A Decade of Experience With Alemtuzumab Therapy for Severe or Glucocorticoid-Resistant Kidney Transplant Rejection.

Alemtuzumab is used as lymphocyte-depleting therapy for severe or glucocorticoid-resistant kidney transplant rejection. However, the long-term efficacy and toxicity of alemtuzumab therapy are unclear. Therefore, all cases of alemtuzumab anti-rejection therapy between 2012 and 2022 in our institution were investigated. Graft survival, graft function, lymphocyte depletion, serious infections, malignancies, and patient survival were analyzed and compared with a reference cohort of transplanted patients who did not require alemtuzumab anti-rejection therapy. A total of 225 patients treated with alemtuzumab were identified and compared with a reference cohort of 1,668 patients. Over 60% of grafts was salvaged with alemtuzumab therapy, but graft survival was significantly poorer compared to the reference cohort. The median time of profound T- and B lymphocyte depletion was 272 and 344 days, respectively. Serious infection rate after alemtuzumab therapy was 54.1/100 person-years. The risk of death (hazard ratio 1.75, 95%-CI 1.28-2.39) and infection-related death (hazard ratio 2.36, 95%-CI 1.35-4.11) were higher in the alemtuzumab-treated cohort. In conclusion, alemtuzumab is an effective treatment for severe kidney transplant rejection, but causes long-lasting lymphocyte depletion and is associated with frequent infections and worse patient survival outcomes.

Outcomes of COVID-19 in peritoneal dialysis patients: A report by the European Renal Association COVID-19 Database.

BACKGROUND: The clinical course of COVID-19 in peritoneal dialysis (PD) patients has so far only been analysed in relatively small, often single-centre case series. Therefore, we studied patient- and disease-related characteristics and outcomes of COVID-19 in a larger European cohort of PD patients. METHODS: We used data from the European Renal Association COVID-19 Database (ERACODA) on PD and haemodialysis (HD) patients with COVID-19 (presentation between February 2020 and April 2021). Hazard ratios (HR) for mortality at 3 months were calculated using Cox proportional-hazards regression. In addition, we examined functional and mental health status among survivors at this time point as determined by their treating physician. RESULTS: Of 216 PD patients with COVID-19, 80 (37%) were not hospitalised and 136 (63%) were hospitalised, of whom 19 (8.8%) were admitted to an intensive care unit. Mortality at 3 months for these subgroups was 18%, 40%, and 37%, respectively (p = 0.0031). Compared with HD patients, PD patients had higher mortality (crude HR: 1.49; 95% CI: 1.33-1.66), even when adjusted for patient characteristics and disease severity (adjusted HR: 1.56; 95% CI: 1.39-1.75). Follow-up data on 67 of 146 patients who survived COVID-19 showed functional recovery to pre-COVID-19 levels in 52 (78%) and mental recovery in 58 patients (87%) at 3 months after the COVID-19 diagnosis. CONCLUSION: The mortality rate in the first 3 months after presentation with COVID-19 is high, especially among PD patients who were hospitalised. PD patients with COVID-19 had a higher mortality risk than HD patients. The majority of surviving patients recovered both functionally and mentally from COVID-19 within 3 months.

Causes of Kidney Graft Failure in a Cohort of Recipients With a Very Long-Time Follow-Up After Transplantation.

Background: Biopsy-proven causes of graft loss many years after kidney transplantation are scarcely documented. Methods: Patients transplanted between 1995 and 2005 (n = 737) in a single center were followed on a regular basis until 2021. The recipients were divided according to age at transplantation into 3 groups; 18-39 years (young), 40-55 years (middle age), and older than 55 years (elderly). For cause biopsies of renal transplants were clustered into the categories, rejection, IFTA, return original disease, and diagnosis of de novo kidney disease. Results: Rejection was the main cause of graft failure censored for death at every time period after transplantation. The incidence of T cell-mediated rejection (TCMR) became rare 6 years after transplantation while the cumulative incidence of antibody-mediated rejection (ABMR) increased over time (1.1% per year). ABMR was not diagnosed anymore beyond 15 years of follow-up in recipients without pre-transplant donor-specific antibodies (DSA). An episode of TCMR was associated with an increased incidence of ABMR diagnosis in the short-term but did not increase the overall incidence of AMBR not in the long-term. Death as a cause of graft failure was an important competitive risk factor long after transplantation and resulted in a significantly lower frequency of rejection-related graft loss in the elderly group (11 vs. 23% in the young group at 15 year follow-up). Conclusion: Rejection is a major cause of graft loss but recipient's age, time after transplantation, and the presence of DSA before transplantation determine the relative contribution to overall graft loss and the type of rejection involved.

