Chylous ascites in a renal transplant recipient under sirolimus (rapamycin) treatment

Ascites is a rare complication of renal transplantation. Ascites has been reported after kidney transplantation due to rejection, decapsulation of the graft, urinary or vascular leak, lymphocele, transudation, or infection. While technical complications of the procedure are the most frequent cause, portal hypertension and graft rejection are other causes. Ascites can occur after renal transplantation independent of kidney function. Usually, a time relation can be made between the surgical procedure and ascites development. Chylous ascites is still more uncommon; it is usually related to traumatic lymphatic injury. Drugs are rarely associated with the genesis of ascites. Sirolimus has been associated with a high rate of lymphoceles, lymphedema, and pulmonary alveolar proteinosis. The exact mechanisms remain unknown. The risk for lymphocele formation with sirolimus is 12% to 15%. Ascites is an adverse effect with an incidence between 3% and 20%, but no relation between sirolimus and chylous ascites was previously established. We present a clinical report of chylous ascites in a renal transplant patient under sirolimus therapy; our investigation pointed to sirolimus as the cause.     

The presence of B-cell nodules does not necessarily portend a less favorable outcome to therapy in patients with acute cellular rejection of a renal allograft

The presence of B-cell nodules in kidney biopsies of patients undergoing acute renal allograft rejection has been reported to be associated with glucocorticoid resistance and a high risk of graft failure. In an attempt to corroborate this observation, biopsies of renal transplants that evidenced Banff grade I A acute rejection were examined for the presence of B- or T-cell nodules, the detection of which was correlated with the therapeutic response. Biopsies from 14 consecutive renal transplant recipients with a diagnosis of acute cellular rejection were examined for the presence of T (CD3-positive) or B (CD20-positive) cells by immunohistochemistry. All patients were biopsied because of a rise in serum creatinine. No biopsy showed evidence of acute humoral rejection. Immunofluorescence microscopy was negative for C4d deposition in peritubular capillaries. There were no neutrophils in the peritubular or glomerular capillaries. Five patients had T-cell nodules; four had B-cell nodules; three had both T- and B-cell nodules; two had no nodules. All biopsies contained CD3-positive cells in the tubules and in the interstitium. In all but one of the patients, episodes of acute rejection were treated with steroids (one received thymoglobulin). Furthermore two patients received mycophenolate mofetil and one, sirolimus. There were no significant differences among the groups in either the initial creatinine or the creatinine after therapy. The presence of B-cell nodules in renal allograft biopsies of patients experiencing acute cellular rejection did not portend a less favorable outcome.     

Immunosuppressive strategies to improve outcomes of kidney transplantation

The introduction of several immunosuppressive agents over the past decade has reduced the rate of acute rejection significantly and has improved short-term renal allograft survival. However, their impact on long-term outcomes remains unclear. Current immunosuppressive strategies are focused on improving long-term graft and patient survival along with maintaining allograft function. The approval of the new immunosuppressive agents: rabbit antithymocyte globulin, basiliximab, daclizumab, tacrolimus, mycophenolate, and sirolimus, also has facilitated the development of steroid- and calcineurin inhibitor-sparing regimens in kidney transplantation. We discuss the impact of various immunosuppressive regimens on the outcome measures of kidney transplantation: acute rejection episodes, allograft survival, and renal function.     

Renal allograft rupture caused by acute tubular necrosis

Renal allograft rupture is a rare but potentially lethal complication of kidney transplantation. A renal allograft recipient receiving quadruple immunosuppressive therapy developed a spontaneous allograft rupture 13 days after kidney transplantation. Warm ischaemia time during the transplant was 80 minutes. The ruptured kidney graft could not be salvaged because of the patient's haemodynamic instability. The histopathological examination showed interstitial oedema with severe acute tubular necrosis with no signs of acute rejection. The most common causes of renal graft rupture are acute rejection and vein thrombosis, while acute tubular necrosis may only rarely be responsible for this complication. Renal graft rupture may be the result of interstitial damage attributed both to the prolonged warm ischaemia time during the transplant and to post-transplant acute tubular necrosis in the absence of graft rejection. In those patients whose haemodynamic status cannot be stabilized by appropriate aggressive haemodynamic support therapy, graft nephrectomy should be considered the only definitive treatment.     

