Lower tacrolimus trough levels are associated with subsequently higher acute rejection risk during the first 12 months after kidney transplantation

The premise that lower TAC trough levels are associated with subsequently higher first BPAR risk during the first 12 mo post‐transplant was recently questioned. Using our prospectively followed cohort of 528 adult, primary kidney transplant recipients (pooled across four randomized trials) who received reduced TAC dosing plus an IMPDH inhibitor, TAC trough levels measured at seven time points, 7, 14 days, 1, 2, 3, 6 and 9 months post‐transplant, were utilized along with Cox's model to determine the multivariable significance of TAC level(t) (a continuous time‐dependent covariate equaling the most recently measured TAC level prior to time t) on the hazard rate of developing first BPAR during the first 12 months post‐transplant. The percentage developing BPAR during the first 12 months post‐transplant was 10.2% (54/528). In univariable analysis, lower TAC level(t) was associated with a significantly higher BPAR rate (P = 0.00006), and its significance was maintained even after controlling for 2 significant baseline predictors (African‐American/Hispanic Recipient and Developed DGF) in Cox's model (multivariable P = 0.0003). Use of a cutpoint, TAC level(t) <4.0 vs. ≥4.0 ng/ml, yielded an even greater association with BPAR rate (univariable and multivariable P < 0.000001), with an estimated hazard ratio of 6.33. These results suggest that TAC levels <4.0 ng/ml should be avoided during the first 12 months post‐transplant when TAC is used in combination with fixed‐dose mycophenolate with or without corticosteroids and induction therapy.     

Higher tacrolimus trough levels on days 2–5 post-renal transplant are associated with reduced rates of acute rejection

Abstract:  We analyzed the association between whole-blood trough tacrolimus (TAC) levels in the first days post-kidney transplant and acute cellular rejection (ACR) rates. Four hundred and sixty-four consecutive, deceased-donor kidney transplant recipients were included. All were treated with a combination of TAC, mycophenolate mofetil and prednisolone. Patients were analyzed in four groups based on quartiles of the mean TAC on days 2 and 5 post-transplant: Group 1: median TAC 11 ng/mL (n = 122, range 2–13.5 ng/mL), Group 2: median 17 ng/mL (n = 123, range 14–20 ng/mL), Group 3: median 24 ng/mL (n = 108, range 20.5–27 ng/mL) and Group 4: median 33.5 ng/mL (n = 116, range 27.5–77.5 ng/mL). A graded reduction in the rates of ACR was observed for each incremental days 2–5 TAC. The one-yr ACR rate was 24.03% (95% CI 17.26–32.88), 22.20% (95% CI 15.78–30.70), 13.41% (95% CI 8.15–21.63) and 8.69% (95% CI 4.77–15.55) for Groups 1–4, respectively (p = 0.003). This study suggests that higher early TACs are associated with reduced rates of ACR at one yr.     