ABO-incompatible kidney transplantation in perspective of deceased donor transplantation and induction strategies: a propensity-matched analysis.

Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity-matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor [hazard ratio (HR) for death of HR 0.69 (0.49-0.96)] and non-significantly different from ABOc living donor recipients [HR 1.28 (0.90-1.81)]. Rate of graft failure was higher compared with ABOc living donor transplantation [HR 2.63 (1.72-4.01)]. Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab-treated recipients (P < 0.001). ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared with matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy [NTR7587, www.trialregister.nl].

Comparison of Alemtuzumab and Anti-thymocyte Globulin Treatment for Acute Kidney Allograft Rejection.

Rabbit anti-thymocyte globulin (rATG) is currently the treatment of choice for glucocorticoid-resistant, recurrent, or severe acute allograft rejection (AR). However, rATG is associated with severe infusion-related side effects. Alemtuzumab is incidentally given to kidney transplant recipients as treatment for AR. In the current study, the outcomes of patients treated with alemtuzumab for AR were compared with that of patients treated with rATG for AR. The patient-, allograft-, and infection-free survival and adverse events of 116 alemtuzumab-treated patients were compared with those of 108 patients treated with rATG for AR. Propensity scores were used to control for differences between the two groups. Patient- and allograft survival of patients treated with either alemtuzumab or rATG were not different [hazard ratio (HR) 1.14, 95%-confidence interval (CI) 0.48-2.69, p = 0.77, and HR 0.82, 95%-CI 0.45-1.5, p = 0.52, respectively). Infection-free survival after alemtuzumab treatment was superior compared with that of rATG-treated patients (HR 0.41, 95%-CI 0.25-0.68, p < 0.002). Infusion-related adverse events occurred less frequently after alemtuzumab treatment. Alemtuzumab therapy may therefore be an alternative therapy for glucocorticoid-resistant, recurrent, or severe acute kidney transplant rejection.

Treatment with intravenous immunoglobulins and methylprednisolone may significantly decrease loss of renal function in chronic-active antibody-mediated rejection.

BACKGROUND: Chronic-active antibody mediated rejection (c-aABMR) is a major contributor to long-term kidney allograft loss. We conducted a retrospective analysis to establish the efficacy of treatment with intravenous immunoglobulins (IVIG) and pulse methylprednisolone (MP) of patients with c-aABMR. METHODS: Sixty-nine patients, in the period 2005-2017, with the diagnosis (suspicious for) c-aABMR that were treated with IVIG and MP were included. Patients were administered three doses of 1 g intravenous MP combined with a single dose of IVIG (1 g/kg body weight). Primary outcome was the decline in allograft function one year post treatment. Responders to IVIG-MP therapy were defined by an eGFR one year after treatment which was at least 25% above the projected allograft function. RESULTS: Patients showed an average decline in eGFR of 9.8 ml/min/1.73m2 the year prior to treatment. Following treatment, a significant reduction (p < 0.001) in eGFR decline was observed (6.3 ml/min/1.73m2). Furthermore, a significant improvement in proteinuria was observed upon treatment (p < 0.001). Sixty-two percent (n = 43) of the patients were considered a responder and showed considerable slowing of graft function deterioration in the year after treatment (p < 0.001). Three and 5-year graft survival was significantly superior in responders. CONCLUSIONS: More than 60% of patients with c-aABMR with a progressive decline in eGFR respond favorably to treatment with IVIG-MP resulting in a significant improvement of graft survival (Sablik, Am J Transplant 18, 2018).

