Perioperative blood transfusions after allogenic renal transplantation

Summary The requirement of blood transfusions was evaluated in a two compartment (retrospective/prospective) study in our renal transplantation program. Between July 1st, 1993 and December 31st, 1994 (observation period I) we retrospectively investigated 110 patients with end stage renal disease and anemia undergoing kidney transplantation. Between January 1st, 1995 and December 31st, 1996 (observation period II) the requirement of blood transfusions was followed prospectively in 134 patients after allogenic renal transplantation. The amount of blood drawn for preoperative diagnostic investigations was in observation period I significantly higher (280 ml) than in observation period II (150 ml) (p = 0.02). For postoperative diagnostic tests in observation period II significantly less blood (240 ml) was needed than in observation period I (510 ml) (p = 0.01). The intraoperative bloodloss was similar in both periods (170 ml vs. 190 ml; p = 0.6). The need for closer graft observation was the reason for significantly increased amount of blood transfusions in patients with delayed graft function. The number of blood transfusions was significant lower in patients with primary graft function (p = 0.0001). There was no correlation between blood transfusions and the use of ATG/OKT3, surgical complications and reoperations. With an improved management of blood drawing for diagnostic tests after allogenic kidney transplantation the number of perioperative blood transfusions can be reduced significantly.      

Are blood transfusions beneficial in the cyclosporine era?

In patients treated with conventional immunosuppression (azathioprine and prednisone) after renal transplantation, there is a beneficial effect of pre-transplant blood transfusions on graft survival; in patients treated with cyclosporine, this effect may be lost. In 66 children who received living-related donor transplants after donor-specific transfusions (DST) and were treated with azathioprine-prednisone in our center, 1- and 5-year graft survival rates were 99% and 77% respectively. These rates were similar to those reported for children who did not receive DST but were treated with cyclosporine in other centers. There were 634 adult and pediatric recipients of cadaver transplants in our center who were treated with cyclosporine and prednisone (non-sequential therapy,n=89) or antilymphoblast globulin, azathioprine preduisone, and cyclosporin (sequential therapy,n=545). When all patients were considered, graft survival rates were higher in transfused than in non-transfused patients at 3–5 years, but in the sequential therapy group, there were no differences in graft survival rates between transfused and non-transfused patients. The results suggest that transfusions do not improve cadaver graft survival in patients receiving optimal cyclosporine therapy and that equally good related donor graft survival can be achieved with DST and conventional immunosuppression or no DST and cyclosporine.     

Compliance with cyclosporine in adolescent renal transplant recipients

  Inadequate compliance with prescribed medication regimens in children is complex and poorly understood. We measured the extent and pattern of noncompliance with cyclosporine in our adolescent renal transplant population and attempted to determine factors associated with poor compliance. After informed consent, each patient was provided cyclosporine capsules in a medication bottle equipped with an electronic monitoring device (MEMS-4) in the lid. Of the 24 patients eligible, 19 patients (8 female, 11 male) completed the study. Four (21%) patients took less than 80% of the prescribed cyclosporine doses. Five (26%) patients took drug holidays involving ≥3 consecutive doses. There was a trend towards improved compliance with the evening dose (88.5% vs. 93.4%, P = 0.09) and a downward trend in compliance over the course of the study (P = 0.17). None of the variables tested were found to be associated with noncompliance. Experienced physicians and nurses were able to identify 2 of the 4 individuals who were identified by MEMS as noncompliant. Additionally, 2 of the 4 noncompliant patients demonstrated low cyclosporine trough levels (<50 ng/ml). Noncompliance with cyclosporine regimens occurs commonly in adolescent renal transplant recipients. Unexpectedly low cyclosporine levels are strongly suggestive of noncompliance, whereas other variables, including prediction by physicians and nurses intimately involved in the care, were not reflective of noncompliance. Received October 19, 1996; received in revised form February 18, 1997; accepted March 18, 1997     

Long-term outcome of focal segmental glomerulosclerosis after Japanese pediatric renal transplantation

