Independent Predictor Of Graft Loss Research Articles

Analysis of FOXP3 Gene and Protein Expressions in Renal Allograft Biopsies and Their Association with Graft Outcomes

Background: The transcription factor FOXP3 is increased in acute renal rejection, but its influence on graft outcomes is unclear. This study correlated FOXP3 with dendritic cells and graft outcomes. Methods: We assessed 96 kidney transplants undergoing allograft biopsy for cause. FOXP3 mRNA was analyzed by real-time polymerase chain reaction (PCR) and FOXP3 protein and DCsCD83+ by immunohistochemistry. Graft function and survival were assessed at 5 years post-transplantation, as well as by independent predictors of graft loss. Results: Intragraft FOXP3 gene and protein expression were significantly correlated (r = 0.541, p < 0.001). Both FOXP3 mRNA and protein were increased in patients with acute rejection (AR). High expression of FOXP3 mRNA or protein in biopsies did not correlate with clinical variables, but there was a trend to higher positive variation in the glomerular filtration rate (GFR) from biopsy to last follow-up. Patients with FOXP3-mRNAhigh had more DCsCD83+ in biopsy, but these cells did not associate with AR. Five-year graft survival was not influenced by either FOXP3 mRNA or protein expressions. Conclusions: FOXP3 mRNA and protein had a good correlation in archival renal graft tissue. Increased FOXP3 expression was found in AR and FOXP3 associated with high numbers of DCs. However, both FOXP3 mRNA and protein was not associated with better allograft outcomes.

Concurrent Acute Cellular Rejection Is an Independent Risk Factor for Renal Allograft Failure in Patients With C4d-Positive Antibody-Mediated Rejection

Identification of risk factors for renal allograft failure after an episode of acute antibody-mediated rejection (AMR) may help the outcome of this difficult-to-treat complication. During December 2003 to February 2011, 833 kidney graft recipients underwent 1120 clinically indicated biopsies at our center. We reviewed the biopsy results and identified 87 biopsy specimens from 87 patients positive for the degradation product of complement component 4 (C4d) and acute AMR. We generated Kaplan-Meier survival curves and performed a multivariable analysis using the Cox proportional hazards regression model to identify risk factors for allograft failure after C4d+ acute AMR. Among the 87 patients, 26 had a diagnosis of acute AMR according to the Banff '09 classification schema, 29 had acute AMR and chronic active AMR, 18 had acute AMR and acute T-cell mediated rejection (TCMR), and 14 had acute AMR, chronic active AMR, and acute TCMR. Kaplan-Meier survival estimates showed that concurrent acute TCMR (P=0.001, Mantel-Cox log-rank test), concurrent chronic active AMR (P=0.03), and time to biopsy (P=0.04) are associated with graft survival. The Cox proportional hazards regression analysis identified that concurrent acute TCMR (hazard ratio, 2.59 [95% confidence interval, 1.21-5.55]; P=0.01) and estimated glomerular filtration rate (hazard ratio, 0.65 [95% confidence interval, 0.48-0.88]; P=0.01) are independent risk factors for allograft loss. Concurrent chronic active AMR or time to biopsy was not associated with graft failure by the multivariable Cox analysis. Our single-center study has elucidated that concurrent acute TCMR in kidney transplant recipients with C4d+ acute AMR is an independent risk factor for graft failure. Level of allograft function at the time of diagnosis was also an independent predictor of graft loss.

Outcomes of liver transplant recipients with hepatitis C and human immunodeficiency virus coinfection

