Due to differences in diagnostic criteria, discrepancies have been reported in recurrence rates, with a range from 9-61%[5]. Genetic factors play a role in IgAN recurrence and exhibit familial clustering[15]. We noted that IgAN in renal allografts were significantly more frequent in low HLA-mismatched living donor transplantation patients, which was consistent with a review of the Australia-New Zealand registry[6]. Therefore, we suggest that further attention should be paid to family history in cases involving transplantation from living donors.
Early research suggested that IgAN in renal allografts exhibited relatively slow progression and benign outcomes with little impact on graft function compared to other risk factors, such as rejection, drug toxicity and infection[9], but recent studies confirmed that IgAN reduced the long-term survival rate of the graft and indicated a poor prognosis, especially in patients with asymptomatic hematuria and/or proteinuria[10,11,16]. Floege et al.[17] reported that ∼5% of patients lost their grafts due to occurrence at 5 years after transplantation, and our study demonstrated a similar result. However, the 4-year graft cumulative survival rate was only 59.6% after the IgAN diagnosis, which showed a worse outcome in our study.
IgAN may occur at any time after transplantation. We found that it occurred frequently within 5 years postoperatively and then declined sharply in subsequent years, which was consistent with a previous report[18]. Most patients diagnosed with IgAN in renal allografts accepted a biopsy for initial asymptomatic hematuria and/or mild proteinuria, whereas few patients accepted a biopsy for an increased sCr level, which was contrary to the rejection and CNI toxicity[2]. As reported in previous study on IgAN in renal allografts, it had little impact on graft function in the early years after transplantation[19], but Ortiz et al.[20] found that the histopathological injury was not accompanied by abnormalities in the urinalysis in half of early recurrent IgAN patients. Therefore, the disease progression could be concealed, a protocol biopsy was recommended to prevent missed diagnoses, especially in clinically silent patients.
An increased sCr level or declined eGFR as the initial symptoms was generally associated with a high risk of graft failure. This result was confirmed in a previous study on native IgAN[21]. Another independent predictive factor related to renal failure in native and graft IgAN was the 24-h urinary protein level, which was confirmed in our and other recent studies[22,23]. This risk was obviously increased when proceeding to hypoproteinemia. Hematuria is a typical clinical symptom of IgAN, and one prognostic factor study in Chinese patients concluded that hematuria was a useful marker for patients who were at high risk for disease progression of native IgAN[24]. However, no correlation was found between hematuria and graft failure in our study, possibly for the following reasons: 1) IgAN in renal allografts is not the only cause of hematuria following transplantation, which is different than native IgAN, and drug toxicity damage, infection, use of a Double-J catheter and other factors may induce hematuria in these patients; 2) some patients with initial asymptomatic hematuria did not accept a biopsy in a timely manner; and 3) only 26 cases of graft failure were observed in this series. Thus, more samples and a longer-term follow-up are needed to test the predictive value of hematuria.