The impact of late acute rejection after cadaveric kidney transplantation

BACKGROUND: Acute graft rejection (AR) following renal transplantation results in reduced graft survival. However, there is uncertainty regarding the definition, aetiology and long-term graft and patient outcome of AR occurring late in the post-transplant period. AIM: To determine if rejection episodes can be classified by time from transplantation by their impact on graft survival into early acute rejection (EAR) and late acute rejection (LAR). MATERIALS AND METHODS: 687 consecutive adult renal transplant recipients who received their first cadaveric renal transplant at a single centre. All received cyclosporine (CyA)-based immunosuppression, from 1984 to 1996, with a median follow-up of 6.9 yr. Details were abstracted from clinical records, with emphasis on age, sex, co-morbid conditions, HLA matching, rejection episodes, patient and graft survival. ANALYSIS: Patients were classified by the presence and time to AR from the date of transplantation. Using those patients who had no AR (NAR) as a baseline, we determined the relative risk of graft failure by time to rejection. The characteristics of patients who had no rejection, EAR and LAR were compared. RESULTS: Compared with NAR, the risk of graft failure was higher for those patients who suffered a rejection episode. A much higher risk of graft failure was seen when the first rejection episode occurred after 90 d. Thus, a period of 90 d was taken to separate EAR and LAR (relative risk of 3.06 and 5.27 compared with NAR as baseline, p<0.001). Seventy-eight patients (11.4%) had LAR, 271 (39.4%) had EAR and 338 (49.2%) had NAR. The mean age for each of these groups differed (LAR 39.6 yr, EAR 40.8 yr compared with NAR 44 yr, p<0.003). The 5-yr graft survival for those who had LAR was 45% and 10-yr survival was 28%. HLA mismatches were more frequent in those with EAR vs. NAR (zero mismatches in HLA-A: 36 vs. 24%, HLA-B: 35 vs. 23% and HLA-DR: 63 vs. 41%, p<0.003). There was no difference in mismatching frequency between NAR and LAR. CONCLUSIONS: AR had a deleterious impact on graft survival, particularly if occurring after 90 d. AR episodes should therefore be divided into early and late phases. In view of the very poor graft survival associated with LAR, it is important to gain further insight into the main aetiological factors. Those such as suboptimal CyA blood levels and non-compliance with medication should be further investigated with the aim of developing more effective immunosuppressive regimens in order to reduce the incidence of LAR.     

Association of four DNA polymorphisms with acute rejection after kidney transplantation

Renal transplant outcomes exhibit large inter-individual variability, possibly on account of genetic variation in immune-response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open-label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR)] investigating renal function and biopsy-proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50–6.67]; P  =   0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42–8.09]; P  =   0.006). BPAR was almost fivefold more likely in patients homozygous for IL-10 -592A (OR: 4.71, 95% CI [1.52–14.55]; P  =   0.007) and twice as likely in patients with at least one A allele of TNF-α G-308A (OR: 2.18, 95% CI [1.08–4.41]; P  =   0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant.     

A case of acute vascular rejection after overseas deceased kidney transplantation

Abstract:  A 54-yr-old Japanese male received overseas deceased kidney transplantation in January 2006. His allograft functioned immediately and he received immunosuppression with cyclosporine A (CyA), mycophenolate mofetil (MMF), and prednisone (PR). On day 24 after transplantation, he came back to Japan. His serum creatinine level (s-Cr) was 1.39 mg/dL at two months after transplantation when he was admitted into Toda Central General Hospital on March 2006, for follow-up his renal allograft. He had taken only two immunosuppressive drugs, MMF and PR, and had not taken CyA at that time. His serum creatinine gradually rose after hospitalization. Allograft biopsy performed on April 6, 2006, showed acute vascular rejection (Banff 97 acute/active cellular rejection Grade III), together with suspicious for acute humoral rejection (Banff 97 antibody-mediated rejection Grade II). After treatment of two courses of steroid pulses and five d of gusperimus, acute vascular rejection and acute humoral rejection were relieved, which had been proven by the third allograft biopsy. In conclusion, this was a case of acute vascular rejection after overseas deceased kidney transplantation, resulted from non-compliance with immunosuppressive therapy.     

Compliance and late acute rejection after kidney transplantation: a psycho-medical perspective

INTRODUCTION: We examined the relationship between late acute rejection (LAR) after cadaveric kidney transplantation and medical compliance utilizing a modified version of the Long-term Medication Behaviour Self-efficacy Scale (LTMBS-scale), a validated patient self-report questionnaire. The original LTMBS-scale uses a five-point scale, however, our pilot study showed that patients found it difficult to discriminate between the five options. We therefore modified this to a three-point scale. PATIENTS AND METHODS: We carried out a retrospective analysis of all patients who received a kidney transplant in our unit in the cyclosporin (CyA) era. We divided rejections into early and late rejection based on the time interval after transplantation. Graft rejection was confirmed by biopsy; LAR was defined as acute rejection occurring after 90 d. We retrospectively administered the modified LTMBS-scale to determine individual patient confidence and self-efficacy in taking their medications in a variety of situations (home, work, leisure, psychological and physical). Individual patient confidence and self-efficacy was analysed in relationship to compliance behaviour. RESULTS: Twenty-four questionnaires were distributed, 22 (92%) were returned fully completed. The overall results suggested that our patients surveyed were not particularly confident (mean score 2.17 out of maximum possible 3) in taking their medications in a variety of contexts. They demonstrated significantly less confidence (mean score 1.0) when experiencing physical (brittle bones, feeling 'ill') and psychological ('sadness') side-effects of medication and emotional reactions to the experience of chronic illness. CONCLUSION: Negative physical and psychological states were related to low self-efficacy with the taking of immunosuppressive medication, non-compliance and subsequent LAR in our cohort of patients.     

