IgA Nephropathy

Practice Essentials

Immunoglobulin A (IgA) nephropathy is characterized by predominant IgA deposition in the glomerular mesangium.^[1]  It is one of the most common causes of glomerulonephritis in the world.^{[2, 3]}  IgA nephropathy was first described by Berger and Hinglais in 1968, and is also known as Berger disease.^{[4]  [5]}

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 illnesses 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.

For patient education resources, see Blood in the Urine.

For further information, see Mayo Clinic - Kidney Transplant Information.

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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]  Immune complexes formed by IgG or IgA antibodies with galactose-deficient IgA lead to deposition in the glomerulus.

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. Any bacterial or viral infections can precipitate IgA nephropathy.

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. 

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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 socioeconomically deprived areas compared with the least deprived ones. The variation was not explained by the demographics of the underlying population.^[8] .

In a study by Zhou from east China utilizing renal biopsies from 2001-2017, IgA nephropathy was the most common type of primary glomerulonephritis, accounting for 50% of cases. The diagnosis rate of IgA nephropathy remained steady over that 15-year period; however, the prevalence of membranous nephropathy increased, becoming the second most common type.^[9]

In Asia, routine urinalyses are performed for schoolchildren, and kidney 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.^[10]  

The prevalence of IgA nephropathy is highest in geographic areas with large numbers of endemic helminthic species that infest humans, and most of the IgA nephropathy susceptibility loci identified by genome-wide association studies include genes involved in the maintenance of the intestinal epithelial barrier and response to mucosal pathogens, which would confer protection against helminthic infestation. Thus, the increased risk of IgA nephropathy in these populations may be an untoward consequence of a protective adaptation to helminthic infections. It would also explain the association of mucosal infections as a frequent trigger for IgA nephropathy.^[11]

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 Asians and whites 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.^[12] 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.

Lifestyle and risk of progression to end stage renal disease

In a study by Huang et al in Chinese subjects with IgA nephropathy, which compared cases that progressed to end-stage renal failure (ESRF) with controls that did not, the proportion of patients who were males, smokers, alcohol drinkers, and physically inactive was signficantly higher in cases than in controls. Alcohol use proved to be an independent risk factor for progression to ESRF, while regular exercise was associated with decreased risk; males who did not exercise seemed especially likely to progress to ESRF. These authors concluded that physical exercise should be encouraged in IgA nephropathy patients, especially in males, for a better renal outcome, and cessation of alcohol use might help prevent disease progression.^[13]

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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. Efforts have been made to determine clinical and histological features associated with progression to ESRD.^{[14, 15]}

The Oxford classification of IgA nephropathy, or MEST score, published in 2009, comprises four histological features that are independent predictors of clinical outcome.^[2] The IgA Nephropathy Classification Working Group added crescents to the Oxford classification, to form the MEST-C score.^[16]  The features that determine the MEST-C score are as follows: 

• M – Mesangial cellularity, defined as more than four mesangial cells in any mesangial area of a glomerulus: M0 is mesangial cellularity in < 50% of glomeruli; M1 ≥50%
• E – Endocapillary proliferation, defined as hypercellularity due to an increased number of cells within glomerular capillary lumina: E0 is absence of hypercellularity; E1 is hypercellularity in any glomeruli
• S – Segmental glomerulosclerosis, defined as adhesion or sclerosis (obliteration of capillary lumina by matrix) in part of but not the whole glomerular tuft: S0 is absence of segmental glomerulosclerosis, S1 is presence of segmental glomerulosclerosis in any glomerulus
• T – Tubular atrophy/interstitial fibrosis, defined as the estimated percentage of cortical area showing tubular atrophy or interstitial fibrosis, whichever is greater: T0 is 0-25%; T1 is 25-50%; T2 is >50%
• C – Crescents: C0 (no crescents), C1 (crescents in less than one-fourth of glomeruli), and C2 (crescents in over one-fourth of glomeruli).

