IgA Nephropathy Treatment & Management

Updated: Feb 16, 2018
  • Author: Sohail Abdul Salim, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
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Treatment

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 renal disease (ESRD) 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.

Current 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 to aim for a blood pressure of 130/80 mm Hg. [20]
  • Steroids are most beneficial if more than 1 g of proteinuria is present in a 24-hour urine specimen. [21]

Renin-angiotensin blockade

Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are the preferred agents for lowering blood pressure and decreasing proteinuria. [22]  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). [23]  

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. [24]  Combined use of an ACEI and an ARB is not recommended; although it decreases proteinuria, it is associated with greater risk of acute renal failure 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.

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. [25]  

Corticosteroid regimens studied have included the following [26] :

  • 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 [27]
  • Oral prednisone for 6 months at 1 mg/kg/day for 2 months followed by 0.2 mg/kg/day [24]
  • 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 [28]

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 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). [29]

In contrast, the TESTING trial (Therapeutic Evaluation of STeroids in IgA Nephropathy Global study) showed that high-dose oral methylprednisone was associated with significantly increased rates of serious adverse outcomes in participants with >1 g/day proteinuria. This trial included patients with GFRs of 20-120 mL/min. The trial was stopped after 1.5 years due to serious adverse events. [30]

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. [25]  Use of mycophenolate mofetil has been controversial, as studies have been small in size and some negative studies have been reported. [20, 31]  The KDIGO guidelines do not recommend use of mycophenolate mofetil. [25]

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. Nevertheless, 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). The 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. [32]

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. [33]  

The phase 2b NEFIGAN trial demonstrated a 24% decrease in mean urinary protein:creatinine ratio in patients receiving a novel targeted-release formulation of oral budesonide that delivers the drug to the distal ileum, thus targeting the Peyer patches. Budesonide 16 mg/day, added to optimized renin-angiotensin system blockade, reduced proteinuria by around 30% compared to placebo. The authors conclude that the results support the hypothesis that mucosal immune dysfunction has a significant role in the pathogenesis of IgA nephropathy. [34]

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. [35, 9] Deficiencies of essential fatty acids have been detected in IgA nephropathy, and fish oil is rich in long-chain omega-3 polyunsaturated fatty acids. These produce altered and less biologically effective prostaglandins and leukotrienes, as well as reduced platelet aggregation.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. [36]

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, Gd-IgA1 levels, or on IgG autoantibodies. Consequently, the authors do not recommend use of rituximab in these patients. [37]

 

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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. [38, 39]

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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. [40]

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. [41] 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. [42]

Especially in Japan, tonsillectomy has been combined with steroid pulse administration for clinical remission. [43] Japanese guidelines from 2014 note that evidence supporting the benefit of tonsillectomy is weak, but recommend that tonsillectomy, by itself or combined with steroid pulse therapy, may be considered a treatment option. [9]   In contrast, KDIGO guidelines suggest that tonsillectomy not be used for IgA nephropathy. [25]  Currently, most experts reserve tonsillectomy for patients who have tonsillar infection or tonsillitis.

 

 

 

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Renal Transplantation

Renal 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. [44]

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. [45]

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. [46]

 

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