IgA nephropathy is one of the most common kidney diseases in young adults. In Asian populations, IgA nephropathy accounts for 30% to 45% of primary kidney disease, and its clinical and pathological manifestations, rate of progression, and prognosis vary widely. 20% of patients with IgA nephropathy progress to end-stage renal disease within 10 years, and 30% eventually progress to end-stage renal disease.
In March 2011, Kidney Disease: Improving Global Outcomes (KDIGO) issued clinical guidelines for the diagnosis, treatment and prognosis of IgA nephropathy in Singapore, Japan and Australia, but due to the lack of large sample RCT studies, the evidence for most of the guidelines is only B and C.
KDIGO classifies guideline recommendation levels as Grade 1, Grade 2 or ungraded, and the evidence-based grades are A, B, C and D (see Tables I and II). 19 KDIGO IgA nephropathy guidelines are available. Recommendation grade, 1 (5.3%) for grade 1, 12 (63.2%) for grade 2, and 6 (31.6%) for ungraded. Grade of evidence, 0 in grade A, 3 in grade B (23.1%), 6 in grade C (46.2%), and 4 in grade D (30.8%).
1. Assessing the risk of kidney disease progression
The clinical manifestations of IgA nephropathy are diverse, ranging from isolated hematuria to rapidly progressive glomerulonephritis; the rate of progression to renal failure also varies, and the prognosis of similar clinical manifestations may be very different. A national study of patients with isolated hematuria followed for 12 years found that 14% of patients with hematuria disappeared and nearly 1/3 developed proteinuria (>1g/d) or decreased GFR during the course of the disease.
Therefore, a comprehensive risk assessment is essential to determine treatment options and balance the risk of treatment. the KDIGO guidelines state that: the assessment includes an evaluation of secondary etiology in all patients with IgA nephropathy confirmed by renal biopsy (ungraded); observation of proteinuria, blood pressure and eGFR at diagnosis and during follow-up to assess the risk of progression of renal disease (ungraded); an assessment of the risk of progression of renal disease , prognosis is recommended to be assessed by renal pathological features (ungraded).
Several large observational studies have confirmed that proteinuria is the strongest independent predictor of prognosis in IgA nephropathy, with a “dose-dependent” effect, and that the higher the urinary protein quantification, the worse the prognosis. A urine protein quantification of 1g/d is a watershed for prognosis, but it is still unclear whether there is a difference in prognosis between urine protein quantification of 0.5-1g/d and <0.5g. For children, only experts recommend urine protein quantification of 0.5 g/d/1.73m2 as an indicator of partial remission and 0.16 g/d/1.73m2 as complete remission. Uncontrolled hypertension leads to increased urinary protein and promotes disease progression. Although two recent observational studies have found that not the lower the initial GFR level, the faster their renal function declines, it is still believed that GFR level is associated with the risk of ESRD.
Therefore, observation of proteinuria, blood pressure and eGFR at diagnosis and during follow-up is recommended. numerous studies have confirmed the value of pathology in prognostic assessment. the Oxford staging of IgA nephropathy, proposed in 2009, has independent pathological indicators that predict prognosis of kidney disease including thylakoid proliferation, segmental glomerulosclerosis, intracapillary hyperplasia and tubular atrophy/interstitial fibrosis. There is currently insufficient evidence-based evidence on the association between histopathological manifestations of renal biopsies and poor prognosis, and it is expected that the ongoing VALIGA study (Advances in the European Validation Studyof the Oxford Classification of IgA Nephropathy) will bring updated results.
2. Proteinuria and blood pressure lowering therapy
ACEI and ARB are recommended for patients with proteinuria >1g/d for a long period of time, with gradual upward dose adjustment according to blood pressure (1B). ACEI and ARB are recommended for patients with urinary protein in the range of 0.5-1g/d (0.5-1g/d/1.73m2 in children) (2D). It is recommended that the dose of AECI/ARB be increased gradually to the extent tolerated to reduce proteinuria to <1g/d (2C). The target target value of blood pressure should be <130/80 mmHg in patients with IgA nephropathy with proteinuria <1g/d and <125/75 mmHg (ungraded) in those with initial proteinuria >1g/d. The findings suggest that renal decompensation is associated with increased urinary protein volume; that patients with persistent proteinuria ≥3 g/d have a 25-fold faster rate of renal decompensation than patients with <1 g/d; and that patients whose proteinuria decreases from ≥3 g/d to less than 1 g/d can achieve a similar disease course as patients with proteinuria consistently <1 g/d and have a much better disease course than patients with proteinuria consistently ≥3 g/d.
