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Introduction

Immunoglobulin A nephropathy (IgAN) is a renal disorder, which is characterized by symptomatic and pathological changes caused by diffuse deposition of IgA or IgA-containing immune complexes in the glomerular mesangial area and capillary loops. IgAN is increasingly common in males than in females and has been observed in a high percentage of renal biopsies in Asia. Bi (1) and Li (2) identified that IgAN accounts for 26–34% of all primary glomerular diseases in China and is one of the main causes of end stage renal disease (ESRD).

Kidney transplantation is considered the optimal therapeutic strategy for ESRD. Berger et al (3) were the first to report recurrent IgAN in kidney allograft recipients and recurrent IgA deposition in the mesangial area of kidney allograft recipients. Additionally, they found that recurrent IgAN in kidney allograft recipients had a relatively benign clinical course. Earlier studies have shown that recurrent IgAN does not have a negative impact on the clinical course of kidney transplantation (4). However, studies published in the 1990’s that employed longer follow-up periods reported that recurrent IgAN was a major cause of graft loss (5,6). In particular, recurrent IgAN was observed in 20–60% of patients following transplantation and certain transplant recipients experienced de novo IgAN (7–11).

At present, the prognostic factors associated with recurrent IgAN in kidney allograft recipients in China remain to be fully elucidated. Although there have been numerous Western studies of the incidence rate and risk factors of recurrent IgAN in kidney allograft recipients, there are few studies focusing on the prognostic factors of recurrent IgAN following kidney transplantation (12,13). In the present study, the prognostic factors associated with recurrent IgAN in kidney allograft recipients from a single institution in China were investigated.

Materials and methods

Clinical data

Patients undergoing renal graft biopsy (n=197)who were hospitalized at the Organ Transplant Center of the Fuzhou General Hospital (Fuzhou, China) between June, 2004 and December, 2010 were screened. A total of 202 kidney allograft biopsy specimens were obtained. Forty-two patients (20.8%, including 31 males and 11 females) met the diagnostic criteria for IgAN following clinical and pathological examinations. Thirty-eight cases received one transplantation and four cases received two transplantations. There were 41 cadaveric donor kidney transplants and 1 live-donor kidney transplant. Follow-up was every three months and the final follow-up occured on August 31, 2012. The study was approved by the Ethics Committee of the Organ Transplant Institute, Fuzhou General Hospital, Fuzhou, China (Review board IRB00006161) and written informed consent was obtained from the patients.

The 42 patients who met the diagnostic criteria for IgAN were divided into two groups, the graft loss group (n=17) and the functional graft group (n=25). The graft loss group included patients with graft dysfunction, those who required resumption of dialysis or a second transplant. Pathological diagnosis was based on conventional hematoxylin and eosin, periodic acid-schiff, Masson and immunohistochemical staining for IgG, IgM, IgA, C3d, C1q and C4d. The pathological changes of kidney grafts were observed by light microscopy (Leica Microsystems, Ltd., Hong Kong, China). The Banff 97 score of allograft nephropathy was calculated as described previously (14).

Clinical and pathological characteristics

The following demographic and clinical data were recorded: Age, gender, date of transplantation, requirement for repeat transplantation, cadaveric or live donor transplantation, date of IgAN onset, renal graft biopsy and graft dysfunction, height, weight, blood pressure, pulse, urine output at the time of biopsy, edema, gross hematuria and immunosuppressant regimen and dose. The following clinical indicators were measured 1 week prior to renal graft biopsy: Routine urine test, 24-h urinary protein levels for patients with proteinuria, serum creatinine (SCr), blood urea nitrogen (BUN), uric acid (UA), glomerular filtration rate, hemoglobin (Hb), triglycerides (TG), total cholesterol (CHO), serum total protein (TPR) and serum albumin (Alb) levels. The following pathological characteristics were also recorded: Renal allograft nephropathy score, glomerular sclerosis, crescent formation, fibrinoid necrosis, tubular atrophy, interstitial fibrosis and arteriolopathy.

Statistical analysis

All data were recorded in a database. Quantitative data were compared using Student’s t-test. If the data had non-normal distribution and/or heterogeneity of variance, a rank sum test was performed. Qualitative data were compared using the χ2 test. Renal graft survival rate was calculated using the Kaplan-Meier method, and differences in survival were examined with the log-rank test. All data were analyzed using SPSS software, version 13.0 (SPSS, Inc., Chicago, IL, USA). P<0.05 was considered to indicate a statistically significant difference.