Hepatitis C virus (HCV) is a controversial indication for liver transplantation (LT) in human immunodeficiency virus (HIV)-infected patients because of reportedly poor outcomes. This prospective, multicenter US cohort study compared patient and graft survival for 89 HCV/HIV-coinfected patients and 2 control groups: 235 HCV-monoinfected LT controls and all US transplant recipients who were 65 years old or older. The 3-year patient and graft survival rates were 60% [95% confidence interval (CI) = 47%-71%] and 53% (95% CI = 40%-64%) for the HCV/HIV patients and 79% (95% CI = 72%-84%) and 74% (95% CI = 66%-79%) for the HCV-infected recipients (P < 0.001 for both), and HIV infection was the only factor significantly associated with reduced patient and graft survival. Among the HCV/HIV patients, older donor age [hazard ratio (HR) = 1.3 per decade], combined kidney-liver transplantation (HR = 3.8), an anti-HCV-positive donor (HR = 2.5), and a body mass index < 21 kg/m(2) (HR = 3.2) were independent predictors of graft loss. For the patients without the last 3 factors, the patient and graft survival rates were similar to those for US LT recipients. The 3-year incidence of treated acute rejection was 1.6-fold higher for the HCV/HIV patients versus the HCV patients (39% versus 24%, log rank P = 0.02), but the cumulative rates of severe HCV disease at 3 years were not significantly different (29% versus 23%, P = 0.21). In conclusion, patient and graft survival rates are lower for HCV/HIV-coinfected LT patients versus HCV-monoinfected LT patients. Importantly, the rates of treated acute rejection (but not the rates of HCV disease severity) are significantly higher for HCV/HIV-coinfected recipients versus HCV-infected recipients. Our results indicate that HCV per se is not a contraindication to LT in HIV patients, but recipient and donor selection and the management of acute rejection strongly influence outcomes.

Conversion to sirolimus in pediatric renal transplant patients: A single‐center experience

We studied efficacy and safety of conversion from CNI- to SRL-based immunosuppression in 92 kidney TX recipients, mainly due to CAN (69%). Median time of conversion was 31 months (r: 0.3-165); median time of follow-up: 36 months (r: 2-102). In the whole group mean eGFR increased from 53 ± 22 to 67 ± 26mL/min/1.73 m(2) at three months (p = 0.02) and did not change subsequently. Patients with grade I CAN had higher eGFR than those with grade II CAN. Patient and graft survival was 96% and 70% 10 yr after conversion. Patients with grade I CAN had better graft survival than those with grade II CAN: 89% vs. 65% at six yr (p = 0.02) post conversion. There were two episodes of BPAR. Baseline proteinuria >20 mg/kg/day (HR: 10) and baseline eGFR <50 mL/min/1.73 m(2) (HR: 8) were independent predictors of graft loss. Sixty-seven of 92 subjects had ≥1 AEs: diarrhea (n = 52), urinary tract infections (n = 35), and lower respiratory tract infections (n = 12) were the most frequent. Patients with >2 AEs had SRL blood levels >9 ng/mL at month 3 (p = 0.01). In conclusion, patients converted from CNI to SRL had good graft survival and tolerable but frequent AEs. Independent predictors of graft loss were baseline proteinuria and eGFR.

Serum Phosphate Measured at 6 and 12 Months After Successful Kidney Transplant Is Independently Associated With Subsequent Graft Loss

Serum phosphate concentrations have been shown to predict graft loss in prevalent, but not incident, kidney transplant populations. The reasons for this are unknown. We investigated whether serum phosphate at 6 or 12 months posttransplant was associated with graft loss in the same cohort. Data were collected for 325 patients transplanted and followed up at a single center (1996-2004). The association between serum phosphate at 6 and 12 months posttransplant and graft failure was analyzed. Univariable associations with death-censored graft failure were seen for serum phosphate at 6 and 12 months (hazard ratio [HR] 1.33; 95% confidence interval [CI] 1.20-1.48; P < .001, and HR 1.40; CI 1.27-1.54; P < .001). On bivariable analysis (phosphate at 6 vs 12 mo), a significant association remained for both variables and increased graft failure rate (HR 1.19; CI 1.07-1.34; P = .002, and HR 1.37; CI 1.21-1.55; P < .001). These associations persisted in multivariable models (HR 1.27; CI 1.07-1.51; P = .007, and HR 1.34; CI 1.14-1.57; P < .001 for phosphate at 6 and 12 mo). Serum phosphate at 6 and 12 months posttransplant is an independent predictor of graft loss. Any future trial designed to investigate the benefits of phosphate lowering should consider recruiting patients as early as 6 months posttransplant.

