A new HLA allocation procedure of kidneys from deceased donors in the current era of immunosuppression.

INTRODUCTION: It has recently been proposed to replace the current Eurotransplant kidney allocation based primarily on mismatches (MM) at the 3 HLA loci by a simpler system based on full HLA-DR compatibility. The present study analyzes this system in the current era of immunosuppression. METHODS: From 1999 to 2012, 723 renal grafts were performed on 586 patients who were treated with a calcineurin inhibitor, mycophenolate mofetil, and in most cases antilymphocyte globulins. Four groups of HLA MM were compared: (A) A+B 2-4/DR 1-2 MM (n = 397), (B) A+B 2-4 MM/DR 0 MM (n = 106), (C) A+B 0-1 MM/DR 1-2 MM (n = 138), and (D) A+B 0-1/DR 0 MM (n = 82). RESULTS: Acute rejection episodes were less frequent during the first post-transplantation year in group D than in the other groups (P = .018). Patient survival was lower in group A than in the other groups (P = .008). Immunologic graft survival was higher in group D than in the other groups in univariate (P = .015) and multivariate analyses (P = .033; 96.4% vs 90.1% at 10 years). CONCLUSIONS: In the current era of immunosuppression, allocation of kidneys from deceased donors could be performed primarily according to full DR compatibility then to the best A+B matching, affording excellent graft outcome to most recipients.

Patient and graft outcome in current era of immunosuppression: a single centre pilot study.

OBJECTIVES: The present single centre study aims at analyzing the impact on renal allograft outcome of the important changes which occurred in the transplant population and immunosuppressive therapy during the last two decades. METHODS: From 2000 to 2013, 779 single kidney transplantations were performed on 635 patients who all received on an intent-to-treat basis steroids, a calcineurin inhibitor, mycophenolate mofetil and an induction therapy with either antithymocyte globulin or an antagonist directed to the interleukin (IL)-2 receptor. Uni- and multivariate analyses of patient and immunologic graft survival were conducted. RESULTS: The sole factor predicting patient survival is recipient's age: 10-year survival rates are 94·7, 81·6 and 57·9% for the <45, 45-60 and >60 years age groups, respectively (P<0·001). Peak (>50% panel reactive antibodies) anti-human leucocyte antigens (HLA) sensitization, cold ischaemia time and HLA-B and -DR mismatches (MM) influence graft outcome: at 10 years, the difference in 10-year survival rates is 5·9% between grafts from sensitized and not sensitized patients (90·9 vs 96·8%, P = 0·002), 3·8% between grafts with <18 and ≧18 hours cold ischaemia (96·6 vs 92·8%, P = 0·003), 7·3% between grafts with no MM and either B or DR MM versus those with B and DR MM (96·8 vs 89·5%, P = 0·002). CONCLUSION: In our single centre experience, graft survival was most strongly determined by HLA matching, offering excellent long term graft outcome to most patients.

Prognosis of HIV infected sub-Saharan patients on renal replacement therapy (RRT) in Brussels, Belgium: a single centre retrospective pilot study and review of the literature.

BACKGROUND: Few data exist documenting the survival experience of immigrated sub-Saharan patients infected by the human immunodeficiency virus (HIV) on renal replacement therapy (RRT). METHODS: This retrospective single centre pilot study includes 105 consecutive patients of sub-Saharan origin who started RRT in our unit, between January 1986 and April 2010. The aim was to analyse the characteristics and the survival rate on RRT of these patients. RESULTS: Out of 105 patients 81/105 (77%) were HIV-negative and 24/105(23%) were HIV-positive. HIV-positive patients were younger than HIV-negative patients and they were more often treated with peritoneal dialysis (PD) (21/24) than with haemodialysis (HD). Dialysis peritonitis was equally distributed between HIV-positive and HIV-negative patients. Because of opportunistic infections, duration of hospitalisation was longer for HIV-positive than for HIV-negative patients. In PD-treated patients, the number of hospitalisations tended to be greater in patients who experienced at least one peritonitis episode and the duration of hospitalisation also tended to be longer. The survival rate was better in patients younger than 50 years and in patients on HD, but was similar for both positive and negative HIV patients. CONCLUSIONS: To the best of our knowledge, these are the first data concerning patients who have emigrated from sub-Saharan Africa to Belgium, and who are on RTT. Their survival rate is better if they are younger than 50 years and on HD. As the majority of HIV patients were treated by PD in our center, a conclusion regarding survival on different dialysis modalities is not possible for this group of patients. Survival rates were similar for HIV-positive and HIV-negative patients despite longer duration of hospisalization for HIV-positive patients.