Focal segmental glomerulosclerosis (FSGS) is known to recur in some patients after renal transplantation. Over a prolonged period, we followed 13 pediatric patients with FSGS who had undergone transplantation from living-related donors, analyzing risk factors for recurrent disease. Native nephrectomies were performed bilaterally in all patients at least 1 month prior to transplantation. Immunosuppressive therapy consisted of cyclosporine (CyA), mizoribine, prednisone, and antilymphocytic globulin or deoxyspergualin. We examined age at onset, time in months between diagnosis and end-stage disease (dialysis or transplantation), the duration of dialysis, age at transplantation, time since nephrectomy, doses of immunosuppressive agents, and HLA mismatch. Five patients (42.8%) developed recurrent disease in the graft; all showed proteinuria within 24 h of transplantation. However, all allografts have functioned well for 34–156 months following transplantation despite the recurrences, although 1 of these patients now shows proteinuria. The remaining 8 patients have had no recurrence for 104.6±30.4 months (mean±SD). The serum level of creatinine in patients with recurrence and without recurrence was 1.1±0.42 mg/dl and 0.98±0.29 mg/dl, respectively. The interval from diagnosis to initiation of dialysis was significantly shorter in patients with recurrence than those without recurrence (P<0.05), but no other variables differed between these two groups. No recurrence of FSGS was observed in the protocol biopsy at 100 days after transplantation. We believe that CyA and native nephrectomy may limit or reverse progression of recurrent FSGS in renal allografts of Japanese pediatric patients, although this is a limited study. Received: 22 December 2000 / Revised: 6 September 2001 / Accepted: 10 September 2001     

Posttransplant lymphoproliferative disorder in pediatric renal transplantation

Of 84 renal transplants performed in our center since 1986, six recipients (7.1%) developed posttransplant lymphoproliferative disorder (PTLD). All received quadruple immunosuppression with Minnesota anti-lymphoblastic globulin or anti-thymocyte globulin, methylprednisolone, cyclosporine, and azathioprine or mycophenolate mofetil. Five were seronegative for Epstein-Barr virus (EBV) when they received their renal transplant. All patients received prophylactic acyclovir treatment postrenal transplant and none developed a cytomegalovirus (CMV) infection. All patients were positive for EBV by serology and polymerase chain reaction at the time of diagnosis of PTLD. Clinical features at presentation included fever (6/6), adenopathy (4/6), hypertrophied adenoids (4/6), liver involvement (2/6), and allograft involvement (2/6), 2–78 months (4/6<6 months) postrenal transplant. Histopathology of PTLD tissue revealed T cell rich/ Hodgkin disease-like B cell PTLD in one patient, polymorphic PTLD in four, and monomorphic (large B cell lymphoma) PTLD in one. Immunophenotyping of the PTLD biopsy specimen revealed predominant T cells in three, mixed B and T cells in two patients, and B cell in one. No aneuploid populations were identified by flow cytometric DNA ploidy assay. DNA from the PTLD tissue revealed weak to moderate IgH gene rearrangement in four of six patients but no T cell receptor β-chain or c-myc gene rearrangement on Southern blot analysis. The child with monomorphic (large B cell lymphoma) PTLD was clonal with λ light chain restriction on immunophenotyping. Treatment consisted of reduced immunosuppression and ganciclovir/ acyclovir in all patients. CMV hyperimmune globulin was used as an adjunctive therapy in two patients. Chemotherapy was needed in only one patient. A single rejection episode occurred in two children following reduction in immunosuppression, which reversed following intravenous methylprednisolone therapy. PTLD resolved in all patients and at present all patients are alive with functional grafts 2–54 months post diagnosis. Our experience suggests that reduced immunosuppression and anti-viral treatment is adequate in most cases of PTLD, but chemotherapy and hyperimmune globulin therapy may be beneficial in cases resistant to first-line therapy. Since all but one of our patients were EBV seronegative at the time of transplant, vigilance is especially important for early detection of PTLD in this group of the pediatric renal transplant population. Received: 17 November 1998 / Revised: 4 February 1999 / Accepted: 4 February 1999     

