Double filtration plasma pheresis was effective on the recurrence of pulmonary hemorrhage after renal transplantation: report of a case]

A 35-year old female with an autoimmune disease complaining of recurrent hemoptysis and macrohematuria had received a renal transplantation from her mother. After transplantation, recurrence of pulmonary hemorrhage occurred twice. First recurrence followed the peritonitis with ileal perforation. Steroid pulse therapy had no effect on this recurrence, while double filtration plasmapheresis was effective. During this treatment, renal function was not failed. Second recurrence followed acute rejection that was cured with the OKT3-rescue therapy. DFPP therapy was effective on this episode. Pulmonary hemorrhage was caused by auto immune reaction and acute rejection caused by transplant immune reaction were recognized independently, and they needed different treatment. According to this clinical course, we consider the relation between auto immune reaction and transplant immune reaction was as follows. T cell activation caused by primary transplant immune reaction may have no direct influence on auto immune reaction. Peritonitis and rejection may induce auto immune reaction. We suppose that this auto immune reaction was caused by humoral factor, because auto immune reaction was controlled by DFPP.     

Steroid Withdrawal in Simultaneous Pancreas-Kidney Transplantation: A 7-Year Report

Simultaneous pancreas-kidney transplantation (SPK) is the treatment of choice for selected diabetic patients with end-stage renal disease. Maintenance steroid therapy is associated with significant morbidity and mortality among SPK transplant recipients. Steroid withdrawal regimens are becoming more common, albeit with reservations regarding its safety and efficacy. We performed a retrospective review of 77 SPK transplant recipients from May 2000 to December 2007. The subjects received induction therapy with thymoglobulin followed by maintenance immunosuppression with tacrolimus and mycophenolate mofetil. A late steroid withdrawal protocol was adopted. The rates of acute rejection, graft and patient survival, and side effects were analyzed. One-year patient, kidney, and pancreas survivals were 93%, 91%, and 86%, respectively. Eleven patients experienced acute rejection. Mean follow-up time was 1155.5 ± 776.1 days. Prednisolone withdrawal was carried out between 6 and 12 months posttransplantation in 42 patients (77.8%) with at least 1 year follow-up; no case of acute rejection occurred. At present, 72 patients have a functioning kidney graft, and 65 patients also have a functioning pancreas graft. The mean serum creatinine is 1.12 ± 0.49 mg/dL and the mean HbA1c concentration is 4.5% ± 0.4%. The patients have a low prevalence of hypertension, hyperlipidemia, and obesity. Steroid withdrawal was successful and safe in the majority of in-study patients and safe without an increase of immune events. Our patient and graft outcomes are within other international SPK transplant units standards.     

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.     

Humoral immune response after kidney transplantation is enhanced by acute rejection and urological obstruction and is down-regulated by mycophenolate mofetil treatment

The anti-allograft immune response may have a cellular and a humoral component. Lymphocytotoxic antibodies (Ab) and anti-human leucocyte antigen (HLA) Ab present before kidney transplantation carry an enhanced risk of acute rejection. Current immunosuppressive drugs act predominantly upon the cellular immune pathway which may leave unopposed the humoral mechanisms of anti-allograft response. We studied the production of lymphocytotoxic Ab and anti-HLA Ab after kidney transplantation under different drug therapies. Two hundred and sixty-four consecutive kidney transplant recipients treated with different immunosuppressive drugs, either stable and or with previous acute rejection or acute urologic obstruction, entered this study. Lymphocytotoxic Ab and anti-HLA Ab were evaluated by complement-dependent cytotoxicity and by ELISA. Ab donor-specificity was determined by flow cytometry. Both lymphocytotoxic Ab and anti-HLA Ab were significantly increased in acute rejection whatever the immunosuppressive regimen and almost significantly in urologic obstruction treated with azathioprine (AZA) groups. The presence of antidonor-specific Ab was associated with a significantly higher rate of graft loss. Mycophenolate mofetil (MMF) therapy significantly down-regulated Ab synthesis in all patients groups when compared with AZA. The development of humoral antidonor response post-transplantation is associated with a dismal graft prognosis. This is the first report that acute urologic obstruction may be followed by unspecific lymphocytotoxic and anti-HLA Ab synthesis, surmising that a protracted obstruction may promote renal fibrosis through antibody mediation. The significant down-regulation of the humoral response by MMF when compared with AZA may herald a lower risk to mount a chronic rejection process.     