[Twenty-five years of calcineurin inhibitors use in kidney transplantation at Erasme Hospital]. / Vingt-cinq ans d'utilisation des inhibiteurs de la calcineurine en transplantation rénale à l'Hôpital Erasme.

The results and risk factors within a cohort of 1.380 renal allografts treated with a calcineurin inhibitor from 1983 to 2008 at Erasme Hospital were analyzed. Three groups corresponding to successive periods were compared: A, from 1983 to 1992 (n = 463); B, from 1993 to 2000 (n = 470); C, from 2001 to 2008 (n = 447). Patient's survival was lower during period C than during periods A and B (89 vs 85% at 8 years, P = 0,044), due to the recipients age. In contrast, graft survival raised gradually (64, 76 and 81% at 8 years for periods A, B and C respectively, P < 0,001). Several factors significantly influence graft survival: in decreasing order, they are the recipient's age (reduced risk of rejection with age), immunosuppressive protocol (superiority of mycophenolate mofetyl and induction with antibodies directed to the IL2 receptor), HLA sensitization, number of HLA-B+Dr mismatches between recipient and donor, and gender (opposite effects of recipient's and donor's gender). The permanent evaluation of results using multivariate analyses would allow to promptly adapt selection and therapeutic strategies within each transplantation center.

Thrombophilic factors do not predict outcomes in renal transplant recipients under prophylactic acetylsalicylic acid.

A cohort of recipients of renal transplant after 2000 (N=310) was prospectively screened on the day of transplantation and 1 month later for a panel of 11 thrombophilic factors to assess their effect on posttransplant outcomes. All patients received prophylactic acetylsalicylic acid, started before transplantation. The rate of thromboembolic events or acute rejection episodes during the first posttransplant year (primary composite endpoint) was 16.7% among patients free of thrombophilic factor (N=60) and 17.2% in those with >or=1 thrombophilic factor (N=250) (p>0.99). The incidence of the primary endpoint was similar among patients free of thrombophilic factors and those with >or=2 (N=135), or >or=3 (N=53) factors (16.3% and 15.1% respectively; p=1) and in patients who remained thrombophilic at 1 month (15.7%; p=0.84). None of the individual thrombophilic factor present at the day of transplantation was associated with the primary endpoint. The incidence of cardiovascular events at 1-year, serum creatinine at 1-year, 4-year actuarial graft and patient survival were not influenced by the presence of >or=1 thrombophilic factor at baseline (p=NS). In conclusion, the presence of thrombophilic factors does not influence thromboembolic events, acute rejection, graft or patient survival in patients transplanted after 2000 and receiving prophylactic acetylsalicylic acid.

[Experience about more than 2000 renal transplantations at the university of Brussels]. / A propos de 2000 greffes rénales a l'U.L.B.: le parcours d'un patient transplanté rénal en 2007.

