractants produced by the mesangial cell, thus causing the inflammatory infiltrate to initiate and maintain the interstitial injury.

Aberrant O-galactosylation has been found in serum IgA1, in IgA1 isolated from tonsillar lymphocytes, and in IgA1 eluted from mesangial deposits. Evidence suggests that changes in IgA1 O-galactosylation lead to IgA immune complex formation and mesangial IgA deposition. Mesangial cells exposed to these IgA immune complexes proliferate and adopt a proinflammatory phenotype; they secrete cytokines, chemokines, growth factors, and extracellular matrix components, promoting glomerular inflammation and glomerulosclerosis.

Recent evidence suggests that the control of IgA1 O-glycosylation is linked to class switching from IgD to IgA1 synthesis and that the pattern of IgA1 O-glycosylation may be programmed at the time of initial antigen encounter. IgA1 glycosylation varies between systemic and mucosal sites, and the association of aberrant IgA1 galactosylation with low-affinity, polymeric IgA1 antibodies against mucosal antigens suggests undergalactosylated IgA1 may, in fact, be a mucosal glycoform of IgA1. Although suited to the mucosal compartment, when these IgA1 glycoforms enter the systemic circulation in appreciable quantities, they deposit in the mesangium and trigger glomerular inflammation.[7]

Clinical onset is frequently heralded by synpharyngitic hematuria, macroscopic hematuria during an upper respiratory tract infection. Clinical and laboratory data support a postulated extrarenal origin of the glomerular IgA1, likely derived from circulating immune complexes containing polymeric IgA1, deficient in galactose in the hinge-region O-glycans, bound by antiglycan antibodies. The galactose deficiency affects IgA1 induced by mucosal antigens and elevated circulating levels of this abnormal IgA1 are hereditable, suggesting interactions of genetic and environmental factors.

An abnormal mucosal immune response resulting in production of galactose-deficient IgA1 in IgA nephropathy patients is supported by several observations: the aberrant glycosylation affects mostly polymeric IgA1 produced by mucosal-associated IgA1-secreting cells (including those from tonsils), the synpharyngitic nature of the macroscopic hematuria, and the association of disease severity with polymorphisms of a pattern-recognition receptor, TLR9.[8]

Recurrence of IgA nephropathy has been reported in allograft, and rapid disappearance of IgA deposits is observed when kidneys with IgA deposits are transplanted in a patient without IgA nephropathy.

In the next few years, advances recently added to the knowledge of the pathogenesis of nephropathy IgA1 could provide new variables that may allow classification of patients based not only on clinical and morphological criteria but also on a greater understanding of the pathogenic basis.

IgA nephropathy and Henoch-Schonlein purpura (HSP)

IgA nephropathy and HSP share many morphologic and immunopathologic features. The most striking similarities between IgA nephropathy and HSP nephropathy (HSN) are mesangial IgA deposition, elevated serum IgA level, and IgA circulating immune complexes. The glomerular changes (diffuse or focal mesangial proliferation) in HSN are essentially the same as those in IgA nephropathy. An infective episode precedes HSN in 30-50% of patients, and the presence of Haemophilus influenzae antigen in the glomerular mesangium and the presence of IgA antibody against H influenzae in sera have been reported in patients with HSN.

Both have broadly similar geographic distributions and are rare in black persons. Coexistence in different members of the same family has been reported. Both can be encountered consecutively in the same patient. They have been described in twins, and they bear identical pathological and biological abnormalities. Kidney biopsy does not reveal any differences between the 2 conditions.

Despite these similarities, the 2 conditions are clinically different, and the pathogenesis is not clear. HSP is an acute condition, with a glomerular lesion, and mostly nonprogressive after the onset. Meanwhile, IgA nephropathy is a chronic progressive lesion, which may eventually lead to renal failure. IgA nephropathy has a male predominance. HSP occurs mostly in young children and is rare in adults, whereas IgA nephropathy mainly occurs in older children and young adults. The following are a number of useful distinctive features:

  • The peak age ranges from 15-30 years for a diagnosis of IgA nephropathy, whereas HSP is mainly seen in childhood

  • The extrarenal manifestations of HSP (skin, GI, CNS, joints) are not seen in IgA nephropathy

  • HSP has been described in association with hypersensitivity

  • Endocapillary and extracapillary inflammations, as well as fibrin deposits in the glomerulus, are more frequent in HSP

  • No major biological differences have been found between the 2 illnesses, except for a larger size of circulating IgA-containing complexes (and a greater incidence of increased plasma IgE levels in HSP

  • As tissue infiltration by leukocytes is a major feature of HSP vasculitis, a possible role of a more potent activation of the latter cells by IgA-containing complexes and/or circulating chemokines in HSP can be considered

Oxford classification of IgA nephropathy

A Working Group of the International IgA Nephropathy Network and the Renal Pathology Society have developed a consensus on the pathologic classification of IgA nephropathy.[9] The goal of the new classification was to identify specific pathological features that more accurately predict risk of progression of renal disease in IgA nephropathy. Clinical data and adequate renal biopsy material from 265 patients with IgA nephropathy were collected from 8 countries on 4 continents. Five centers from Asia, 6 from Europe, 2 from United States, 1 from South America, and 2 multicenter networks (Canada and the United States) participated in the study. The proportion of children was similar in each continent (approximately 30%). These patients were followed for a median of 5 years.