The clinical significance of the individual MEST-C features is as follows:

• M1- Worse outcomes than M0
• E1- Worse renal survival in patients not on immunosuppression and improved renal survival with immunosuppression
• S1- Predictive of worse outcomes
• T- Strongest predictor of worse outcomes
• C1 - Predictive of worse outcomes if no immunosuppression is given, but not if immunosuppression is used; C2 is predictive of worse outcomes regardless of Immunosuppression

Other predictors of poor renal outcomes include the following:

• High serum creatinine level (>120 mmol/L) at presentation
• Hypertension (diastolic >95 mm hg or need for antihypertensive treatment)
• Proteinuria: Urinary protein excretion < 1 g/24 hr is associated with 56% renal survival and >3.5 g/24 hr with 7% renal survival^[17]
• Extensive interstitial fibrosis and tubular atrophy on renal biopsy
• C4d staining on biopsy

A calculator for estimating the risk of progression to ESRD in patients with IgA nephropathy has been developed by Xie et al, based on a cohort of 619 Chinese patients.^[18] It has yet to be validated in other ethnic groups. The calculator uses four variables: glomerular filtration rate, hemoglobin level, serum albumin level, and systolic blood pressure.

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History

Patients with Iga nephropathy may be asymptomatic, with persistent microscopic hematuria and proteinuria and often hypertension. This presentation occurs mostly in adults. Impairment of renal function can occur in such cases, and remission is uncommon. 

Symptomatic presentations in patients with IgA nephropathy include the following:

• Episodic gross hematuria
• Rapidly progressive glomerulonephritis –  This is sometimes seen as a late presentation; these patients  may progress to needing renal replacement therapy rapidly.
• Proteinuria- less than 3 gms/day. (More common)
• Nephrotic syndrome – More than 3.5 gms of proteinuria with edema, hypoalbuminemia, hypertension, and hyperlipidemia.
• Chronic renal failure 

Episodic gross hematuria from IgA nephropathy has the following features:

• Eighty percent of these episodes are associated with upper respiratory tract infections, mainly acute pharyngotonsillitis; this synchronous association of pharyngitis and macroscopic hematuria has been dubbed synpharyngitic nephritis.
• Gross hematuria usually appears simultaneously or within the first 48-72 hours after the infection begins; persists less than 3 days; and, in about a third of patients, is accompanied by loin pain, presumably due to renal capsular swelling
• Seen mostly in children and young adults
• These patients have a high likelihood of remission.

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Physical

Physical examination findings in patients with IgA nephropathy are usually unremarkable. A minority of patients present with hypertension. More commonly, however, hypertension manifests later in the course of the disease or when patients develop chronic kidney disease and end-stage renal disease (ESRD). Nephrotic syndrome could manifest as edema in lower extremities.

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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 more than one-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.^[19] 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.^[20] 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.^[21] 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.^[22]

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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 or CKD-EPI. 

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 should be 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:

• Acute severe immune injury can manifest as necrotizing glomerulonephritis and crescent formation
• Alternatively, only mild glomerular injury is observed with gross hematuria, and kidney injury is presumably due to tubular occlusion by RBCs; this is reversible, and renal function recovers with supportive measures

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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.

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

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. A few patients have segmental necrotizing lesions with crescent formation due to extensive disruption of the capillaries. These findings can be helpful prognostic tools in patients with IgA nephropathy (see Follow-up/Prognosis).

Electron microscopy

Electron microscopy shows mesangial hypercellularity and increased mesangial matrix. The important finding is electron-dense deposits of IgA 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. Subendothelial deposits are often present when there is endocapillary hypercellularity.

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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. The deposits are predominantly polymeric IgA of the IgA1 subclass; in addition, IgG is found in 43% of cases, and IgM in 54%.^[11] C3 is often present. Polyclonal deposits, often with more lambda than kappa light chains, are seen. Presence of C4d indicates a worse prognosis.

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

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Approach Considerations

The treatment of IgA nephropathy in any individual patient should be tailored to that patient's presentation, given the conflicting results of many studies of this disease. All patients should be given supportive therapy with renin-angiotensin system blockade and dietary sodium restriction. Tonsillectomy is appropriate only for patients with recurrent tonsillar infections.

Control of proteinuria is prudent, since there is a mostly linear association between the severity of proteinuria and decline in estimated glomerular filtration rate (GFR). Use of immunosuppression should be determined by considering the rate of progression, comorbidities, and whether alarming features are present on biopsy. Currently, corticosteroids are the option with the most convincing evidence to support their use; however, steroids preferably should not be given for more than 6 months.