Since 1965, more than 2000 renal transplantations (including more than 100 living-donor transplantations) have been performed at the University of Brussels. An end-stage renal disease patient candidate to renal transplantation will be therefore followed from his enrolment on the waiting list to the long-term post-transplant period. Improvement in the outcome of renal transplantation is achieved due to better knowledge in many fields of medicine, such as immunology, infectious disease, metabolic diseases (hyperlipemia, diabetes mellitus), pharmacology, use of immunosuppressive regimen, a more adequate cardiovascular prevention and treatment. If the best results were achieved with kidneys from living donors, the graft survival rate at the University of Brussels was nearly 80% for the last period (2000-2006). Unfortunately, renal transplantation cannot cure certain comorbid conditions and even may promote them: infectious diseases, neoplasia, metabolic disorders (e.a diabetes mellitus, hyperlipemia). Many efforts have to be done to develop less toxic and more immune selective therapeutic strategies. Living donation and extension of the pool of cadaveric donors will reduce the length of time spent on the waiting list and will significantly impact on mortality and morbidity after kidney transplantation.

Value of the MELD score for the assessment of pre- and post-liver transplantation survival.

The MELD score has now been implemented in the United States for liver allocation, but it has not been validated in Europe. Its association with posttransplant outcome is unclear. Optimal cutoff values of MELD and Child-Pugh scores to predict death on the liver waiting list were defined in a series of 137 cirrhotic patients listed for liver transplantation. Six-month actuarial survival while on the waiting list was 90% with a Child-Pugh <11 and MELD <17, whereas it decreased progressively to 40% at 6 months after listing for those having a Child-Pugh and MELD score >10 and >16. Analysis of a series of 112 patients (85 chronic liver disease and 27 hepatocellular carcinoma) revealed no change in MELD value at the time of transplantation compared to the score at the time of listing (mean +/- SD: 15.5 +/- 7.7 vs 15 +/- 5.8) with a mean waiting time of 118 days. Using either the optimal cutoff for MELD score (<17 or >16) or seven different strata (3 to 7, 8 to 10, 11 to 13, 14 to 16, 17 to 19, 20 to 22, 23 to 39), whether measured at listing or just before liver transplantation, there was no significant difference (chi(2) 4.97, P = .58) in survival: 82.7% and 63% at 6 and 60 months, overall. Our data confirm that the MELD score with only three parameters is as good as the Child-Pugh score to predict mortality on the Eurotransplant waiting list. The optimal cutoff to assess higher priority for the bad category is >16. There was no negative impact on short- or long-term prognosis of the bad categories of MELD.

[Update on the outcome of kidney transplantation at the Free University of Brussels]. / Actualisation des résultats de la transplantation rénale à l'Université libre de Bruxelles.

The present analysis shows that the results of renal transplantation at the "Université libre de Bruxelles" still have improved in recent years: patient and graft survival at 5 years has risen to 99% and 86% respectively during the 1995-1999 period. This progress is primarily related to the use of less deleterious and more potent immunosuppressants. However, graft failures due to causes other than rejection or patient's death remained unchanged. Among transplantations from living related donors, those from parents yield poorer results than those from children or from one-haploidentical brothers and sisters. Four factors influence cadaveric graft survival: immunosuppression, quality of the graft, donor's age and HLA compatibility, in decreasing order of statistical significance. The immunosuppressive protocols used since 1996 appear particularly promising: thanks to them, 3-year graft survival rate presently reaches 97%.

Persistent hyperparathyroidism requiring surgical treatment after kidney transplantation.

There are not many publications describing long-term follow-up of persistent hyperparathyroidism requiring surgical treatment after kidney transplantation (PHSKT). In some patients adenomas, rather than multiglandular disease, have been incriminated as the cause of PHSKT. We reviewed the charts of 45 patients followed for 12 to 146 months (median 45 months) after parathyroidectomy for PHSKT. We compared them with (1) those of 951 patients receiving a kidney graft during the same period but not submitted to parathyroidectomy or (2) 90 matched controls selected from this cohort to determine the characteristics of PHSKT patients. The duration of pretransplant dialysis was significantly longer in PHSKT patients than in controls (5.78 +/- 0.41 vs. 3.41 +/- 0.24 years; p < 0.0001). A total of 166 glands were removed or biopsied. Except for one questionable case, no true adenoma was observed even when only one gland was enlarged. The outcome of surgery was not influenced by the technique (subtotal parathyroidectomy versus total parathyroidectomy and autografting) but depended on the amount of resected parathyroid tissue: no failures and 4 cases of hypoparathyroidism in 34 cases with no missing gland at cervical exploration; 3 failures and no permanent hypoparathyroidism in 11 cases with one or two missing glands. Excision of the enlarged glands only was sufficient to cure the patient. No recurrence was observed. Our results suggest that single gland enlargement in PHSKT results in most cases from different rates of involution of the parathyroids after successful kidney transplantation. When fewer than four glands are discovered, resection of all visible glands with or without grafting corrects hypercalcemia in more than 70% of the cases.

