Recurrence Of IgA Nephropathy After Kidney Transplantation Ⅱ

3 Risk factors for recurrence of IgAN after renal transplantation
Because risk factors were identified through analysis of population-based cohort studies the true causality is difficult to determine, and the results of different studies vary somewhat. However, several retrospective studies with a long follow-up period have examined the risk of IgAN recurrence after transplantation. However, several retrospective studies with a long follow-up period have investigated the effects of young age at transplantation, rapid progression of the primary disease, absence of glucocorticoids (hormones) or early discontinuation of glucocorticoid use. However, several retrospective studies with a long follow-up period have reported on the relationship between young age at transplantation, rapid progression of primary disease, immunotherapy regimens without glucocorticoids (hormones) or early discontinuation of hormones, donor factors and HLA allele subsets.
There is a consensus on several risk factors for HLA allele subtypes [4,33]. Younger age at transplantation is a risk factor for relapse, probably because formation and deposition of abnormal immune complexes in young IgAN patients compared to older patients and therefore a relatively higher recurrence rate [34-35]. Rapid progression of the primary disease progression, including the number of crescents, the severity of preoperative proteinuria correlates with poor outcome after recurrence [34,36]. The duration of postoperative follow-up longer postoperative follow-up and postoperative immunosuppressive regimens also have an impact on the recurrence of IgAN The impact of postoperative follow-up and postoperative immunosuppressive regimens on the recurrence of IgAN [35,37]. Studies have shown that hormone use reduces the risk of recurrence and that postoperative hormone withdrawal time is associated with IgAN recurrence [35,37].

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The timing of postoperative hormone withdrawal is associated with the recurrence rate of IgAN [38]. Other immunosuppressive The association of other immunosuppressive drugs, including cyclosporine, morte-macrolimus, and tacrolimus, with recurrent IgAN has not been clearly established. The association of other immunosuppressive drugs, including cyclosporine, morte-macrolimus, and tacrolimus, with recurrent IgAN has not been conclusively established [22]. Moroni et al [27] showed that the absence of morte-macrolide or the use of less than three immunosuppressive Moroni et al [27] showed that the absence of mortification or the use of less than three immunosuppressive drugs was a risk factor for the recurrence of IgAN. In contrast, Di Vico et al [38 showed that mortifamolates, tacrolimus, and mammalian rapamycin target protein inhibitors were associated with disease relapse. target protein inhibitors were not associated with disease recurrence. Several biomarkers, including serum Gd-Igg including serum Gd-IgA1, IgG autoantibodies, and IgA-sCD89 complexes are predictive of IgAN recurrence [7-8]. In addition, previous graft loss, time on postoperative dialysis The duration of postoperative dialysis is also a risk factor for the recurrence of IgAN [22,34].

A long-term follow-up study in Chinese population showed that living relative donor kidney transplantation was an independent risk factor for recurrence of IgAN, with a higher rate of graft loss than non-relative living donor kidney transplantation. In a long-term follow-up study of Chinese patients, it was shown that living relative donor kidney transplantation was an independent risk factor for recurrence of IgAN, with a higher rate of graft loss than unrelated living donor kidney transplantation [39]. The long-term graft survival rate of living relative donor kidney transplantation The lower long-term graft survival rate of relative living donor kidney transplantation may be related to familial genetic factors [20,35]. This may be related to familial genetic factors [20,35]. Therefore, preoperative exclusion of relatives with a potential familial risk of IgAN is required. The risk of living donor relatives with potential familial IgAN needs to be excluded preoperatively. Several studies have also shown that donor glomerular tract IgA deposition in the donor glomerular tract is also a risk factor for postoperative recurrence [22]. There are also studies Sofue et al [40] found that IgA deposition in the donor kidney was associated with the survival of the transplanted kidney. In contrast, Sofue et al [40] found that IgA deposition in the donor's kidney was not correlated with survival, renal function, abnormal urinalysis, or recurrence of IgAN in the transplanted kidney. There was no correlation between IgA deposition in the donor kidney and survival, renal function, abnormal urinalysis and recurrence of IgAN.