Pre transplant serum magnesium level predicts outcome after pediatric living donor liver transplantation

Hypomagnesaemia is a frequent complication after liver transplantation (LTx) however; magnesium is not routinely replaced in the perioperative period. The incidence of hypomagnesaemia before and after pediatric LTx was studied in 673 pediatric patients who underwent living-donor liver transplantation (LDLT). The mean serum Mg levels before LTx was normal, 2.03 ± 0.28 mg/dl, exhibited marked decrease on 5th postoperative (PO) day, 1.79 ± 0.45, p<0.001, comparing with the pre-transplant value. It reached its nadir in the 1st PO month, p<0.001. Up to the 5th PO year, serum Mg did not achieve the lower limit of normal, 1.77 ± 0.24, p<0.001 and incidence of hypomagnesaemia was 60.7% (242/399). Univariate analyses of variables that can predict graft loss and patient death after LDLT demonstrated that recipient factors, pre and post transplant serum Mg and blood product transfusions were potentially risk factors significantly affected the outcome. Multivariate analysis of potential risk factors showed that pre transplant serum Mg <1.8 mg/dl, (Hazard ratio (HR) 2.362 [confidence interval (CI) 1.350-4.133]; p=0.003) and pre transplant BUN, (HR 1.046 [CI 1.014-1.079]; p=0.005) were independent predictors of graft loss and patient death. hypomagnesaemia is common before and after pediatric LDLT. Pre transplant hypomagnesaemia and high BUN are independent risk factors for graft loss or patient death. Pre transplant hypomagnesaemia patients exhibited decreased survival of their graft. Post transplant hypomagnesaemia was a potentially risk factor for graft loss.

Análise de 10 anos de seguimento de transplantesrenais com doador vivo não aparentado

In the current era of scarcity of kidneys available for transplantation, and chronic anti-HLA-mediated rejection as a main cause of graft loss, continuous demonstration of the long-term survival of grafts from living unrelated kidney donors (LURD) is paramount. Analyze long-term kidney graft and patient outcomes using LURD, and compare them with living related donors (LRD). We analyzed the 389 first renal transplantations performed with a living donor (281 LRD and 108 LURD), in a single center, from January 1998 through December 2007. There were no significant differences between LRD and LURD as refers to patient survival (89.1% vs. 84.7%, p = 0.40, respectively) and graft survival (81.1% vs. 68.9%, p = 0.77, respectively), 10 years post-transplantation. On Cox proportional regression model of multivariate analysis, panel reactive antibodies (PRA) > 10% and the occurrence of acute rejection in the first year posttransplantation were the only independent predictors of graft loss (HR 2.54, 95% CI 1.35 -4.78; p < 0.05 and HR 4.1, 95% CI 2.04 - 4.78; p < 0.05, respectively). LURD are an important source of organs for renal transplantation, with results similar to those obtained with LRD, regardless of HLA matching.

Extended criteria donors in liver transplant candidates with hepatorenal syndrome

Hepatorenal syndrome (HRS) is a complication of cirrhosis with a poor prognosis without transplantation. The aim of this study is to analyze the influence of extended criteria donors (ECD) on the postoperative outcome of recipients with HRS. The last 498 patients were divided according to pre-transplant type 1 or 2 HRS. Sixty-six (13.25%) recipients fulfilled HRS criteria. Three-month graft survival was 84% with at-listing recipient serum creatinine ranging from 0-0.8 mg/dL; 80% with s-creatinine = 0.9-1.5 mg/dL; 79% with s-creatinine = 1.6-2.5 mg/dL; and 58% with s-creatinine >2.6 mg/dL (log-rank = 18.039; p = 0.001). Recipients with HRS presented higher levels of pre-transplant creatinine and lower levels of sodium, more episodes of hemodialysis and ascitis, and higher model of end-stage liver disease-scores. Three-month graft survival in recipients with HRS relative to ECD-variables showed differences in univariate analysis according to graft steatosis (85% in absent steatosis = 0-10%; 78% in mild steatosis = 10-30%; 76% in moderate steatosis = 30-60%; and 49% when severe steatosis >60%; log-rank = 5.146; p = 0.023). Cox-proportional-hazard-model revealed that graft macrosteatosis per-30%-increments (p = 0.000; HR = 1.303 [1.24-1.33] per-30%-increment) and donors >65 yr (p = 0.089; HR = 1.622 [1.17-1.94]) were independent predictors of graft loss in recipients with HRS. In conclusion, the use of ECD in recipients with cirrhosis and HRS is a good option. However, grafts from moderate-to-severe steatosis and those from aged donors must be carefully allocated in candidates with HRS.