移植肾自发性破裂的诊治

目的：探讨移植肾自发性破裂的原因及防治措施。方法：回顾分析本院３９２例同种肾移植术后发生移植肾自发性破裂２０例临床资料。结果：发生率为５．１％。１４例保留肾脏功能，其中２例经保守治疗痊愈。６例肾切除者中有４例为急性排斥反应引起。结论：肾破裂的发生与排斥反应、肾缺血性损害、肾静脉引流不畅及尿路梗阻有关。对于出血量少、肾功能好者，可采用保守治疗。预防要从肾脏摘取与灌洗、植肾手术、合理应用免疫抑制剂、及     

Corticosteroid avoidance in pediatric renal transplantation

Corticosteroids have played a central role in the evolution of renal transplant as the modality of choice for renal replacement in end stage kidney disease. Their use is associated with significant, dose related morbidity including osseous, cardiovascular, metabolic complications, body disfigurement and growth retardation in children. The strategies that have been employed to minimize these side effects include reduction in the daily administered dose of steroids, use of alternate day dosing regimens, steroid withdrawal post-transplantation and complete steroid avoidance. Steroid dose minimization has been associated with increased rates of acute rejection, though introduction of newer and more potent immunosuppressives has helped reduce the incidence of this complication. Steroid minimization will benefit patient morbidity due to cataracts, cardiovascular and osseous complications, but may offer little benefit towards improving linear growth. Alternate day steroid therapy may have a greater impact on growth improvement, but may be troubled by regimen non-adherence. Steroid withdrawal post-transplant, the ultimate target, is successful in a cohort of patients, but overall, has been historically associated with unacceptably high rates of clinical acute rejection, and has thus been used sparingly in adults and even less so in children. Complete corticosteroid avoidance, using newer induction and immunosuppressive agents, has been associated with an 8–23% incidence of acute rejection in pediatric renal transplant patients, significant catch-up growth post-transplant, improvements in post-transplant hypertension and hyperlipidemia, and a high safety profile at current follow-up. Newer induction protocols may allow complete steroid-free immunosuppression thus offering significant advantages in preventing the above-mentioned steroid related morbidity, which could also possibly be applicable to other areas of solid organ transplantation in all age groups.This work was presented in part at the IPNA Seventh Symposium on Growth and Development in Children with Chronic Kidney Disease: The Molecular Basis of Skeletal Growth, 1–3 April 2004, Heidelberg, Germany     

Increased Metallothionein Expression Reflects Steroid Resistance in Renal Allograft Recipients

Steroid‐refractory acute rejection is a risk factor for inferior renal allograft outcome. We aimed to gain insight into the mechanisms underlying steroid resistance by identifying novel molecular markers of steroid‐refractory acute rejection. Eighty‐three kidney transplant recipients (1995–2005), who were treated with methylprednisolone during a first acute rejection episode, were included in this study. Gene expression patterns were investigated in a discovery cohort of 36 acute rejection biopsies, and verified in a validation cohort of 47 acute rejection biopsies. In the discovery set, expression of metallothioneins (MT) was significantly (p < 0.000001) associated with decreased response to steroid treatment. Multivariate analysis resulted in a predictive model containing MT‐1 as an independent covariate (AUC = 0.88, p < 0.0000001). In the validation set, MT‐1 expression was also significantly associated with steroid resistance (p = 0.029). Metallothionein expression was detected in macrophages and tubular epithelial cells. Parallel to the findings in patients, in vitro experiments of peripheral blood mononuclear cells from 11 donors showed that nonresponse to methylprednisolone treatment is related to highly elevated MT levels. High expression of metallothioneins in renal allografts is associated with resistance to steroid treatment. Metallothioneins regulate intracellular concentrations of zinc, through which they may diminish the zinc‐requiring anti‐inflammatory effect of the glucocorticoid receptor.     