Several pathologists identified histologic variables by repeated analysis of biopsies that were consistently interpreted with a high degree of reproducibility. The following variables were identified that correlated with renal outcomes (see the image below):

  • Mesangial hypercellularity

  • Segmental glomerulosclerosis

  • Endocapillary hypercellularity

  • Tubular atrophy/interstitial fibrosis

    Glomerulus with mesangial hypercellularity and int Glomerulus with mesangial hypercellularity and intact capillary loops. Trichrome Stain, original magnification 400x. Image courtesy of Patrick D Walker, MD.

Based on these data, the committee developed the numerical scores on the presence or absence of these variables. The suggested scoring system is as below:

Mesangial cells are counted per mesangial area and a score of 0-3 is assigned for each glomerulus. A score of 0 indicates that fewer than 4 mesangial cells are present per mesangial area; a score of 1 indicates that 4-5 mesangial cells are present per mesangial area; a score of 2 indicates that 6-7 mesangial cells are present per mesangial area; and a score of 3 indicates that greater than 8 mesangial cells are present per mesangial area. Scores obtained for all glomeruli are averaged, and the resulting assigned hypercellularity score is either M0 if the mean score is less than 0.5 or M1 if the mean score is greater than 0.5.

Segmental glomerulosclerosis is defined as present (S1) if any part of the glomerular tuft is involved in sclerosis or absent (S1) if no segmental glomerulosclerosis is present.

Endocapillary hypercellularity is defined as present (E1) if hypercellularity is present within the glomerular capillary lumina and results in narrowing of the lumina or absent (E0) if no hypercellularity is present within lumina.

The percentage of the cortical area involved by tubular atrophy or interstitial fibrosis is quantitated. A score of T0, T1, or T2 is given if the percentage of involved cortical area is 0-25%, 26-50%, or more than 50%, respectively.

Biopsies with fewer than 8 glomeruli should be considered of uncertain value for prognosis.

Epidemiology

Frequency

United States

IgA nephropathy accounts for 5-10% of all primary glomerular diseases occurring in the United States. The prevalence of IgA nephropathy in the general population has been estimated to be about 25-50 cases per 100,000 population. Almost 5% of all biopsied patients have at least some IgA deposits in their glomeruli. The incidence of end-stage renal disease (ESRD) due to IgA nephropathy was 5.5 cases per million population per year; about 8.4 cases for males and 2.7 cases for females.

International

IgA nephropathy has been diagnosed worldwide, but its prevalence in different countries varies. In Pacific countries, particularly in Japan, it accounts for approximately 50% of all primary glomerular diseases. In Europe, it is responsible for 20-30%. The explanation of this apparent variability is uncertain but may be related, in part, to differing indications for renal biopsy in different centers. High incidence rates are reported in Asia, France, Italy, Finland, and southern Europe. Genetic and environmental factors may contribute to geographic differences in prevalence. Population studies in Germany and France have calculated an incidence of 2 cases per 10,000, although autopsy studies performed in Singapore suggest that 2-4.8% of the population may have IgA deposition in their glomeruli.

In the United Kingdom, Canada, and the United States, it is common practice not to recommend renal biopsy for patients presenting with isolated hematuria or mild proteinuria; examination of renal tissue is reserved for those in whom increasing proteinuria or worsening renal function develops. Such reluctance to perform biopsies inevitably reduces the number of cases of IgA nephropathy reported in the general populations of these countries.

Mortality/Morbidity

Although IgA nephropathy was thought to carry a relatively benign prognosis, an estimated 1-2% of all patients with IgA nephropathy develop end-stage renal failure each year from the time of diagnosis. In a study of 1900 patients derived from 11 separate series, the long-term renal survival was estimated to be 78-87% within a decade of presentation. Similarly, European studies have suggested that renal insufficiency may occur in 20-30% of patients within 2 decades of the original presentation.

In a study from Hong Kong, patients with mild IgA nephropathy were prospectively followed.[10] Significant proteinuria or renal insufficiency was found in numerous patients, suggesting that a significant risk of progression is present, even in patients who present with milder forms of disease.

Several studies have assessed features that predict a poor prognosis. Sustained hypertension, persistent proteinuria (especially proteinuria >1 g), impaired renal function, and the nephrotic syndrome constitute poor prognostic markers.

Typically, mortality associated with IgA nephropathy is secondary to renal failure or its complications. Morbidity may be subsequent to hypertension, electrolyte abnormalities, or other consequences of reduced renal function.

Familial IgA nephropathy has an increased risk of end-stage renal disease.

Race

The distribution of IgA nephropathy varies in different geographic regions throughout the world. It is the most common form of primary glomerular disease in Asia, accounting for as much as 30-40% of all biopsy findings, for 20% of biopsies in Europe, and for 10% of all biopsies performed for glomerular disease in North America. The reason for this wide variance in incidence is partly attributable to indications for renal biopsy in Asia compared to those in North America. In the United States, incidence of IgA nephropathy is increased in children who are Asian or white; incidence is lowest in blacks.