Cyclophosphamide should be reserved for rapidly progressive crescentic glomerulonephritis. Most nephrologists agree with not using immunosuppression when the GFR is less than 30 mL/min/1.73 m², although others would suggest a different GFR threshold. Regardless, the lower the GFR, the higher the risk of adverse events and the lower the likelihood of benefiting from immunosuppressants. Immunosuppression should definitely be avoided when the biopsy shows large amounts of interstitial fibrosis and tubular atrophy. 

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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 kidney disease (ESKD) occur in about 20-40% of patients within 20 years of presentation. Currently, multiple treatment options are available; no one therapy is appropriate for all patients. No randomized controlled trial has verified the value of the MEST-C score (see Overview/Prognosis) in making treatment decisions, but proteinuria seems to be the biggest prognostic factor. There are no trials in patients with a urinary protein-to-creatinine ratio (UPCR) of < 0.5 g/day.

General recommendations include the following:

• In patients with isolated hematuria (ie, without proteinuria or hypertension) monitor with urinalysis, renal function testing, and blood pressure measurement.
• Treat hypertension early and aggressively with renin-angiotensin blockade; a reasonable goal is a blood pressure of 130/80 mm Hg if proteinuria is < 1g/day.^[23]  If proteinuria is > 1 g/day, then 125/75 mm Hg should be the goal.
• Steroids are most beneficial if more than 1 g of proteinuria is present in a 24-hour urine specimen.^[24]
• Goal UPCR is < 0.5-0.75 g/day with renin-angiotensin blockade.
• If UPCR is > 1.5 g/day despite maximum renin-angiotensin blockade for 4-6 months, steroids can be added, but not if the GFR is < 25 mL/min/1.73m².^[25]
•  If UPCR is persistently 0.75-1.5 g/day, the short-term benefits of steroid ues remain uncertain.
• The presence of crescents on biopsy in a sample with more than 10 glomeruli is an indication for treatment with cyclophosphamide.
• The role of direct renin inhibitors and mineralocorticoid receptor antagonists have not been evaluated in a randopmize controlled trial.
• If GFR > 25 mL/min/1.73 m² and UPCR is > 0.6 g/day there is a benefit to treatment.^[26]

Renin-angiotensin blockade

Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are the preferred agents for lowering blood pressure and decreasing proteinuria.^[27]  In a randomized, controlled trial in 44 patients with biopsy-proven IgA nephropathy who had proteinuria and normal or moderately reduced renal function, Kaplan-Meier renal survival after 7 years was 92% in patients treated with enalapril versus 55% in the control group (P < 0.05).^[28]  

Results of a prospective, open-label, multicenter, centrally randomized, controlled trial in 97 patients suggested that the combination of the ACEI ramipril with prednisone was more effective than ramipril alone in discouraging progression of renal disease associated with IgA nephropathy.^[29]  The combination of an ACEI with an ARB is used by some clinicians, especially if serum creatinine is monitored cautiously, but this approach is not supported by randomized controlled trial data; although it decreases proteinuria, it is associated with greater risk of acute kidney injury and hyperkalemia. 

Corticosteroids and other immunosuppressive agents

Some trials of corticosteroid therapy for IgA nephropathy have shown positive outcomes. However, the possible benefit from corticosteroids should be weighed against the risks of immunosuppression for the individual patient.

In general there is no benefit gained by adding corticosteroids to renin-angiotensin blockade when proteinuria < 1 g/day. When proteinuria is 1-3 g/day, steroids can be added, but benefits take 6-8 years to become manifest. If proteinuria is > 3 g/day, the benefit of steroids with renin-angiotensin blockade takes 2-3 years to manifest.

Guidelines for IgA nephropathy from Kidney Disease: Improving Global Outcomes (KDIGO) suggest that a 6-month course of corticosteroid therapy may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control), and a glomerular filtration rate (GFR) > 50 ml/min/1.73m².^[30]  

Corticosteroid regimens studied have included the following^[31] :

• Intravenous methylprednisolone ,1 g/day for 3 consecutive days at months 1,3, and 5; plus oral prednisone for 6 months at 0.5 mg/kg every other day^[32]
• Oral prednisone for 6 months at 1 mg/kg/day for 2 months followed by 0.2 mg/kg/day^[29]
• Oral prednisone for 6-8 months at 0.8-1 mg/kg/day for 2 months, then reduced to 5-10 mg every 2 weeks^[33]

