Preemptive reduction of immunosuppression upon high urinary polyomavirus loads improves patient survival without affecting kidney graft function.

BACKGROUND: Polyomavirus (PV) is a major cause of kidney graft disease. Monitoring by polymerase chain reaction (PCR) on blood is currently recommended. In order to avoid irreversible lesions, we investigated the clinical impact of preemptive reduction of immunosuppression (IS) in kidney transplant recipients (KTR) upon detection of high urinary PV (Upv) load, including BK virus and JC virus. MATERIAL AND METHODS: From 2000 to 2011, in our single center, 789 consecutive KTR were distributed into 4 groups, according to the maximal Upv levels (by PCR) during the first year and the therapeutic option: (A) Upv <104 copies (cp)/mL (n=573), (B) ≥104 Upv <107 cp/mL (n=100), and (C) Upv ≥107 cp/mL (n=116); in group C, the IS drug doses were reduced in subgroup Ca (n=102) only, as 14 patients (subgroup Cb) were at risk for graft rejection. RESULTS: The preemptive reduction of IS (group Ca) increased patient survival as compared with all other groups (P<.05), did not modify graft function, and increased graft survival vs group A (risk ratio: 5.7, confidence interval: 1.8-18.1, P=.003). Differences for risk factors are as follows (groups Ca vs A): incidence of human leukocyte antigen (HLA) immunization (>5% panel reactive antibodies): 3% vs 8% (P=.05), number of HLA mismatches: 2.7 vs 2.5 (P=.049), and incidence of acute rejection: 9.8% vs 24.2% (P=.005). PV-associated nephropathy occurred only in group Ca (2% of total grafts) without effect on patient or graft outcome. CONCLUSION: The reduction of IS in patients with high Upv loads is beneficial for patient survival and does not affect graft survival or graft function.

Large decrease of anti-tetanus anatoxin and anti-pneumococcal antibodies at one year after renal transplantation.

AIMS: In kidney transplant recipients (KTR), antibody (Ab) synthesis is hampered by AZA and CsA. We here report in a prospective cohort study, the effects of mycophenolate mofetil (MMF) associated to a calcineurin inhibitor on plasma levels of anti-tetanus anatoxin Ab (TAnAb) and anti-pneumococcal Ab (PnPsAb). METHODS: Serum titers of the TAnAb and the PnPsAb against serotypes 14, 19F and 23F were measured in 94 KTR on Day 0 (T0) and 1 year (T12) after renal transplantation and in 49 healthy controls. RESULTS: 1) At T0, TAnAb were detected in only 71% of patients vs. 98% of controls (p < 0.0001) and the titers were significantly lower in KTR (1.46 UI/ml vs. 2.74 in controls, p = 0.01); they further decreased between T0 and T12 (1.46 UI/ml to 0.31, p < 0.0001). The calculated half-life (t1/2) of TAnAb was 7.7 months, as compared to more than 10 years in a normal population. 2) In KTR, PnPsAb titers decreased significantly between T0 and T12 (p < 0.005); the t1/2 of the different PnPsAb ranged from 9.2 to 11.9 months. CONCLUSIONS: In KTR treated by MMF and CNI, the TAnAbs and PnPsAbs titers decrease significantly and profoundly during the first year. Immunization pre-transplantation should be encouraged to maintain adequate post-transplant Abs levels.

Shipping donor kidneys within Eurotransplant: outcomes after renal transplantation in a single-centre cohort study.