Hypercholesterolemia is associated with increased kidney graft loss caused by chronic rejection in male patients with previous acute rejection.

BACKGROUND: Whereas acute rejection is the main risk factor for the occurrence of chronic rejection, mechanisms in addition to the donor-specific immune response probably contribute to late allograft failure. In this study, we investigated the possible role of hypercholesterolemia in the incidence of chronic kidney graft loss. METHODS: By using the actuarial method, we retrospectively analyzed the long-term loss of cadaveric kidney grafts in patients who had a functioning graft at 1 year and had received a transplant and undergone cyclosporin A therapy in our center between 1983 and 1997. RESULTS: As observed previously, patients with acute rejection during the 1st posttransplant year (n=198) had significantly higher actuarial graft loss at 10 years compared with those free of acute rejection (n=244). In patients free of acute rejection at 1 year, hypercholesterolemia (> or =250 mg/dl) had no impact on graft loss at 10 years. On the contrary, in patients with previous acute rejection, those with hypercholesterolemia (n=59) had a higher immunological (36.0% vs. 19.2%; P<0.01) and overall (50.0% vs. 25.3%; P<0.01) graft loss at 10 years compared with patients with serum cholesterol <250 mg/dl (n=139). Among patients with 1st year acute rejection, hypercholesterolemia was associated with a significant increase in graft loss in male but not in female recipients. Multivariate analysis confirmed that hypercholesterolemia was an independent risk factor for chronic graft loss in male patients (P<0.05). CONCLUSION: Hypercholesterolemia is an independent risk factor for kidney graft loss from chronic rejection in male patients with previous acute rejection. Correction of hypercholesterolemia could help to reduce kidney graft loss caused by chronic rejection in this category of patients.

Urothelial carcinoma associated with the use of a Chinese herb (Aristolochia fangchi)

BACKGROUND: Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. METHODS: The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. RESULTS: Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46 percent; 95 percent confidence interval, 29 to 62 percent): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. CONCLUSIONS: The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.

Male recipients of kidneys from female donors are at increased risk of graft loss from both rejection and technical failure.

The aim of the present retrospective study was to uncover the factor(s) responsible for the poor outcome of cadaver kidney grafts from female donors in male recipients. The 741 transplantations performed at our center from August 1983 to September 1997 were distributed into four groups according to recipient and donor gender: female donor to female recipient (F to F: n = 117), male donor to female recipient (M to F: n = 172), female donor to male recipient (F to M: n = 170), and male donor to male recipient (M to M: n = 282). All the patients received immunosuppressive therapy based on corticosteroids and cyclosporine, associated or not with either azathioprine or prophylactic anti-lymphocyte globulin. Overall graft survival was lower in the F to M group than in the three other groups (p = 0.009). Failures due to rejection were more frequent during the 1st post-transplant trimester in female than in male donor grafts, irrespective of recipient gender (p = 0.025). All failures due to technical problems occurred during the first 3 months post-transplantation: they were more frequent in the F to M group than in the three other groups (p = 0.040): this could be related to the older age of the donors in the former group. After the first post-transplant year, failures due to causes other than rejection remained low in the F to F group but increased steadily in the three other groups (p = 0.007). Specific survival rates were not correlated with the time-evolution of mean serum creatinine values, daily doses and trough levels of cyclosporine in the four groups of grafts. In conclusion, the poor outcome of F to M grafts results from combined immunologic and technical factors exerting their effects early in the course of transplantation.