Results

General characteristics of patients

Between June, 2004 and December, 2010, 197 patients underwent renal graft biopsy at the Organ Transplant Center, Fuzhou General Hospital and 202 kidney allograft biopsy specimens were obtained. Forty-two patients (20.8%; including 31 males and 11 females) met the diagnostic criteria for IgAN. Thirty-eight patients underwent transplantation once and four patients underwent transplantation twice. Forty-one cases received cadaveric donor kidneys and one case received a kidney from a living donor. The examination results indicated the presence of concomitant proteinuria and hematuria in 25 patients (59.5%) and proteinuria, but no hematuria in six patients (14.3%). The concentration of urinary protein in these 31 patients indicated a mean of 3.6±2.1 g/24 h (range, 0.312–8.13 g/24 h). Analysis of all 42 biopsy specimens indicated the presence of 17.2±13.0 glomeruli. All specimens met the Banff 97 criteria for renal biopsy (14).

The graft loss and functional graft groups showed no statistically significant differences in gender, age, human leukocyte antigen (HLA) matching, immunosuppressant regimen and dose, blood pressure and urine output at the time of biopsy (Table I).

Table I Demographic and clinical characteristics of enrolled patients with IgAN.

Table I

Demographic and clinical characteristics of enrolled patients with IgAN.

Characteristics	Graft loss (n=17)	Functional graft (n=25)	P-value
Gender
Males	12	19
Females	5	6	0.733
Mean age (years)	36.1±9.2	38.1±4.3	0.823
HLA mismatches	2.29±0.69	2.36±0.95	0.881
HLA-A	0.82±0.64	0.8±0.82	0.804
HLA-B	0.71±0.69	0.76±0.66	0.777
HLA-DR	0.76±0.66	0.8±0.82	0.989
Immunosuppressive drugs at time of diagnosis
Prednisolone (mg/day)	8.6±2.0	9.1±2.9	0.603
n (%)	17 (100)	25 (100)	1
Ciclosporin (mg/day)	225.0±35.4	133.3±28.9	0.076
n (%)	4 (23.5)	9 (36.0)	0.391
Tacrolimus (mg/day)	2.2±1.1	2.0±1.0	0.606
n (%)	13 (76.5)	16 (64.0)	0.296
MMF (mg/day)	892.9±349.3	863.6±171.9	0.961
n (%)	14 (82.3)	20 (80.0)	0.758
Bredinin (mg/day)	87.5±17.7	75±15.6	0.317
n (%)	2 (11.8)	2 (8.0)	0.758
Azathioprine (mg/day)	50	50	1.00
n (%)	1 (5.9)	3 (12.0)	0.758
Blood pressure (mmHg)
Systolic	136.4±19.4	135.8±18.5	0.926
Diastolic	86.4±12.4	85.6±12.0	0.833
Urine volume (ml/24 h)	1872.7±392.7	1742.5±595.0	0.636

[i] IgAN, immunoglobulin A nephropathy; HLA, human leukocyte antigen; MMF, mycophenolate mofetil.

Analysis of clinical indicators

Analysis of the clinical data of the two groups indicated that patients in the graft loss group were more likely to exhibit proteinuria (P=0.014), higher SCr levels at the time of biopsy (P=0.009), lower epidermal growth factor receptor levels (P=0.013), lower TPR (P=0.01) and lower serum Alb levels (P=0.043) (Table II). However, the two groups showed no significant differences in hematuria, BUN, UA, Hb, TG and CHO levels (Table II).

Table II Clinical indicators of patients in the graft loss and functional graft groups.

Table II

Clinical indicators of patients in the graft loss and functional graft groups.

Indicators	Graft loss (n=17)	Functional graft (n=25)	P-value
Proteinuria, n (%)	16 (94.1)	15 (60)	0.014a
Hematuria, n (%)	13 (76.5)	16 (64)	0.391
Proteinuria (g/24 h)	4.1±2.4	2.6±1.7	0.047a
SCr (μmol/l)	373.6±267.5	220.9±164.9	0.009a
BUN (mmol/l)	16.9±9.5	13.5±10.7	0.081
UA (mmol/l)	489.9±157.8	480.7±133.8	0.769
eGFR (ml/min)	29.3±18.2	51.9±32.1	0.013a
Hb (g/l)	97.8±24.8	107.9±21.8	0.173
TG (mmol/l)	1.5±1.0	1.5±0.7	0.397
CHO (mmol/l)	5.8±3.5	6.1±2.1	0.182
TPR (g/l)	57.9±7.5	66.5±10.9	0.01a
Alb (g/l)	34.3±5.1	38.7±8.2	0.043a

{ label (or @symbol) needed for fn[@id='tfn2-mmr-09-04-1179'] } SCr, serum creatinine; BUN, blood urea nitrogen; UA, uric acid; eGFR, epidermal growth factor receptor; Hb, hemoglobin; TG, triglycerides; CHO, total cholesterol; TPR, serum total protein; Alb, serum albumin.

a P<0.05 compared to the function graft group.

