It has been reported that kidney retransplant patients had high rates of early acute rejection due to previous sensitization. In addition to the acute antibody-mediated rejection (ABMR) that has received widespread attention, the early acute T-cell-mediated rejection (TCMR) may be another important issue in renal retransplantation. In the current single-center retrospective study, we included 33 retransplant patients and 90 first transplant patients with similar protocols of induction and maintenance therapy. Analysis focused particularly on the incidence and patterns of early acute rejection episodes, as well as one-year graft and patient survival. Excellent short-term clinical outcomes were obtained in both groups, with one-year graft and patient survival rates of 93.9%/100% in the retransplant group and 92.2%/95.6% in the first transplant group. Impressively, with our strict immunological selection and desensitization criteria, the retransplant patients had a very low incidence of early acute ABMR (6.1%), which was similar to that in the first transplant patients (4.4%). However, a much higher rate of early acute TCMR was observed in the retransplant group than in the first transplant group (30.3% versus 5.6%,
Renal transplantation is regarded as the optimal treatment for patients with end-stage renal disease. However, as long-term graft survival is still limited, most transplant patients will face graft loss after 9-10 years [
It has been reported that the best approach to treat most patients suffering from chronic renal allograft failure is to perform a kidney retransplant, in hopes of avoiding the high risk of morbidity and mortality with a return to dialysis [
Renal retransplant patients had high rates of acute rejection, from 33% to 69%, as reported in previous studies [
Here, we report on the early transplant outcomes of 33 second, third, and fourth kidney transplants performed at our hospital within the last 3 years. Analysis focused particularly on the incidence and patterns of the early acute rejection episodes, as well as one-year graft and patient survival.
Between January 2013 and December 2015, a total of 703 kidney transplants were performed at Tongji Hospital, including 521 transplants from deceased donors (donation after brain death or cardiac death) and 182 from living-related donors. Of these, 662 (94%) were first transplantations and 41 (6%) were retransplantations.
In the current retrospective study, for the retransplant group, we included 33 adult patients, who received a second, third, or fourth renal allograft with Thymoglobulin induction therapy and Tacrolimus-based maintenance therapy. The exclusion criteria were as the following: (1) pediatric recipients; (2) renal allografts from pediatric donors; (3) patients who received no induction therapy or received induction therapy other than Thymoglobulin; (4) patients who received a multiorgan transplant. For the control group, we selected 90 patients who received a first renal allograft during the same period and fulfilled the same inclusion and exclusion criteria. This study was performed after approval by the ethics committee at Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology.
Data on transplantations and hospital stays, as well as follow-up data, were collected from hospital records. Baseline characteristics, such as recipient age and gender, donor type (deceased or living), number of previous transplants, cold ischemia time, number of HLA mismatches, pretransplant panel reactive antibody (PRA) percentages divided into groups (0–10%, >10%–50%, and ≥50%), and preformed DSA, were collected and analyzed. In addition, early clinical outcomes, including the generation of de novo DSA, rate of delayed graft function (DGF), the frequency and type of acute allograft rejection (cellular or antibody-mediated rejection), and one-year graft and patient survival, were analyzed. DGF was defined as the need for more than 1 dialysis during the first week after transplant. HLA class I and II antibody screenings were performed using FlowPRA® (One Lambda, Inc., Canoga Park, CA), and the specificity determination was measured by Luminex using LABScreen® single antigen beads (One Lambda, Inc., Canoga Park, CA).
All patients received induction therapy with Thymoglobulin and maintenance immunosuppression with Tacrolimus, mycophenolate mofetil, and steroids. Because of differences in immunological risk, the dosage and duration of the Thymoglobulin administration were slightly different for the retransplant group, compared to the control group. The initial administration of Thymoglobulin was finished intraoperatively, before the graft reperfusion, at a dose of 50 mg in the retransplant group and a dose of 25 mg in the control group. Then, it was used daily by the retransplant group from day 1 to day 4, reaching a total dosage of 125–150 mg. In the control group, Thymoglobulin was given from day 0 to day 2 at a daily dose of 25 mg. The peripheral blood lymphocyte counts were frequently monitored within the first 2 weeks after renal transplantation. Methylprednisolone was given intravenously from day 0 to day 2 (500 mg/d), followed by oral doses of prednisone at 50 mg/d, which was then tapered every other day to a maintenance dose of 10 mg/d. Mycophenolate mofetil was administered at a dose of 1.5 g/d and was subsequently reduced to 1 g/d depending on the individual’s white blood cell count. Tacrolimus was started at day 3, with a targeted trough level of 8–10 ng/ml initially and 6–8 ng/ml one month after transplantation.
In our center, the decision of desensitization was mainly based on the laboratory testing results for pretransplant PRA, preformed DSA, HLA mismatch (MM), and flow complement-dependent cytotoxicity (CDC). As shown in Figure
Indications of desensitization therapy for our retransplant patients. No desensitization was initiated if patients had HLA 0 MM, or HLA MM ≥ 1, but PRA < 50% with negative DSA and CDC. Desensitization was suggested if patients had (1) HLA MM ≥ 1, DSA positive, and negative or weakly positive flow CDC (<15%) or (2) HLA MM ≥ 1 and PRA ≥ 50% with negative DSA and CDC.