As HLA is a donor-recipient-related factor, one study reported that The recurrence of IgAN in the recipient has been reported to be associated with HLA specificity. The current study found that HLA-B35, DR4, B8 and DR3 are more common in the post-transplant recurrent IgAN population [22]. The current study found that HLA-B35, DR4, B8, and DR3 are more common in the post-transplant recurrent IgAN population [22]. Relative living donor kidney transplant recipients with recurrent IgAN The recurrence of IgAN in living donor kidney transplant recipients correlates with the degree of donor-recipient HLA match, whereas in non-relative living donor or cadaveric donor kidney transplant recipients, the recurrence of IgAN is more common.
The recurrence of IgAN in living relative donor kidney transplant recipients correlates with donor-recipient HLA match, but not in unrelated living donor or cadaveric donor kidney transplants [41]. It was found that compared to zero The study found that kidney transplant recipients with one or more HLA mismatches had a lower rate of IgAN recurrence compared to zero mismatch donors. IgAN recurrence rate was lower in kidney transplant recipients with one or more HLA mismatches compared to zero mismatched donor kidneys, suggesting that transplant kidney failure may be caused by factors other The study found a lower recurrence rate of IgAN in kidney transplant recipients with one or more HLA mismatches compared to zero mismatched donors, suggesting that transplant renal failure may be caused by factors other than rejection [42].

4 Treatment of IgAN recurrence after renal transplantation
Considering the immunosuppressive status of kidney transplant recipients, the clinical course of IgAN recurrence may be different from that of other patients, and there are also large differences between individuals. At present, there is no effective prevention and treatment plan for IgAN recurrence, and individualized treatment should be carried out according to the condition of the recipient. 

4.1 Conservative treatment
According to the guidelines of the Global Organization for Improving the Prognosis of Kidney Diseases, the principles of treatment for recurrent IgAN are the same as those for primary IgAN, aiming at controlling blood pressure, reducing proteinuria, and suppressing inflammatory state. Therefore, the mainstay of treatment includes the use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor antagonists
(angiotensin Ⅱ receptor blocker, ARB) etc. block the renin-angiotensin-aldosterone system (renin-angiotensin-aldosterone system, RAAS), reduce systemic blood pressure and glomerular internal pressure, reduce protein excretion, and secondary renal failure Ball injury [43].
The treatment standards for IgAN patients are as follows: patients with proteinuria >0.5 g/d use ACEI or ARB; patients with proteinuria <1 g/d strictly control blood pressure <130/80 mmHg (10 mmHg=1.33 kPa); g/d patients with controlled blood pressure <125/75 mmHg; persistent proteinuria >1 g/d and estimated glomerular filtration rate (estimated
Glomerular filtration rate, eGFR)>50 mL/(min·1.73m2)
Steroids are recommended for patients [43]. A two-center retrospective cohort study confirmed that RAAS blockers can improve the prognosis of IgAN recurrence by reducing proteinuria [44]. However, whether RAAS blockade can reduce the recurrence rate of IgAN after kidney transplantation and whether it can benefit recipients is still controversial [45].
Studies have shown that the use of ACEI and ARB has no benefit in improving graft survival, and 57.6% of recipients receiving ACEI therapy experienced graft loss [38].