High risk of obstructive sleep apnea is a risk factor of death censored graft loss in kidney transplant recipients: An observational cohort study

Objectives Obstructive sleep apnea (OSA) is associated with increased risk of cardiovascular morbidity in the general population. The clinical significance of OSA among kidney transplant patients is unknown. Our aim was to investigate the association of “high risk of OSA” with death-censored graft loss and mortality in a large cohort of kidney transplant recipients. Patients and methods Using the Berlin questionnaire 1067 prevalent kidney transplant recipients were assessed for risk of OSA. Socio-demographic variables, laboratory parameters and data about graft loss and mortality were obtained from the medical records. Multivariable-adjusted associations of OSA risk with graft loss and with all-cause mortality was assessed in competing-risks regression models. Results Of the 823 patients who completed the Berlin questionnaire 28% had high risk of OSA (HRO) at baseline. Patients with HRO were older (52 ± 11 vs. 47 ± 13 years, p < 0.001), had a higher prevalence of diabetes (22 vs. 15%, p = 0.018), worse baseline kidney function (estimated glomerular filtration rate: 46 ± 18 vs. 51 ± 19 ml/min/1.73m 2, p = 0.001) and higher BMI (27 ± 5 vs. 24 ± 4 kg/m 2, p < 0.001). In multivariate models HRO was an independent predictor of graft loss among females after adjusting for age, comorbidity, hypertension, BMI, kidney function, duration of chronic kidney disease, other laboratory parameters and transplant-related data (HR = 3.05; CI: 1.24–7.51; p = 0.015), while HRO did not predict graft survival among males. HRO at baseline was not independently associated with all-cause mortality in the sample. Conclusion High risk of OSA is an independent predictor of graft loss among female kidney transplant patients.

Impact of body mass index on graft loss in normal and overweight patients: retrospective analysis of 206 renal transplants

Excess body mass is increasingly prevalent in transplant recipients. Currently, most investigators consider body mass index (BMI) a categorical variable, which assumes that all risk factors and transplant outcomes will be similar in all patients within the same category. We investigated the effect of categorical and continuous BMI increments on renal transplant outcome in normal weight (NW: BMI 18.5-24.9) and overweight (OW: BMI 25-30) patients. We retrospectively studied 206 patients. The mean BMI of our population was 24.3 ± 2.83 kg/m(2) . Patients of each group were similar regarding age, gender, time on dialysis, donor type, cold ischemia time, and number of HLA mismatches. The independent association of BMI with survival was determined using Cox multivariate regression. OW patients showed a higher prevalence of co-morbidities. In patients with graft loss, there was a higher incidence of delayed graft function, chronic allograft nephropathy, acute rejection, and hypertension. Graft survival was significantly lower in OW patients compared to NW patients upon Kaplan-Meier analysis (p = 0.008). In a multivariate Cox regression analysis, the initial BMI, evaluated as a continuous variable, remained an independent predictor of graft loss (hazard ratio 1.21, 95% CI 1.04-1.47). However, with patient stratification into World Health Organization BMI category and, further, into quartiles of initial BMI, no significant correlation between BMI category and graft loss was found. We suggest that increasing BMI value, although without categorical variation, may represent an independent risk factor for graft loss. Our retrospective analysis of a small sample population will require further studies to confirm these data.