Chronic-active antibody-mediated rejection with or without donor-specific antibodies has similar histomorphology and clinical outcome - a retrospective study.

Chronic-active antibody-mediated rejection (c-aABMR) is defined as histological evidence of chronic endothelial injury (cg), also known as transplant glomerulopathy, and either microvascular inflammation (MVI) or positivity for C4d. Importantly, the presence of donor-specific antibodies (DSA) is currently still mandatory for the diagnosis of c-aABMR. This retrospective study of 41 c-aABMR patients investigates whether cases suspicious for c-aABMR (DSA negative, n = 24) differ from cases of c-aABMR (DSA positive, n = 17) with respect to renal histology, allograft function and long-term graft survival. All included patients had progressive loss of allograft function and were diagnosed by for cause biopsy and scored according to the Banff '15 criteria. In all DSApos cases, DSA were de novo and the majority was directed against HLA-II being mostly anti-HLA-DQ antibodies. There were no statistically significant differences in clinical characteristics, decline in allograft function and renal allograft survival in cases with or without DSAs. All cases showed chronic histomorphological damage and inflammation, irrespective of the presence of DSA. Renal histology and clinical outcome of patients suspicious for c-aABMR (DSAneg) do not significantly differ from patients with a diagnosis of c-aABMR (DSApos). We believe that our study adds to the ongoing debate regarding the need for DSAs to be present for the diagnosis of c-aABMR.

A Successful Approach to Kidney Transplantation in Patients With Enteric (Secondary) Hyperoxaluria.

BACKGROUND: Enteric hyperoxaluria due to malabsorption may cause chronic oxalate nephropathy and lead to end-stage renal disease. Kidney transplantation is challenging given the risk of recurrent calcium-oxalate deposition and nephrolithiasis. METHODS: We established a protocol to reduce plasma oxalic acid levels peritransplantation based on reduced intake and increased removal of oxalate. The outcomes of 10 kidney transplantation patients using this protocol are reported. RESULTS: Five patients received a living donor kidney and had immediate graft function. Five received a deceased donor kidney and had immediate (n = 1) or delayed graft function (n = 4). In patients with delayed graft function, the protocol was prolonged after transplantation. In 3 patients, our protocol was reinstituted because of late complications affecting graft function. One patient with high-output stoma and relatively low oxalate levels had lost her first kidney transplant because of recurrent oxalate depositions but now receives intravenous fluid at home on a routine basis 3 times per week to prevent dehydration. Patients are currently between 3 and 32 months after transplantation and all have a stable estimated glomerular filtration rate (mean, 51 ± 21 mL/min per 1.73 m2). In 4 of 8 patients who underwent for cause biopsies after transplantation oxalate depositions were found. CONCLUSIONS: This is the first systematic description of kidney transplantation in a cohort of patients with enteric hyperoxaluria. Common complications after kidney transplantation impact long-term transplant function in these patients. With our protocol, kidney transplantation outcomes were favorable in this population with unfavorable transplantation prospects and even previous unsuccessful transplants.

Pretransplant Tacrolimus Dose Requirements Predict Early Posttransplant Dose Requirements in Blood Group AB0-Incompatible Kidney Transplant Recipients.

BACKGROUND: The aim of this study was to investigate whether pretransplant tacrolimus (Tac) dose requirements of patients scheduled to undergo living donor kidney transplantation correlate with posttransplantation dose requirements. METHODS: The predictive value of Tac dose requirements (defined as the ratio of the Tac predose concentration, C0, divided by the total daily Tac dose, D) pretransplantation on this same parameter posttransplantation was assessed retrospectively in a cohort of 57 AB0-incompatible kidney transplant recipients. These patients started immunosuppressive therapy 14 days before transplant surgery. All patients were using a stable dose of glucocorticoids and were at steady-state Tac exposure before transplantation. RESULTS: Tac dose requirements immediately before transplantation (C0/Dbefore) explained 63% of the Tac dose requirements on day 3 after transplantation: r = 0.633 [F (1, 44) = 75.97, P < 0.01]. No other clinical and demographic variables predicted Tac dose requirements early after transplantation. CONCLUSIONS: Steady-state Tac dose requirement before transplantation largely predicted posttransplantation Tac dose requirements in AB0-incompatible kidney transplant recipients. The importance of this finding is that the posttransplantation Tac dose can be individualized based on a patient's pretransplantation Tac concentration/dose ratio. Pretransplant Tac phenotyping therefore has the potential to improve transplantation outcomes.