BACKGROUND: Shipment of organs during the allocation process aims to improve human leucocyte antigen (HLA) matching but can also have a detrimental effect by prolonging cold ischaemia. The overall effect of organ exchange on post-transplant outcomes in the Eurotransplant (ET) region has not been investigated. METHODS: This is a retrospective single-centre cohort study to investigate the effect of shipment of renal allografts on cold ischaemia times and the incidence of acute rejection (AR) and graft survival in 661 transplantations of deceased donor kidneys. RESULTS: Forty-six per cent (N = 301) of the patients received a locally procured and 54% (N = 360) a shipped donor kidney. Locally procured donors tended to be older, more often hypertensive and had less frequently died from trauma. Recipients of shipped kidneys were at higher immunological risk, being younger, more frequently retransplanted and immunized against HLA antigens. Shipped kidneys had a 2.2-h prolongation of cold ischaemia time (18.0 versus 20.2 h; P < 0.0001) but significantly less HLA A, B and DR mismatches (2.20 versus 2.84; P < 0.0001). Recipients of shipped kidneys had an increased incidence of first-year AR [19 versus 13%; odds ratio 1.62 (1.06-2.49); P = 0.026] and death-censored graft loss [hazard ratio 1.6 (1.1-2.4); P = 0.01] that was no longer statistically significant after adjustments for risk factors by multivariable modelling. CONCLUSIONS: Shipment of kidneys in the ET region is associated with a modest increase in cold ischaemia time and significantly better HLA matching. This allows for successful transplantation of higher risk patients with no significant penalty with regard to AR rates or death-censored graft survival.

Thrombophilic factors in Stage V chronic kidney disease patients are largely corrected by renal transplantation.

BACKGROUND: The aim of our study was to evaluate the prevalence of acquired thrombophilic factors in Stage V chronic kidney disease (CKD) patients according to dialysis modality, the rate of correction of these factors 1 month after renal transplantation and their impact on cardiovascular or thromboembolic events at 1 year. METHODS: Three hundred and ten patients were prospectively screened for seven thrombophilic factors at transplantation; 215 of them were also assayed 1 month after. All the patients received prophylactic acetylsalicylic acid, started before transplantation. RESULTS: The prevalence of thrombophilic factors was significantly higher in patients under dialysis (n = 289) than in patients not yet on dialysis (n = 21) (74 versus 52.4%; P = 0.03) but was similar in haemodialysis and peritoneal dialysis patients (74.2 versus 73.2%). One month after transplantation, the global prevalence of thrombophilic factors had dropped from 74.4 to 44.7% (P < 0.001). Most thrombophilic factors had disappeared after transplantation: antithrombin deficiency: 13.5 versus 0.9%; P < 0.001, protein C deficiency: 12.1 versus 1.9%; P < 0.001, protein S deficiency: 3.7 versus 1.4%; P = 0.1, lupus anticoagulant: 37.7 versus 8.4%; P < 0.001 and antiphospholipid antibodies: 29.3 versus 12.6%; P < 0.001. The prevalence of activated protein C resistance, which reflects inherited factor V (FV) Leiden, was unchanged (1.9%), while the prevalence of elevated factor VIIIc increased from 20.9 to 30.7%, P < 0.001. The incidence of cardiovascular or thromboembolic events 1 year after transplantation was similar in patients with more than or equal to one thrombophilic factor at 1 month (5.2%) versus thrombophilic-free patients (6.7%). CONCLUSION: Acquired thrombophilic factors are highly prevalent among Stage V CKD patients. Most thrombophilic factors are corrected 1 month after transplantation.

Ineligibility for renal transplantation: prevalence, causes and survival in a consecutive cohort of 445 patients.

Little is known about the proportion of renal transplant candidates who are considered ineligible by the transplant center, the reasons of their ineligibility and their survival during dialysis. In this retrospective, single-center study of 445 adult patients referred between 2001 and 2006, 36 (8%) were deemed ineligible for medical contraindications. The leading reason was cardiovascular (CV) (75%), specifically aorto-iliac, and/or limb vessels atheromatosis or calcifications; ischemic heart disease; or a combination thereof. Nine patients had other contraindications that were absolute for three of them; six patients displayed a combination of relative contraindications. When compared to eligible patients (N = 409), those ineligible were significantly older (60 yr vs. 48), more often diabetics (50% vs. 15%), obese (39% vs. 17%) suffering from coronary artery disease (53% vs. 11%) and peripheral arterial disease (86% vs. 11%). Their primary nephropathy was more often diabetic and/or hypertensive/nephroangiosclerosis (61% vs. 23%), and their median dialysis vintage prior to evaluation was longer (29 months vs. 10, p < 0.0001). The actuarial survival of ineligible patients was significantly lower than that of eligible patients (at five yr: 53% vs. 88%). Adequate control of CV risk factors before dialysis and early referral for transplantation might help to improve eligibility of renal transplant candidates.

Cold ischemia is a major determinant of acute rejection and renal graft survival in the modern era of immunosuppression.