Sex

Incidence is higher in males than in females. Male-to-female ratios of 2:1 and 6:1 have been reported.

Age

IgA nephropathy occurs in persons of all ages but is still most common in the second and third decades of life and is much more common in males than females. IgA nephropathy is uncommon in children younger than 10 years. In fact, 80% of patients are between the ages of 16-35 years at the time of renal biopsy.

 

Presentation

History

Immunoglobulin A (IgA) nephropathy (IgAN) is characterized by recurrent episodes of macroscopic hematuria accompanied by upper respiratory tract infections or persistent asymptomatic microscopic hematuria with or without proteinuria. IgA nephropathy is frequently classified as primary (idiopathic) or secondary (associated with some other known condition).

Primary IgA nephropathy

Although the clinical presentation of IgA nephropathy varies from asymptomatic urinary abnormalities to acute renal failure, 5 different clinical syndromes are generally recognized.

The most common presentation (approximately 60-80%) of IgA nephropathy is asymptomatic microscopic urinary abnormalities with one or more episodes of intermittent gross hematuria. The recurrent macroscopic hematuria often associated with upper respiratory infection (viral pharyngitis) is traditionally regarded as the hallmark of childhood IgA nephropathy, compared with poststreptococcal glomerulonephritis (PSGN), in which hematuria usually occurs 1-2 weeks after infection. The hematuria is usually painless, but loin pain has been reported. Blood pressure may be within the reference range or elevated. Renal clearance function is within the reference range or reduced.

The second most common presentation (approximately 26%) is asymptomatic microscopic hematuria with or without mild proteinuria, hypertension, or reduced renal clearance function.

Acute nephritic presentation (approximately 12%) with heavy proteinuria, normal or low clearance function, and normal or high blood pressure is the third most common presentation.

Nephrotic syndrome may be the initial presentation in as many as 10% of patients.

Rarely, IgA nephrology may present as an acute crescentic glomerulonephritis with oliguria, edema, and hypertension.

Secondary IgA nephropathy

When renal mesangial IgA deposition occurs because of another specific clinical condition (secondary IgA nephrology), the history of that disease or signs and symptoms related to the primary condition may be present.

Physical

In the early stages of primary IgA nephropathy, no physical signs may be observed. However, early diagnosis might be suggested by a urinalysis that reveals microscopic hematuria with or without proteinuria.

Hypertension is infrequent, is mild to moderate, and is usually a late presentation of disease.

Edema due to nephrosis is reported in approximately 10% of patients.

If renal function is compromised at presentation, the patients may have signs of uremic syndrome, anemia, pallor, and lethargy.

If IgA nephrology is secondary to underlying disease, such Henoch-Schönlein purpura (HSP) or systemic lupus erythematosus (SLE), the signs and symptoms of that specific primary disease may be apparent.

Causes

The cause of primary IgA nephropathy is unknown. The conditions producing secondary mesangial IgA deposition include the following:

  • HSP

  • Celiac disease

  • Chronic ulcerative colitis

  • Crohn disease

  • Dermatitis herpetiformis

  • Psoriasis[11]

  • Cystic fibrosis

  • Sarcoidosis

  • Lung cancer

  • Colon cancer

  • Monoclonal IgA gammopathy

  • Non-Hodgkin lymphoma

  • Pancreatic cancer

  • Human immunodeficiency virus (HIV)

  • Mycoplasma infection

  • Toxoplasmosis

  • Cirrhosis

  • Pulmonary hemosiderosis

  • Cryoglobulinemia

  • Polycythemia

  • Hepatitis B

  • Systemic lupus erythematosus

  • Sjögren syndrome

  • Rheumatoid arthritis

 

DDx

 

Workup

Laboratory Studies

The diagnosis of IgA nephropathy is based on clinical history and laboratory data, but it can only be confirmed by kidney biopsy. The IgA deposits within mesangium visualized by immunofluorescence or immunoperoxidase studies confirm the IgA nephropathy.

Although circulating autoantibodies, including antiendothelin antibodies, have been reported in IgA nephropathy, none appears to be disease specific.

The following studies are used to identify immunoglobulin A (IgA) nephropathy and to rule out other causes of nephropathy:

  • Urinalysis (UA) usually reveals hematuria, proteinuria, and leukocytes. Microscopic examination shows dysmorphic RBCs and RBC casts suggestive of glomerular origin of RBC but not specific for IgA nephropathy

  • CBC count with differential to identify anemia, leukocytosis, and thrombocytopenia help exclude other underlying causes for nephritis

  • A 24-hour urine collection estimates creatinine clearance (CrCl) and protein excretion; proteinuria is associated with histologic lesions and a risk for progression; proteinuria also helps determine therapeutic course as discussed in the treatment section

  • The ratio of urine calcium (Ca) to creatinine (Cr) measures hypercalciuria (normal is < 0.2), a common cause for microhematuria

  • Serum electrolyte levels; Na, K+, Cl, and HCO3 could help detect early abnormalities