In general, acute rejection was diagnosed using kidney biopsies upon Banff 2007 or 2013 classification. When a tissue analysis was not available, the clinical diagnosis was based on an otherwise unexplained elevation of serum creatinine levels, coupled with appropriate physical signs (including edema, oliguria, fever, or weight gain). All allograft biopsies were routinely stained for hematoxylin and eosin (HE) and immunohistochemistry for C4d, CD3, CD4, and CD8. The diagnosis of acute TCMR was based on the following criteria: IA, cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3), and foci of moderate tubulitis (t2); IB, cases with significant interstitial infiltration (>25% of parenchyma affected, i2 or i3), and foci of severe tubulitis (t3); IIA, cases with mild-to-moderate intimal arteritis (v1); IIB, cases with severe intimal arteritis comprising >25% of the luminal area (v2); III, cases with “transmural” arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic inflammation (v3) [
In our descriptive statistical analysis, results are expressed as numerical values and percentages for categorical variables and as mean values with standard deviation (SD) for continuous variables. The frequencies procedure was used to compare baseline characteristics between the two groups. Graft and patient survival was evaluated according to Kaplan-Meier survival statics. Statistical analysis was performed using SigmaStat software version 3.5.
The patient cohort included 33 kidney retransplants and 90 first transplants. The retransplant group comprised 28 (84.9%) second, 4 (12.1%) third, and 1 (3%) fourth kidney transplants. Baseline and demographic characteristics are shown in Table
Demographics and early transplant outcomes.
Second and subsequent transplant | First transplant | | |
---|---|---|---|
Recipient age, year | 46 ± 11 | 43 ± 11 | 0.170 |
Recipient gender | 0.334 | ||
Male | 25 (75.8) | 60 (66.7) | |
Female | 8 (24.2) | 30 (33.3) | |
Type of donor | |||
Deceased | 24 (72.7) | 90 (100) | NA |
Living-related | 9 (27.3) | 0 | |
Times of previous transplant | NA | ||
1 | 28 (84.9) | 0 | |
2 | 4 (12.1) | 0 | |
3 | 1 (3.0) | 0 | |
Cold ischemia time (h) | 7.7 ± 5.8 | 8.6 ± 4.6 | 0.122 |
HLA-A, B, DR MM | 3.3 ± 1.2 | 3.5 ± 0.8 | 0.261 |
Pretransplant PRA | <0.001 | ||
Class I and class II < 10% | 14 (42.4) | 87 (96.7) | |
Class I or class II 10~50% | 8 (24.3) | 2 (2.2) | |
Class I or class II ≥ 50% | 11 (33.3) | 1 (1.1) | |
Preformed DSA+ | 3 (9.1) | 0 | NA |
Delayed graft function | 4 (12.1) | 16 (17.8) | 0.451 |
De novo DSA+ | 4 (12.1) | 5 (5.6) | 0.215 |
TCMR | | 5 (5.6) | <0.001 |
ABMR | 2 (6.1) | 4 (4.4) | 0.712 |
1 yr graft survival | 93.9% | 92.2% | 0.746 |
1 yr patient survival | 100% | 95.6% | 0.218 |
The incidence of DGF in both groups was not high, with 12.1% in the retransplant group and 17.8% in the control group
The rates of acute ABMR in both groups were similarly low, with 6.1% (2/33) in the retransplant group and 4.4% (4/90) in the control group
In the control group, acute TCMR was only seen in 5.6% (5/90) of the patients with an induction therapy of low Thymoglobulin doses. However, even when a higher total dosage of Thymoglobulin was administered, resulting in a satisfactory decline in peripheral blood lymphocyte count (Figure
The average blood lymphocyte counts in retransplant patients before and after Thymoglobulin induction therapy. A satisfactory decline of peripheral blood lymphocyte count in the retransplant group was achieved with a 5-day period of Thymoglobulin induction therapy (total dosage: 125–150 mg).
A typical example of TCMR in the retransplant group is shown in Figure
The clinical course of a second graft recipient who had early acute TCMR twice after transplantation. A 47-year-old male patient received his second kidney transplantation. (a) Early clinical course after retransplantation: renal graft gained immediate function with serum creatinine (sCr) levels decreasing rapidly and reaching normal levels at day 7. Increased sCr was observed at around day 14 and 3 doses of Methylprednisolone (MP, 500 mg/d) were then administered. After treatment, sCr levels decreased to 117
Interestingly, almost all the episodes of TCMR were observed in lower presensitized retransplant patients with pretransplant PRA < 50% (Table
Impact of desensitization on incidence of TCMR in retransplant
TCMR | TCMR | | |
---|---|---|---|
| | ||
PRA 10% < 50% | 9 (42.9) | 12 (57.1) | |
PRA ≥ 50% | | 9 (90) | 0.067 |
Nondesensitization | 10 (41.7) | 14 (58.3) | |
Desensitization | 0 | 7 (100) | <0.05 |
Both groups had high rates of graft and patient survival at the one-year mark (Table
Since the recipients of retransplantation are usually sensitized to certain mismatched HLA antigens because of exposure to previous allograft(s), they are at high risk for the development of acute ABMR. This process is mediated by either preformed or induced DSA that is produced as a result of an anamnestic response by memory B cells [
It is well known that despite attempts devoted to improving outcomes in highly sensitized patients by using desensitization protocols, acute ABMR rates remain high, afflicting about 28%–40% of all cases [
Notably, even with more potent Thymoglobulin induction therapy, the retransplant patients in our study had a much higher incidence of early acute TCMR compared to the first transplant group. This phenomenon has been rarely reported and emphasized in the literature. One study showed a relatively higher rate of both ABMR (22%) and TCMR (40%) in 37 presensitized kidney transplant patients without any desensitization treatment [
In conclusion, our data on kidney retransplantation show excellent clinical outcomes with low incidence of early acute ABMR and satisfactory one-year patient and graft survival. However, the retransplant patients are at higher risk for the development of early acute TCMR, which requires accurate diagnosis and prompt treatment.
The authors declared that they have no conflict of interests.
The study was supported by the National Natural Science Foundation of China (81001323) and the special project of the Ministry of Health, China (201302009).