BACKGROUND: The aim of our study was to examine, in a recent cohort of kidney transplant recipients who have received modern immunosuppressive therapy, the respective role of cold ischemia time (CIT) and delayed graft function (DGF) on acute rejection (AR) rates and long-term graft survival. METHODS: We retrospectively reviewed the charts of 611 renal transplantations between 1996 and 2005. Most patients received a calcineurin inhibitor as maintenance therapy, either cyclosporine (43%) or tacrolimus (52%) and 76% of the patients received an antilymphocyte induction therapy. Study endpoints were DGF, first-year AR, and long-term graft survival. Uni- and multivariate analyses were performed to determine factors that may have influenced the study outcomes. RESULTS: DGF was observed in 16.2% of patients. Both older donor age and longer CIT were significant risk factors for DGF. DGF rates were similar whether patients received a calcineurin inhibitor before transplantation or not. AR occurred in 16.5% of grafts during the first year. Independent predictors of AR by multivariate analysis were duration of dialysis, CIT, current panel-reactive lymphocytotoxic antibody more than 5%, and the number of human leukocyte antigen-A, B, and DR mismatches. Each hour of cold ischemia increases the risk of rejection by 4%. With respect to death-censored graft survival, three pretransplant parameters emerged as independent predictors of graft loss: younger recipient age, peak panel-reactive lymphocytotoxic antibody more than 5% and longer CIT. The detrimental effect of CIT on graft survival was entirely because of its propensity to trigger AR. When AR was added to the multivariate Cox model, CIT was no longer significant whereas first-year AR became the most important predictor of graft loss (Hazards ratio, 4.6). CONCLUSION: Shortening CIT will help to decrease not only DGF rates but also AR incidence and hence graft loss. Patients with prolonged CIT should receive adequate immunosuppression, possibly with antilymphocyte preparations, to prevent AR occurrence.

HLA mismatches remain risk factors for acute kidney allograft rejection in patients receiving quadruple immunosuppression with anti-interleukin-2 receptor antibodies.

BACKGROUND: New immunosuppressive drugs such as anti-interleukin-2 receptor antibodies (aIL2R) and mycophenolate mofetil (MMF) have reduced the incidence of acute rejection after renal transplantation. Whether matching donor and recipient human leukocyte antigen (HLA) antigens is still relevant in patients receiving modern immunosuppression has been questioned. METHODS: We retrospectively analyzed the incidence and risk factors of acute rejection during the first posttransplant year and the impact of acute rejection on long-term graft survival in a cohort of 208 renal transplant patients treated with aIL2R (basiliximab, n=166; daclizumab, n=42), calcineurin inhibitors (tacrolimus, n=180; cyclosporin, n=28), mycophenolate mofetil, and steroids. Graft and patient survival were calculated by the Kaplan-Meier method. Risk factors for acute rejection were analyzed by logistic regression modeling. RESULTS: Twenty-seven patients were treated for acute rejection (26 biopsy-proven) during the first posttransplant year. The Kaplan-Meier estimate of first-year acute rejection was 13.2%. The number of HLA mismatches (odds ratio [OR] 1.65 per HLA mismatch) and long periods of dialysis before transplantation (OR 3.1 for more than 4 years of dialysis) were the only independent risk factors for first-year acute rejection. First-year acute rejection was associated with a significant reduction in overall and death-censored graft survival at 5 years after transplantation. CONCLUSIONS: Although infrequent in patients receiving modern immunosuppressive drugs, acute rejection remains an important risk factor for graft loss after renal transplantation. Our results suggest that better HLA matching and shorter periods of dialysis before transplantation could reduce acute rejection rates and further improve outcomes under current immunosuppressive regimens.

Outcome of patients with hepatocellular carcinoma listed for liver transplantation within the Eurotransplant allocation system.

