Immunosuppressive thrapy
erapyA meta-analysis of 623 patients who included 13 RCTs in a previous study concluded that immunosuppressive therapy is a promising strategy that needs further investigation. This field of research, like many other kidney diseases, is hampered by the slow progression of disease (more than 85% of 10-year survival), significant patient heterogeneity, and lack of animal models resembling human IgAN.
Glucocorticoid
Relatively large amounts of data on glucocorticoids were contributed by Japanese researchers at an early stage. A meta-analysis of 386 patients enrolled in seven RCTs suggested that glucocorticoids had a significant protective effect on renal function and proteinuria, but their gastrointestinal response needs to be addressed.
A meta-analysis of 1,542 patients enrolled in 15 quasi-randomized and uncontrolled trials suggested that glucocorticoid therapy was associated with reduced proteinuria and a significant reduction in end-stage renal failure risk. In addition, the subgroup analysis also revealed that long-term hormone therapy is more effective than standard therapy and short-term treatment.
A recent meta-analysis of 537 patients with urinary protein excretion> 1 g / day and normal renal function in a total of 9 trials suggested that high-dose and short-term hormone therapy had significant renal protection, whereas low- and long- Use does not have this effect.
The KDIGO Clinical Practice Guidelines for glomerulonephritis suggest that evidence of additional benefit from the use of glucocorticoids based on optimized supportive care is low. The KDIGO Working Group recommended a six-month course of steroid therapy in patients who had adequate ACE inhibitors or ARBs and continued proteinuria> 1 g / day with good blood pressure control and GFR> 50 ml / min / 1.73 m2.
A multi-center clinical trial aimed at determining the efficacy and safety of hormone therapy in IgAN is underway.
Recently, a European Union VALIGA study included 1147 patients in 13 countries covering the entire spectrum of IgAN disease. Median follow-up of 4.7 years, 86% of patients receiving RAS blocker treatment, 42% of patients receiving glucocorticoid or immunosuppressive therapy. Pathological MEST scores with independent predictive value were reduced by treatment with glucocorticoid or immunosuppressive agents according to the pathological classification of the kidneys according to the Oxford pathology type of IgAN.
A retrospective subgroup analysis compared patients treated with glucocorticoid plus RAS blockers to matched patients who received ACEI / ARB alone, confirming that the former had the effect of lowering proteinuria and slowing the rate of renal dysfunction. These benefits extended to patients with eGFR ≤ 50 ml / min / 1.73m2, in proportion to the severity of proteinuria.
2. Cyclophosphamide combined with glucocorticoids
Several research groups worldwide have provided evidence that glucocorticoid shock therapy combined with cyclophosphamide intravenous or oral therapy delays the progression of advanced IgAN. These studies suggest that combination therapy with cyclophosphamide and hormones may benefit patients with a very high risk of renal failure (ie, those with very rapid GFR reduction and / or severe crescentic damage).
Short-term use of cyclophosphamide combined with glucocorticoid therapy in patients with true crescentic or aggressive glomerulonephritis due to side effects is reasonable. The KDIGO clinical practice guidelines for glomerulonephritis suggest similar schemes (evidence of low quality).
3. tonsillectomy combined with glucocorticoids
For a long time, tonsillectomy is a treatment option for IgAN that is designed to remove pathogens from related sources that can multiply in tonsil crypts where macrophages and B cells can multiply in follicular tonsils. The challenge of this specific antigen is thought to lead to superior IgA synthesis since lymphocytes from the tonsils of IgAN appear to produce higher levels of dimer and non-glycosylated IgA1 than the control.
In Japan, tonsillectomy / hormone shock therapy is often used in the treatment of early-stage IgAN patients with better prognosis. A meta-analysis of 858 patients (534 with tonsillectomy and 324 without resection) with a recent nonrandomized study (6 from Japan and 1 from China) showed that tonsillectomy, regardless of the combination of standard hormone Treatment or hormone shock therapy have a higher response rate and favorable long-term efficacy (after 5-year follow-up and 10-year follow-up data) than tonsillectomy alone or with hormone alone.
In addition to Japan, the benefits of tonsillectomy are largely less impressive. A retrospective review of 61 white patients showed that tonsillectomy did not change the rate of disease progression after 20 years of follow-up.
Recently, a Hungarian study included 166 patients with IgAN who had undergone tonsillectomy and 98 patients underwent tonsillectomy. The results suggest that tonsillectomy may delay progression of kidney disease, especially in patients with gross hematuria . An interesting finding is that a decrease in serum IgA1 levels following galactose deprivation after tonsillectomy indicates that palatine tonsil is the main site for IgA1 cells that produce galactose-deficient.