Alternative Living Kidney Donation Programs Boost Genetically Unrelated Donation.

Donor-recipient ABO and/or HLA incompatibility used to lead to donor decline. Development of alternative transplantation programs enabled transplantation of incompatible couples. How did that influence couple characteristics? Between 2000 and 2014, 1232 living donor transplantations have been performed. In conventional and ABO-incompatible transplantation the willing donor becomes an actual donor for the intended recipient. In kidney-exchange and domino-donation the donor donates indirectly to the intended recipient. The relationship between the donor and intended recipient was studied. There were 935 conventional and 297 alternative program transplantations. There were 66 ABO-incompatible, 68 domino-paired, 62 kidney-exchange, and 104 altruistic donor transplantations. Waiting list recipients (n = 101) were excluded as they did not bring a living donor. 1131 couples remained of whom 196 participated in alternative programs. Genetically unrelated donors (486) were primarily partners. Genetically related donors (645) were siblings, parents, children, and others. Compared to genetically related couples, almost three times as many genetically unrelated couples were incompatible and participated in alternative programs (P < 0.001). 62% of couples were genetically related in the conventional donation program versus 32% in alternative programs (P < 0.001). Patient and graft survival were not significantly different between recipient programs. Alternative donation programs increase the number of transplantations by enabling genetically unrelated donors to donate.

Post-Transplantation Immunoadsorption Can Be Withheld in ABO-Incompatible Kidney Transplant Recipients.

After ABO-incompatible kidney transplantation, postoperative plasma exchange (PE) or immunoadsorption (IA) is performed per protocol or depending on postoperative A/B-titers to prevent acute rejection. However, the need for postoperative PE or IA is not known. Since 2006, 30 consecutive patients received three standard postoperative IAs. Starting from 2009, the last 46 patients received only preoperative IA. Preoperative desensitization consisted of rituximab, tacrolimus, mycophenolate mofetil, prednisone and intravenous immunoglobulins. Antigen-specific IA was performed pre-operatively with the Glycosorb device. Biopsy-proven acute rejections either antibody-mediated (AMR) or mixed cellular and antibody-mediated (MAR) within 3 months were recorded. The postoperative titer in patients with postoperative IA did not exceed 1:16 (IgG 1:4 [<2-16] median and range). The postoperative IgG titer was not significantly different after abandoning postoperative IA, although three patients had titers of 1:32 and one patient even 1:128. Rejections tended to be more frequent in the group with postoperative IA: 6 AMR and 3 MAR were recorded in 30 patients, vs. 4 AMR and 1 MAR in the 46 patients without postoperative IA (30 vs. 11%, P = 0.067). Baseline characteristics differed however: in the group with postoperative IA the vast majority had blood group O (87 vs. 52%, P = 0.003). Also, the IgG titer on the day of transplantation was higher (1:4 [<2-16] vs. 1:2 [<2-32], P = 0.007). All 14 patients with AMR and MAR rejections had postoperative IgG titers ≤1:16. Postoperative removal of A/B-antibodies can be safely removed from the ABOi transplantation protocol using strict preoperative criteria for antibody lowering.

ABO-incompatible kidney transplant recipients have a higher bleeding risk after antigen-specific immunoadsorption.