Although hepatocellular carcinoma (HCC) has become a recognized indication for liver transplantation, the rules governing priority and access to the waiting list are not well defined. Patient- and tumor-related variables were evaluated in 226 patients listed primarily for HCC in Belgium, a region where the allocation system is patient-driven, priority being given to sicker patients, based on the Child-Turcotte-Pugh (CTP) score. Intention-to-treat and posttransplantation survival rates at 4 years were 56.5 and 66%, respectively, and overall HCC recurrence rate was 10%. The most significant predictors of failure to receive a transplant in due time were baseline CTP score equal to or above 9 (relative risk [RR] 4.1; confidence interval [CI]: 1.7-9.9) and alpha fetoprotein above 100 ng/mL (RR 3.0; CI: 1.2-7.1). Independent predictors of posttransplantation mortality were age equal to or above 50 years (RR 2.5; CI: 1.0-3.7) and United Network for Organ Sharing pathological tumor nodule metastasis above the Milan criteria (RR 2.1; CI: 1.0-5.9). Predictors of recurrence (10%) were alpha fetoprotein above 100 ng/mL (RR 3.2; CI:1.1-10) and vascular involvement of the tumor on the explant (RR 3.6; CI: 1.1-11.3). Assessing the value of the pretransplantation staging by imaging compared to explant pathology revealed 34% accuracy, absence of carcinoma in 8.3%, overstaging in 36.2%, and understaging in 10.4%. Allocation rules for HCC should consider not only tumor characteristics but also the degree of liver impairment. Patients older than 50 years with a stage above the Milan criteria at transplantation have a poorer prognosis after transplantation.

Delayed Graft Function in Kidney Transplants: Time Evolution, Role of Acute Rejection, Risk Factors, and Impact on Patient and Graft Outcome.

Background. Although numerous risk factors for delayed graft function (DGF) have been identified, the role of ischemia-reperfusion injury and acute rejection episodes (ARE) occurring during the DGF period is ill-defined and DGF impact on patient and graft outcome remains controversial. Methods. From 1983 to 2014, 1784 kidney-only transplantations from deceased donors were studied. Classical risk factors for DGF along with two novel ones, recipient's perioperative saline loading and residual diuresis, were analyzed by logistic regression and receiver operating characteristic (ROC) curves. Results. Along with other risk factors, absence of perioperative saline loading increases acute rejection incidence (OR = 1.9 [1.2-2.9]). Moreover, we observed two novel risk factors for DGF: patient's residual diuresis ≤500 mL/d (OR = 2.3 [1.6-3.5]) and absence of perioperative saline loading (OR = 3.3 [2.0-5.4]). Area under the curve of the ROC curve (0.77 [0.74-0.81]) shows an excellent discriminant power of our model, irrespective of rejection. DGF does not influence patient survival (P = 0.54). However, graft survival is decreased only when rejection was associated with DGF (P < 0.001). Conclusions. Perioperative saline loading efficiently prevents ischemia-reperfusion injury, which is the predominant factor inducing DGF. DGF per se has no influence on patient and graft outcome. Its incidence is currently close to 5% in our centre.

Lean non-alcoholic fatty liver disease (Lean-NAFLD): a major cause of cryptogenic liver disease.

AIMS: Non-alcoholic fatty liver disease (NAFLD) is strongly associated to obesity and type 2 diabetes, but may occur in the absence of these factors. Based on a large series of liver biopsies, we have evaluated the clinical, biochemical, metabolic and pathological characteristics of a new entity, which we refer to as "lean-NAFLD". METHODS: Among 1,777 patients, who underwent liver biopsy for chronic liver disease, Lean-NAFLD, defined as patients with NAFLD without obesity (BMI < 30 kg/m2) and without diabetes was found in 50 of them (2.8%), being the most frequent cause (38%) of cryptogenic liver disease. Thirty-one patients from the Lean-NAFLD group were compared to 48 Obese-NAFLD patients diagnosed during the same period and 8 healthy control patients. Insulin resistance was determined using the homeostasis model assessment method. RESULTS: In the Lean-NAFLD group as compared to the obese-NAFLD group, patients were younger : median 40 vs. 49 years, p = 0.047, with male predominance: 71 vs. 46%, p = 0.037. Fasting glucose and HbA1c were lower, as was insulin sensitivity: 1.7 vs. 3.0, p = 0.049. Blood pressure was significantly lower (p = 0.001) while triglycerides and HDL-cholesterol were similar. Although there was less inflammation (p = 0.038) and fibrosis (p = 0.029), non-alcoholic steatohepatitis and fibrosis were present in 61% and 55% of the Lean-NAFLD group, respectively. Compared to healthy controls, Lean-NAFLD were less insulin sensitive, with a insulin sensitivity index of 59 vs. 110 (p = 0.015), and more hypertriglyceridemic (p = 0.003). CONCLUSIONS: Lean-NAFLD is a new unrecognized clinicopathological entity, a frequent cause of cryptogenic liver disease.