Center volume effects in pediatric renal transplantation

 An inverse relationship between mortality and center volume has been established for several surgical procedures. Given the distinctiveness of pediatric renal transplantation and the large variation in center volume, investigation for relationships between center volume and graft outcome was pursued using the North American Pediatric Transplant Cooperative Study database. Center volume groups were based on the total number of pediatric transplants reported from 1987 to 1995. Centers reporting >100, 51–100, or ≤50 transplants were grouped as high- (n=11), moderate- (n=28), or low-volume (n=65), respectively. Differences between groups included increasing rates of cadaver donor graft thrombosis (2.4%, 4.3%, and 5.7%, P<0.01) and acute tubular necrosis (ATN) (10.2%, 11.5%, and 14.0%, P<0.01) with decreasing center volume. Treatment differences included a higher rate of induction with an anti-T-cell antibody preparation in the larger-volume groups, 60.2%, 51.8%, and 39.2% (P<0.001). Decreasing graft survival for decreasing center size groups was noted at 3 months post transplant, 90.4%, 90.2%, and 88.4%. These differences were significant only with the exclusion of anti-T-cell induction from the proportional hazards model (relative risk=0.81 and =0.70 for the moderate- and high-volume groups, P<0.02). Superior graft survival in the high-volume centers noted at 3 months post transplant appears predominantly the result of lower rates of cadaver donor graft thrombosis and ATN. Analysis points to the need for low-volume centers to identify risk factors influencing these outcomes. Received: 13 May 1998 / Revised: 22 September 1998 / Accepted: 23 September 1998     

Reduced variability of Neoral pharmacokinetic studies in pediatric renal transplantation

In adult renal transplant recipients the Neoral area under the curve (AUC) displays less inter- and intra- individual variability than Sandimmune, and those renal transplant recipients with reduced intra-individual variability of the AUC have a lower risk for chronic rejection. As variability of Neoral pharmacokinetic (Pk) parameters has not been investigated in pediatric renal transplant recipients, we retrospectively analyzed 453 Pk profiles in 14 pediatric patients who were switched from Sandimmune to Neoral and compared the inter- and intra-individual variability of the Pk profiles on both formulations. After the switch, we observed less inter- and intra-individual variability of AUC, the 2-h concentration, and the oral clearance. As clearance with both formulations is supposedly equal, the significantly lower intra-individual variability of oral clearance is most likely an effect of less variable absorption. While the lower inter-individual variability of the Pk parameters suggests increased success in keeping cyclosporine concentrations on target, the lower intra-individual variability leads to the hypothesis that with Neoral, a lower incidence of chronic rejection might be achieved. Received: 8 February 2000 / Revised: 17 May 2000 / Accepted: 22 May 2000     

大黄制剂对肾移植受者环孢素血药浓度的影响分析

目的研究肾移植受者服用大黄制剂对环孢素血药浓度的影响。方法 2008年1月至2012年12月,湖州市第一人民医院10例肾移植受者术后采用环孢素＋吗替麦考酚酯/硫唑嘌呤＋泼尼松三联免疫抑制方案,环孢素用量为5~7 mg·kg-1·d-1,受者术后2~5年因便秘同时服用大黄苏打片（每片含大黄0.15 g,碳酸氢钠0.15 g）,3片/次,3次/d。服用当天及15 d监测受者环孢素血药浓度谷值（C0）、2h后血药浓度峰值（C2）以及肝肾功能,停药15d复查环孢素C0和C2。结果服用大黄苏打片15 d受者环孢素C0、C2均高于服用当天检测值,差异均有统计学意义（t=11.754和12.822,P均〈0.05）。停用大黄苏打片15 d复查环孢素C0、C2均低于服用15 d时检测值,差异均有统计学意义（t=10.020和13.596,P均〈0.05）;与服用当天检测值比较,差异均无统计学差异（t=1.375和0.251,P均〉0.05）。服用大黄苏打片15 d,受者肝肾功能指标与服用当天比较差异均无统计学差异（P均〉0.05）。结论肾移植术后服用环孢素的受者在长期使用含有大黄制剂的药物时,应注意监测环孢素血药浓度,必要时适当调整环孢素用量。     

Safe conversion from cyclosporine to azathioprine with improved renal function in pediatric renal transplantation

Although cyclosporine has improved allograft survival in renal transplant patients, problems with drug toxicity remain, raising the question whether cyclosporine should be stopped at some point post-transplant. However, the relative safety of converting from cyclosporine to another immunosuppressive agent, or simply stopping cyclosporine remains an issue of debate and has not been evaluated in children. We have developed a protocol to convert children, who are 6 months post-transplant and have stable kidney function, from cyclosporine and prednisone to azathioprine and prednisone. Eleven children have undergone conversion because of suspected/potential nephrotoxicity or because of other difficulties with cyclosporine (expense, hirsutism). These children were compared with a control group of 12 children who met all criteria for conversion at 6 months but remained on cyclosporine. Allograft survival was similar in both groups but the children converted from cyclosporine experienced an improvement in renal function as measured by calculated creatinine clearance. There were no episodes of rejection for a period of 4 months postconversion and all rejection episodes that developed subsequently occurred during or after the change from daily to alternate-day prednisone. We believe that conversion from cyclosporine to azathioprine can be accomplished safely in children with stable allograft function but long-term risks and benefits need further evaluation.     