Pretransplant removal of antiblood group ABO antibodies is the cornerstone of all current ABO-incompatible (ABOi) transplantation programmes. In our protocol, plasmapheresis (PP) is performed with a plasmafilter followed by immunoadsorption (IA) of anti-ABO antibodies. The bleeding complications of this technique are not known. We analysed the data of all 65 consecutive ABOi kidney transplantations between March 2006 and October 2013 and compared these with matched 130 ABO-compatible (ABOc) kidney transplantations. Cases differed from controls in the pre-operative regimen, which included IA-PP and rituximab, tacrolimus, mycophenolate mofetil, prednisone and immunoglobulines. Data on platelet count, blood loss and red blood cell (EC) transfusions during 48 h postoperatively were collected. ABOi patients received EC transfusions more frequently than controls (29% vs. 12%, P = 0.005). Intra-operative blood loss was higher (544 vs. 355 ml, P < 0.005) and they experienced more major bleeding (≥3 EC within 24 h, 15% vs. 2%, P < 0.0005). Platelet count decreased by 28% after the pre-operative IA. In a multivariate model, only the number of pre-operative IAs was associated with the number of ECs given (OR per IA 1.9, P < 0.05). ABOi kidney transplant recipients have a high postoperative bleeding risk, correlating with the number of pre-operative IA sessions performed.

The First Fifty ABO Blood Group Incompatible Kidney Transplantations: The Rotterdam Experience.

This study describes the single center experience and long-term results of ABOi kidney transplantation using a pretransplantation protocol involving immunoadsorption combined with rituximab, intravenous immunoglobulins, and triple immune suppression. Fifty patients received an ABOi kidney transplant in the period from 2006 to 2012 with a follow-up of at least one year. Eleven antibody mediated rejections were noted of which 5 were mixed antibody and cellular mediated rejections. Nine cellular mediated rejections were recorded. Two grafts were lost due to rejection in the first year. One-year graft survival of the ABOi grafts was comparable to 100 matched ABO compatible renal grafts, 96% versus 99%. At 5-year follow-up, the graft survival was 90% in the ABOi versus 97% in the control group. Posttransplantation immunoadsorption was not an essential part of the protocol and no association was found between antibody titers and subsequent graft rejection. Steroids could be withdrawn safely 3 months after transplantation. Adverse events specifically related to the ABOi protocol were not observed. The currently used ABOi protocol shows good short and midterm results despite a high rate of antibody mediated rejections in the first years after the start of the program.

Late antibody-mediated rejection after ABO-incompatible kidney transplantation during Gram-negative sepsis.

BACKGROUND: The major challenge in ABO-incompatible transplantation is to minimize antibody-mediated rejection. Effective reduction of the anti-ABO blood group antibodies at the time of transplantation has made ABO-incompatible kidney transplantation a growing practice in our hospital and in centers worldwide. ABO antibodies result from contact with A- and B-like antigens in the intestines via nutrients and bacteria. We demonstrate a patient with fulminant antibody-mediated rejection late after ABO-incompatible kidney transplantation, whose anti-A antibody titers rose dramatically following Serratia marcescens sepsis. CASE PRESENTATION: A 58-year-old woman underwent an ABO-incompatible kidney transplantation for end-stage renal disease secondary to autosomal dominant polycystic kidney disease. It concerned a blood group A1 to O donation. Pre-desensitization titers were 64 for anti-blood group A IgM and 32 for anti-blood group A IgG titers. Desensitization treatment consisted of rituximab, tacrolimus, mycophenolate mofetil, corticosteroids, immunoadsorption and intravenous immunoglobulins. She was readmitted to our hospital 11 weeks after transplantation for S. marcescens urosepsis. Her anti-A IgM titer rose to >5000 and she developed a fulminant antibody-mediated rejection.We hypothesized that the (overwhelming) presence in the blood of S. marcescens stimulated anti-A antibody formation, as S. marcescens might share epitopes with blood group A antigen. Unfortunately we could not demonstrate interaction between blood group A and S. marcescens in incubation experiments. CONCLUSION: Two features of this post-transplant course are remarkably different from other reports of acute rejection in ABO-incompatible kidney transplantation: first, the late occurrence 12 weeks after kidney transplantation and second, the very high anti-A IgM titers (>5000), suggesting recent boosting of anti-A antibody formation by S. marcescens.