Viral Endomyocardial Infection Is an Independent Predictor and Potentially Treatable Risk Factor for Graft Loss and Coronary Vasculopathy in Pediatric Cardiac Transplant Recipients

This study sought to evaluate the outcome and prevalence of viral endomyocardial infection after cardiac transplantation. Viral myocardial infection causes heart failure, but its role after cardiac transplantation is unclear. We hypothesized that viral infection of the cardiac allograft reduces graft survival. Between June 1999 and November 2004, 94 pediatric cardiac transplant patients were screened for the presence of viral genome in serial endomyocardial biopsies (EMBs) using polymerase chain reaction (PCR) assays. Graft loss, advanced transplant coronary artery disease (TCAD), and acute rejection (AR) were compared in the PCR-positive (n = 37) and PCR-negative (n = 57) groups, using time-dependent Kaplan-Meier and Cox regression analyses. From November 2002 to November 2004, intravenous immunoglobulin therapy (IVIG) was administered to patients with PCR-positive EMBs. The outcomes of the IVIG-treated, PCR-positive patients (n = 20) were compared with IVIG-untreated, PCR-positive patients (n = 17). Viral genomes were detected in EMBs from 37 (39%) patients; parvovirus B19, adenovirus, and Epstein-Barr virus (EBV) were the most common. The PCR-positive group (n = 37, 25% graft loss at 2.4 years) had decreased graft survival (p < 0.001) compared with the PCR-negative group (n = 57, 25% graft loss at 8.7 years) and developed advanced TCAD prematurely (p = 0.001). The number of AR episodes was similar in both groups. On multivariate analysis, presence of viral genome was an independent risk factor for graft loss (relative risk: 4.2, p = 0.015). The time to advanced TCAD after becoming PCR-positive was longer in the IVIG-treated patients (p = 0.03) with a trend toward improved graft survival (p = 0.06). Viral endomyocardial infection is an independent predictor of graft loss in pediatric cardiac transplant recipients. This effect appears to be mediated through premature development of advanced TCAD. IVIG therapy in this subgroup may improve survival and merits further investigation.

A molecular classifier for predicting future graft loss in late kidney transplant biopsies

Kidney transplant recipients that develop signs of renal dysfunction or proteinuria one or more years after transplantation are at considerable risk for progression to renal failure. To assess the kidney at this time, a "for-cause" biopsy is performed, but this provides little indication as to which recipients will go on to organ failure. In an attempt to identify molecules that could provide this information, we used microarrays to analyze gene expression in 105 for-cause biopsies taken between 1 and 31 years after transplantation. Using supervised principal components analysis, we derived a molecular classifier to predict graft loss. The genes associated with graft failure were related to tissue injury, epithelial dedifferentiation, matrix remodeling, and TGF-beta effects and showed little overlap with rejection-associated genes. We assigned a prognostic molecular risk score to each patient, identifying those at high or low risk for graft loss. The molecular risk score was correlated with interstitial fibrosis, tubular atrophy, tubulitis, interstitial inflammation, proteinuria, and glomerular filtration rate. In multivariate analysis, molecular risk score, peritubular capillary basement membrane multilayering, arteriolar hyalinosis, and proteinuria were independent predictors of graft loss. In an independent validation set, the molecular risk score was the only predictor of graft loss. Thus, the molecular risk score reflects active injury and is superior to either scarring or function in predicting graft failure.

Skin-Autofluorescence Is an Independent Predictor of Graft Loss in Renal Transplant Recipients

Skin-autofluorescence (skin-AF) noninvasively measures the tissue accumulation of advanced glycation end products (AGEs). AGEs are nephrotoxic and potential effectors of cardiovascular mortality. We investigated whether skin-AF predicted graft loss after kidney transplantation. A total of 302 renal transplant recipients were enrolled at a median time of 6.1 (2.6-12.1) years after transplantation and were subsequently followed up for first occurrence of graft loss (i.e., graft failure or all-cause mortality) for 5.2 (4.6-5.4) years. The association of baseline skin-AF with graft loss was investigated with univariable and multivariable Cox-regression and receiver-operator-characteristic curve analyses. Baseline skin-AF was 2.7+/-0.8 arbitrary units. Skin-AF predicted graft loss in a univariable Cox regression analysis (Hazard ratios 2.40 [1.75-3.29], P<0.001) and in a multivariable model (Hazard ratios 1.83 [1.22-2.75], P=0.003), adjusted for other identified risk-factors, including patient age, creatinine clearance, protein excretion, high sensitivity C-reactive protein (hsCRP), and human leukocyte antigen-DR mismatching. The area under the receiver-operator-characteristic curve for skin-AF as predictor of graft loss was significantly different from 0.5. Skin-AF was also a significant predictor of graft failure and mortality as separate end points. We conclude that skin-AF is an independent predictor of graft loss in kidney transplant recipients. Although skin-AF is not a direct measurement for AGEs, we believe that our results do support the hypothesis that accumulation of AGEs in renal transplant recipients contributes to the development of graft loss.