Infection and chronic allograft dysfunction

With the advent of more potent immunosuppressive regimens, the incidence of acute rejection following renal transplantation has declined sharply in recent years. In spite of this, long-term graft outcomes remain suboptimal because of relentless attrition by cumulated insults to the allograft. As acute rejection rates have declined, other causes of graft injury and loss have recently emerged. Among these, infectious diseases remain a persistent threat and can be associated with allograft dysfunction. This group includes nephropathy due to polyoma (BK) virus infection, cytomegalovirus disease, and bacterial infection (the latter most commonly arising from the urinary tract). Rarer infectious causes of chronic allograft dysfunction include cryoglobulinemia associated with hepatitis C, Epstein-Barr virus-associated posttransplant lymphoproliferative disease, and direct cytotoxicity from adenoviral infection or parvovirus B19.     

Isolated Hepatic Chronic Ductopenic Rejection Requiring Liver Retransplant in the Absence of Kidney Graft Rejection After Combined Liver-Kidney Transplant: A Case Report

The liver is considered the most immunotolerant organ among all solid-organ transplants. Liver transplant recipients have a lower incidence of rejection and better outcomes after episodes of rejection, with spontaneous operational tolerance developing in up to 20%. In multiorgan transplants, a protective effect of the liver allograft on simultaneously transplanted organs from the same donor has been demonstrated. We describe an unusual case of isolated liver allograft rejection in a patient with polycystic liver and kidney disease who received a combined liver-kidney transplant from the same donor. After initial discharge from the hospital, our patient had 2 episodes of biopsy-proven late acute cellular rejections, despite higher levels of immunosuppression required for her kidney allograft, which were addressed with pulsed steroid therapy. She had no evidence of ischemic cholangiopathy on imaging. Later, a subsequent liver biopsy demonstrated features consistent with chronic ductopenic rejection. She was eventually listed for liver retransplant and has recently received a second liver transplant while continuing to have no concerns with her kidney allograft function. Examination of the explanted liver confirmed graft loss from chronic ductopenic rejection. The exact reasons why our patient developed acute graft rejection progressing to chronic end-stage rejection of the liver allograft despite not developing graft rejection in the kidney allograft from the same donor remains elusive. Our experience demonstrates that graft tolerance in multiorgan transplant recipients can be organ specific and despite the belief of “immunologic privilege,” isolated liver allograft rejection can occur in multiorgan transplant, resulting in graft loss.     

在移植肾功能稳定的受者中主动撤除环孢素A的临床研究

目的 研究在移植肾功能稳定的受者中主动撤除环孢素A(CSA)对急性排斥反应发生率及肾功能的影响.方法 选择35例肾功能稳定的肾移植受者,其中尸体肾移植23例,亲属活体肾移植12例.除2例为再次肾移植外,其余均为初次肾移植.分别在肾移植术后6个月～6年时停用CsA,平均为术后(13.3±9.1)个月.撤除CsA后免疫抑制方案为:霉酚酸酯(MMF)+西罗莫司(SRL)+泼尼松(Pred).撤除CsA前有9例做了移植肾穿刺活检,8例测定了抗HLA抗体.结果 对35例受者随访6个月～4.5年,平均14.8个月.撤除CsA前、后血肌酐平均值分别为(88.1±15.5)μmol/L和(92.3±23.7)/μmol/L(P0.05).撤除CsA后,有2例经活检证实发生急性排斥反应,治疗后均逆转;CsA所致的毒副作用,如牙龈增生、糖耐量异常和多毛症等明显改善.9例移植肾活检中,有3例肾功能正常的受者已出现轻度慢性移植肾肾病表现.抗HLA抗体检测中,7例阴性者在撤除CsA前、后肾功能无明显变化.1例抗HLA抗体呈强阳性者在撤除CsA后进展为慢性移植肾肾病,恢复血液透析.结论 对移植肾功能稳定的受者在移植6个月后撤除CsA,转换为"霉酚酸酯+西罗莫司+泼尼松"的免疫抑制方案是安全的,不增加急性排斥反应风险;撤除CsA有利于消除一些与其相关的毒副作用;对抗HLA抗体呈强阳性者.撤除CsA后很难改变肾功能的进展.     