Analysis of the pathological characteristics

Analysis of the pathological characteristics of the two groups indicated that patients in the graft loss group were more likely to have a high Banff score (P=0.001), severe glomerular sclerosis (P=0.002), increased crescent formation (P=0.01), greater tubular atrophy (P=0.013) and interstitial fibrosis (P=0.033) compared with those of the functional graft group (Table III).

Table III Pathological characteristics of patients in the graft loss and functional graft groups.

Table III

Pathological characteristics of patients in the graft loss and functional graft groups.

Characteristics	Graft loss (n=17)	Functional graft (n=25)	P-value
Banff score (0–30)	15.6±6.0	8.8±4.6	0.001a
Concomitant CAN, n (%)	4 (23.5)	8 (32.0)	0.551
Concomitant AR, n (%)	1 (5.9)	2 (8.0)	0.794
Calcineurin inhibitor toxicity (%)	0 (0.0)	1 (4.0)	0.404
Glomerular sclerosis n (%)			0.002a
0%	2 (11.8)	7 (28.0)
1–25%	3 (17.7)	14 (56.0)
>25%	12 (70.6)	4 (16.0)
Crescent	7 (41.8)	2 (8.0)	0.01a
Tubular atrophy			0.013a
0%	0 (0)	3 (12.0)
1–25%	2 (11.8)	11 (44.0)
>25%	12 (70.6)	11 (44.0)
Interstitial fibrosis			0.033a
0–5%	0 (0)	4 (16.0)
6–25%	4 (23.5)	12 (48.0)
>25%	13 (76.5)	10 (40.0)
Vascular
Normal	1	7
Hyalinosis	1	18	0.073

a P<0.05 compared with the functional graft group.

{ label (or @symbol) needed for fn[@id='tfn5-mmr-09-04-1179'] } CAN, chronic allograft nephropathy; AR, acute rejection.

Analysis of renal graft survival

During the same period (between June, 2004 and December, 2010), in 88 kidney allograft recipients who underwent renal graft biopsy at Fuzhou General Hospital, pathological examination confirmed the presence of other glomerular diseases, including acute diffuse proliferative glomerulonephritis, rapidly progressive glomerulonephritis, membranous glomerulonephritis, minimal change glomerulonephritis, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis and chronic glomerulonephritis, based on the diagnostic criteria previously described (15). In addition, 36 of these patients demonstrated glomerular lesions, including renal interstitial lesions free of glomerular lesions, tubular lesions, arteriolopathy, acute and chronic rejection, and immunosuppressant toxicity.

The cumulative graft survival rates of the three groups (patients with IgAN and patients with or without other glomerular diseases) over 10 years are shown in Fig. 1. The renal graft survival rate was calculated using the Kaplan-Meier method and identified no significant differences in the graft survival rates of the three groups over 10 years (P=0.122).

Figure 1 Cumulative renal graft survival rates in patients with IgAN and patients with or without other glomerular diseases over 10 years. IgAN, immunoglobulin A nephropathy.

Discussion

The presence of IgAN in kidney allograft recipients may be due to recurrence of IgAN, de novo IgAN or transmission of IgA deposits from the donor kidney. The majority of patients with kidney disease also presented with ESRD at medical examination and such patients are not suitable for biopsy. Thus, histopathological diagnosis of the primary disease is not available for the majority of kidney allograft recipients. In addition, time-zero biopsy data of donor grafts are generally not available. This renders it difficult or even impossible to differentiate recurrent IgAN, de novo IgAN and donor-transmitted IgAN. However, long term clinical observations at Fuzhou General Hospital indicated that the majority of donor kidneys with IgA deposition at the baseline biopsy did not result in IgA deposition during postoperative allograft biopsy. In addition, Sanfilippo et al (16) showed that mesangial IgA deposition can quickly dissipate following transplantation. Thus, it was hypothesized that the majority of patients in the present study had recurrent IgAN or de novo IgAN.

This study screened 197 hospitalized patients who underwent renal graft biopsy at the Organ Transplant Center of the Fuzhou General Hospital (Fuzhou, China) between June, 2004 and December, 2010. Of these, 42 patients (20.8%) met the diagnostic criteria for IgAN, indicating that IgAN was common among the kidney allograft recipients. Previous studies did not identify any clinical abnormalities in approximately one-third of patients with confirmed IgAN (5,17,18); therefore, it was suggested that there may have been increased cases of IgAN if renal allograft biopsies were performed for all kidney allograft recipients.