The First Year Renal Function as a Predictor of Long-Term Graft Survival After Kidney Transplantation

This study examined the impact of graft function at the end of the first year after kidney transplantation on long-term graft survival. We analyzed the roles of serum creatinine (Scr) and other variables as predictors of graft survival among 235 adult kidney transplant patients. The subjects were divided into 3 groups according to their Scr at the end of the first year: group 1, Scr < 100 μmol/L; group 2, 100 μmol/L ≤ Scr ≤ 150 μmol/L; and group 3, Scr >150 μmol/L. The annual rate of graft loss of 0.7% (95% confidence interval [CI], 0.63–0.77) in group 1, was lower than those in group 2 (2.1%; 95% CI, 2.02–2.18; P < .0001) and group 3 (6%; 5.74–6.26; P < .0001). Regression analysis showed the role of recipient age at the time of operation, and Scr level at the end of the first year to be independent predictors of graft loss. Graft survival was not influenced by any other studied parameter, including donor age, year of procedure, warm ischemia time, history of acute tubular necrosis, and occurrence of an acute rejection episode. We conclude that the 1-year Scr value predicts long-term renal graft survival, representing a simple, practical tool to identify recipients with an high risk for late graft failure.

Progression From Acute Kidney Injury to Chronic Kidney Disease: A Pediatric Perspective

Although emerging evidence indicates that the incidence of both acute kidney injury (AKI) and chronic kidney disease (CKD) in children is rising and the etiologies are dramatically changing, relatively little is currently known regarding the potential for transition from AKI to CKD. In both situations, early intervention can significantly improve the dismal prognosis. However, the lack of a uniform AKI definition and the paucity of early, predictive biomarkers have impaired our ability diagnose AKI early to institute potentially effective therapies in a timely manner. Fortunately, recent data has validated a multidimensional AKI classification system for children. In addition, the application of innovative technologies has identified candidates that are emerging as early biomarkers of both AKI and CKD. These include neutrophil gelatinase-associated lipocalin, liver-type fatty acid-binding protein, and kidney injury molecule-1. Studies to validate the sensitivity and specificity of these biomarkers in clinical samples from large cohorts and from multiple clinical situations are currently in progress, facilitated by the development of commercial tools for the reproducible measurement of these biomarkers across different laboratories.

Cold Ischemia is a Major Determinant of Acute Rejection and Renal Graft Survival in the Modern Era of Immunosuppression

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. 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. 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). 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.

High Urinary Excretion of Kidney Injury Molecule-1 Is an Independent Predictor of Graft Loss in Renal Transplant Recipients

Chronic transplant dysfunction is characterized by renal function decline and proteinuria. Kidney injury molecule (KIM)-1, a transmembrane tubular protein with unknown function, is undetectable in normal kidneys, but markedly induced after injury. Urinary KIM-1 excretion has been quantified as biomarker of renal damage. We prospectively studied whether urinary KIM-1 predicts graft loss, independent of renal function and proteinuria. Renal transplant recipients (n=145) visiting our outpatient clinic between August 2001 and July 2003 collected 24-hour urine samples for assessment of baseline urinary KIM-1 excretion (microsphere-based Luminex technology), and were followed for graft loss. Recipients participated at a median (interquartile range) of 6.0 (2.5-12.0) years posttransplant in baseline measurements. Follow-up beyond baseline was 4.0 (3.2-4.5) years. Urinary KIM-1 excretion was 0.72 (0.42-1.37) ng per 24 hours. Occurrence of graft loss increased over tertiles of KIM-1 excretion: 3 (6.3%), 11 (22.4%), and 17 cases (35.4%; P=0.001), respectively. High KIM-1 excretion was associated with proteinuria, low creatinine clearance, and high donor age (all P<0.01). In multivariate Cox regression analyses, prediction of graft loss by KIM-1 appeared independent of creatinine clearance, proteinuria, and donor age. Hazard ratios (95% CI) for the second and third tertile of KIM-1 excretion were 3.6 (0.9-13.5) and 5.1 (1.5-17.8) in the final model. Urinary excretion of KIM-1 is an independent predictor of long-term graft loss and therefore a promising new biomarker in early prediction of graft loss.