A retrospective study of 1147 patients from the European Validation Study of the Oxford Classification of IgAN (VALIGA) cohort classified according to the Oxford-MEST classification (see Overview/Prognosis) showed a significant reduction in proteinuria, a slower rate of renal function decline, and greater renal survival with corticosteroid therapy. In contrast to KDIGO recommendations, corticosteroids reduced the risk of progression even in patients with an initial estimated GFR ≤50 mL/min/1.73 m² and in direct proportion to the extent of proteinuria. Over median follow-up of 4.7 years, the annual decline in renal function with corticosteroid therapy versus no steroid use was 1.0 versus 3.2 mL/min/1.73 m², respectively (P = 0.004).^[34]  

In contrast, the TESTING trial (Therapeutic Evaluation of STeroids in IgA Nephropathy Global study), which enrolled patients with proteinuria > 1 g/d and estimated GFR (eGFR) of 20 to 120 mL/min/1.73 m², showed that high-dose oral methylprednisone was associated with significantly increased rates of serious adverse outcomes in participants with >1 g/day proteinuria. Patients were randomized 1:1 to oral methylprednisolone (0.6-0.8 mg/kg/d; maximum, 48 mg/d) or placebo for 2 months, with subsequent weaning over 4-6 months. While proteinuria and eGFR levels were improved in the methylprednisone arm, the trial was stopped after 1.5 years due to serious adverse events.^[35]  The TESTING-2 trial is in progress in Asian countries and Australia and Canada; results are expected in 2023. 

The KDIGO guidelines suggest not treating with corticosteroids combined with cyclophosphamide or azathioprine unless the patient has crescentic IgA nephropathy with rapidly deteriorating kidney function.^[30]  Use of mycophenolate mofetil has been controversial, as studies have been small in size and studies have reported negative results.^{[23, 36]}  The KDIGO guidelines do not recommend use of mycophenolate mofetil.^[30]

The Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) trial showed that after 3 years, full clinical remission had occurred in 5% of patients in the supportive-care group, as compared with 17% of patients who received immunosuppression with steroids plus cyclophosphamide followed by azathioprine. STOP-IgAN enrolled patients 18-70 years of age with proteinuria > 0.75 g/day with hypertension and GFR of 30-90 mL/min/1.73 m². Patients with crescentic lesions were excluded.^[37]

The primary end point was UPCR < 0.2 g/day and a decrease in eGFR < 5 mL/min/1.73 m² from baseline at 3 years. There was no significant difference in the annual decline in eGFR between the two groups, and patients in the immunosuppression arm were more likely to experience significant adverse effects (severe infections, impaired glucose tolerance, and weight gain of more than 5 kg in the first year of treatment).^[37]

The STOP-IgAN authors note that the study results do not apply to patients who have proteinuria > 3.5 g/day, as such patients have a very high risk of progression and have been reported to have a particularly good response to corticosteroids.^[37]  Thus, use of immunosuppression should be considered only for patients with active disease and rapid progression.

A 2015 Cochrane review of immunosuppressive therapy for IgA nephropathy concluded that corticosteroid therapy may lower risks of kidney disease progression, proteinuria, doubling of serum creatinine, and need for dialysis or transplantation. However, the review concluded that the optimal management of IgA nephropathy remains uncertain, and larger controlled trials are needed.^[38]  

The phase 2b NEFIGAN trial demonstrated a 24% decrease in mean UPCR in patients receiving a novel targeted-release formulation of oral budesonide that delivers the drug to the distal ileum, thus targeting the Peyer patches; this agent is twice as potent as prednisone. Mean UPCR of participants was 1.2 g/day and mean eGFR was 78 mL/min/1.73 m². Budesonide 16 mg/day, added to optimized renin-angiotensin system blockade, reduced proteinuria by around 25-30% compared with placebo. Patients in the treatment group experienced an increased rate of steroid-related events including acne, hypertension, cushingoid features, mood swings, and hirsutism. The authors conclude that the results support the hypothesis that mucosal immune dysfunction has a significant role in the pathogenesis of IgA nephropathy.^[39]  A phase 3 trial of targeted-release budesonide, the NefigArd trial, is currently in progress.