One-month mortality rate after liver transplantation for parenchymal cirrhosis: analysis of risk factors in a ten year period.

Accurate prediction of short-term survival rate after liver transplantation is one way of selecting recipients and should improve organ allocation. We observed, during the first ten years of our program a striking decline in postoperative mortality with time, a well known observation in Europe as well as in the United States. In 65 adults with parenchymal cirrhosis having received a liver transplant between 1984 and 1994, we examined the possible influence of various preoperative risk factors on one-month mortality rate which was 13.8% in this series. Univariate analysis led to the identification of five significant risk factors: date of transplantation, low serum sodium, previous history of jaundice, ascites and encephalopathy. In the final multivariate analysis however, the date of transplantation emerged as the sole predictive factor of early mortality rate. Therefore, factors such as pretransplantation state of the patient and poor hepatic reserve are counterbalanced by the improvement of surgical skill and other technical aspects, as well as by better perioperative management which have all contributed to the improved results of liver transplantation with time.

Reactivation of hepatitis B after transplantation in patients with pre-existing anti-hepatitis B surface antigen antibodies: report on three cases and review of the literature.

BACKGROUND: Patients who have been exposed to the hepatitis B virus (HBV) and who were able to clear the hepatitis B surface antigen from the serum and to develop anti-hepatitis B surface antigen (anti-HBs) antibodies are not considered at risk for HBV reactivation after solid organ transplantation. METHODS AND RESULTS: We, however, observed three solid organ transplant recipients who demonstrated clinically significant HBV reactivation after transplantation. All patients presented normal liver enzymes and serological stigmates of healed HBV infection at the time of transplantation, as indicated by the absence of hepatitis B surface antigen and the presence of anti-HBs and anti-hepatitis B core antibodies in the serum. Patient 1, a renal transplant recipient, presented HBV reactivation 3 years after transplantation and developed chronic HBV hepatitis. Patient 2 developed HBV reactivation 7 months after a second cadaveric renal graft and died of cirrhosis four and a half years after transplantation. Patient 3, a heart-lung transplant recipient, developed HBV reactivation within months after transplantation, but died of unrelated causes. HBV reactivation in the presence of anti-HBs antibodies has been previously reported in other settings of immunosuppression, mainly in patients with acquired immunodeficiency syndrome and after bone marrow transplantation, and may lead to fatal liver disease. Data from our renal transplant recipients suggest that the incidence of HBV reactivation among patients with anti-HBs and anti-hepatitis B core antibodies is about 5%. CONCLUSIONS: Transplant physicians should be aware of the risk of HBV reactivation in patients presenting with healed HBV infection before transplantation.

Experience with the Wujciak-Opelz allocation system in a single center: an increase in HLA-DR mismatching and in early occurring acute rejection episodes.

The present single-center, retrospective study was undertaken to assess the impact of the Wujciak-Opelz allocation system (XCOMB), currently used within Eurotransplant for renal allografts, on the incidence of early occurring rejection episodes (RE). Implementation of the system resulted in an increase of HLA-DR mismatches (MM), while the incidence of HLA-A + B + DR MM remained unchanged. During the 1st post-transplant month, the total number of RE, expressed per patient-months, increased by 64% (0.326 vs 0.199, P = 0.007); when considering only severe and irreversible RE, the increase was 76% (0.158 vs 0.090, P = 0.011). In contrast, from the 2nd to the 12th post-transplant month, the incidence of RE, regardless of severity, was similar before and after implementation of XCOMB. As early occurring RE have detrimental effects on long-term graft outcome, these observations, if confirmed on a larger scale, would justify changes in the allocation algorithm.

Mycophenolate mofetil, together with cyclosporin A, prevents anti-OKT3 antibody response in kidney transplant recipients.