AcylMPAG plasma concentrations and mycophenolic acid-related side effects in patients undergoing renal transplantation are not related to the UGT2B7-840G>A gene polymorphism.

Mycophenolic acid (MPA) is metabolized primarily by glucuronidation to form the biologically inactive 7-O-glucuronide conjugate (MPAG), which is the major urinary excretion product. MPA is also converted to acyl-glucuronide metabolite (AcylMPAG), which has been suggested to be involved in the generation of MPA-related adverse events such as diarrhea or leucopenia. This conversion of MPA to AcylMPAG is catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). We studied the impact of the -840G>A polymorphisms in the UGT2B7 gene on the pharmacokinetics of AcylMPAG. We also investigated whether the plasma concentrations of AcylMPAG are correlated with MPA-related toxicity to further evaluate its potential clinical significance. In a randomized, controlled trial, comparing fixed-dose mycophenolate mofetil (MMF) with concentration-controlled MMF therapy, patients undergoing renal transplantation were treated with a calcineurin inhibitor, MMF, and corticosteroids. Informed consent was obtained from 332 patients for genotyping. In all patients, blood samples were drawn (three samples within the first 2 hours after administration) on Day 3, Day 10, Week 4, and Months 3, 6, and 12 to measure MPA and AcylMPAG plasma concentrations. The pharmacokinetics of AcylMPAG were correlated with the -840G>A single nucleotide polymorphism (SNP) in the UGT2B7 gene. Heterozygosity for the -840G>A SNP in the UGT2B7 gene was found in 145 patients (145 of 332 [44%]) and 93 (93 of 332 [28%]) patients were homozygous for the -840G>A allele. No difference was found in the dose-normalized AcylMPAG trough (C0) levels and dose-normalized AcylMPAG areas under the concentration-time curve (AUCs) at each visit between carriers and noncarriers of the -840G>A SNP. Also, metabolic ratios, expressed as AcylMPAG/MPA and AcylMPAG/MPAG, were not related to UGT2B7 genotype. The dose-normalized AcylMPAG-C0 and AcylMPAG AUC were higher in the cyclosporine-treated group compared with the tacrolimus-treated patients at each visit. There was no difference in AcylMPAG concentrations (trough or AUC) or AcylMPAG/MPAG ratio between patients with compared with patients without diarrhea. None of the -840G>A UGT2B7 SNPs was disproportionately present among the patients with diarrhea. There was a higher incidence of diarrhea in tacrolimus-treated patients [26 of 163 (16.0%)] compared with cyclosporine-treated individuals [five of 51 (9.8%)], although AcylMPAG concentrations were lower in tacrolimus-treated patients. In this study, we have found no influence of the -840G>A UGT2B7 SNP on AcylMPAG exposure in patients undergoing renal transplantation. There also was no association between this variant genotype and the incidence of diarrhea or leucopenia, two adverse events for which a role for AcylMPAG has been suggested.

CYP3A5 genotype is not associated with a higher risk of acute rejection in tacrolimus-treated renal transplant recipients.

OBJECTIVE: Patients expressing the tacrolimus-metabolizing enzyme, cytochrome P450 (CYP) 3A5, require more tacrolimus to reach target concentrations. We studied the influence of the CYP3A5(*)3 allele, which results in the absence of CYP3A5 protein, on tacrolimus dose and exposure, as well as the incidence of biopsy-proven acute rejection (BPAR) after renal transplantation. METHODS: A total of 136 patients participating in a prospective, randomized-controlled clinical trial with the primary aim of comparing the efficacy of a fixed-dose versus a concentration-controlled mycophenolate mofetil immunosuppressive regimen, were genotyped for CYP3A5(*)3. The patients described herein, participated in a pharmacogenetic substudy and were all treated with mycophenolate mofetil, corticosteroids and tacrolimus. Tacrolimus predose concentrations (C(0)) were measured on day 3 and 10, and month 1, 3, 6 and 12. RESULTS: Compared with CYP3A5(*)3/(*)3 individuals (n=110), patients carrying at least one CYP3A5(*)1 (wild-type) allele (CYP3A5 expressers; n=26) had a lower tacrolimus C(0) on day 3 only (16.6 versus 12.3 ng/ml, respectively), whereas dose-corrected tacrolimus C(0) were significantly lower in the latter group at all time points. After day 3, the overall daily tacrolimus dose was 68% higher in CYP3A5 expressers (P<0.001). The incidence of BPAR was comparable between CYP3A5 expressers and nonexpressers (8 versus 16%, respectively; P=0.36). CONCLUSION: We conclude that patients expressing CYP3A5 need more tacrolimus to reach target concentrations and have a lower tacrolimus exposure shortly after transplantation. This delay in reaching target concentrations, however, did not result in an increased incidence of early BPAR and therefore, genotyping for CYP3A5 is unlikely to improve short-term transplantation outcome.