  • BUN and Cr levels estimate renal function and help in further management decisions

  • Serum C3 and C4 levels are usually normal; C3 is routinely measured to eliminate the diagnosis of postinfectious glomerulonephritis (PSAGN) or membranoproliferative glomerulonephritis (MPGN); low C3 and C4 suggest lupus nephritis

  • Antistreptolysin-O (ASO) titer or streptozyme tests help exclude PSAGN

  • Plasma polymeric IgA1 levels are elevated in 30-50% of cases, but this suggestive finding is not sufficiently specific to establish the diagnosis; measurement of the proportion of poorly galactosylated IgA1 O-glycoforms in the serum with or without measurement of poorly galactosylated IgA1-specific IgG has been proposed as a clinically useful diagnostic test[12]

Imaging Studies

Renal ultrasonography is an excellent diagnostic tool to detect structural abnormalities leading to hematuria, such as renal stone, neoplasm, cystic lesion, hydronephrosis, dilated urinary tract, and bladder abnormalities. However, it cannot be used to confirm, support, or reject the diagnosis of IgA nephropathy.

Procedures

Percutaneous renal biopsy is essential for the confirmation of IgA nephropathy. The diagnosis of IgA nephropathy is based on the presence of IgA in the glomerular mesangium. The indications for biopsy include the following:

  • Macroscopic (gross) hematuria

  • Microscopic hematuria with significant proteinuria (>2 mg/kg/d)

  • Acute nephritic syndrome (hematuria with hypertension or renal insufficiency)

  • Nephrotic syndrome

A skin biopsy, looking for IgA deposition in the dermal capillaries, has not proven to be sufficiently predictive in IgA nephropathy.[13]

Histologic Findings

The diagnostic histopathologic hallmark of IgA nephropathy by light, immunofluorescence, and electron microscopy is the presence of IgA in the glomerular mesangium. See the images below.

Glomerulus with mesangial hypercellularity and int Glomerulus with mesangial hypercellularity and intact capillary loops. Trichrome Stain, original magnification 400x. Image courtesy of Patrick D Walker, MD.
Mesangial deposits of immunoglobulin A (IgA). Fluo Mesangial deposits of immunoglobulin A (IgA). Fluoresceinated Anti-IgA Antibody, Immunofluorescence microscopy, original magnification 400x. Image courtesy of Patrick D Walker, MD.
Electron photomicrograph showing mesangial electro Electron photomicrograph showing mesangial electron dense deposits (arrow). Uranyl acetate and lead citrate stain, original magnification 12,000x. Image courtesy of Patrick D Walker, MD.

With light microscopy, the most characteristic abnormality is mesangial enlargement produced by hypercellularity and mesangial matrix increase. The severity of renal involvement can be graded based on mesangial cell proliferation.

Immunofluorescence microscopy demonstration of predominately mesangial deposition of IgA is pathognomonic of IgA nephropathy. Mesangial immunoglobulin G (IgG), immunoglobulin M (IgM), C3, and properdin may also be observed. Electron microscopy reveals mesangial or perimesangial deposits occurring in the same distribution as observed with immunofluorescence microscopy.

A retrospective cohort study on 47 pediatric patients with IgAN by Fabiano et al considered whether glomerular C4d immunostaining can be a prognostic marker in pediatric IgAN. The study found that C4d-positive patients presented higher baseline proteinuria, a progressive decline in baseline estimated glomerular filtration rate, and end-stage renal disease when compared with C4d-negative patients.[14]

Minimal lesion

The glomeruli appear normal. The number of mesangial cells per peripheral mesangial area does not exceed 3. Small foci of tubular atrophy and interstitial lymphocyte infiltration may be present.

Focal mesangial proliferation

The glomeruli show moderate to severe mesangial cell proliferation (ie, >3 mesangial cells per peripheral mesangial area). The proliferation may be associated with increased matrix, small crescent, capsular adhesions and prolapsed.

Diffuse mesangial proliferative and crescentic glomerulonephritis can occur. A small number of patients may have global sclerosis, tubular atrophy, interstitial fibrosis, and interstitial lymphocyte infiltrate.

 

Treatment

Medical Care

Immunoglobulin A (IgA) nephropathy (IgAN) is a therapeutic challenge for physicians. The optimal approach to the treatment of IgA nephropathy is uncertain. The slow progression of renal disease (ie, glomerular filtration rate [GFR] loss of 1-3 mL/min/y) hampers the ability to perform adequate studies. The 2 primary approaches to therapy for primary IgA nephropathy are nonimmunosuppressive interventions and immunosuppressive therapy.

Nonimmunosuppressive interventions to slow progression that are not specific to IgA nephropathy, include blood pressure control and, in patients with proteinuria, angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). In addition, statin therapy may be beneficial in patients with chronic kidney disease and serum low-density lipoprotein (LDL) cholesterol concentrations above goal values. Fish oil (omega-3 fatty acid) may be effective in selected patients.

Immunosuppressive therapy to treat the underlying inflammatory disease includes glucocorticoids with or without other immunosuppressive agents (eg, cyclophosphamide, cyclosporine, mycophenolate).