Does tacrolimus cause more severe anemia than cyclosporine A in children after renal transplantation?

Abstract Initial reports indicated the possibility of severe anemia associated with tacrolimus (TC) therapy. We investigated the degree of anemia under TC treatment in comparison to cyclosporine A (CsA) treatment in children after renal transplantation. A cross-sectional analysis of 95 children successfully transplanted for at least 3 months was performed. Eighty-five children received CsA and 10 TC. TC-treat-ed patients were compared with CsA-treated patients who were matched according to age, gender, creatinine clearance, and time after transplantation. No patient received additional therapy with mycophenolate mofetil or azathioprine. The creatinine clearance of the whole group of transplanted children was 58 ml/min per 1.73 m². The patients within the matcheD-pair analysis had a lower creatinine clearance (TC 46 and CsA 48 ml/min per 1.73 m²). The hemoglobin was 10.3 g/dl for the TC-treated children and 10.4 g/dl among the CsA-treated patients. Numerically, EPO was higher and iron lower in the TC group than in the CsA group. Among children with functioning renal grafts, a correlation exists between Hb and creatinine clearance. A significant difference in the degree of anemia between TC- and CsA-treated children could not be found.     

尼卡地平对肾移植受者环孢素A血浓度的影响

目的：研究尼卡地平对肾移植受者血压和环孢素A（CaA)全血谷值浓度的影响。方法：试验组62例肾移植术后肾功能恢复正常的受者服用尼卡地平，服药前后作自身对照；23例受者服用硝苯地平作为对照组，以CsA全血谷值浓度、CsA剂量、肌酐、血压作为临床评价指标。结果：试验组受者服用尼卡地平后CsA血药浓度显著升高、血压下降并维持在正常范围，与服用尼卡地平前比较，差异均有显著性意义（P＜0．01），6个月后环孢素剂量A减少达34．2％，对血肌酐无明显影响。结论：尼卡地平用于肾移植术后能有效治疗和预防高血压，并可提高CsA血药浓度，减少CsA用量和费用，并不增加CsA的毒性反应。尼卡地平与CsA合用可节省费用。     

Effect of blood transfusions on oncological outcomes of surgically treated localized renal cell carcinoma

Objective

To assess the associations between perioperative allogeneic blood transfusions (ABTs) and recurrence, overall and renal cell carcinoma (RCC)-specific survival in patients undergoing surgical treatment for clinically localized disease.

Experience with deflazacort in children and adolescents after renal transplantation

Deflazacort (DFZ) has been proposed as an alternative drug for immunosuppression after renal transplantation (TX), with fewer side effects than conventional glucocorticoids. We investigated renal function, body growth, body fat, and bone mineral density (BMD) after switching from oral methylprednisolone (MPR) to equivalent doses of DFZ 1–9 years after TX in 20 patients aged 5–20 years, selected because of severe adverse effects from previous steroid therapy. At conversion the patients received a mean dose of 7.4±2.4 mg DFZ/m² per day. The drug was continued for a mean of 3.7 (1.2–5.5) years. Under DFZ, the glomerular filtration rate dropped slightly (NS). A single rejection episode occurred. Growth velocity significantly improved in the 1st year on DFZ treatment and height standard deviation score (SDS) increased steadily after introduction of DFZ (from –2.64 to –1.96 after 4 years, P=0.06). However, in 10 prepubertal children the height gain (+0.20 SDS in 2 years on DFZ) was not significant and the overall mean annual growth rate after TX was similar to that in 10 matched prepubertal TX children on continued MPR treatment. Relative obesity, estimated from mean body mass index corrected for height, was reduced from +1.11 SDS at the start of DFZ to +0.71 SDS after 2 years (P=0.03) and to +0.39 SDS after 4 years (NS). BMD-SDS of the lumbar spine (L_2–4) increased after 1 year on DFZ (P=0.005). In conclusion, DFZ is well tolerated and safe in pediatric patients after TX. It improves relative obesity and bone mineralization. However, body growth is not significantly influenced pre puberty. Received: 19 October 1999 / Revised: 28 February 2000 / Accepted: 28 February 2000     