Steroid withdrawal at 3 months after kidney transplantation: a comparison of two tacrolimus-based regimens

The 6 month prospective, randomized study compared the steroid-sparing potential of two tacrolimus-based regimens after renal transplantation. A total of 489 patients were randomized (1:1) to receive tacrolimus/mycophenolate mofetil (MMF)/steroids (n = 243; group Tac/MMF/S) or tacrolimus/azathioprine/steroids (n = 246; group Tac/Aza/S). At 3 months, steroids were tapered off in 267 (54.6%) patients free from steroid-resistant acute rejection and with serum creatinine concentrations <160 micromol/l. The incidence of biopsy-confirmed acute rejection at month 3 was lower in group Tac/MMF/S compared with group Tac/Aza/S (18.1% vs. 26.0%,P = 0.035). Moreover, more patients in the Tac/MMF/S group met the criteria for steroid withdrawal than in the Tac/Aza/S group (60.5% vs. 48.8%; P < 0.01). The incidence of acute rejection during months 4-6 was low in all groups, both for patients on steroid-free dual therapy (Tac/MMF: 2.7%, Tac/Aza: 0.8%) and for patients who continued steroid maintenance therapy (Tac/MMF/S: 3.5%, Tac/Aza/S: 7.1%). Moreover, kidney function was well preserved in steroid-free patients with month 6 median serum creatinine levels of 119.5 micromol/l (Tac/MMF), and 115.1 micromol/l (Tac/Aza). For patients who continued to receive steroids, month 6 median creatinine levels were 130.5 micromol/l (Tac/MMF/S) and 132.8 micromol/l (Tac/Aza/S). The criteria for the selection of patients to discontinue steroids were adequate. Both tacrolimus-based regimens allowed the safe discontinuation of steroids in low-risk patients at month 3. The Tac/MMF combination was superior in the prevention of acute rejections and more patients met the chosen criteria for steroid withdrawal.     

A case of plasma cell-rich acute rejection 18 months after kidney transplantation successfully treated with steroid pulse therapy

Abstract:  A 45-yr-old Japanese male underwent living-related kidney transplantation in August 2005, and immunosuppression consisted of tacrolimus, mycophenolate mofetil, methylprednisolone, basiliximab, and rituximab 200 mg. Allograft function was good, and the protocol biopsy post-transplant day 11 showed no evidence of rejection. The serum creatinine (s-Cr) level was maintained at the 1.2 mg/dL for 18 months. On February 2007, the patient's s-Cr level had increased to 2.03 mg/dL, and an episode biopsy was performed. The biopsy specimen demonstrated moderate to severe tubulitis and moderate interstitial infiltration of plasma cells and lymphocytes. The inflammatory cell infiltrate consisted of >30% plasma cells. The histopathological findings were consistent with plasma cell-rich acute rejection (PCAR). The PCAR was treated by steroid pulse therapy, and his s-Cr level decreased to 1.58 mg/dL. A biopsy three months after the steroid pulse therapy showed no evidence of rejection. The patient's allograft function is currently stable, and s-Cr level is 1.7 mg/dL. This is a case of PACR, that was successfully treated with steroid pulse therapy alone.     