Cytomegalovirus glomerulopathy: a controversial lesion

Seven autopsies performed on immunosuppressed bone marrow transplant recipients who died with documented herpes virus infection were reviewed. The kidneys were studied by light and electron microscopy and revealed no pathological findings, specifically no glomerulopathy or tubular interstitial nephritis. Seven renal biopsies performed on kidney transplant recipients in whom a diagnosis of cytomegalovirus glomerulopathy was entertained were also studied. These patients exhibited clinical parameters suggestive of cytomegalovirus infection. Three patients had subsequent nephrectomies and two showed severe acute vascular rejection. The one kidney without demonstrable acute vascular rejection was negative for cytomegalovirus on culture. Three additional patients improved or stabilized their renal function under therapy for rejection. Light, electron microscopic and immunofluorescent studies, although confirmatory of endothelial cell damage, did not substantiate active cytomegalovirus renal infection in these patients. An additional group of fifteen children with disseminated cytomegalovirus infection revealed no evidence of glomerulopathy. Finally, two kidney transplant recipients with proven cytomegalovirus infection (one with associated tubular interstitial nephritis) also showed no glomerular alterations. It is the author's opinion that the entity that has been considered as cytomegalovirus glomerulopathy probably represents rejection, either a peculiar anti-endothelial type of rejection or a protracted, early, or partially resolved acute vascular rejection without residual or identifiable acute vascular rejection changes in the tissue sampled.     

“Out of Sight,Out of Mind”: The Failed Renal Allograft as a Cause of ESA Resistance

Approximately 10% of patients treated with erythropoiesis‐stimulating agents (ESAs) for the anemia of chronic kidney disease are unresponsive or relatively resistant to therapy. The etiology of this is usually linked to iron deficiency or an independent underlying illness. We describe a hemodialysis patient with a failed renal transplant 1.5 years earlier, who developed progressive erythropoietin resistance and anemia without an apparent cause. He simultaneously developed nonspecific malaise and fatigue. By exclusion, the only possible cause of these signs and symptoms was inflammation from acute and chronic rejection in the retained failed renal allograft. Following pulse steroids and transplant nephrectomy, the patient's symptoms resolved and both his hemoglobin improved and his erythropoietin requirements decreased significantly. The patient never required a blood transfusion and was successfully relisted for a deceased donor renal transplant. Hence, inflammation from a retained transplant allograft may be an under‐recognized cause of erythropoietin resistance in dialysis patients. Although transplant nephrectomy remains a controversial practice due to concerns of alloantibody production, it may be considered in patients with failed renal allografts and anemia refractory to treatment with ESAs.     

Effects of heparin and steroids on hyperacutely rejected renal xenografts

Heparin and steroid-treated recipients of pig-to-dog renal transplants were compared with untreated animals. Renal blood flow, platelet counts, fibrinogen levels and euglobulin lysis times were measured. Heparin improved the initial blood flow through the kidney but did not otherwise influence the ultimate fate of the transplant. Steroid therapy reduced the degree of coagulation and fibrinolysis which occurred within the hyperacutely rejected kidney; but a pig kidney transplanted to a dog pretreated with steroids was rejected as violently as in the other two groups of animals. Striking reductions in platelet counts were found in the renal vein effluent of all pig kidneys transplanted to dogs; irrespective of the pretreatment. These data support the view that cellular aggregates produced by antigen-antibody-complement complexes plug the cortical renal vessels and are responsible for the rapid rejection reaction.     