Major histocompatibility complex class 1 chain-related antigen a antibodies: sensitizing events and impact on renal graft outcomes.

BACKGROUND: Major histocompatibility complex class 1 chain-related antigen A (MICA) antibodies (Abs) have been associated with renal graft loss in one large cohort. The triggering factors for MICA Abs and their autologous or allogeneic specificity have not been well defined. More data on the impact of MICA on renal grafts outcome are needed. METHODS: We tested sera from 494 controls and 597 patients with chronic kidney disease (CKD) for MICA using Luminex. Forty CKD MICA+ patients were genotyped for MICA alleles to determine their auto- or allospecificity. We compared MICA+ with MICA- renal transplant recipients with regard to acute rejection episodes and long-term survival. RESULTS: Blood transfusions, previous transplantation, and more than two pregnancies were independent risk factors for the presence of MICA Abs, as were CKD stage V status and male gender. Among the 40 genotyped patients, allo-Abs alone were present in 32 patients, both auto- and allo-Abs in 4 patients, and auto-Abs alone in 4 patients. When we compared MICA+ with MICA- patients, the incidence of acute rejection episodes during the first year (10.2% vs. 12.8%), as well as 1-year creatinine and proteinuria, were similar in both groups. At 10 years, actuarial patient (97.8% vs. 87.6%) and overall graft survival (76% vs. 72%) were similar between MICA+ and MICA- patients. CONCLUSIONS: In summary, (1) sensitizing events for MICA Abs are the same as for human leukocyte antigen Abs; (2) MICA Abs did not adversely affect renal graft outcomes in our cohort.

Progression rate of Chinese herb nephropathy: impact of Aristolochia fangchi ingested dose.

BACKGROUND: Renal failure after ingestion of Chinese herbs between 1990 and 1992 was related to the replacement of Stephania tetrandra by Aristolochia fangchi (ST-AF), containing nephrotoxic and carcinogenic aristolochic acids. However, the relationship between ST-AF and renal failure is still a matter of debate. We therefore tested the impact of the ST-AF ingested dose on the progression of renal function deterioration. METHODS: Analysis of medical charts and prescriptions between 1990 and 1992 was carried out to determine the presence of risk factors for kidney failure and the cumulative dose of pill components. Individual progression rate of renal impairment was studied by the time-course of the inverse of blood creatinine level (1/P(creat)). RESULTS: Patients were divided into an end-stage renal disease (ESRD) group (n=44) and a chronic renal failure (CRF) group (n=27) according to their P(creat) at the time of this study. The mean number of risk factors (+/-SD) was equally distributed within both groups (1.50+/-0.18 vs 1.59+/-0.17, P=0.74). Patients from the ESRD group ingested significantly higher cumulative doses of ST--AF (192+/-13.1 g vs 138+/- 16.3 g), Magnolia officinalis, (80.1+/-6.3 g vs 59.8+/-11.7 g), diethylpropion (14.7+/-1.4 g vs 10.0+/-1.4 g) and fenfluramine (14.1+/-1.6 g vs 8.7+/-1.3 g). In the ESRD group, some patients who had received steroids had a slower progression to ESRD than the others. In multiple regression analysis, ST-AF emerged as the only significant drug predicting the slope of the progression of renal failure. Moreover, hypothesizing a linear dose-response relationship, the risk of developing ESRD linearly increased with ST-AF doses. CONCLUSIONS: The relationship between the cumulative ST-AF dose and the renal failure progression rate confirms that regular ingestion of Aristolochia sp. extracts is causally involved in the onset of chronic interstitial nephropathy leading to ESRD.

Predictive models of short- and long-term survival in patients with nonbiliary cirrhosis.