Pretransplant identification of acute rejection risk following kidney transplantation

Lack of an accepted definition for ‘high immunological risk’ hampers individualization of immunosuppressive therapy after kidney transplantation. For recipient‐related risk factors for acute rejection, the most compelling evidence points to younger age and African American ethnicity. Recipient gender, body mass, previous transplantation, and concomitant infection or disease do not appear to be influential. Deceased donation now has only a minor effect on rejection risk, but older donor age remains a significant predictor. Conventional immunological markers (human leukocyte antigen [HLA] mismatching, pretransplant anti‐HLA alloantibodies, and panel reactive antibodies) are being reassessed in light of growing understanding about the role of donor‐specific antibodies (DSA). At the time of transplant, delayed graft function is one of the most clear‐cut risk factors for acute rejection. Extended cold ischemia time (≥24 h) may also play a contributory role. While it is not yet possible to establish conclusively the relative contribution of different risk factors for acute rejection after kidney transplantation, the available data point to variables that should be taken into account at the time of transplant. Together, these offer a realistic basis for planning an appropriate immunosuppression regimen in individual patients.     

A case of acute rejection with adenovirus infection after ABO-incompatible kidney transplantation

Abstract:  We report clinical and histopathologic findings of a case of acute rejection with adenovirus infection after kidney transplantation. A 63-yr-old woman with end-stage renal disease caused by lupus nephritis received an ABO-incompatible living kidney transplantation from her husband. On the 7th post-operative day (POD), she had fever, hematuria, and bladder irritation. Although she was treated with an antibiotic, the symptoms were not improved. We diagnosed adenovirus infection as positive with the urine shell vial method and blood PCR analysis. Cyclophosphamide was interrupted and immunoglobulin therapy was performed. However, urine output decreased and serum creatinine levels increased. An episode biopsy was performed on POD 20. We diagnosed acute antibody-mediated rejection. She was treated with plasma exchange for acute rejection and antiviral drug (rivabirin) for active adenovirus infection. However, the renal graft dysfunction was deemed irreversible and the renal graft was removed on POD 34. The graftectomy specimen showed acute rejection and acute tubular necrosis with adenovirus infection.     

Severe acute-hybrid rejection occurring nine months after kidney transplantation: a report of rescue by orchestration of antirejection therapies

Abstract:  Although a majority of acute rejection (AR) in non-sensitized recipients is T-cell-mediated by primed T cells, recent studies have shown that antibody-mediated acute rejection occurs in 20–30% of AR, and that it is often refractory to conventional antirejection therapy; possibly leading to graft loss. We report a case of severe acute-hybrid rejection consisting of both features in a non-sensitized kidney recipient, which was rescued by the orchestration of antirejection therapies. A 33-yr-old Japanese male, with advanced-stage chronic kidney disease with an unknown etiology, underwent a HLA 3/6 mismatch and ABO-compatible living-related kidney transplantation preemptively. He had an excellent clinical course, except for initial cytomegalovirus infection, with good graft function [serum creatinine (sCr) 1.1 mg/dL]. Nine months later, his creatinine abruptly increased to 2.1 mg/dL, when graft biopsy revealed acute T cell-mediated rejection (ATMR) grade IA, and simultaneous acute antibody-mediated rejection (AAMR) grade I. Antirejeciton therapy, comprising methyl-prednisolone pulse and 15-deoxyspergualin, and second line rituximab and plasmapheresis, was ineffective. Moreover, histologically and clinically, the rejection status deteriorated (ATMR grade III and AAMR grade III, max sCr 4.0 mg/dL). Next, we administered muromonab CD3 and basiliximab, which could eradicate the complicated severe AR without opportunistic infection, even under the strong immunosuppression. The present case implies that high-grade combined rejection can respond to anti-CD 20 and anti-CD25 mAbs, without serious complication; however, post-operative, thorough appropriate monitoring of immunosuppression is important because its effects are limited.     