Not all patients need immunosuppressives; the selection of patients for therapy is based, in part, on the perceived risk of progressive kidney disease: (1) patients with isolated hematuria, (2) patients with persistent proteinuria, and (3) patients with more severe or rapidly progressive disease.

Patients with isolated hematuria, no or minimal proteinuria (< 500 mg/d), and a normal GFR typically are not treated and do not undergo biopsy and, therefore, are identified as having IgA nephropathy. However, these patients should be periodically monitored at 6- to 12-month intervals since they have an appreciable risk of progressive disease as manifested by increases in proteinuria, blood pressure, and serum creatinine.

Patients with persistent proteinuria (>500 mg/d), a normal or only slightly reduced GFR that is not declining rapidly, and only mild-to-moderate histologic abnormalities on renal biopsy are managed with nonimmunosuppressive therapies to slow progression and, perhaps, with fish oil.

Patients with more severe or rapidly progressive disease (nephrotic-range proteinuria or proteinuria persisting despite ACE inhibitor/ARB therapy, rising serum creatinine, and/or renal biopsy with more severe histologic abnormalities, but with no significant chronic changes) may benefit from immunosuppressive therapy in addition to nonimmunosuppressive interventions to slow disease progression.

The Oxford histologic classification system may assist to select patients with the worst prognosis at the time of renal biopsy.

Nonimmunosuppressive therapies

The 3 nonimmunosuppressive therapies in IgA nephropathy are (1) ACE inhibitors and/or , which are used blood pressure and/or proteinuria control to slow the rate of progression of the renal disease; (2) statin therapy, which is for lipid lowering in selected patients (with elevated LDL cholesterol) to lower cardiovascular risk, although no evidence is available to show that such therapy slows the rate of progression of renal disease; and (3) fish oil (omega-3 fatty acids at prescription strength and quality), but its role is less clear.

Angiotensin inhibition

Angiotensin inhibition with an ACE inhibitor or ARB slows the rate of progression of most proteinuric chronic kidney diseases, an effect that is mediated at least in part by lowering both the systemic blood pressure and the intraglomerular pressure, thereby minimizing both proteinuria and secondary glomerular injury (ie, not due to the primary glomerular disease itself).

Clinical trials supporting the efficacy of angiotensin inhibition in patients with IgA nephropathy are limited, but it is presumed that the mechanisms of secondary progression (ie, progression not due to the activity of the underlying disease) are similar to those in other forms of proteinuric chronic kidney disease. ACE inhibitors and ARBs significantly reduce protein excretion to a comparable degree compared with placebo or the dihydropyridine calcium channel blocker, an effect that is seen in normotensive as well as hypertensive patients.

Angiotensin inhibitors also lower the blood pressure, and evidence suggests that a goal blood pressure below the 90th percentile is associated with improved renal outcomes.[15]

Combination of ACE inhibitor and ARB

The addition of an ARB to an ACE inhibitor in patients with IgA nephropathy produces a further antiproteinuric effect.[16] This finding is consistent with meta-analyses, which found a significant (18-25%) greater reduction in proteinuria with combined ACE inhibitors and ARBs compared with monotherapy.[17] As mentioned above, a more pronounced antiproteinuric effect to below 1 g/day is a marker for better outcomes.

Despite these observations, the clinical role of combined therapy in the treatment of IgA nephropathy is uncertain. The authors suggest the use of combination ACE inhibitor and ARB therapy if the proteinuria goal of less than 500 mg/day is not reached with monotherapy at the maximum recommended dose.

Lipid-lowering therapy

Chronic kidney disease is associated with a marked increase in cardiovascular risk and is considered a coronary artery disease risk equivalent. The goal LDL cholesterol is similar to that in other patients.

Fish oil

The possible role of fish oil (prescription-strength omega-3 fatty acids, not over-the-counter food supplements) in patients with IgA nephropathy, which might act by anti-inflammatory mechanisms, is not well defined.[18]

Immunosuppressive therapy

The optimal role of immunosuppressive therapy IgA nephropathy is uncertain.[19] A variety of regimens have been used, mostly consisting of anti-inflammatory doses of glucocorticoids alone or in combination with other immunosuppressive drugs. Immunosuppressive therapy should only be attempted in patients with clinical evidence (eg, hematuria plus an increased serum creatinine or proteinuria value >1 g/day after maximal antiproteinuric therapy) and histologic evidence (eg, proliferative or necrotizing glomerular changes) of active inflammation.

Indications for immunosuppressive therapy

Indications for the use of glucocorticoids alone or in combination with other immunosuppressive agents in patients with IgA nephropathy are not well defined, and one must take into account the potential toxicity of these drugs. Most nephrologists do not treat mild, stable, or very slowly progressive IgA nephropathy with glucocorticoids or other immunosuppressive therapies.[20]

Immunosuppressive therapy should be considered only in patients with clinical features (eg, hematuria with an elevated or increasing serum creatinine value and/or protein excretion >1 g/day despite maximum antiproteinuric therapy) and histologic features (eg, active inflammation with necrotizing glomerular lesions) suggesting an adverse renal prognosis.