OKT3 monoclonal antibody, a murine IgG2a monoclonal antibody targeting the T cell CD3 antigen, elicits a neutralizing humoral response in 20 to 50% of kidney transplant recipients when the concomitant immunosuppression consists of CsA-Sandimmun (SAND) and azathioprine (AZA). In the present study, we investigated the impact of the newer agents, CsA-Neoral (NEO) and mycophenolate mofetil (MMF) on OKT3 sensitization. Sixty-two consecutive kidney transplant recipients received prophylactic OKT3 (5 mg/d) from days 0 to 13, together with steroids. Concomitant immunosuppression consisted of either AZA + SAND (n=20), AZA + NEO (n=31), or MMF + NEO (n=11). The following doses were used: AZA, 2 mg/kg per d from days 0 to 13, then 1 mg/kg per d; MMF, 2 g/d starting on day 1; and CsA, either SAND or NEO, 6 mg/kg per d from day 6. At least two serum samples per month were available during the initial 3 mo for each patient. IgG anti-OKT3 antibodies were first evaluated by enzyme-linked immunosorbent assay. Patients were considered sensitized if their serum scored positive at a dilution > or = 1/1000. Peak titers of IgG anti-OKT3 antibodies and the incidence of patients harboring neutralizing anti-idiotypic antibodies were also determined. A first reduction in OKT3 sensitization was seen in patients receiving Neoral instead of Sandimmun (AZA + SAND: 10 of 20 [50%] patients sensitized versus 6 of 31 [19%] in the AZA + NEO group; P=0.03). This was probably related to the achievement of higher mean CsA trough blood levels in the NEO group during the first month (253+/-44 versus 186+/-49 ng/ml in SAND patients). Peak antibody titers and the proportion of patients with anti-idiotypic antibodies were similar in the AZA + SAND and AZA + NEO groups. A further reduction in the sensitization rate was observed with the replacement of AZA by MMF (MMF + NEO: 0% sensitized patients; P=0.0013). It is concluded that the combination of CsA-Neoral and MMF efficiently prevents sensitization against OKT3.

A pilot trial of recombinant human interleukin-10 in kidney transplant recipients receiving OKT3 induction therapy.

BACKGROUND: We conducted a randomized, double-blind, placebo-controlled, rising single-dose study to investigate the effects of recombinant human (rh) interleukin (IL) 10 in renal transplant patients who received OKT3 as induction therapy. METHODS: Patients received 0.1 (n=6), 1 (n=6), or 10 microg/kg (n=3) rhIL-10 or placebo (n=6) intravenously 30 min before the first injection of 5 mg of OKT3. We monitored IL-10 serum levels, the effect of rhIL-10 on OKT3-induced cytokine production, clinical toxicity, and the incidence of immunization against OKT3. RESULTS: Serum IL-10 levels in the three experimental groups reached 0.8+/-0.2, 7.9+/-1.3, and 118.6+/-7.3 ng/ml (mean+/-SEM), respectively, 30 min after rhIL-10 injection. Peak plasma levels of tumor necrosis factor-alpha (TNF-alpha) were reduced from 2953+/-1599 pg/ml in patients injected with OKT3 and placebo to 447+/-155, 703+/-246, and 459+/-246 pg/ml in patients injected with 0.1, 1, and 10 microg/kg rhIL-10, respectively. Values for 24-hr TNF-alpha area under the curve decreased from 8988+/-3551 pg x hr/ml in control patients to 2284+/-494, 3950+/-955, and 2420+/-931 pg x hr/ml for the 0.1, 1, and 10 microg/kg rhIL-10 dose groups, respectively (P=0.045). There was also a trend toward reduced plasma levels of IL-2, IL-8, and interferon-gamma in rhIL-10-pretreated patients. Although none of the patients who received placebo or 0.1 or 1 microg/kg rhIL-10 developed an IgM antibody response directed against OKT3 during the first 10 days, this occurred in all three patients who received the highest rhIL-10 dose. In two of these patients, neutralization of OKT3 was associated with a reversible acute rejection episode. CONCLUSIONS: Pretreatment with doses of up to 1 microg/kg rhIL-10 is safe and reduces the release of TNF-alpha induced by OKT3. However, higher doses might promote early sensitization to OKT3.