The limited number of donor organs has placed a burden on the medical community to improve patient selection and timing of liver transplantation (LT). We aim to evaluate short- and long-term survival of 124 consecutive patients with a diagnosis of nonbiliary cirrhosis. Seventeen clinical, biochemical, functional, and hemodynamic parameters were computed. Patient survival was evaluated in the short term (3 months) by logistic regression, and the predictive power of the model was evaluated using receiver operating characteristic curves and the log likelihood ratio. For the long-term (up to 5 years) prognosis, the Cox proportional model was used. During follow-up, 54 patients died and 20 patients underwent LT. In the short-term study, the Model for End-Stage Liver Disease score (including bilirubin level, international normalized ratio [INR], and creatinine level) was as predictive as our score, which contained only two independent indicators (bilirubin and creatinine levels). In the long-term study, three independent variables (albumin level, INR, and creatinine level) emerged from the Cox model, and patients were classified into three survival-risk groups according to a prognostic index (PI): -1.039 x albumin (grams per deciliter) + 1.909 x log(e) INR + 1.207 x log(e) serum creatinine (milligrams per deciliter). Survival probabilities at 1 and 5 years were 89% and 80%, 63% and 52%, and 23% and 10% with a low, medium, and high PI, respectively. The validation study using the split-sample technique and data from independent patients confirmed that a high PI (>-2.5) identifies patients with a poor prognosis within 5 years. We thus have shown and validated that risk for death at the short and long term of patients with nonbiliary cirrhosis can be predicted with great accuracy using models containing a few simple and easily obtained objective variables, and these survival models are useful tools in clinical decision making, especially in deciding to list patients for LT and prioritization on the liver waiting list.

High prevalence of fenfluramine-related aortic regurgitation in women with end-stage renal disease secondary to Chinese herb nephropathy.

BACKGROUND: Non-controlled studies have noted a high prevalence of valvular regurgitation in patients with Chinese herb nephropathy; most of these patients had taken appetite suppressants. We aimed to determine the prevalence of valvular regurgitation and the role of appetite suppressants in patients with Chinese herb nephropathy. METHODS: This case-controlled echocardiographic study included 40 patients with end-stage renal failure due to Chinese herb nephropathy and 37 age-matched controls with end-stage renal disease due to nephropathy of other origin. Quantification of cumulative doses of appetite suppressants was performed. RESULTS: Aortic regurgitation was detected in 52.5% of patients with Chinese herb nephropathy, 72+/-1 months after stopping appetite suppressants, and in 21.6% of controls (P=0.009). No difference was found in the incidence of mitral or tricuspid regurgitation. A history of slimming medication was the only significant determinant for aortic regurgitation (P=0.009). Higher cumulative doses of Chinese herbs, (dex)fenfluramine and diethylpropion were observed in patients with Chinese herb nephropathy with, when compared to those without, aortic regurgitation. The dose-response relationship between the cumulative dose of drugs and the presence of aortic regurgitation was significant for fenfluramine only (chi-square=5.16, P=0.024). CONCLUSIONS: Six years after stopping appetite suppressants, aortic regurgitation remains highly prevalent among patients with end-stage Chinese herb nephropathy. The dose-related association with fenfluramine intake strongly confirms a determinant pathogenic role of anorectic drugs.

Aminopyrine breath test compared to the MELD and Child-Pugh scores for predicting mortality among cirrhotic patients awaiting liver transplantation.

Better tools for predicting the risk of death while awaiting transplantation are urgently needed because organ shortage is increasing the numbers on transplantation waiting lists. The aminopyrine breath test (ABT), model for end-stage liver disease (MELD), and Child-Pugh (C-P) score were compared as predictors of this risk in 137 cirrhotic candidates for liver transplantation. Eighty-three were transplanted within 3 months of registration, 35 others survived, 13 died before transplantation, and 6 were removed from the list. By univariate analysis, the continuous variables significantly associated with death while awaiting transplantation were: history of infected ascites, C-P score, ABT, and international normalized ratio or prothrombin time. Receiver operating characteristic curves for quantitative variables showed that the area under the curve was greatest for ABT (0.858 +/- 0.067). By Youden curve analysis, the best cut-off points for identifying cirrhotic patients at high risk of death while on the waiting list were: > 10, > 16, and < 0.7% for the C-P score, MELD score, and ABT, respectively. These results show that ABT is as good as the MELD and C-P scores, or better, as a predictor of death among cirrhotic patients awaiting liver transplantation.