Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant.

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.

Percentiles for skeletal muscle index, area and radiation attenuation based on computed tomography imaging in a healthy Caucasian population.

BACKGROUND/OBJECTIVES: Muscle mass is a key determinant of nutritional status and associated with outcomes in several patient groups. Computed tomography (CT) analysis is increasingly used to assess skeletal muscle area (SMA), skeletal muscle index (SMI) and muscle radiation attenuation (MRA). However, interpretation of these muscle parameters is difficult since values in a healthy population are lacking. The aim of this study was to provide sex specific percentiles for SMA, SMA and MRA in a healthy Caucasian population and to examine the association with age and BMI in order to define age- and BMI specific percentiles. SUBJECTS/METHODS: In this retrospective cross-sectional study CT scans of potential kidney donors were used to assess SMA, SMI and MRA at the level of the third lumbar vertebra. Sex specific distributions were described and, based on the association between age/BMI and muscle parameters, age, and BMI specific predicted percentiles were computed. The 5th percentile was considered as cut-off. RESULTS: CT scans of 420 Individuals were included (age range 20-82 years and BMI range 17.5-40.7 kg/m2). Sex specific cut-offs of SMA, SMI and MRA were 134.0 cm2, 41.6 cm2/m2 and 29.3 HU in men and 89.2 cm2, 32.0 cm2/m2 and 22.0 HU in women, respectively. Correlations were negative between age and all three muscle parameters, positive between BMI and SMA/SMI and negative between BMI and MRA, resulting in age- and BMI specific percentiles. CONCLUSIONS: This study provides sex specific percentiles for SMA, SMI, and MRA. In addition, age- and BMI specific percentiles have been established.

Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial.

In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.

How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?

Solid-phase multiplex-bead assays are widely used in transplantation to detect anti-human leukocyte antigen (HLA) antibodies. These assays enable high resolution detection of low levels of HLA antibodies. However, multiplex-bead assays are costly and yield variable measurements that limit the comparison of results between laboratories. In the context of a Dutch national Consortium study we aimed to determine the inter-assay and inter-machine variability of multiplex-bead assays, and we assessed how to reduce the assay reagents costs. Fifteen sera containing a variety of HLA antibodies were used yielding in total 7092 median fluorescence intensities (MFI) values. The inter-assay and inter-machine mean absolute relative differences (MARD) of the screening assay were 12% and 13%, respectively. The single antigen bead (SAB) inter-assay MARD was comparable, but showed a higher lot-to-lot variability. Reduction of screening assay reagents to 50% or 40% of manufacturers' recommendations resulted in MFI values comparable to 100% of the reagents, with an MARD of 12% or 14%, respectively. The MARD of the 50% and 40% SAB assay reagent reductions were 11% and 22%, respectively. From this study, we conclude that the reagents can be reliably reduced at least to 50% of manufacturers' recommendations with virtually no differences in HLA antibody assignments.

Virus-Specific CD8(+) T Cells Cross-Reactive to Donor-Alloantigen Are Transiently Present in the Circulation of Kidney Transplant Recipients Infected With CMV and/or EBV.

T cells play a dual role in transplantation: They mediate transplant rejection and are crucial for virus control. Memory T cells generated in response to pathogens can cross-react to alloantigen, a phenomenon called heterologous immunity. Virus-specific CD8(+) T cells cross-reacting to donor-alloantigen might affect alloimmune responses and hamper tolerance induction following transplantation. Here, we longitudinally studied these cross-reactive cells in peripheral blood of 25 kidney transplant recipients with a cytomegalovirus and/or Epstein-Barr virus infection. Cross-reactive T cells were identified by flow cytometry as virus-specific T cells that proliferate in response to donor cells in a mixed-lymphocyte reaction. In 13 of 25 patients, we found cross-reactivity to donor cells for at least 1 viral epitope before (n = 7) and/or after transplantation (n = 8). Cross-reactive T cells were transiently present in the circulation, and their precursor frequency did not increase following transplantation or viral infection. Cross-reactive T cells expressed interferon-γ and CD107a in response to both alloantigen and viral peptide and resembled virus-specific T cells in phenotype and function. Their presence was not associated with impaired renal function, proteinuria, or rejection. In conclusion, virus-specific T cells that cross-react to donor-alloantigen are transiently detectable in the circulation of kidney transplant recipients.