ACEI and ARB are the only “recommended” therapies in this guideline, with a high level of evidence. Numerous RCTs have confirmed that ACEI and ARB reduce proteinuria, but there is a lack of long-term follow-up studies to confirm their ability to reduce ESRD, and no data to show which ACEI or ARB is superior. Therefore, the choice should be based on the magnitude of their side effects. Some studies have shown that the combination of ACEI and ARB provides greater benefit in reducing urinary protein, but more evidence-based medical evidence is needed to confirm this.
3. Glucocorticoids
Glucocorticoid therapy for 6 months is recommended for patients with persistent proteinuria ≥1 g/d and GFR >50 ml/min after 3-6 months of appropriate supportive therapy (including ACEI or ARB and blood pressure control) (2B). Studies from China and Italy both confirmed that hormones combined with ACEI slowed the rate of creatinine elevation compared with ACEI alone, thus providing an additional benefit of hormone therapy over rational supportive therapy. However, the quality of the evidence was lower because both studies included low-risk patients who had a better prognosis with ACEI alone. A Japanese RCT study in which a low-dose hormone (prednisolone 20 mg/d and tapered to 5 mg/d over 2 years) was applied showed no significant benefit in terms of renal function, although proteinuria was reduced.
Since none of the previous studies included patients with IgA nephropathy with GFR <50 ml/min, there is no evidence to confirm the efficacy of hormones in this group of patients. A recent meta-analysis showed that hormones reduced doubling of serum creatinine, but 85% of the data for this analysis came from the Pozzi C and Kobayashi Y studies, neither of which achieved the currently recommended standards for proteinuria and blood pressure control. Because serious side effects were not reported in the current study, no recommendations can be given for the use and dosage of hormones or the duration of administration. The treatment plan can be formulated after a comprehensive assessment of the patient's clinical and pathological manifestations and the side effects of hormones with reference to other nephritis treatment measures.
4. Immunosuppressants (CTX, AZA, MMF, CsA)
The combination of hormones with CTX or AZA is not recommended (unless crescent formation is accompanied by rapid deterioration of renal function) (2D); the application of immunosuppressive agents is not recommended in patients with GFR <30 ml/min (unless crescent formation is accompanied by rapid deterioration of renal function) (2C); the application of MMF is not recommended (2C).
Two RCTs comparing the efficacy of CTX, dipyridamole and warfarin with controls have been conducted and found no benefit. Considering the adverse effects of CTX treatment alone, treatment with CTX alone is not recommended. Regarding azathioprine, two RCTs have applied AZA in combination with hormones for the treatment of IgAN in adults. one is a Turkish RCT that enrolled patients with IgA nephropathy with simple hematuria and almost normal GFR. However, the current consensus is that these patients have a good prognosis and do not require immunosuppression. In a small sample of UK RCTs, patients with Scr 130-250umol/L and a 15% increase from the previous year were treated with hormone combined with CTX and then switched to AZA for maintenance for several years. Renal survival was significantly higher at 5 years compared to controls (72% vs. 6%). However, the study was deficient in that there was no hormone-only group, and the supportive therapy did not meet the now-recommended criteria.
Another RCT of 207 patients treated with hormones plus AZA or AZA alone for 6 months with a median follow-up of 4.9 years found similar cumulative renal survival rates for both treatment modalities (88% vs. 89%, p = 0.83), with associated adverse effects being more common (17% vs. 6%, p = 0.01). Therefore, it is currently believed that hormones combined with AZA do not benefit patients with IgA nephropathy.
The conclusions about MMF for IgAN are inconsistent across studies. The Belgian study applied MMF 2 g/d for 3 years in 34 patients with mean GFR > 70 ml/(min・1.73m2) and proteinuria > 1.8 g/d and controlled with placebo, showing no statistical difference in proteinuria reduction and GFR levels between the two groups. A study from North America treated patients with GFR > 40 ml/(min・1.73m2) and proteinuria > 2.7 g/d with MMF 2g/d versus placebo control for 1 year and found no treatment benefit after 2 years of observation. In contrast, a study from China treated 40 patients with mean GFR >72 ml/(min・1.73m2) and proteinuria >1.8 g/d with MMF for 6 months, which significantly reduced proteinuria compared to the control group. The same study with 6 years of follow-up showed benefit to renal survival. Due to inconsistent findings, the application of MMF for IgA nephropathy (2C) is not recommended and more studies are needed to confirm this (by race and at different doses).