Patients with an acute onset of nephrotic syndrome and diffuse foot process fusion on renal biopsy are treated as if they have minimal change disease.

Glucocorticoids plus angiotensin inhibitors

Simultaneous treatment with glucocorticoids plus an angiotensin inhibitor is preferred to glucocorticoids alone and may be superior to angiotensin inhibitors alone.[21]

Glucocorticoids plus cyclophosphamide

Patients with severe or progressive disease (eg, rising creatinine, nephrotic-range proteinuria, and/or marked proliferation without crescents) who do not have significant evidence of chronic damage on kidney biopsy may benefit from combined immunosuppressive therapy with prednisone and cyclophosphamide.[22]

The treatment of crescentic, rapidly progressive glomerulonephritis in patients with IgA nephropathy has not been evaluated in randomized trials. Observational data suggest possible benefit from regimens similar to those used in idiopathic crescentic glomerulonephritis: intravenous pulse methylprednisolone followed by oral prednisone, intravenous or oral cyclophosphamide, and/or plasmapheresis.[23]

Mycophenolate mofetil

Data concerning the efficacy of mycophenolate mofetil (MMF) in the primary treatment of progressive IgA nephropathy are limited. The trials had conflicting results, ranging from no benefit, particularly in patients with advanced fibrotic disease,[24] to a reduction in proteinuria and a decrease in the rate of decline in the GFR.[25]

A short course (< 6 mo) of MMF may be considered in patients with hematuria, persistent proteinuria (>1.5 g/day), and a serum creatinine value of less than 1.5 mg/dL (133 µmol/L) despite maximum therapy with an angiotensin inhibitor in patients without marked glomerular or tubulointerstitial fibrosis on renal biopsy. Current evidence does not support the use of MMF in patients with advanced disease (serum creatinine >2.5 mg/dL).[26]

Cyclosporine

Cyclosporine has been investigated in small series of patients with IgA nephropathy. Although proteinuria may be reduced, the use of cyclosporine has been limited by the associated nephrotoxicity, leading to a rise in the serum creatinine concentration that is greater than that seen in untreated patients.[27] In addition, relapse occurs soon after the drug is discontinued.

Other possible interventions

Other interventions that have been evaluated in an uncontrolled fashion include tonsillectomy, a low-antigen diet, intravenous immunoglobulin (IVIG), and wormwood. Other drugs, such as vitamin D analogs, phenytoin, antiplatelet agent, and danazol, have also been evaluated but data are limited.

Tonsillectomy

Tonsillitis has been associated with hematuria and proteinuria in IgA nephropathy. It has been proposed that the tonsils are a source of abnormal IgA that forms immune complexes and deposits in the glomeruli.[28] The role of tonsillectomy in IgA nephropathy remains unclear, but in several studies, tonsillectomy in combination with some immunosuppressive therapy improved renal outcomes in patients with relatively mild renal injury.[29] However, other studies reported no benefit following tonsillectomy.[30]

Low-antigen diet

A low-antigen diet consists of avoiding gluten, dairy products, eggs, and most meats. The rationale for this regimen is that dietary macromolecules may be responsible for activating the mucosal IgA system. When given to 21 consecutive patients with IgA nephropathy, protein excretion was markedly reduced or fell into the normal range in 11 of 12 patients whose baseline rate was more than 1 g/day. In addition, repeat renal biopsy showed significant reductions in mesangial IgA and complement deposition and mesangial cellularity.[31]

The benefits in the above study have not been confirmed, and a report describes using a gluten-free diet alone for several years that did not demonstrate improvement in either proteinuria or renal function despite a reduction in the level of circulating IgA-containing immune complexes.

Intravenous immunoglobulin

High-dose IVIG has been tried in severe IgA nephropathy characterized by heavy proteinuria and a relatively rapid decline in GFR.[32] Eleven patients (9 with IgA nephropathy and 2 with the related disorder Henoch-Schönlein purpura) were treated with IVIG at a dose of 1 g/kg for 2 days per month for 3 months, followed by an intramuscular preparation given every 2 weeks for another 6 months. IVIG therapy was associated with a reduction in protein excretion (5.2 to 2.3 g/day), prevention of a continued reduction in GFR (loss of 3.8 mL/min per month prior to therapy vs stable GFR after therapy), and decreased inflammatory activity and IgA deposition on repeat renal biopsy. The benefit of IVIG needs to be confirmed in a larger number of patients.

Wormwood

The herbal supplement wormwood (Artemisia absinthium) may inhibit inflammatory cytokines such as tumor necrosis factor-alpha and nuclear factor-kappa B. One study examined the effect of wormwood (1.8 g/day for 6 mo) on protein excretion in 10 patients with biopsy-proven IgA nephropathy, a creatinine clearance greater than 90 mL/min; and protein excretion greater than 500 mg/day despite angiotensin inhibition.[33] At 6 months, the mean urine protein-to-creatinine ratio decreased from 2.3 to 0.3. The reduction in proteinuria persisted for 6 months after stopping the herbal supplement. The creatinine clearance remained unchanged. The long-term effects of wormwood on the course of IgA nephropathy have not been evaluated.