Abnormal routine urine test results were common in the renal allograft recipients with IgAN (83.3%), and microscopic examination indicated concomitant proteinuria and hematuria in 25 patients (59.5%). Statistical analysis indicated that proteinuria, but not hematuria, was significantly associated with graft loss. The 24-h urinary protein level was also significantly greater in the graft loss group than that in the functional graft group. Moreover, the results indicated that serum TRP and Alb levels were significantly lower in the graft loss group compared with those in the functional graft group. Collectively, these results suggested that the substantial loss of protein in the urine is associated with poor graft outcome.

The results also indicated that higher SCr levels were significantly associated with graft loss. In particular, the mean SCr level was 373.6±267.5 μmol/l in the graft loss group and 220.9±164.9 μmol/l in the functional graft group at the time of biopsy. BUN and UA levels were not correlated with renal graft prognosis. Concurrent with the results of the present study, Wang et al (19) demonstrated that patients with graft loss exhibited higher SCr levels at the time of renal graft biopsy and Kiattisunthorn et al (13) suggested that higher SCr and urinary protein levels were associated with poor graft function.

The present study did not identify a significant correlation between HLA matching and the prognosis of kidney allografts in patients with IgAN. However, previous studies have shown that females and patients with positive HLA matching were more prone to recurrent IgAN and had a lower 5-year graft survival rate (20,21). In addition, Andresdottir et al (22,23) investigated the graft survival of 1,207 patients with IgAN and 7,935 patients with no glomerular disease, and reported that the presence of the HLA-B8 and DR3 haplotype increased the risk of graft loss.

Namba et al (9) found that progressive graft loss in patients with recurrent IgAN was associated with the deterioration of renal graft function, hypertension and angiotensin converting enzyme inhibitor deficiency at the time of biopsy. However, the present study demonstrated no significant correlation between graft loss and hypertension, hypotension or pulse rate at the time of biopsy. The results also indicated that the levels of serum TG and CHO were not significantly associated with graft loss.

Increased crescent formation suggested a poor prognosis of the renal allograft. In the present study, a significant increase in the number of patients with crescent formation was observed in the graft loss group (n=7; 41.8%) compared with the functional graft group (n=2; 8.0%). Tang et al (24) proposed that IgAN with crescent formation is increasingly common in patients who received renal grafts or were diagnosed with primary glomerulonephritis in China. Such patients developed rapid progression of renal insufficiency, progressed to kidney dysfunction and ultimately required hemodialysis. Kowalewska et al (25) found that early renal dysfunction or resumption of dialysis occurred in approximately half of renal allograft recipients with IgAN who presented with crescent formation. Soler et al (21) showed that the 5-year graft survival rate was 71% in patients with crescentic glomerulonephritis who were diagnosed with IgA or Henoch-Schonlein purpura, but was 100% in patients with glomerular mesangial hyperplasia or focal segmental glomerulosclerosis.

Oka et al (26) showed that the pathological characteristics of IgAN in renal graft recipients were different from those in patients with IgAN who had not undergone transplantation. In particular, graft recipients with IgAN seldom displayed active damage, such as extracapillary proliferation, but often exhibited chronic damage, such as glomerulosclerosis and interstitial fibrosis. It was speculated that this difference was associated with the use of immunosuppressive agents. In the present study, the incidence of glomerulosclerosis, tubular atrophy, interstitial fibrosis and arteriosclerosis were compared in the graft loss and functional graft groups. The results showed that glomerulosclerosis, tubular atrophy and interstitial fibrosis were significantly more common in the graft loss group than in the functional graft group. However, the rate of arteriosclerosis was similar in the two groups.

Furthermore, the results of the current study showed no significant difference between the renal graft survival rate in patients with IgAN and patients with or without other glomerular diseases. It was suggested that these results may be explained by the similar disease severity of the three groups. Concurrent with these results, Kiattisunthorn et al (13) found no significant difference in renal graft survival among these three groups. However, the large population study of Andresdottir et al (21) demonstrated a greater 1-year graft survival rate in renal graft recipients with IgAN than in those without glomerular diseases. They speculated that the results may be due to the better immune status of patients with IgAN. However, the results also indicated that the graft survival rate tended to decrease more rapidly in renal graft recipients with IgAN than in those without IgAN.

In conclusion, renal transplantation is considered the optimum treatment for patients with IgAN-induced ESRD as such patients have a high 5- and 10-year graft survival rate even in the presence of recurrent IgAN. Following renal transplantation, the presence of numerous prognostic factors indicated poor graft survival, which should result in caution and the implementation of appropriate interventions.

Acknowledgements

The authors would like to thank Dr Feng Zheng for their input regarding the experimental procedures. This study was supported in part by grants from the Key Laboratory of Fujian Province (grant no. 2010Y2006), the Fujian Natural Science Foundation (grant no. 2012J01404) and the Fujian Science and Technology Project Foundation (grant no. 2012Y5006).

References