Immunization after renal transplantation: current clinical practice.

BACKGROUND: The use of potent immunosuppressive drugs and increased travel by renal transplant recipients (RTR) has augmented the risk for infectious complications. Immunizations and changes in lifestyle are protective. The Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group has developed guidelines on vaccination following solid organ transplantation. The degree of adherence to these guidelines is unknown, as is which barriers must be overcome to improve adherence. METHODS: We performed a cross-sectional national survey among Dutch nephrologists to assess vaccination policy and adherence to the KDIGO guidelines. In addition, to investigate awareness and attitude of RTR regarding their risk of infection, we performed a cross-sectional survey of RTR in our outpatient clinic. RESULTS: A total of 132 (63%) nephrologists completed the survey. Reported immunization rates were 90.8% for influenza and 27.3% for hepatitis B. However, pneumococcal, tetanus toxoid, and meningococcal immunization rates were low. Twenty-seven percent of respondents were familiar with the guideline contents. The most frequent perceived barrier to guideline adherence was expectation of low effectiveness. A total of 403 RTR (62%) completed the survey. Sixty-eight percent perceived more risk for complicated infection. A significant correlation was found between education level and variables concerning awareness and attitude toward risk of infection. CONCLUSIONS: Our results show that nephrologists' knowledge of and adherence to the recommendations regarding immunization after renal transplantation is suboptimal. Most Dutch RTR are aware of their increased risk and the possible seriousness of infectious complications. However, their behavior does not match their awareness. This disparity points to an important role for nephrologists in providing adequate counseling.

The PROCARE consortium: toward an improved allocation strategy for kidney allografts.

Kidney transplantation is the best treatment option for patients with end-stage renal failure. At present, approximately 800 Dutch patients are registered on the active waiting list of Eurotransplant. The waiting time in the Netherlands for a kidney from a deceased donor is on average between 3 and 4 years. During this period, patients are fully dependent on dialysis, which replaces only partly the renal function, whereas the quality of life is limited. Mortality among patients on the waiting list is high. In order to increase the number of kidney donors, several initiatives have been undertaken by the Dutch Kidney Foundation including national calls for donor registration and providing information on organ donation and kidney transplantation. The aim of the national PROCARE consortium is to develop improved matching algorithms that will lead to a prolonged survival of transplanted donor kidneys and a reduced HLA immunization. The latter will positively affect the waiting time for a retransplantation. The present algorithm for allocation is among others based on matching for HLA antigens, which were originally defined by antibodies using serological typing techniques. However, several studies suggest that this algorithm needs adaptation and that other immune parameters which are currently not included may assist in improving graft survival rates. We will employ a multicenter-based evaluation on 5429 patients transplanted between 1995 and 2005 in the Netherlands. The association between key clinical endpoints and selected laboratory defined parameters will be examined, including Luminex-defined HLA antibody specificities, T and B cell epitopes recognized on the mismatched HLA antigens, non-HLA antibodies, and also polymorphisms in complement and Fc receptors functionally associated with effector functions of anti-graft antibodies. From these data, key parameters determining the success of kidney transplantation will be identified which will lead to the identification of additional parameters to be included in future matching algorithms aiming to extend survival of transplanted kidneys and to diminish HLA immunization. Computer simulation studies will reveal the number of patients having a direct benefit from improved matching, the effect on shortening of the waiting list, and the decrease in waiting time.

Treatment efficacy of hypertension in kidney transplant recipients in the Netherlands.