Acute Renal Allograft Rejection Following Pegylated IFN-α Treatment for Chronic HCV in a Repeat Allograft Recipient on Hemodialysis: A Case Report

Interferon alpha (IFN-alpha) can be effective therapy for patients with chronic kidney disease who have chronic hepatitis C (HCV). However, acute allograft rejection has been reported in association with IFN-alpha following kidney transplantation, and therefore IFN therapy is recommended prior to, rather than after, kidney transplantation whenever feasible. The special case of repeat allograft recipients who contract HCV after the first transplantation presents special difficulties. This report features the case of a repeat allograft recipient who presented with neutropenic fevers after 5 months of pegylated IFN-alpha therapy, initiated 6 months following the functional loss of his third graft and the reinitiation of hemodialysis (HD). Physical exam, radiographic and laboratory findings led to allograft nephrectomy. The pathologic findings supported a diagnosis of acute-on-chronic rejection. This represents a rare case of IFN-alpha induced rejection following allograft failure and return to HD in a repeat allograft recipient. It also calls attention to the need for a high index of suspicion for the development of allograft rejection, which may require allograft nephrectomy even after allograft 'failure'.     

Complete Avoidance of Calcineurin Inhibitors in Renal Transplantation: A Randomized Trial Comparing Sirolimus and Tacrolimus

Calcineurin inhibitors have decreased acute rejection and improved early renal allograft survival, but their use has been implicated in the development of chronic nephrotoxicity. We performed a prospective, randomized trial in kidney transplantation comparing sirolimus-MMF-prednisone to tacrolimus-MMF-prednisone. Eighty-one patients in the sirolimus group and 84 patients in the tacrolimus group were enrolled (mean follow-up = 33 months; range 13-47 months). At 1 year, patient survival was similar in the groups (98% with sirolimus, 96% with tacrolimus; p = 0.42) as was graft survival (94% sirolimus vs. 92% tacrolimus, p = 0.95). The incidence of clinical acute rejection was 10% in the tacrolimus group and 13% in the sirolimus group (p = 0.58). There was no difference in mean GFR measured by iothalamate clearance between the tacrolimus and sirolimus groups at 1 year (61 +/- 19 mL/min vs. 63 +/- 18 mL/min, p = 0.57) or 2 years (61 +/- 17 mL/min vs. 61 +/- 19 mL/min, p = 0.84). At 1 year, chronicity using the Banff schema showed no difference in interstitial, tubular or glomerular changes, but fewer chronic vascular changes in the sirolimus group. This study shows that a CNI-free regimen using sirolimus-MMF-prednisone produces similar acute rejection rates, graft survival and renal function 1-2 years after transplantation compared to tacrolimus-MMF-prednisone.     

Renal rupture after transplantation

Nine instances of spontaneous allograft rupture have been identified in a series of 325 renal transplantations. Repair of the graft was accomplished in 4 cases. One graft functioned for five and one-half years, one kidney was removed immediately because of uncontrolled hemorrhage, and two grafts were subsequently removed because of rejection. Immediate nephrectomy was performed in 5 cases of irreversible rejection. The duration of ischemia and method of preservation appeared to have no etiologic importance. Evidence of severe acute rejection was present in all 9 cases. The recent increase in graft rupture parallels the increasing frequency of severe early acute rejection reactions.     

Conversion to sirolimus in a population of kidney and kidney-pancreas transplant recipients