Fish Oil

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 administered to patients with declining renal function.^{[40, 10]} 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.Current evidence does not support the use of fish oil as monotherapy, but some physicians combine fish oil with other therapies.

Calcitriol

A study by Liu examined the effect of calcitriol on urinary protein excretion in patients with IgA nephropathy. The study found that adding calcitriol to a renin-angiotensin system inhibitor resulted in a safe decrease in proteinuria.^[41]

Rituximab

CD19 B-cells are increased in IgA nephropathy. However, in a randomized controlled trial in 34 patients with proteinuria and renal dysfunction, treatment with rituximab did not significantly improve renal function or proteinuria over the course of 1 year.  Rituximab had no significant effect on GFR, proteinuria, galactose-deficient IgA1 levels, or IgG autoantibodies. Consequently, the authors do not recommend the use of rituximab in these patients.^[42]

Miscellaneous drugs

See the list below:

• Mycophenolate mofetil: Not effective in Americans or Europeans; possibly useful in Asians.
• Azathioprine: Ineffective and possibly even harmful
• Calcineurin Inhibitors: Possibly effective; nephrotoxic and not studied in randomized controlled trials
• Adrenocorticotropic hormone (ACTH) gel (Acthar gel): A prospective pilot study of ACTH gel in a dose of 80 units subcutaneously twice weekly for 6 months reported that patients with  urinary protein >1 g/24-hour and eGFR >30 ml/min had a significant reduction in 24-hour urinary protein with stable eGFR at 12-month follow-up^[43]
• Hydroxychloroquine: A randomized controlled study with 30 patients in each arm demonstrated that when added to optimized renin-angiotensin-aldosterone system inhibition, hydroxychloroquine significantly reduced proteinuria in patients with IgA nephropathy over 6 months without evidence of adverse events; however, the short treatment period and lack of post-withdrawal observations limit conclusions about long-term efficacy and safety.^[44]
• Cyclophosphamide: Effective in 1 small controlled study in patients with crescentic disease^[45] ; efficacy not confirmed in the STOP-IgAN trial, which excluded crescentic disease

Drug trials

Trials of the following agents are in progress or completed:

• Atacicept: Atacicept blocks the effects of BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand), both of which are increased in IgA nephropathy and correlate with disease activity.
• OMS721: OMS721 (narsoplimab) is a human monoclonal antibody that targets mannan-binding lectin-associated serine protease–2 (MASP-2), the effector enzyme of the lectin pathway of the complement system. 
• Sparsentan: This agent is a dual angiotensin II and endothelin-1 receptor antagonist

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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.^{[46, 47]}

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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.^[48]

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.^[49] 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.^[50]

Especially in Japan, tonsillectomy has been combined with steroid pulse administration for clinical remission.^[51] 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.^[10]   In contrast, KDIGO guidelines suggest that tonsillectomy not be used for IgA nephropathy.^[30]  Currently, most experts reserve tonsillectomy for patients who have tonsillar infection or tonsillitis.

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Kidney Transplantation

Kidney transplantation is effective in patients with IgA nephropathy, but the disorder frequently recurs after transplantation (20-60%). The higher recurrence rates in transplantation from living related donors suggest genetic susceptibility to the disease and high risk especially is disease is aggressive with cresents and treatment can be very difficult.^[52]  

Some patients with post-transplantation IgA nephropathy present with microscopic hematuria and proteinuria, while 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. There is little evidence that any specific immunosuppressive regimen decreases recurrence, but analysis of the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) suggests increased risk with steroid withdrawal.^[53]

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.^[54]

• References

Guidelines Summary

Kidney Disease: Improving Global Outcomes (KDIGO) Guidelines

In its clinical practice guidelines for glomerulonephritis, Kidney Disease: Improving Global Outcomes (KDIGO) recommends the following for patients with IgA nephropathy^[30] :

• All patients should be assessed by biopsy for secondary causes of IgA nephropathy
• Risk of progressession should be evaluated by measurement of proteinuria, blood pressure, and estimated glomerular filtration rate (eGFR) at the time of diagnosis and during follow-up
• Pathological findings can be used to assess prognosis

KIDGO recommendations for IgA nephropathy treatment include the following^[30] :