Panel reactive HLA antibodies,soluble CD30 levels,and acute rejection six months following renal transplant

Domingues EMFL, Matuck T, Graciano ML, Souza E, Rioja S, Falci MC, Monteiro de Carvalho DB, Porto LC. Panel reactive HLA antibodies, soluble CD30 levels, and acute rejection six months following renal transplant.
Clin Transplant 2010: 24: 821–829. © 2009 John Wiley & Sons A/S. Abstract: Background: Specific anti‐human leukocyte antigen antibodies (HLA) in the post‐transplant period may be present with acute rejection episodes (ARE), and high soluble CD30 (sCD30) serum levels may be a risk factor for ARE and graft loss. Methods: HLA cross‐matching, panel reactive antibodies (PRA), and sCD30 levels were determined prior to transplantation in 72 patients. Soluble CD30 levels and PRA were re‐assessed at day 7, 14, 21, and 28, and monthly up to the sixth. Results: Twenty‐four subjects had a positive PRA and 17 experienced ARE. Nine of 17 ARE subjects demonstrated positive PRA and 16 had HLA mismatches. Positive PRA was more frequent in ARE subjects (p = 0.03). Eight subjects with ARE had donor‐specific antibodies (DSA) in serum samples pre‐transplantation, two subjects developed DSA. Three subjects without ARE had positive PRA only in post‐transplantation samples. Soluble CD30 levels were higher in pre‐transplant samples and ARE subjects than non‐ARE subjects (p = 0.03). Post‐transplant sCD30 levels were elevated in subjects who experienced rejection and were significantly higher at seven d (p = 0.0004) and six months (p = 0.03). Conclusions: Higher sCD30 levels following transplant were associated with ARE. Elevated sCD30 levels may represent a risk factor for acute rejection.     

Tacrolimus combined with mycophenolate mofetil can effectively reverse C4d-positive steroid-resistant acute rejection in Chinese renal allograft recipients.

BACKGROUND: Tacrolimus (TAC) combined with mycophenolate mofetil (MMF) has been suggested to play a critical role in the reversal of C4d-positive acute humoral rejection (AHR) in renal transplantation, but the efficacy of using only TAC-MMF without immunoadsorption or plasmapheresis has not been investigated. On the other hand, Chinese recipients of renal grafts usually need lower doses of immunosuppressants, and their optimal treatment for acute humoral rejection has not been established. METHODS: Since 1999, we have used TAC-MMF to treat steroid-resistant acute rejection (AR). C4d staining was retrospectively performed in 32 patients with steroid-resistant AR, and the treatments of 19 patients with C4d-positive steroid-resistant AR were investigated. RESULTS: Thirteen of 19 patients received TAC-MMF treatment only; 11 episodes of rejection in them were reversed (7 completely, 4 partially) and only 2 recipients lost their graft. Another 6 patients received immunoadsorption also. One of them failed to respond and lost her graft. Four of 5 patients treated with immunoadsorption and TAC-MMF recovered (3 completely, 1 partially), but 3 of them had severe pneumonia, a complication rate statistically higher than in patients treated with only TAC-MMF (P<0.05). AR occurring during the first two weeks after transplantation had a statistically better outcome than that occurring later (P = 0.003). CONCLUSION: Our study suggests that the combination of TAC and MMF is a potentially safe and economic treatment for most Chinese renal allograft recipients with C4d-positive steroid-resistant AR, especially for rejections developing within the first two weeks after transplantation.     

Aggressive treatment of the first acute rejection episode using first-line anti-lymphocytic preparation reduces further acute rejection episodes after human kidney transplantation

Abstract The detrimental effect of acute rejection episodes on long-term outcome of renal allografts in cyclosporin-treated patients is well established, although has not been seen by all investigators. To analyse the possibility that aggressive treatment of the first episode may ameliorate this detrimental effect, we performed an open label, randomised prospective trial in cyclosporin-based, immunosuppressed recipients of postmortem renal allografts in order to compare two different treatment protocols during primary acute rejection episodes: (1) group 1 of 25 patients received 3 × 250 mg methylprednisolone (MP) i.v.; (2) group 2 of 25 patients received 7 × anti-thymocyte globulin (ATG)-Fresenius i.v. (4 mg/kg body weight). During a period of 4 years, the following clinical observations were made: (1) The incidence of an acute re-rejection episode was significantly reduced in the ATG-treated study group (16%) compared to the MP-treated study group (72 %); (2) The severity of the first acute rejection episode (intensity of renal dysfunction measured in terms of 10-day creatinine area under curve) showed no significant difference between the groups (37 mg × 10-d/dl to 58 mg × 10-d/dl); and (3) The half-lives of allografts in both groups have not shown any significant differences so far. In conclusion, aggressive treatment of the first rejection episode of renal allografts with the use of ATG reduced the incidence of re-rejection episodes which, however, are not reflected so far by improvement of the 4-year survival rate of these allografts. Since it could be observed that re-rejection is an even worse predictor for chronic transplant failure, a better long-term outcome of renal allografts in ATG-treated patients may be expected during a longer observation period. The incidence of a third episode was also reduced in the ATG-treated group (0 %) compared to the MP-treated group (12%).     