Monitoring disease activity

There are no immunologic-specific markers to identify continued immunologic activity. As a result, clinical parameters are typically used, whether or not the patient is receiving immunosuppressive therapy. The major parameters that are serially monitored are the urine sediment, serum creatinine concentration or estimated GFR, and protein excretion.

Hematuria

Persistent hematuria is generally a marker of persistent immunologic activity, but not necessarily of progressive disease. Hematuria alone does not require any form of therapy, but monitoring over time is essential since some patients develop proteinuria and progressive disease.

Proteinuria

Protein excretion above 1 g/day is a marker of more severe disease and is a major risk factor for disease progression unless the degree of proteinuria is reduced. Because of the prognostic importance of the degree of proteinuria, an initial 24-hour urine collection for both protein and creatinine is recommended. Increasing proteinuria may be due to ongoing active disease and/or secondary glomerular injury due to nonimmunologic progression. It is often not possible to distinguish between these 2 possibilities, except for a rapid increase in protein excretion, which is only seen with active disease.

A study by Kamei et al found that proteinuria persisted in 34% (27 out of 79 patients) of child and adolescent patients after 2-year combination therapy. The study concluded that risk factors for persistent proteinuria after 2-year combination therapy were 24 hour urinary protein excretion and the rate of glomeruli with crescents at diagnosis.[34]

Serum creatinine

Serum creatinine concentration, unless it is rapidly rising, permits an estimation of the GFR. Most patients with chronic IgA nephropathy have stable or slowly progressive disease. The rate of loss of GFR is often as low as 1-3 mL/min per year, a change that may not raise the serum creatinine level to above normal values for a number of years. Because of a compensatory rise in single-nephron GFR among less injured glomeruli, a stable normal serum creatinine level or estimated total kidney GFR does not necessarily indicate stable disease.

Pregnancy

Pregnancy is generally well tolerated in patients with IgA nephropathy and a normal or near-normal GFR. As with most other chronic kidney diseases, the risk of worsening renal disease with pregnancy is increased in women with an initial GFR below 70 mL/min, uncontrolled hypertension, or severe arteriolar and tubulointerstitial disease on renal biopsy.[35]

Angiotensin inhibitors and some immunosuppressive drugs, particularly cyclophosphamide and MMF, should be discontinued at the earliest indication of pregnancy or prior to attempted conception because of risks to the fetus.

End-stage renal disease

Patients who progress to end-stage renal disease can be treated with dialysis or transplantation.

Surgical Care

Generally, surgical care is not necessary except for dialysis access or renal transplantation.

Renal transplantation

Transplantation is the treatment of choice for individuals with end-stage renal disease (ESRD) due to IgA nephropathy. Renal allografts in IgA nephropathy recipients exhibited a similar 10-year survival rate compared with allografts in recipients with either non–IgA glomerular or nonglomerular disease. Several retrospective analyses have found no increased risk of recurrence based on living versus deceased donor status.[36]

Histologic recurrence, with or without evidence of clinical disease, is observed in most cases. Recurrent of IgA deposition may result in a wide spectrum of manifestations, ranging from an incidentally noted histologic finding to mesangioproliferative glomerulonephritis associated with hematuria, proteinuria, and progressive renal dysfunction.[37]

It is possible that in some renal transplant recipients with primary IgA nephropathy, the donor source may have an effect on the timing and likelihood of recurrence in the allograft. Therefore, the expected advantage in allograft survival with a living-related compared with deceased donor source may be negated. Overall, however, there does not seem to be any basis for avoiding a living-related donor source, given the reported equivalence of graft survival independent of IgA nephropathy recurrence, the expected deceased donor waiting list time, and a reported decrease in patient mortality and increase in graft survival with earlier transplantation in relation to time on dialysis.[38]

Consultations

Because IgA nephropathy has the potential to progress to end-stage renal disease, consultation with a pediatric nephrologist is necessary.

Diet

An American Heart Association step I diet is recommended for all children older than 2 years. Patients may require consultation with a dietitian to determine a renal diet if renal insufficiency develops.

Activity

Typically, no activity restriction is necessary.

 

Medication

Medication Summary

The risks and benefits of immunoglobulin A (IgA) nephropathy (IgAN) treatment with steroids, fish oil, ACE inhibitors, or ARB and immunosuppressant (eg, mycophenolate mofetil) should be discussed with patients and parents. These agents theoretically may protect the kidney and prolong the interval between onset and renal failure.

Anti-inflammatory and immunosuppressive agents

Class Summary

These agents elicit anti-inflammatory and immunosuppressive properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli and reduce immune-mediated renal injury resulting from IgA deposition in the kidney.

Prednisone (Deltasone, Prednisone Intensol, Rayos)

Potent anti-inflammatory and immunosuppressive therapy with corticosteroids has been reported to reduce the rate of progression of IgAN.

Methylprednisolone (DepoMedrol, Medrol, Medrol Dosepak)

Potent anti-inflammatory and immunosuppressive therapy with corticosteroids has been reported to reduce the rate of progression of IgAN

Fish oil

Class Summary

Several investigators have suggested that fish oil delays the progression of renal disease. The precise mechanism is not fully understood.