INTRODUCTION: Calcineurin inhibitors (CI) are associated with nephrotoxicity that might reduce long-term graft survival. We report our experience with sirolimus (SRL) conversion among a population of kidney and kidney pancreas transplant recipients. METHODS: Thirty transplant recipients (6 women, 24 men; age 41 +/- 10.5 years old) were converted to SRL therapy at 25.97 +/- 32.5 months after transplantation. Indications for conversion were: intolerance to mycophenolate mofetil (n = 13), diabetes mellitus (n = 3), CI nephrotoxicity (n = 11), CI nephrotoxicity with chronic allograft rejection (n = 2), and side effects of azathioprine (n = 1). Follow-up after conversion is 3 to 45 months. RESULTS: No significant changes were observed in the 3 months postconversion in renal function, hematological profile, and mean arterial blood pressure. In contrast there was a significant increase in cholesterol values (pre: 198.7 +/- 49.4, versus post 221.2 +/- 60.8, P = .018). At a follow-up of 15.2 +/- 9.9 months after conversion two patients (6.7%) died with functioning allograft (one because of infection and one to myocardial infarct) three kidney allografts (10.7%) have been lost: two chronic rejection; one infection. In two patients SRL therapy was discontinued (one infection, one refractory edema). Neither significant change in renal function nor episodes of acute rejection were observed. CONCLUSIONS: Conversion to SRL was safe. There was no deterioration in renal function nor episodes of acute rejection. There was a significant increase in cholesterol values after conversion. The size of the sample and the time of follow-up may have determined our results.     

肾移植一年后急性排斥反应时移植肾组织中C4d表达阳性的临床研究

目的 观察肾移植1年后发生急性排斥反应时移植肾组织中补体片段C4d的表达情况,分析其对移植肾功能及预后的影响.方法 选择肾移植时间超过1年,临床诊断为急性排斥反应并经病理穿刺活检证实的肾移植受者36例为研究对象.以第1例受者移植肾组织穿刺时间为观察起点(2006年3月),以此项研究结束时间为观察终点(2010年4月).应用C4d多克隆抗体对移植肾穿刺组织行免疫组织化学染色,检测C4d在移植肾组织中的表达情况;根据检测结果,分为C4d阳性组和阴性组,分析和比较两组在观察时间段内移植肾功能的变化及存活时间.结果 在36例受者的移植肾穿刺标本中,C4d阳性16例(44.4%),C4d阴性20例(55.6%);C4d阳性组和阴性组移植肾组织中嗜酸性粒细胞浸润数量分别为(9.4±4.5)个和(2.6±1.8)个,两组比较,差异有统计学意义(P＜0.05).在观察时间段内,所有受者血清肌酐均有不同程度上升,但C4d阳性组上升幅度与C4d阴性组比较,差异无统计学意义(P＞0.05);C4d阳性组和C4d阴性组受者移植肾功能丧失率分别为31.3%(5/16)和30.0%(6/20),两组比较,差异无统计学意义(P＞0.05).C4d阳性组和C4d阴性组受者移植肾穿刺后的巾位存活时间分别为(19.3±5.3)个月和(22.5±7.4)个月,两组比较,差异无统计学意义(P＞0.05).结论 肾移植1年后发生急性排斥反应时,移植肾组织中C4d表达阳性对其功能及存活时间无明显影响.     

Human leukocyte antigen-G expression after kidney transplantation is associated with a reduced incidence of rejection

HLA-G is a non-classic Human Leukocyte Antigen (HLA-G) Class I of low polymorphism and restricted tissue distribution that displays tolerogenic functions. In heart transplantation and in combined liver/renal allograft transplantation, the expression of HLA-G has been associated with a lower incidence of acute graft rejection episodes and absence of chronic dysfunction. Since the expression of HLA-G in renal biopsies has been investigated only in few patients who received a combined kidney and liver transplant, in this study we performed a cross-sectional study, systematically comparing the expression of HLA-G in post-transplanted renal grafts, stratifying patients according to the presence or absence of rejection. PATIENTS AND METHODS: Seventy-three renal specimens (10 with acute rejection and 13 with chronic allograft nephropathy, and 50 with no signs of rejection) were immunohistochemically evaluated for HLA-G expression. RESULTS: In the group as a whole, HLA-G molecules were detected in 40 cases (54.8%). Among specimens that presented HLA-G expression, 2 out of 40 (5%) exhibited acute rejection, 2 (5%) exhibited chronic allograft nephropathy, and the remaining 36 (90%) exhibited no signs of rejection. The comparison between patients with rejection and those without rejection showed that the expression of HLA-G was significantly increased in specimens exhibiting no signs of rejection (p<0.0001). Considering only patients with acute rejection, 8 out of 10 patients showed no HLA-G expression in their kidney biopsies when compared to patients exhibiting no signs of rejection and absence of HLA-G was observed in 14 out of 50 (p=0.0032). Similarly, considering only patients with chronic allograft nephropathy, absence of HLA-G expression was observed in 11 out of 13 specimens, whereas in patients without rejection absence of HLA-G was observed in 14 out of 50 (p=0.003). Therapy with tacrolimus was significantly associated with the expression of HLA-G and a better graft prognosis. CONCLUSIONS: Our results suggest that HLA-G expression in the kidney allograft and the use of tacrolimus are associated with a lower frequency of acute renal rejection and chronic allograft nephropathy.     