血浆置换治疗肾移植术后抗体介导的急性排斥反应的疗效观察

目的 探讨血浆置换治疗肾移植术后抗体介导的急性排斥反应的效果. 方法 2011年1月至2013年9月行同种异体肾移植术后发生抗体介导的急性排斥反应患者5例,男2例,女3例.年龄41252岁,平均46岁.术前诊断均为慢性肾功能不全尿毒症期,行规律血液透析.术后采用环孢素[5 mg/(kg·d)]或他克莫司[0.1 mg/(kg·d)],以及吗替麦考酚酯(1.5 g/d)和糖皮质激素行免疫抑制治疗.术后2周内均经移植肾穿刺病理检查及血清供者特异性抗体测定诊断为抗体介导的急性排斥反应.予甲泼尼龙(1 000 mg/d)和抗淋巴细胞球蛋白(250 mg/d)治疗无效,在环孢素[5 mg/(kg·d)]或他克莫司[0.1 mg/(kg·d)],以及吗替麦考酚酯(1.5 g/d)和糖皮质激素免疫抑制治疗的基础上,5例患者均分别行血浆置换7次.4例原发病为慢性肾小球肾炎,术前血清肌酐为(784±154) μmol/L,术后2周内开始进行血浆置换;1例原发病为抗肾小球基底膜肾病,术前血清肌酐水平为935 μmol/L,术后35 d开始进行血浆置换. 结果 4例原发病为慢性肾小球肾炎患者分别经7次血浆置换治疗后排斥反应得到逆转,肾功能恢复良好,随访3个月时血清肌酐水平为(113±12) μmol/L.原发病为抗肾小球基底膜肾病患者,血浆置换后排斥反应未得到纠正,移植肾功能未恢复,随访3个月时血清肌酐水平524 μmol/L,继续血液透析治疗,随访12个月时血清肌酐水平758 μmol/L,超声检查示移植肾萎缩,予口服他克莫司0.5mg/d治疗. 结论 2周内应用血浆置换能有效地逆转肾移植术后患者抗体介导的急性排斥反应.     

Validation of genetic variants associated with early acute rejection in kidney allograft transplantation

Numerous reports have identified genetic variants associated with kidney transplant outcome, but only a few have been validated in subsequent studies. We analyzed the association of 21 previously reported genetic variants associated with acute rejection (AR), in an effort to validate these associations in our kidney transplant population. All recipients (n = 585) received Ab induction, rapid discontinuation of prednisone, and calcineurin inhibitors with either mycophenolate mofetil or sirolimus. Both univariate analysis and logistic regression were used for determining the association between the genotypes and AR. Univariate analysis detected one significant single-nucleotide polymorphism (p = 0.03), rs1801133, within the methylenetetrahydrofolate reductase (MTHFR) gene associated with AR. Logistic regression analysis identified two variants associated with AR, the 32-bp deletion within chemokine (C-C motif) receptor 5 gene (rs333) and the p.222A/V variant (rs1801133) within the MTHFR gene. Although our analysis utilized a much larger cohort than used in previous reports, we were only able to detect an association with two of these variants. The lack of validation for the other 19 variants may be due to the small effect size, or that, they are not associated with AR. These results stress the need for larger cohorts for both future studies as well as for validation studies.