4.2 Immunosuppressive therapy
In addition to symptom management, how to effectively prevent the recurrence of IgAN is also the focus of clinicians. Therefore, immunosuppressive treatment for IgAN recurrence should be considered. Immunosuppressive therapy may be considered for patients whose disease cannot be controlled by conservative treatment.
Hormone is currently the only immunosuppressive drug proven to be effective in the treatment of IgAN. IgAN patients should maintain low-dose hormone use after kidney transplantation to reduce the risk of recurrence. To avoid adverse effects of hormone therapy, early withdrawal of hormones is a safe intervention in living donor kidney transplantation,
However, caution should be exercised in recipients with a high risk of recurrence. Studies have shown that withdrawal of steroids may lead to IgAN recurrence and increase the risk of graft loss without affecting overall recipient and graft survival [38]. An international multicenter, double-blind, randomized controlled trial showed that hormone use
Potentially beneficial to patients with urinary protein >2 g/d, it can reduce the risk of worsening renal function and ESRD, but when treated with sufficient dose, the risk of serious adverse events mainly infection and death is higher, indicating that careful evaluation is required Intervention after adverse reactions of hormones [46]. Therefore, the root
Based on experience, renal transplant recipients with primary IgAN can be treated with low-dose corticosteroids (0.6 mg/kg oral prednisone every other day) [13]. For recurrent IgAN with rapid progression, especially for recipients with urinary protein >1 g/d and eGFR >50 mL/(min·1.73m2), most centers still
High-dose hormone therapy [prednisone 1 mg/(kg·d)] will be used, which will be slowly reduced to a low dose after several months [22].
When the disease progresses rapidly and hormones cannot be controlled, clinicians will recommend recipients to receive combined hormone-based immunosuppressive therapy. Commonly used immunosuppressive drugs include azathioprine, calcineurin inhibitors, cyclophosphamide, mycophenolate mofetil, rituximab, and leflunomide, etc., but the research data on their efficacy are mixed. There is still a lack of prospective studies to confirm [47]. Calcineurin inhibitors can inhibit the synthesis of interleukin (interleukin, IL-2, IL-4, TNF-α) by inhibiting the activation and proliferation of T cells, but they can protect the renal function of IgAN relapse recipients after renal transplantation. Data on the effect of ciclosporine are relatively limited, and relapse rates were significantly lower in recipients of tacrolimus than in recipients of cyclosporine [22]. Mycophenolate mofetil can improve the inflammatory response of glomerulonephritis by selectively inhibiting lymphocyte proliferation, antibody synthesis, etc. Its combined use with hormones can reduce the dose of hormones. Proteinuria had comparable effects and a lower incidence of adverse events [48]. There have also been case reports of rapidly progressive and histologically crescentic IgAN relapse recipients who may benefit from cyclophosphamide or rituximab, but were not successful in reversing the disease course and further study is needed [49]. Immune induction therapy is an important means to prevent the recurrence of IgAN after renal transplantation, the most commonly used is antithymocyte globulin (antithymocyte globulin).
globulin, ATG) [50]. A study in South Korea conducted 218 IgAN kidney transplant recipients from 1995 to 2015 with no immune induction, anti-CD25 antibody immune induction and ATG immune induction therapy, and found that the recipients who used ATG for immune induction therapy had more The low recurrence rate in 4 and 5 years indicated that ATG can delay the recurrence of IgAN, but due to lack of data and limited follow-up time, prospective studies are still needed to further confirm [51].
Clinical trials of new drug preparations for the intestinal mucosal immune system are also being carried out step by step. A recent double-blind, randomized controlled trial showed that in patients with primary IgAN, a targeted-release formulation of budesonide targeting the intestinal mucosal immune system reduced proteinuria and may represent a new specific agent for IgA recurrence after renal transplantation. Treatment methods [52].

4.3 Other treatments
Since Gd-IgA1-producing immune cells are present in mucosa-associated lymphoid tissues such as the tonsil, the tonsil may be an important therapeutic target for IgAN, with benefits independent of hormone therapy [53]. A single-center retrospective cohort study in Japan suggests that 1 year after kidney transplantation
Tonsillectomy reduces the rate of histological recurrence of IgAN [54]. Tonsillectomy for recurrent IgAN recipients after kidney transplantation can not only relieve clinical symptoms and reduce the degree of proteinuria, but also improve the histological damage caused by it [55]. Research by Deng Ronghai et al. [56] in my country showed that tonsillectomy can help recipients with recurrent IgAN after renal transplantation maintain stable renal function, but the effect may be poor for those with severe pathological manifestations. Given that the complement system is involved in regulating the pathogenesis of IgAN, blocking complement-mediated renal inflammatory responses may have a therapeutic effect on IgAN recurrence after renal transplantation, such as the anti-C5 antibody eculizumab can rescue renal function in patients with rapidly progressive IgAN , reduce proteinuria, and lower serum creatinine levels [57]. In addition, some cases have reported that treatment with the somatostatin analog octreotide can delay the progression of IgAN recurrence after renal transplantation [58]. Combination therapy with the mammalian target of rapamycin inhibitor everolimus and hormones has also been shown to reduce the risk of relapse in IgAN [59]. However, the phase II clinical trials of native IgAN targeting BAFF, APRIL antagonists and spleen tyrosine kinase inhibitors are gradually carried out, and the benefit of new treatment methods on IgAN remains to be evaluated [50].

5 Summary
Early identification of high-risk recipients with IgAN recurrence after renal transplantation can not only reduce the recurrence rate, but also help optimize the IgAN treatment process. However, due to the lack of specificity of clinical symptoms of IgAN, its diagnosis depends on the programmed renal biopsy before and after surgery, and the willingness of recipients without clear symptoms to undergo renal biopsy is low, and the follow-up time and diagnostic methods of different studies are also different. For IgAN The recurrence rate and graft loss rate may be underestimated. Therefore, it is necessary to standardize the diagnostic process, promote the procedure of renal biopsy, and promote the multidisciplinary cooperation of clinical, laboratory, and pathology in order to diagnose IgAN recurrence early.
At present, the risk factors and optimal treatment plan for IgAN have not yet been determined, and it needs to be evaluated in a large-scale, randomized, and long-term follow-up cohort study conducted by multi-center cooperation. In-depth research on the pathogenesis of the disease will also help to improve its diagnostic accuracy and provide new ideas for treatment options.