BACKGROUND: Hypertension in kidney transplant recipients jeopardises graft and patient survival. Guidelines suggest blood pressure targets of ≤130/80 mmHg and sodium intake <90 mmol/day. METHODS: Since the efficacy of antihypertensive treatment among kidney transplant recipients is unknown, we analysed data on office-based blood pressure and use of antihypertensive drugs from the Netherlands Organ Transplant Registry on 5415 kidney transplant recipients. Additionally, we studied dosages, prevalence of treatment-resistant hypertension and 24-hour sodium excretion in 534 kidney transplant recipients from our centre to explore possibilities for therapy optimisation. RESULTS: In patients registered in the Netherlands Organ Transplant Registry, median blood pressure was 134/80 mmHg (interquartile range 122-145/70-85). In 77.2%, the blood pressure was ≥130/80 mmHg; of these patients 10.4% had no registered use, 30.0% used one and 25.9% used ≥3 classes of antihypertensive agents. Parameters from our centre were comparable: 78.7% had a median blood pressure of ≥130/80 mmHg of whom 14.5% had no registered use of antihypertensives and 26.4% used ≥3 classes. Sub-maximal dosages were prescribed in 74.0% of the kidney transplant recipients with a blood pressure of ≥130/80 mmHg while using at least one antihypertensive agent. Treatment-resistant hypertension was present in 7.7%. Median 24-hour sodium excretion was 147 mmol/day (interquartile range 109-195). CONCLUSIONS: This study suggests that therapeutic optimisation of antihypertensive treatment in kidney transplant recipients is, in theory, frequently possible by intensifying pharmacological treatment and by providing more advice on dietary sodium restrictions.

Duplicated ureters and renal transplantation: a case-control study and review of the literature.

INTRODUCTION: Complications of the transplant ureter are the most important cause of surgical morbidity after renal transplantation. The presence of ureteral duplication in the renal graft might result in an increased complication rate. We analyzed our data of double-ureter renal transplantations using a case-control study design. Additionally, we performed a review of the literature. METHODS: From January 1995 to April 2012, 12 patients received a donor kidney with a double ureter (0.8%). We created a control group of 24 patients matched in age, sex, donor type, and ureteral stenting. Patient charts and surgical reports were reviewed retrospectively. RESULTS: In 7 patients both ureters were separately anastomosed to the bladder. In 4 patients a common ostium was created. In 1 patient 1 of the 2 ureters was ligated. No postoperative urologic complications occured. In the single-ureter group, the urologic complication rate was 17% (P = .71). Mean creatinine levels after transplantation were comparable between both groups. DISCUSSION: A double-ureter donor kidney is not associated with an increased complication rate after renal transplantation and yields equal outcomes as compared to single-ureter donor kidneys. We conclude that transplantation of a kidney with a duplicated ureter is safe.

Chylous ascites after laparoscopic hand-assisted donor nephrectomy: Is it specific for the left-side?

We describe a case-report of a chylous ascites after laparoscopic donor nephrectomy, summarize the current literature, and hypothesize on the etiology of this complication.

Polyomavirus BK in the pathogenesis of bladder cancer.

Polyomaviruses are able to drive malignant transformation in rodent models, and have been implicated in the aetiology of a variety of human malignancies. However, the reports on this association in humans are strongly conflicting. Here we describe a renal transplant (RT) recipient with ureteral stenosis against the background of polyomavirus BK (BKV) activity. Six and a half years after transplantation, this patient developed metastasised bladder cancer. Prior to the diagnosis of cancer, atypical cells were detected in the urine that were denoted as 'decoy cells': virally infected epithelial cells that are frequently seen in the urine of RT recipients with BKV (re)activation, which may morphologically resemble malignant cells. Intriguingly, the primary urothelial carcinoma, as well as the mesenterial and two intestinal metastases, stained positive with antibodies against polyomavirus virus large T antigen protein, whereas the adjacent healthy tissue did not. This case suggests a role for BKV in the pathogenesis of bladder cancer, at least in the context of immunodeficiency.

First clinical experience with polysol solution: pilot study in living kidney transplantation.

In this study, we assessed the safety of the new organ preservation solution polysol solution in the clinical setting of living kidney transplantation. We conducted a prospective pilot study in nine adult donor-recipient couples using polysol solution for washout and cold storage of kidney grafts. Adverse reactions possibly related to the use of polysol solution as well as renal function at 1, 6, and 12 months after transplantation were monitored. All living kidney transplantation performed in adults in our center within 2002 to 2008 using the University of Winconsin solution served as controls (n = 190). The use of polysol solution was associated with a higher acute rejection rate compared to University of Wisconsin solution at all time points. Also, antibody-mediated rejection occurred more frequently in the polysol group. Renal function at all time points was also comparable between the groups. This pilot study in living kidney transplantation is the first clinical study on the use of polysol solution. Although the study was not powered on the endpoint rejection, we observed a high number of acute rejection and antibody-mediated rejection episodes in recipients of polysol solution preserved grafts as compared to University of Wisconsin solution controls. As a consequence the study was terminated prematurely.