Withdrawal of steroid therapy in African American kidney transplant recipients receiving sirolimus and tacrolimus

BACKGROUND: Withdrawal of corticosteroids from the immunosuppressive regimens of kidney transplant recipients has been associated with an increased risk of acute and chronic allograft rejection. Previous studies indicate that the risk of rejection is particularly high in African Americans. METHODS: We prospectively enrolled 44 African American kidney transplant recipients to participate in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids. No patient received antibody induction therapy. Prednisone was withdrawn from eligible patients free of acute rejection beginning as early as 3 months posttransplant, and followed for a minimum of 9 months posttransplant. Patients were followed for acute rejection and for changes in blood pressure, body weight, and serum creatinine concentrations before and after withdrawal of steroids. RESULTS: Thirty of 44 patients (68%) were weaned off of prednisone. Follow-up after withdrawal of prednisone ranged from 3 to 26 months (mean, 14.3+/-7.7 months). Two of 30 patients (6.7%) developed acute rejection. At last follow-up, 27 of 30 patients (90%) remain steroid-free. Steroid withdrawal was associated with significant reductions in blood pressure. CONCLUSIONS: Use of sirolimus and tacrolimus, without the use of induction antibody therapy, allows withdrawal of prednisone as early as 3 months posttransplant with low rates of subsequent acute rejection in African American kidney transplant recipients. Withdrawal of prednisone was associated with lower blood pressures and the need for fewer antihypertensive medications.     

Donor calculi induced acute renal failure

Nephrolithiasis is an infrequent complication following renal transplantation and acquisition of a stone with the donor kidney is rare. Indeed only a few cases of donor stones causing renal failure have been reported. Since the grafted kidney is denervated, stone disease may not present with the classic renal colic but rather with acute renal failure secondary to the obstruction. Identification of the precise cause is critical in order to avoid inappropriate therapy. We present our experience of two renal transplant patients who developed obstructive uropathy by stones originating from the donor kidneys.     

Transplant ureteral obstruction masquerading as recurrent rejection episodes: management by percutaneous antegrade balloon dilatation

We report a 52-year-old male renal transplant recipient who had three "rejection episodes." The first of these responded to conventional antirejection therapy; however, the next two episodes showed incomplete responses to treatment for rejection. At subsequent presentation with deteriorating renal function, ureteral obstruction was evident and was relieved with percutaneous antegrade balloon dilatation with a return of his plasma creatinine to normal. Obstruction of the ureter was a major component in our patient's course given the lack of response to conventional antirejection therapy and the normalization of renal function with relief of the documented ureteral stenosis. This case illustrates that ureteral obstruction can mimic rejection in the renal transplant recipient. Management of ureteral stenosis in transplant patients with percutaneous antegrade balloon dilatation appears to be an effective procedure and can supplant the need for open surgical procedures.     

Long-term graft outcomes after steroid withdrawal in African American kidney transplant recipients receiving sirolimus and tacrolimus

BACKGROUND: We previously reported excellent short-term outcomes in African American kidney transplant patients receiving tacrolimus/sirolimus and withdrawn from corticosteroid therapy three months after transplantation. We now report the long-term outcomes of patients subjected to this protocol. METHODS: In all, 47 African American kidney transplant recipients were enrolled in an uncontrolled trial in which they were initially treated with sirolimus, tacrolimus, and corticosteroids, without antibody induction therapy. Eligible patients were withdrawn from prednisone between three and five months posttransplant, and followed for acute rejection and changes in renal function. Outcomes (group 1, n=32) were compared to those of patients deemed not to be candidates for steroid withdrawal (group 2, n=15). RESULTS: After a mean follow-up of 48.5 months, 13 of 32 patients (41%) in group 1 developed acute rejection; only 13 patients (41%) remain steroid-free. Nine of 13 rejection episodes were associated with noncompliance. Graft loss occurred in 8 of 32 patients (25%) in group 1 and in 5 of 15 patients (33%) in group 2 (P=NS). Serum creatinine rose from 1.4+/-0.41 to 2.45+/-1.7 mg/dL in group 1 (P=0.004) and from 2.1+/-0.45 to 2.62+/-1.2 mg/dL (P=NS) in group 2. Among 13 patients in group 1 who remain steroid-free, creatinine concentration has risen from 1.28+/-.0.37 prior to steroid withdrawal to 1.64+0.54 at last follow-up (P=0.027). CONCLUSIONS: Late noncompliance and/or rejection in African Americans withdrawn from steroids have a negative impact on long-term graft function and survival. Steroid withdrawal may be associated with long-term deterioration of renal function, even in the absence of overt acute rejection.     