However, the clinical efficacy of tonsillectomy in IgAN was completely destroyed by the latest two studies. Sato et al found that tonsillectomy before renal transplantation does not affect the recurrence of IgAN. Importantly, the first multicenter RCT study in Japan failed to confirm any beneficial effect of tonsillectomy combined with steroid shock compared with single-hormone shock alone. In a cohort of 112 Chinese patients, tonsillectomy was not independently associated with clinical remission and did not improve renal survival.
2010 KDIGO Clinical Practice Guidelines for Glomerulonephritis It is not recommended to perform tonsillectomy (low quality evidence) for IgAN patients.
4. Calcineurin inhibitors
Early experience with the use of cyclosporine in IgAN is not favorable. Patients treated with cyclosporine plus corticosteroids had a greater reduction in proteinuria than patients treated with steroids alone, and a higher rate of remission in patients with mild pathology, but combined therapy had a higher renal function than baseline serum creatinine High and temporary deterioration of renal function. In addition, there were more patients with severe infections in the combination therapy group. These data hinder the use of cyclosporine in IgAN due to potential nephrotoxicity.
Data on other calcineurin inhibitors, such as tacrolimus, are very small. Zhang et al. Reported the use of tacrolimus in the induction of proteinuria in 14 patients with refractory IgAN, which may be mediated by stabilization of the podocyte skeleton. Kim et al. Demonstrated that tacrolimus effectively reduced proteinuria in IgAN patients with normal blood pressure and that tacrolimus could be used as an alternative to glucocorticoids and ACEI / ARB in patients with intolerance to antihypertensive drugs treatment.
5. Azathioprine (Aza)
A retrospective analysis of 74 patients with IgAN in a 10 - year follow - up showed that long - term treatment with Aza plus low - dose prednisone did not alter the clinical course compared with the untreated control group. However, this immunosuppressive regimen reduced the risk of doubling serum creatinine levels in the subgroup of patients with large amounts of proteinuria (> 3 g / day) and baseline serum creatinine levels of 1.4-2.5 mg / dL (27% vs 78%) and delayed progression to end-stage renal failure (17% vs 55%).
The Japanese Pediatric IgAN Treatment Group randomized 78 newly diagnosed IgAN children to either prednisolone, Aza, heparin-warfarin, or dipyridamole alone or in combination with heparin-warfarin and dipyridamole Mo treatment. Including the treatment of Aza reduced urinary protein and serum IgA levels. The shortcomings of this study are the lack of data on baseline proteinuria and creatinine clearance, as well as data on blood pressure control in both groups.
In a prospective, randomized study of 207 patients, a randomized study of patients with proteinuria ≥1 g / day and plasma creatinine ≤ 2.0 mg / dl showed a significant increase in glucocorticoid use compared with glucocorticoids alone , The survival of the kidney can not get additional benefits. Interestingly, in the same patient cohort, the investigators observed patients with plasma creatinine ≥ 2.0 mg / dL. The 6-year renal survival rates were similar in both groups. In Cox analysis, addition of Aza in patients with chronic renal insufficiency, although increased side effects, but may be more than a single glucocorticoid mildly more effective.
Therefore, the current data suggest that the addition of Aza has limited therapeutic advantage and may be potentially toxic.
Mycophenolate mofetil (MMF)
So far, the use of MMF in IgAN published six RCT studies, more controversial than consensus. Although these trials produce contradictory results, they are noteworthy in the selection and treatment of patients with significant differences in treatment.
Overall, MMF appears to be effective in lowering proteinuria among Chinese, but not necessarily in white. So racial differences may be one of the possible causes of different results observed in these trials. Another possible reason is that the extent of disease involvement in different studies may be different and may lead to more favorable outcomes for MMF in patients with severe IgAN.
In addition to reducing IL-6 production and mesangial and IgA binding, MMF may also through other mechanisms to reduce IgAN lesions. A recent study showed that mycophenolic acid (derived from MMF) up-regulates the expression of the core 1β3-Gal-T cell-specific chaperone (Cosmc), thereby reversing abnormal O-glycosylated IgA1 levels in peripheral lymphocytes of IgAN patients . Cosmc expression of impaired and abnormal O-glycosylation-deficient IgA1 plays an important role in the pathogenesis of IgAN.
Further observations and studies on the effectiveness of MMF in IgAN will provide a more definitive answer.
2012 KDIGO Clinical Practice Guidelines for Glomerulonephritis It is not recommended to use MMF (evidence of low quality) in IgAN patients.

Author: kidney1234567
Link: http://neph.dxy.cn/article/139675?trace = related
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