Abdominal wall phlebitis due to Prevotella bivia following renal transplantation in a patient with an occluded inferior vena cava.

Pre-existing occlusion of the inferior vena cava may complicate renal transplantation. Suppurative abdominal wall phlebitis following renal transplantation was diagnosed in a patient with pre-existing thrombosis of the inferior vena cava of unknown cause. The phlebitis developed in the subcutaneous collateral veins of the abdominal wall contra-laterally to the renal transplant. Cultures from abdominal wall micro-abscesses yielded Prevotella bivia as the causative agent. This complication has not been described before in the context of renal transplantation. The pathogenesis and management of this serious complication are discussed in this paper.

Rapid T cell repopulation after rabbit anti-thymocyte globulin (rATG) treatment is driven mainly by cytomegalovirus.

Rabbit anti-thymocyte globulin (rATG) induces a long-lasting lymphocytopenia. CD4(+) T cells remain depleted for up to 2 years, whereas the CD8(+) T cell compartment is refilled rapidly by highly differentiated CD27(-) CD45RA(+) CD57(+) effector-type cells. Because the presence of these highly differentiated CD8(+) T cells has been associated with cytomegalovirus (CMV) infection, we questioned to what extent restoration of CMV T cell immunity contributes to the re-emergence of T cells following rATG treatment. We compared T cell repopulation in six CMV-seropositive patients with CMV reactivation (reactivating CMV(+) ) to that in three CMV(+) patients without reactivation (non-reactivating CMV(+) ), and to that in three CMV-seronegative recipients receiving a kidney from a CMV-seronegative donor (CMV(-/-) ). All patients received rATG because of acute allograft rejection. Total CD4 and CD8 counts, frequency and phenotype of virus-specific CD8(+) T cells were determined. In reactivating CMV(+) patients, total CD8(+) T cells reappeared rapidly, whereas in non-reactivating CMV(+) patients they lagged behind. In CMV(-/-) patients, CD8(+) T cell counts had not yet reached pretransplant levels after 2 years. CMV reactivation was indeed followed by a progressive accumulation of CMV-specific CD8(+) T cells. During lymphocytopenia following rATG treatment, serum interleukin (IL)-7 levels were elevated. Although this was most prominent in the CMV-seronegative patients, it did not result in an advantage in T cell repopulation in these patients. Repopulated CD8(+) T cells showed increased skewing in their Vß repertoire in both CMV(-/-) and reactivating CMV-seropositive patients. We conclude that rapid T cell repopulation following rATG treatment is driven mainly by CMV.

Characteristics of alloreactive T cells measured before renal transplantation.

Several assays to measure pre-existing allospecific T cell immunity in renal transplant candidates have been developed in the past years. In 46 patients, we used flow cytometry-based mixed lymphocyte culture to measure the precursor frequency and phenotype of alloreactive T cells before renal transplantation, using donor-specific or third-party cells for allostimulation. Allostimulation induced up-regulation of co-stimulatory molecules, chemokine receptors relevant for migration of T cells into the graft and effector proteins. Recipients prone for acute rejection had a higher precursor frequency of alloreactive CD8(+) T cells and a lower percentage of interleukin (IL)-7Rα expressing alloreactive CD8(+) T cells than non-rejectors. These data point to quantitative and qualitative differences between T cells of patients who will experience acute cellular rejection episodes from those who will not.

Ureteral reconstruction after renal transplantation: clinical outcome and risk factors.