• Long-term therapy with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) is recommended for patients with proteinuria >1 g/day \ with up-titration of the drug based on blood pressure (grade 1B).
• ACEI or ARB therapy is suggested for proteinuria of 0.5-1 g/d (grade 2D).
• Upward titration of the ACEI or ARB as far as tolerated is suggested, to achieve proteinuria of 1 g/d (grade 2C).
• Blood pressure treatment goals: < 130/80 mm Hg with proteinuria of 1 g/d; < 125/75 mm Hg if initial proteinuria is >1 g/d (not graded)
• A 6-month course of corticosteroid therapy may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control), and a GFR >50 ml/min/1.73m² (grade 2C).
• Fish oil may be given to patients who have persistent proteinuria ≥1 g/d despite 3–6 months of optimized supportive care (including ACEI or ARB treatment and blood pressure control) (grade 2D).

KIDGO guidelines recommend against using mycophenolate mofetil, antiplatelet agents, or tonsillectomy for the treatment of IgA nephropathy (grade 2C). In addition, the following treatments are recommended against unless the patient has crescentic IgA nephropathy with rapidly deteriorating kidney function^[30] :

• Corticosteroids combined with cyclophosphamide or azathioprine (grade 2D)
• Immunosuppressive therapy in patients with GFR < 30 ml/min/1.73m² (grade 2C)

Crescentic IgA nephropathy is defined by KIDGO as IgA nephropathy with crescents in more than 50% of glomeruli in the renal biopsy with rapidly progressive renal deterioration.^[30]  

Japan Ministry of Health Labour and Welfare (MHLW) and the Japanese Society of Nephrology (JSN) Guidelines

Clinical guidelines for managment of IgA nephropathy have been developed by the Japan Ministry of Health Labour and Welfare (MHLW) and the Japanese Society of Nephrology (JSN).^[10] These guidelines are meant to to address the clinical situation and establish a standard treatment in Japan, and recommend focusing the managent of IgA nephropathy on prevention of renal dysfunction. Treatments to suppress IgA nephropathy progression are based on the following patient factors:

• Renal function
• Urinary protein level
• Age
• Renal histopathological findings

Treatments to be considered, if necessary. are as follows:

• Reduce blood pressure
• Reduce salt intake
• Normalize lipid and glucose metabolism
• Reduce body weight
• Smoking cessation 

In patients with urinary protein level ≥1 g/day and chronic kidney disease (CKD) stage G1-3b, the guidelines give a strong recommendation (grade A) for the use of ACEI or ARB therapy to control progression of renal dysfuntion. In patients with urinary protein level ≥1 g/day and chronic kidney disease (CKD) stage G1-2, the guidelines recommendations include the following:

• High-dose oral steroid therapy: prednisolone at 0.8–1.0 mg/kg for about 2 months, followed by gradual tapering over about 6 months (grade B)
• Steroid pulse therapy: methylprednisolone 1 g for 3 days by infusion (or IV) every other month, 3 times plus prednisolone 0.5 mg/kg, every other day, for 6 months (grade B) 

The following treatment options may be considered, but only weak evidence supports these recommendations (grade C1)^[10] :

• ACEI or ARB therapy to reduce proteinuria in patients with urinary protein level of 0.5–1.0 g/day
• Steroid therapy to reduce proteinuria in patients with urinary protein level of 0.5–1.0 g/day and CKD stage G1-2
• Tonsillectomy alone, in patients with recurrent tonsillitis, or combined with steroid pulse therapy to lower the progression of renal dysfunction
• Off-label use of cyclophosphamide, azathioprine, cyclosporine, mycophenolate mofetil, and mizoribine to improve the renal prognosis.
• Antiplatelet agents: dipyridamole to reduce proteinuria and control the progression of renal dysfunction; dilazep to reduce proteinuria
• Fish oil to improve the renal prognosis

• References

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.

• References

Benazepril (Lotensin)

• Dosing, Interactions, etc.

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.

• References

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.

• References

Losartan (Cozaar)

• Dosing, Interactions, etc.

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.

• References

Class Summary

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

• References

Prednisone (Sterapred)

• Dosing, Interactions, etc.

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.

• References

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.

• References

Omega-3 polyunsaturated fatty acid (Fish oil)

• Dosing, Interactions, etc.

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

• References

Class Summary

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

• References

Cyclophosphamide (Neosar, Cytoxan)

• Dosing, Interactions, etc.

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.

• References

Class Summary

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

• References