Sirolimus (rapamycin) reduces the incidence of acute rejection episodes in renal transplantation: an initial experience in Taiwan

BACKGROUND: Acute rejection is the major cause of graft loss in renal transplantation. Sirolimus (rapamycin) inhibits the effects of cytokines on T and B cells; therefore, it provides prophylaxis against acute renal rejection. This open-label trial assessed the incidence of biopsy-confirmed acute rejection episodes, variation in renal function, as well as graft and patient survival rates up to 12 months posttransplantation when using sirolimus in combination with cyclosporine and prednisolone as immunosuppressants. METHODS: Ten kidney transplant recipients received sirolimus 2 mg daily after a 6-mg loading dose. Doses were then adjusted to keep the whole-blood trough level between 5 and 20 mg/mL. All patients received sirolimus in combination with cyclosporine and prednisolone. RESULTS: At 12 months after renal transplantation, the graft and patient survival rates were 90% and 90%, respectively. One patient died at 2 months due to sepsis with a functioning graft. The mean serum creatinine levels at 1, 3, and 6 months were 1.59 mg/dL, 1.71 mg/dL, and 1.65 ml/dL, respectively. There was no biopsy-confirmed acute rejection episode within 12 months. CONCLUSIONS: Sirolimus in combination with cyclosporine and prednisolone significantly protected kidney transplant recipients from acute rejection for up to 1 year of follow-up.     

PG490-88, a new immunosuppressant, effectively prevents acute and chronic rejection in rat renal allografts

PG490-88 is a semisynthetic derivative of the novel compound PG490 (triptolide) purified from a Chinese herb. It has been shown to prolong acute allograft survival in multiple experimental organ transplant models. However, the effect of PG490-88 on prevention of acute and chronic renal allograft rejection has not been determined. Kidneys of ACI or F344 rats were transplanted into bilaterally nephrectomized LEW recipients as the acute or chronic allograft rejection models, respectively. Treatment of LEW recipients with PG490-88 significantly prolonged ACI kidney graft survival in a dose-dependent manner when compared with the untreated allograft controls. LEW recipients of F344 kidney grafts who received PG490-88 for 90 days with a brief course of low-dose FK506 showed normal serum creatinine levels and markedly reduced histological changes of chronic rejection at day 90 after transplantation. These results suggest that PG490-88 significantly prolongs kidney allograft survival in an acute rejection model and prevents chronic allograft rejection in rats.     

Chronic allograft nephropathy

With the advent of calcineurin inhibitors, the success of kidney and other solid-organ transplants has improved significantly from the standpoint of reducing the incidence of acute rejection. Over the past 2 decades, both short-term allograft survival and acute rejection rates have dramatically improved with improved diagnostic and therapeutic techniques such as standardized pathology scoring; potent antirejection drugs such as anti-thymocyte globulin, interleukin-2 receptor antibodies, cyclosporine, tacrolimus, sirolimus, and mycophenolate mofetil; and improved infection control such as valganciclovir and antifungal therapy. However, long-term graft loss has remained at nearly constant levels over the same period of time, with the average half-life of a deceased-donor kidney transplant in the United States remaining approximately 1 decade. In addition to death with a functioning allograft and calcineurin toxicity, a chronic fibrotic process-known at various times as chronic rejection, chronic allograft dysfunction, and chronic allograft nephropathy (CAN)-account for the leading causes of transplant failure.     

