Pediatric IgA Nephropathy Treatment & Management
- Author: Mohammad Ilyas, MD, FAAP; Chief Editor: Craig B Langman, MD more...
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.
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 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.
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. 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. 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.
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.
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.
The optimal role of immunosuppressive therapy IgA nephropathy is uncertain. 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.
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.
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.
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.
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, to a reduction in proteinuria and a decrease in the rate of decline in the GFR.
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).
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. 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.
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. 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. However, other studies reported no benefit following tonsillectomy.
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.
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.
High-dose IVIG has been tried in severe IgA nephropathy characterized by heavy proteinuria and a relatively rapid decline in GFR. 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.
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. 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.
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.
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.
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 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.
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.
Generally, surgical care is not necessary except for dialysis access or 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.
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.
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.
Because IgA nephropathy has the potential to progress to end-stage renal disease, consultation with a pediatric nephrologist is necessary.
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.
Typically, no activity restriction is necessary.
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