Pediatric IgA Nephropathy Treatment & Management

Updated: Jun 03, 2022
  • Author: Mohammad Ilyas, MD, FAAP; Chief Editor: Craig B Langman, MD  more...
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Treatment

Approach Considerations

IgA nephropathy was initially thought to be a benign disease; however, reports on prognosis show that slow progression to end-stage kidney disease occurs in about one-third of patients within 20-25 years of presentation. The remaining patients may remain asymptomatic without progression of hematuria and proteinuria. Prognosis could be difficult to predict in some individuals; these patients may need to be identified and managed. However, spontaneous resolution of IgA nephropathy has also been identified.

Risk factors for the progression of disease include the following:

  • Proteinuria – Persistent proteinuria, particularly greater than 1 g daily, poses a high risk of progression. Increasing proteinuria is related to worsening outcome and is an indicator of severe glomerular disease. 
  • Hypertension – Hypertension is the second most common predictive factor of a worse outcome. Stage II hypertension or blood pressure greater than 140/90 mm Hg was strongly associated with worsening of underlying glomerular disease.
  • Hematuria – The relationship between hematuria and progressive disease has yielded conflicting results. However, a few studies revealed a high degree of microscopic hematuria has been associated with worse kidney outcomes.
  • Histologic predictors – Kidney biopsy findings have been linked to an increased risk of disease progression, such as markers of chronic fibrotic disease (ie, tubular atrophy, interstitial fibrosis, and vascular disease are associated with a poor prognosis).
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Medical Care

Immunoglobulin A (IgA) nephropathy is a therapeutic challenge. In general, the management of primary IgA nephropathy focuses on optimized supportive care, reduction of proteinuria, and better blood pressure control by angiotensin-converting enzyme (ACE) inhibitors and lifestyle modifications as appropriate. Immunosuppressive therapy, which has been shown to improve outcomes in patients with IgA nephropathy but has significant toxicity, should be reserved only for patients who remain at high risk for progression to end-stage kidney disease (ESKD) despite maximal supportive care.

The optimal approach to the treatment of IgA nephropathy is uncertain. In patients who have clinical risk factors for disease progression (eg, proteinuria ≥1 g/day), blood pressure above 140/90 mm Hg or stage II hypertension, the presence of active proliferative lesions (ie, higher M and/or E scores) or crescents (higher C score) may be an indication to treat more aggressively. By contrast, patients with more chronic lesions (ie, higher S and/or T scores) are less likely to be responsive to immunosuppressive therapy.

Optimized supportive care includes blood pressure control, reduction of proteinuria with either an ACE inhibitor or an angiotensin receptor blocker (ARB), treatment with a sodium-glucose co-transporter 2 (SGLT2) inhibitor, and lifestyle modification such as dietary sodium and protein restriction, smoking cessation, weight control, and exercise as appropriate. Supportive care should be continued for 3-6 months. During this period, patients need to be monitored by 24-hour urine protein excretion or urine protein to creatinine ratio in young children, serum creatinine for the determination of estimated glomerular filtration rate (eGFR), and urinalysis to assess hematuria. Follow-up depends on the clinical status of the patient and the severity of the disease; patients are usually followed up every 1-3 months.

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 approach to therapy for primary IgA nephropathy depends on the severity of disease. Patients with proteinuria of < 1 g/day are considered to be at low risk for progressive disease; they could be continuously managed with optimized supportive care and do not need immunosuppressive therapy.

Patients with proteinuria of ≥1 g/day despite at least 3 months of optimized supportive care are considered to be at high risk for progressive disease. Such patients should be encouraged to participate in a clinical trial, where available. If trials are unavailable, or participation is not feasible or desired, we engage in shared decision-making with the patient regarding the use of immunosuppressive therapy.

Nonimmunosuppressive interventions to slow progression that are not specific to IgA nephropathy include blood pressure control and, in patients with proteinuria, ACE inhibitors or 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, which are used for 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. [13]

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. [29] 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. [30] 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. [31]

SGLT2 inhibitors

Patients with IgA nephropathy may benefit from treatment with SGLT2 inhibitors. Although the majority of trials demonstrating kidney protective benefits have been performed in proteinuric patients with diabetic kidney disease, there are data suggesting that these benefits also extend to nondiabetic proteinuric patients, including those with IgA nephropathy. 

Other supportive measures 

The supportive measures include lifestyle modification (dietary sodium and protein restriction, weight control, smoking cessation, and exercise as appropriate) and treatment of dyslipidemia, if present. 

Immunosuppressive therapy

The optimal role of immunosuppressive therapy in IgA nephropathy is uncertain. [32] 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.

Immunosuppressive therapy should be avoided if there is evidence of severe and irreversible kidney damage (eGFR < 30 mL/min/1.73 m2 for >3 months, small echogenic kidneys on kidney ultrasound, or evidence of severe interstitial fibrosis, tubular atrophy, or glomerulosclerosis on kidney biopsy), since immunosuppressive therapy is unlikely to be effective in such patients. 

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. [33]

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. [34]

Glucocorticoids plus cyclophosphamide

The use of cyclophosphamide in patients with IgA nephropathy is generally reserved for those with rapidly progressive (crescentic) disease 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 and may benefit from combined immunosuppressive therapy with prednisone and cyclophosphamide. [35]

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. [36]

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, [37] to a reduction in proteinuria and a decrease in the rate of decline in the GFR. [38]

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). [39]

Azathioprine

The addition of azathioprine to glucocorticoids does not appear to provide further benefit compared with glucocorticoids alone.

Calcineurin inhibitors

Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have been investigated in small studies of patients with IgA nephropathy. [40]  A meta-analysis of seven randomized controlled trials comparing the use of CNIs (in combination with glucocorticoids) with glucocorticoids alone or placebo found higher rates of complete remission of proteinuria with CNI therapy but no differences in creatinine or eGFR between the groups.

Hydroxychloroquine

Hydroxychloroquine is an immunomodulatory drug that has been evaluated for the treatment of IgA nephropathy. It  may help to reduce proteinuria when added to treatment with angiotensin inhibition; however, the long-term benefits on the progression of chronic kidney disease are unknown.

Rituximab 

Rituximab may be beneficial for patients with IgA vasculitis (IgAV) nephritis.

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. [41] 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. [42] However, other studies reported no benefit following tonsillectomy. [43]

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. [44]

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. [45] 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.

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. [46]

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.

Secondary IgA nephropathy

Secondary IgA nephropathy has been attributed to a variety of clinical conditions, including cirrhosis and other forms of severe liver disease, celiac disease, HIV infection,  cystic fibrosis and other disorders. The optimal treatment approach for these forms of secondary IgA nephropathy is not well established. In general, therapy should be directed at the underlying primary disease. In certain conditions, such as celiac disease and inflammatory bowel disease, addressing the underlying disease has led to improvement in urinary abnormalities (eg, proteinuria and microscopic hematuria) or clearance of mesangial IgA deposits.

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. [47]

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

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

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

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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. [48]

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. [49]

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. [50]

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Diet and Activity

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.

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Long-Term Monitoring

All patients who are receiving treatment for primary IgA nephropathy should be closely monitored for clinical response to therapy.  We suggest serum creatinine and eGFR, urine protein excretion (by spot urine protein-to-creatinine ratio or 24-hour urine protein collection), and urinalysis. Monitoring can be performed every 2-3 months. 

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