In conclusion, there is a lack of sufficient evidence on whether the use of immunosuppressive agents (CTX, AZA, MMF, CsA) as first-line agents for the treatment of IgA nephropathy can bring the same or better benefit than hormones, and their use is mainly based on the assessment of the risk-benefit ratio of serious adverse effects of the drugs.
5. Other treatments
5.1 Fish oil is recommended for patients with persistent proteinuria ≥1 g/d despite 3 to 6 months of appropriate supportive therapy (including ACEI or ARB and blood pressure control). There is much low-quality evidence recommending the use of fish oil for the treatment of IgA nephropathy, but RCTs have yielded conflicting results. A recent meta-analysis of 5 studies showed no benefit for proteinuria or delayed renal failure. Fish oil therapy is safe considering its beneficial effects on cardiovascular disease.
5.2 Antiplatelet agents The application of antiplatelet agents is not recommended for the treatment of IgA nephropathy (2C). Pansentine was the most commonly used antiplatelet agent (5 relevant studies), followed by trimetazidine and dilaudid (1 relevant study each). A meta-analysis based on these 7 studies suggested that antiplatelet therapy reduced proteinuria and protected renal function in patients with moderate to severe IgA nephropathy. However, due to the shortcomings of these 7 studies themselves: the quality of their own controls was low; renal survival was not assessed; inconsistent results may occur in long-term follow-up; and patients were on other drugs at the same time, from which the effects of antiplatelet agents could not be distinguished. The results of this meta-analysis have low credibility and insufficient evidence; therefore, the guidelines do not recommend the application of antiplatelet agents for the treatment of IgA nephropathy.
5.3 Tonsillectomy Tonsillectomy is not recommended for patients with IgA nephropathy (2C). Only retrospective studies and one non-randomized study have concluded that tonsillectomy reduces proteinuria and hematuria in patients with mild IgA nephropathy. In these studies, the efficacy of tonsillectomy could not be fully distinguished because it was often combined with other immunosuppressive treatments. Other retrospective studies have found tonsillectomy to be ineffective in the treatment of IgA nephropathy. Tonsillectomy is not recommended because of the low level of evidence and conflicting evidence.
6. Treatment of atypical IgA nephropathy
6.1 Microscopic lesions with thylakoid IgA deposition Treatment of patients presenting with nephrotic syndrome and pathologic changes of microscopic lesions with glomerular IgA deposition is recommended as microscopic lesions (2B). IgA nephropathy (MCD) presents clinically as a nephrotic syndrome with an 80% complete remission rate with hormonal therapy.
6.2 AKI associated with sarcohematuria in IgA nephropathy If AKI associated with sarcohematuria does not improve within 5 days of deterioration in renal function a repeat renal biopsy (unclassified) should be performed. It is recommended that patients with IgA nephropathy who develop AKI should receive general therapy (2C) when a renal biopsy during the sarcoid episode confirms only ATN and intrarenal tubular erythrocyte tubularity. Episodes of sarcoid hematuria often coincide with mucosal infections (usually upper respiratory tract infections) and resolve spontaneously within a few days, with a small proportion progressing to AKI. pathological manifestations in this group of patients are most commonly acute tubular necrosis (ATN) and intrarenal tubular erythrocyte tubular pattern, and renal function recovers in most patients after the hematuria disappears. If renal function continues to deteriorate, a renal biopsy is required to determine whether AKI is due to crescentic IgA nephropathy or some other cause.
6.3 Crescentic IgA nephropathy Crescentic IgA nephropathy is defined as renal biopsy suggesting IgA nephropathy with more than 50% glomerular crescent formation and rapidly progressive renal failure (unclassified). For patients with IgA nephropathy with rapidly progressive crescents, hormone therapy combined with CTX is recommended, with a regimen similar to that for ANCA-associated vasculitis (2D).
Crescentic IgA nephropathy has a poor prognosis, and a recent study on vasculitis IgA nephropathy showed that renal function, current blood pressure, and the amount of chronic damage on renal biopsy significantly affect renal prognosis. There are no RCT studies of crescentic IgA nephropathy. 3 of the largest observational studies have concluded that immunosuppressive therapy is effective. Treatment generally consists of high-dose hormones plus CTX orally or intravenously.
The KDIGO IgA nephropathy clinical practice guidelines are an important reference. However, since most of the RCT studies in the evidence are from European and American populations, the clinical application process should follow all the treatment principles proposed in the guidelines while developing the most reasonable individualized treatment plan in the context of the patient’s specific situation.