The color doppler ultrasound is helpful to evaluate the progress of renal graft diseases, the change in cortical thickness, echo enhancement and the reduced blood flow distribution are typical features of graft dysfunction, like echo enhancement denotes glomerulosclerosis and interstitial fibrosis, which showed in our results. The results indicate that patients with severe histopathological injury (grade IV-V of Lee’s classification) may show lower Vs and higher RI in blood flow than mild or moderate (grade I-III), it coincide partly with early research[25], which is concluded that it can be diagnosed as renal disease when RI > 0.65 in interlobar renal artery (IRA), but we found that the RI fluctuated between 0.6 and 0.7 in most cases of IgAN in renal allografts, even if they had a good graft function, moreover, the blood flow in MRA and ARA had more significant changes than it in IRA. These differences may be concerned with the baseline level influenced by donor factors, in addition, handlers’ skills and experience are important influence factors
Lee’s classification and the Oxford classification are useful prognostic indicators of disease progression and clinical outcomes of native IgAN, but their utility in IgAN in after transplantation remains unknown. Lee’s classification includes criteria for histopathological grading, such as glomerular sclerosis, crescent formation, interstitial inflammation and tubular atrophy, which were established based on and considered suitable for East Asian patients. Patients with mild or moderate (grade I-III) lesions have been reported to have a benign outcome, whereas patients with grade IV or V lesions develop end-stage renal failure[26], which is completely consistent with our results. Thus, Lee’s classification exhibits the same utility for prediction of the outcome of IgAN in renal allografts. The 2009 Oxford classification includes the following histological components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). This classification provided a clear definition and accurate criteria for the various pathological lesions of IgAN. It is widely used, and its utility has been validated in many studies[27,28]. However, the advantages of this classification system for the clinical prediction of IgAN in renal allografts was not observed in our study. We considered that immunosuppressive therapy and donor factors might influence the pathological lesions represented by the four parameters in the Oxford classification. One study confirmed that immunosuppressive therapy reduced the predictive value of the pathological parameters in recurrent IgAN[28] compared with native IgAN. A simple “present” or “absent” for these parameters, such as M and E, cannot precisely reflect the degree of histopathological graft injury. Therefore, these parameters exhibit lower specificity in patients who accept long-term immunosuppressive therapy. The significance of crescent formation was not listed as a prognostic parameter in the 2009 Oxford classification, but in many follow-up validation studies[29,30] this parameter was considered prognostic, as a result, the Oxford classification was updated to MEST-C (crescent) in 2017[31]. This study is the first report to assess the predictive value of these two classifications for IgAN in renal allografts, and the advantages and disadvantages of these classifications should be further assessed. We support the use of a combination of the pathological parameters with clinical features at the time of biopsy to provide earlier risk prediction in IgAN.
Sixteen cases with mesangial C1q deposition in this series. Traditionally, the presence of C1q staining is viewed as a typical pathological lesion of LN rather than IgAN[13]. However, a more recent study[32,33] confirmed that this parameter played a role and occurred in 0 to 45% of patients with IgAN. Lee et al.[32] concluded that mesangial C1q deposition in the glomerulus was associated with a poor renal outcome and severe pathological features in native IgAN. We demonstrated that this parameter exhibited a higher predictive value in IgAN after transplantation. The absence of C1q deposition is a positive predictive sign as a response to steroid pulse therapy and relief of proteinuria[33]. Therefore, steroid-resistance nephrotic syndrome and a poorer outcome should be taken seriously when C1q staining presents during long-term immunosuppression.
Maintenance therapy with medium/low prednisone is used to relieve IgAN progression in combination with angiotensin-converting enzyme inhibitors (ACEIs) to reduce proteinuria. Early steroid withdrawal is a safe intervention in living donor transplantation[34,35], but steroid withdrawal should be handled with caution when choosing maintenance immunosuppressive treatments for patients with a high risk of recurrence. Based on our experience of treatment of native IgAN and related references[36,37], a maintenance therapy of oral prednisone at a dose of 0.6 mg/kg (qod) for Chinese patients after a IgAN in renal allografts diagnosis may be worthwhile. One recent study[38] suggested that other immunosuppressive therapy did not improve outcomes in patients with native IgAN and exhibited a more limited effect in IgAN in renal allografts, which occurred under existing immunosuppression after transplantation. Moreover, patients with IgAN in renal allografts exhibited favorable outcomes after tonsillectomy[39,40], but no reliable treatment strategy was proven to cure it.
Our study analyzed the 5-year graft cumulative survival rates after transplantation, but longer-term follow-up from biopsy is needed to observe more outcome events. In most cases, the primary diseases of the recipients were unknown, only 67 cases have been proven primary IgAN by biopsy for native renal in this series, the differences in clinical and pathological characteristics between de novo and recurrent IgAN couldn't be found in this study. Although major confounding variables were adjusted and our results were consistent with other studies in the literature, bias was unavoidable in the univariate Cox proportional hazards models due to the influence of the lack of information for the intraoperative and donor factors.