Regional citrate versus heparin anticoagulation during venovenous hemofiltration in patients at low risk for bleeding: similar hemofilter survival but significantly less bleeding.

BACKGROUND: Regional citrate anticoagulation (RCA) may be a valuable alternative to systemic heparin anticoagulation during continuous venovenous hemodialysis (CVVH). RCA does not increase the risk of bleeding, but carries the risk of metabolic derangements. Clotting-free circuit survival may be increased with RCA. METHODS: Critically ill patients at low risk for bleeding were randomized for CVVH with RCA or systemic heparin anticoagulation. A maximum of 4 consecutive CVVH circuits were analyzed for every patient. Clotting-free circuit survival, adverse metabolic events and bleeding complications were recorded. RESULTS: Forty-eight patients were included in the study and randomized for RCA (n=21) or systemic heparin (n=27). A total of 142 CVVH circuits were analyzed with a median of 3 circuits per patient. Uncensored circuit survival and median clotting-free circuit survival were similar for both groups. No significant adverse metabolic events occurred in the RCA group. Major bleedings were not recorded in the RCA group, compared with 10 events in the heparin group (p<0.01). The number of red blood cell units given per day of CVVH was significantly higher in the heparin group (0.88 vs 0.43 units/day, p=0.01). Also, the mean decrease in hemoglobin concentration per day in the nontransfused stable patients, was significantly higher in the heparin group. CONCLUSION: RCA during CVVH can be performed safely, with a circuit survival similar to systemic heparin anticoagulation, but significantly lower incidence of bleeding. Citrate anticoagulation should be advocated as first choice, also for critically ill patients considered to be at low risk for bleeding.

Prevention of dialysis catheter-related sepsis with a citrate-taurolidine-containing lock solution.

BACKGROUND: The use of haemodialysis catheters is complicated by catheter-related sepsis. Intraluminal colonization of the catheter with bacteria is important in the pathogenesis of catheter-related sepsis. The use of a catheter lock solution containing the antimicrobial taurolidine might prevent bacterial colonization, thereby reducing the incidence of catheter-related sepsis. METHODS: In a randomized prospective trial, patients receiving a dialysis catheter were included and catheters were locked with either heparin or a citrate-taurolidine-containing solution. Blood cultures drawn from the catheter lumen were routinely taken every 2 weeks and at time of removal of the catheter to detect bacterial colonization. Catheter-related sepsis and exit-site infections were registered for both groups. RESULTS: A total of 76 catheters were inserted in 58 patients. The incidence of catheter colonization progressed slowly over time with no differences between dialysis catheters filled with heparin or citrate-taurolidine-containing solution. The number of exit-site infections was also similar between both groups. In the heparin group, four cases of catheter-related sepsis occurred as opposed to no sepsis episodes in the patients with catheters locked with the citrate-taurolidine-containing solution (P<0.5). No side effects with the use of citrate-taurolidine catheter lock solution were noted. CONCLUSIONS: This study shows that catheter filling with a solution containing the antimicrobial taurolidine may significantly reduce the incidence of catheter-related sepsis. Taurolidine appears to be effective and safe and does not carry the risk for side effects that have been reported for other antimicrobial lock solutions containing gentamicin or high concentrations of citrate.