肝肾联合移植15例报道

目的探讨肝肾联合移植的适应证和疗效。方法对2001年2月至2003年12月施行肝肾联合移植术的15例患者进行了随访。15例中,乙型肝炎后肝硬化合并肝肾综合征8例、合并尿毒症2例、合并糖尿病肾病1例;多囊肝和多囊肾2例;Caroli病合并多囊肾1例;酒精性肝硬化合并尿毒症1例。对肝肾联合移植患者的手术方式,围手术期并发症,术后急、慢性排斥反应和乙型肝炎复发情况及随访结果进行了分析。结果15例肝肾联合移植术后移植物功能均恢复良好,6个月和1年生存率为100%。1例术前有严重营养不良者,术后给与48d的呼吸机支持后康复。术后创面出血和消化道出血各1例,经非手术治疗后治愈。胆道吻合口狭窄1例,用内镜下球囊扩张术治愈。1例术后2周发生急性移植肝排斥反应,给予激素冲击治疗后得到控制。1例术后30个月时因停用拉米夫定后乙型肝炎复发死于移植肝功能丧失。结论肝肾联合移植是终末期肝病合并慢性肾功能衰竭或肾功能损害的安全有效方法。对乙型肝炎患者术后尽早应用拉米夫定和乙型肝炎病毒免疫球蛋白预防肝炎复发。     

Late developing C4d-positive humoral renal allograft rejection associated with withdrawal of mycophenolate mofetil

In renal transplantation, C4d-positive acute humoral rejection (AHR) usually develops in the early stage posttransplantation. It is clear C4d can be detected late after the operation, when it is associated with chronic renal allograft rejection. We report a case of a renal allograft recipient who experienced C4d-positive acute renal allograft rejection associated with withdrawal of mycophenolate mofetil (MMF) at 10 months after transplantation. This 21-year-old single male patient received his first cadaveric renal allograft under immunosuppression with cyclosporine, MMF, and prednisolone. The serum creatinine recovered to the normal range within 4 days. A protocol biopsy performed at 1 month after transplantation revealed no signs of rejection. The graft function was stable until 10 months postoperation, when MMF was converted to mizoribin. Three days later a biopsy showed a C4d-positive rejection. Patient had no response to the MMF combined with tacrolimus and steroid bolus therapy, which generally improves 85% of AHR among Chinese. He finally returned to dialysis. Our report suggested that C4d positive AHR may occur late after transplantation. MMF is important to suppress the body's humoral response to allograft; when MMF was converted to a weaker immunosuppressant, the dose of the other immunosuppressants (cyclosporine for example) must be adjusted properly.     

Detection of B lymphocytes (CD20+) in renal allograft biopsy specimens

Acute allograft rejection represents an important complication after transplantation with significant impact on long-term graft survival. The involvement and relevance of B lymphocytes in this process is still not clear. The aim of this study was to quantify in renal allograft biopsy specimens the number of cells positive for CD20, a specific marker for B lymphocytes. Immunohistochemical techniques using monoclonal anti-CD20 antibody was used on paraffin sections from 38 renal allograft biopsy specimens. The biopsy specimens were classified into 3 groups, according to clinical and histological criteria: normal kidney, acute rejection, and chronic allograft nephropathy (CAN). In the normal kidney, no CD20(+) cells were detected. In contrast, in all cases of acute rejection and CAN, there were CD20(+) cells. The CD20(+) cells occurred in the infiltrate in 2 distinct patterns: scattered or nodular. In cases of acute rejection, the number of CD20(+) cells was significantly higher than in CAN cases (137.0 +/- 57.2 vs 45.4 +/- 9.8 cells/mm(2); P < 0.05). The nodular pattern was observed in 4 of 11 cases (36%) in the acute rejection group, and in 4 of 20 cases (20%) in the CAN cohort. In the acute rejection group, the presence of B-cell clusters tender to be associated with a higher level of serum creatinine (3.7 +/- 1.8 mg/dL vs 2.8 +/- 0.1 mg/dL in the scattered pattern group; not significant [ns]). In conclusion, these preliminary results demonstrated B lymphocytes in cases of renal allograft dysfunction, which were more pronounced in acute allograft rejection. Further analyses are required to determine whether the detection of CD20(+) cells in renal allograft biopsy specimens can be used as a prognostic marker.