Adenovirus pyelonephritis in a pediatric renal transplant patient

Gross hematuria, graft pain, and rising serum creatinine are classic signs of acute rejection, obstruction, or bacterial pyelonephritis for patients with renal transplants. This presentation often prompts percutaneous renal allograft biopsy. If subsequent evaluation fails to show evidence of acute rejection, obstruction, or bacterial infection, viral etiologies should be considered. We report a 14-year-old Hispanic female with a living-related renal transplant who had gross hematuria, graft tenderness, and increased serum creatinine, but did not have evidence of acute rejection, obstruction, or bacterial pyelonephritis. To our knowledge, this is the first report of adenovirus pyelonephritis in a transplanted kidney of a pediatric patient, with isolation of adenovirus in the urine and in the allograft using immunocytochemical techniques.     

Complement 5a receptor inhibition improves renal allograft survival

Complement activation plays a key role in mediating apoptosis, inflammation, and transplant rejection. In this study, the role of the complement 5a receptor (C5aR) was examined in human renal allografts and in an allogenic mouse model of renal transplant rejection. In human kidney transplants with acute rejection, C5aR expression was increased in renal tissue and in cells infiltrating the tubulointerstitium. Similar findings were observed in mice. When recipient mice were treated once daily with a C5aR antagonist before transplantation, long-term renal allograft survival was markedly improved compared with vehicle-treatment (75 versus 0%), and apoptosis was reduced. Furthermore, treatment with a C5aR antagonist significantly attenuated monocyte/macrophage infiltration, perhaps a result of reduced levels of monocyte chemoattractant protein 1 and the intercellular adhesion molecule 1. In vitro, C5aR antagonism inhibited intercellular adhesion molecule 1 upregulation in primary mouse aortic endothelial cells and reduced adhesion of peripheral blood mononuclear cells. Furthermore, C5aR blockade markedly reduced alloreactive T cell priming. These results demonstrate that C5aR plays an important role in mediating acute kidney allograft rejection, suggesting that pharmaceutical targeting of C5aR may have potential in transplantation medicine.     

Impact of mycophenolate mofetil on recurrent rejection in kidney transplant patients

PURPOSE: Mycophenolate mofetil (MMF) has emerged as a valuable adjunctive agent in renal transplantation. However, due to intolerable adverse effects associated with MMF use in our transplant population, we have used MMF selectively in patients at high risk for recurrent graft rejection, since these patients are known to be at risk for poor long-term graft outcomes. The purpose of this study was to assess the efficacy of MMF in preventing the recurrence of acute rejection following an initial rejection episode in kidney transplant patients in the first year following transplantation. METHODS: Forty-four kidney transplant recipients were given MMF prospectively following treatment of their initial rejection episode to prevent recurrent rejection. MMF 1-2 g/d was given. Doses were adjusted based on tolerance; MMF therapy was to be continued for at least 6 months. The control group consisted of 124 consecutive kidney transplant recipients who had received standard anti-rejection therapy without the addition of MMF. Maintenance immunosuppression consisted predominantly of cyclosporine, prednisone+/-azathioprine. Anti-rejection therapy for both groups consisted of either corticosteroids (methylprednisolone 500 mg i.v. for 3 d or oral prednisone 2 mg/kg/d with rapid taper over 3 wk), OKT3 5 mg/d for 10 d or ATG 15 mg/kg/d for 10 d. All rejection episodes were confirmed by biopsy. RESULTS: The majority of rejection episodes were characterized histologically as mild or moderate. Most patients (76%) received corticosteroids for treatment of their first rejection episode. There was a 68% reduction in the incidence of recurrent rejection episodes within the first year of transplant in patients receiving MMF; only 14% of recipients receiving MMF developed recurrent rejection compared to 44% of patients in the control group (p<0.05). Approximately 50% of patients developed MMF-associated adverse effects (leukopenia, GI toxicity). Only 52% of patients remained on MMF at 6 months. One-yr graft survival was 86% in the MMF group and 89% in the control group (p>0.05). One-year patient survival was 93 and 100%, respectively (p>0.05). CONCLUSIONS: The addition of MMF to maintenance therapy for patients experiencing acute renal allograft rejection may prevent recurrent rejection episodes in the subsequent follow-up year.     