INTRODUCTION: The incidence of urological complications after renal transplantation ranges from 2.5 to 30%. Often surgical revision is necessary. The risk factors for surgical revision and which surgical techniques to apply are not elucidated. This study investigates the outcome and risk factors for surgical revision of the ureterocystostomy. MATERIALS AND METHODS: Between January 1995 and March 2009, 1,157 consecutive kidney transplantations were performed. All patient charts and surgical reports were reviewed. RESULTS: Urological complications occurred in 142 (12.3%) patients. In 60 patients (5.2%) surgical revision was necessary. Of these 60 patients, 43 (71.7%) received neoureterocystostomy, 10 (16.7%) ureteropyelostomy reconstruction and 7 (11.7%) other techniques. Independent risk factors for surgical revision were donor ureteral reconstruction (odds ratio (OR) 48.66, 95% confidence interval (CI) 5.01-472.97), recipient age <18 years (OR 4.85, 95% CI 1.50-15.72) and delayed graft function (OR 2.70, 95% CI 1.36-5.36). Ureteral stenting was a protective factor for surgical revision (OR 0.30, 95% CI 0.12-0.81). The urological complication rates after neoureterocystostomy, ureteropyelostomy reconstruction and other techniques were 16, 0 and 0%, respectively. The overall surgical success rate was 92%. CONCLUSIONS: Ureteral stenting, recipient age, delayed graft function and perioperative ureteral reconstruction are significant factors associated with surgical revision of the ureterocystostomy. Surgical revision of the ureterocystostomy is a successful therapy with a low recurrence rate.

Risk factors for delayed graft function after hand-assisted laparoscopic donor nephrectomy.

BACKGROUND: Delayed graft function (DGF) has a negative effect on the results of living-donor kidney transplantation. OBJECTIVE: To investigate potential risk factors for DGF. METHODS: This prospective study included 200 consecutive living donors and their recipients between January 2002 and July 2007. Delayed graft function was defined as need for dialysis within the first postoperative week. RESULTS: Delayed graft function was diagnosed in 12 patients (6%). Intraoperative complications occurred in 10 donors (5%), and postoperative complications in 24 donors (13.5%). One-year kidney graft survival with vs without DGF was 52% and 98%, respectively (P < .002). In donors, 2 univariate risk factors for DGF identified were lower counts per second at peak activity during scintigraphy, and multiple renal veins. In recipients, only 2 or more kidney transplantations and occurrence of an acute rejection episode were important factors. At multivariate analysis, increased risk of DGF was associated with the presence of multiple renal veins (odds ratio, 151.57; 95% confidence interval, 2.53-9093.86) and an acute rejection episode (odds ratio, 78.87; 95% confidence interval, 3.17-1959.62). CONCLUSION: Hand-assisted laparoscopic donor nephrectomy is a safe procedure. The presence of multiple renal veins and occurrence of an acute rejection episode are independent risk factors for DGF.

[Lidocaine: local anaesthetic with systemic toxicity]. / Lidocaïne: een lokaal anestheticum met systemische toxiciteit.

In 4 patients, 3 women aged 63, 17 and 43 years, and a man aged 67 years, lidocain was used as a local anaesthetic for a transthoracic esophageal fundoplication (first patient), severe painful gonarthrosis (fourth patient) and legal abortion (second and third patients). All patients suffered from systemic toxicity as a result, a rare complication. They all had an uneventful recovery, except for the second patient who died from adult respiratory distress syndrome after two weeks in the intensive care unit. The second and third patients had inadvertently been given a solution of lidocain that was too strong (10% instead of 1%). The presenting symptoms of systemic toxicity include numbness of the tongue, dizziness, tinnitus, visual disturbances, muscle spasms, convulsions, reduced consciousness, coma, and respiratory arrest. Physicians who use lidocain as a local anaesthetic should be aware of its systemic toxicity.

[The Montignac method: scientific foundation debatable]. / De methode-Montignac: wetenschappelijke onderbouwing aanvechtbaar.

Obesity is a major health issue in Western society. In the Netherlands every fifth person suffers from obesity and every third person is on a weight-reducing diet. The Montignac method is a very popular diet. The diet is claimed to be a nutritional science. The method is based on several hypotheses about the metabolism of carbohydrates and fatty acids: carbohydrates with a low glycaemic index are preferred, carbohydrates are not to be eaten in combination with fatty acids, fruit is propagated but must not be combined with other components. The scientific literature refutes the hypotheses of Montignac regarding the metabolic effects of carbohydrates and fatty acids. As a method to lose weight, the conventional recommendations of caloric restriction, less intake of saturated fatty acids and more physical activity should be preferred to the Montignac diet.