联苯双酯滴丸降低肾移植受者全血环孢素A浓度

目的　观察肾移植受者术后联苯双酯(BFD)与环孢素A(CsA)合用后对全血CsA浓度的影响。方法选择106例肾移植术后采用CsA 泼尼松(Pred) 硫唑嘌呤(Aza)三联用药方案的受者为研究对象;其中65例服用了BFD的受者为实验组,41例未服用BFD的患者为对照组。分别检测两组的全血CsA浓度及肝、肾功能,作为临床评价指标。结果实验组全血CsA浓度与服用BFD前比较,降幅达26.5%,与对照组比较,亦有显著性降低(P<0.001)。实验组服用BFD后,能有效降低异常升高的血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)含量,对其它肝、肾功能指标无明显影响;停用BFD后,全血CsA浓度明显升高,增幅达37.2%。结论服用BFD能明显降低肾移植受者CsA血药浓度。     

Does cyclosporine affect the duration of action of vecuronium in renal transplant recipients?

The duration of action of vecuronium was tested in 41 surgical patients to evaluate whether cyclosporine modulates the action of vecuronium. The patients were divided into three groups: 12 patients with normal renal function (group A); 14 renal transplant recipients who had received cyclosporine before surgery (group B); and 15 patients with chronic renal failure undergoing surgery other than renal transplantation and who did not receive cyclosporine (group C). The times to 10% and 20% recovery of the first twitch (REC 10 and REC 20) after intravenous administration of vecuronium 0.12 mg·kg⁻¹ were measured using an electromyogram in each group. REC 10 and REC 20 were significantly prolonged in the patients of group B (REC 10: 93±18 min, REC 20: 110±14 min) and group C (REC 10: 80±10 min, REC 20: 89±12 min) than in the patients of group A (REC 10: 39±5 min, REC 20: 45±5 min) (P<0.01). There was no significant difference in the duration of action of vecuronium between the patients of groups B and C. In summary, cyclosporine did not prolong the duration of action of vecuronium in the renal transplant recipients when the same dose was administered compared with the patients with chronic renal failure who did not receive cyclosporine. Presented in part at the 68th Clinical and Scientific Congress of the International Anesthesia Research Society, Orlando, FL, USA, 1994     

Diabetes mellitus in patients with infantile cystinosis after renal transplantation

Diabetes mellitus is a frequent long-term complication of infantile nephropathic cystinosis. We studied 44 cystinotic patients, aged 22.1±5.4 years, transplanted at a mean age of 11.3±2.5 years; 25% were treated with insulin at 20 years of age or 10 years after transplantation, and over half required insulin at latest follow-up. In comparison, diabetes mellitus occurred in only 1% of non-cystinotic transplanted patients. Sequential oral glucose tolerance tests (OGTTs) in these patients showed the progressive deterioration of glucose metabolism. All but 2 patients had an abnormal response at latest follow-up. The high doses of corticosteroid given after transplantation or during rejection episodes were responsible for transient insulin dependency. However, the development of impaired glucose tolerance and diabetes mellitus depended mainly on the cystinotic process, which developed slowly with time. The deterioration of glucose tolerance was correlated with a decreased early phase of insulin secretion, estimated from the plasma insulin level at 30 min of the OGTT, while there was no evidence of insulin resistance. The occurrence of diabetes mellitus correlated with a worsening of the vital prognosis. Received: 28 July 1998 / Revised: 22 September 1998 / Accepted: 23 September 1998     