Omega-3 polyunsaturated fatty acid (Promega, Lovaza)

May be beneficial by decreasing mediators of glomerular injury and decreasing platelet aggregation. Omega-3 fatty acids may be used as nondrug dietary supplements in early high-risk coronary disease and IgAN.

Angiotensin-converting enzyme (ACE) inhibitors

Class Summary

In 1980, captopril became the first ACE inhibitor approved by the US Food and Drug Administration. Subsequently, at least 40 compounds have been identified. ACE inhibitors reduce the production of angiotensin II, thereby, lowering intraglomerular filtration pressure, reducing proteinuria, and slowing the decline of glomerular function in several chronic renal diseases. All ACE inhibitors probably have similar renal protective effects.

Enalapril (Vasotec)

Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion.

Angiotensin Receptor Antagonist

Class Summary

Angiotensin II receptor antagonists may be considered if ACE inhibitors are not tolerated.

Losartan (Cozaar)

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, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.

Angiotensin II receptor blockers reduce blood pressure and proteinuria, protecting renal function, and delaying onset of end-stage renal disease.

Immunosuppressant Agent

Class Summary

Limited data exist for use of mycophenolate mofetil (MMF). A short course (< 6 months) of MMF in patients with persistent proteinuria (>1.5 g/d) and well-maintained renal function (serum creatinine < 1.5 mg/dL) despite maximum ACE inhibitor/ARB therapy may be considered in patients with mild renal histopathology on biopsy.

Mycophenolate (CellCept)

Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.

Two formulations are available and are not interchangeable. The original formulation, mycophenolate mofetil (MMF, Cellcept) is a prodrug that once hydrolyzed in vivo, releases the active moiety mycophenolic acid. A newer formulation, mycophenolic acid (MPA, Myfortic) is an enteric-coated product that delivers the active moiety.

 

Follow-up

Further Outpatient Care

Routine follow up is important for monitoring the progression of disease.

Medications must be taken as prescribed.

A healthy diet and lifestyle is important.

Patients should avoid obesity, smoking, and other activities that negatively influence the cardiovascular system.

Further Inpatient Care

Inpatient care is not necessary in patients with immunoglobulin A (IgA) nephropathy (IgAN), except for complications of renal failure, hypertension, dialysis, or renal transplantation.

Inpatient & Outpatient Medications

No specific change of medication is necessary to transition from inpatient to outpatient therapy.

Transfer

No transfer is necessary.

Deterrence/Prevention

No methods for deterrence or prevention of IgA nephropathy are known.

Complications

Primary complications include those related to uncontrolled hypertension (eg, seizure, stroke, end-organ damage), renal insufficiency (eg, growth failure, bone demineralization, anemia), and adverse reactions to one of the prescribed medications.

Prognosis

IgA nephropathy was initially thought to be a benign disease, but it is now recognized that over 25 years of observation, it can slowly progress to end-stage renal disease in up to 50% of affected patients.[39] The remaining patients may sustain clinical remission or have persistent low-grade hematuria and/or proteinuria. The prognosis is difficult to predict with accuracy in an individual patient, but important risk factors for progressive renal disease have been identified.

Patients with IgA nephropathy who have little or no proteinuria (>500-1000 mg/d) have a low risk of progression, at least in the short term. However, proteinuria and renal insufficiency develop in a substantial proportion of patients over the long term.[40] Among patients who develop overt proteinuria and/or an elevated serum creatinine concentration, the rate of progression to end-stage renal disease is approximately 15-25% at 10 years and 20-30% at 20 years.[41]

The rate of progression is typically slow, with the glomerular filtration rate (GFR) often falling by as little as 1-3 mL/min/y, a change not associated with an elevation in the serum creatinine concentration in the short term. In one report, repeat renal biopsies were performed at 5 years in 73 patients with persistent proteinuria and a normal or near-normal initial serum creatinine value. Histologic improvement occurred in only 4%, with 41% remaining stable and 55% showing progressive glomerular and secondary vascular and tubulointerstitial injury. An increase in serum creatinine to more than 1.5 mg/dL (133 µmol/L) was associated with major pathologic lesions.[42]

The patients who develop progressive disease typically have one or more of the following clinical or laboratory findings at diagnosis, each of which is a marker for more severe disease.

  • A reduction in GFR, as manifested by an elevated serum creatinine concentration at diagnosis or during the course of the disease, is associated with a worse renal prognosis[43]

  • Hypertension (BP >95 percentile for height and sex) is predictive of a worse outcome; a higher mean arterial pressure is associated with a higher risk of progressive renal disease[15]

  • With regard to proteinuria, the rate of progression is very low among patients excreting less than 15 mg/kg/d and is greatest among those excreting more than 50 mg/kg/d[44]

Patient Education

Inform patients about specific disease processes when possible.

Encourage patients to avoid risk factors, such as smoking, drugs, obesity, and poor medication compliance.

For patient education resources, see the Kidneys and Urinary System Center, as well as Blood in the Urine.