Gene therapy in renal diseases

Kidney-targeted gene therapy could be an ideal treatment for renal diseases since the therapeutic molecule is limited in the kidney and the systemic effect may be minimized. The technical development of the gene delivery to kidney and the identification of the responsive gene for a particular disease encourage the challenge to hereditary diseases. Collagen type IV reassembling was reported to be succeeded in Alport syndrome model by introduction of exogenous COL4A5 gene. Many gene therapies are evaluated in various glomerulonephritis models and unilateral ureteral obstruction (UUO) model, and favorable results are accumulated. Transplant kidney is an ideal target for gene therapy, by which ischemia reperfusion, acute rejection and chronic allograft nephropathy can be treated. The importation of the novel technology, for example hybrid stem cell-gene therapy could promote the gene therapy of renal diseases toward clinical application.     

Is acute rejection the key predictor for long-term outcomes after renal transplantation when comparing calcineurin inhibitors?

In the context of modern immunosuppressive regimens, the overall incidence of acute rejection may no longer be the most accurate surrogate marker for long-term kidney graft survival. The type, severity, timing, and clinical course of acute rejection each influence the impact of a rejection episode, and if renal function recovers fully, there appears to be no survival disadvantage. Randomized clinical trials in renal transplant patients have generally shown that there are fewer acute rejection episodes with tacrolimus compared with cyclosporine, although with contemporary regimens, including mycophenolate acid, this difference is less marked than previously. In randomized trials, kidney graft survival rates with cyclosporine and tacrolimus have proven similar. Large-scale registry analyses have consistently shown no graft survival benefit with tacrolimus vs cyclosporine, and indeed, 2 such analyses have reported significantly higher graft survival with cyclosporine-based immunosuppression compared with tacrolimus in living-donor kidney transplant patients receiving mycophenolate mofetil. There are no reports of improved patient survival with either calcineurin inhibitor after kidney transplantation. In conclusion, the perception of better efficacy with tacrolimus vs cyclosporine based on the incidence of acute rejection is not supported by a difference in graft or patient survival after kidney transplantation.     

Conversion from cyclosporine to tacrolimus in pediatric kidney transplant recipients

In pediatric kidney transplant recipients, tacrolimus has been proposed either for primary immunosuppression or as a rescue agent for refractory acute rejection, chronic rejection, and cyclosporine toxicity. This paper describes our experience with tacrolimus conversion from cyclosporine-based therapy in six selected cases: four due to refractory acute rejections unresponsive to conventional therapy, one to chronic graft rejection, and one to cyclosporine-related hypertrichosis. A "simple-switch" conversion was used without any overlap, starting with a dose of 0.2 mg/kg per day. The time to conversion varied from 10 to 730 days after the transplant. In the patients with acute rejection, the median time to reversal after tacrolimus conversion was 12 days. The symptoms of the patient with cyclosporine toxicity completely resolved without any loss of allograft function. The patient with chronic rejection maintained stable renal function for more than 1 year after conversion. A new onset of post-transplant diabetes mellitus and dose-related nephrotoxicity were recorded as adverse events. In conclusion, our experience suggests that tacrolimus can play an important role in the salvage treatment of pediatric kidney transplantations with deteriorating graft function due to acute rejection refractory to standard therapy. Tacrolimus conversion also provides excellent results in the presence of cyclosporine toxicity.