Seizures following renal transplantation in childhood

 Few studies have investigated the incidence of seizures following renal transplantation in childhood. The aim of this study was to determine this incidence and to identify risk factors. Retrospective casenote analysis was carried out on 119 transplants performed in 109 children over 10 years. Twenty-one transplants (in 20 children) were complicated by seizures, the majority of which occurred in the first 55 days after transplantation. Seizures were more common in the 5- to 10-year-old age group (P=0.03), but were no more common in those with a prior history of seizure (P=0.69). Their aetiology was predominantly multifactorial; hypertension (n=15), fever/infection (n=4) and acute allograft rejection (n=6) were commonly identified risk factors; 2 were secondary to intracerebral pathology. Most seizures were short lived, required minimal therapy and had a good long-term neurological outcome. In conclusion, seizures are relatively common following paediatric renal transplantation. Parents are now routinely counselled of this risk. Received: 11 March 1998 / Revised: 15 May 1998 / Accepted: 9 September 1998     

Renal function following kidney transplantation in children treated with cyclosporine

The study was performed to evaluate the longterm renal function of children treated with cyclosporine after kidney transplantation. Renal function was determined with clearances of inulin and aminohippurate sodium for evaluating glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Thirty-six children aged 0.4–16.2 (median 6.9) years at transplantation were examined within 5 months of transplantation and then yearly over 0.3–7.1 years. Twenty-five children and young adults, 1.5–20 (median 7.7) years of age, with solitary kidneys because of renal agenesis or nephrectomy, served as controls. The GFR and ERPF within 1 year of transplantation were significantly lower than those of controls (65±19 and 345±88 vs 96±12 and 474±91 ml/min per 1.73 m², respectively). GFR remained constant 4 years after transplantation, but ERPF decreased significantly. Significant inverse correlations were found between GFR within 5 months of transplantation and the mean cyclosporine concentration and the number of rejection episodes. The frequency of hypertension decreased from 82% within 5 months of transplantation to 0% after 4 years. The absolute GFR increased during follow-up. In conclusion, kidney transplantation results in a reduced renal function compared with that of solitary native kidneys. The reduction in renal function correlated with the number of rejection episodes and the cyclosporine load. The increase in absolute GFR during follow-up suggests a remaining capacity for growth and/or compensatory hypertrophy.     

Risk factors for hyperlipidemia in long-term pediatric renal transplant recipients

Hyperlipidemia (HL) is a common problem in adult renal transplant (TP) recipients, contributing to an increased risk of cardiovascular disease and chronic TP nephropathy. There are multiple causes of HL post renal TP in adult patients, including pre TP HL, immunosuppressive agents, renal dysfunction, hypoalbuminemia secondary to nephrotic syndrome, obesity, and conditions that lead to end-stage renal disease (ESRD). We evaluated the incidence and risk factors of HL in 62 pediatric renal TP recipients (15.4±4.2 years, range-3.0–22.3 years) with long-term (6.7±3.1 years) functioning [glomerular filtration rate (GFR) 66.7±23.2 ml/min per 1.73 m²] allografts. The mean serum cholesterol (C) level was 205.5±43.6 mg/dl. Thirty-two patients (51.6%) exhibited elevated serum C levels. The mean serum triglyceride (TG) level was 157.3±88.4 mg/dl. Serum TG levels were elevated in 32 patients (51.6%). In patients with elevated serum levels of either C or TG, the mean low-density lipoprotein level (LDL) was 138.6±44.1 mg/dl (normal <130 mg/dl) and the high-density lipoprotein (HDL) level 54.6±15.9 mg/dl (normal>34 mg/dl). Of those patients studied, 45.5% had high LDL levels, whereas 9.1% exhibited low HDL levels. The two risk factors for elevated serum C levels in our patient population were pre-TP HL and increased years since TP. The only risk factor for elevated serum TG levels was reduced GFR. A family history of HL had a significant deleterious impact upon serum levels of C (P=0.01), but did not affect serum TG levels (P=0.7). Years on dialysis prior to TP, history of prior TP, gender, body mass index, and disease leading to ESRD had no influence upon the development of post-TP HL. We conclude that post-renal TP HL is a significant problem in pediatric renal TP recipients. Received: 13 January 1999 / Revised: 19 May 1999 / Accepted: 21 May 1999     

Pediatric renal transplantation in Laurence-Moon-Biedl syndrome

Two cases of renal transplantation in pediatric patients with Laurence-Moon-Biedl syndrome are reported. Immunosuppressive therapy consisted of cyclosporine, prednisone and azathioprine. Renal function has been good but both patients developed morbid obesity.