Impact of Graft Type on Outcome in Pediatric Liver Transplantation

To examine the outcome of technical variant liver transplant techniques relative to whole organ liver transplantation in pediatric liver transplant recipients. Technical variant liver transplant techniques comprising split, reduced, and live-donor liver transplantation evolved to address the need for timely and size appropriate grafts for pediatric recipients. Analysis of data from the Studies of Pediatric Liver Transplantation (SPLIT) registry, a multicenter database of 44 North American pediatric liver transplant programs. The outcome (morbidity and mortality) of each of the technical variants were compared with that of whole organ recipients. Data were available on 2192 transplant recipients (1183 whole, 261 split, 388 reduced, and 360 live donor). Recipients of all technical variant graft type were significantly younger than whole organ recipients, but on average spent 2.3 months less on the waiting list. Thirty-day post-transplant morbidity was increased for each type of technical variant relative to whole organ (45.1% whole, 66.7% split, 65.5% reduced, 51.9% live-donor). Biliary complications (30 day: 7.5% whole, 18.8% split, 16% reduced, 17.5% live-donor) and portal vein thrombosis (30 day: 3.6% whole, 8% split, 8% reduced, 7.5% live-donor) were more common in all technical variant types. Graft type was an independent predictor of graft loss (death or retransplantation) in a multivariate analysis. Split and reduced (relative risk = 1.74 and 1.77, respectively) grafts had a worse outcome when compared with whole organ recipients. Technical variant techniques expand the pediatric donor pool and reduce time from listing to transplant, but they are associated with increased morbidity and mortality.

Early Low‐Grade Proteinuria: Causes, Short‐Term Evolution and Long‐Term Consequences in Renal Transplantation

Proteinuria 1 year after transplantation is associated with poor renal outcome. It is unclear whether low-grade (<1 g/24 h) proteinuria earlier after transplantation and its short-term change affect long-term graft survival. The effects of proteinuria and its change on long-term graft survival were retrospectively assessed in 484 renal transplant recipients. One- and 3-month proteinuria correlated with donor age, donor cardiovascular death, prolonged cold and warm ischemia times and acute rejection. One- and 3-month proteinuria (per 0.1 g/24 h, hazard ratio (HR): 1.07 and 1.15, p<0.0001)-especially low-grade proteinuria (HR: 1.20 and 1.26, p<0.0001)-were powerful, independent predictors of graft loss. Its short-term reduction correlated with arterial pressure (AP) (the lower the 3-month diastolic and 12-month systolic AP, the lower the risk of increasing proteinuria during 1-3 months and 3-12 months periods, respectively: Odds ratio (OR) per 10 MmHg: 0.78, p=0.01 and 0.85, respectively, p=0.02), and was associated with decreased long-term graft loss (per 0.1 g/24 h: HR: 0.88 and 0.98, respectively, p<0.0001), independently of initial proteinuria. Early low-grade proteinuria due to pre-transplant renal lesions, ischemia-reperfusion and immunologic injuries is a potent predictor of graft loss. Short-term reduction in proteinuria is associated with improved long-term graft survival.

Hepatitis C Virus Infection and de Novo Glomerular Lesions in Renal Allografts

In the present study we examine whether hepatitis C virus (HCV) infection status influences glomerular pathologic findings in renal allografts and its effect on graft outcome. Renal allograft biopsies performed between January 1991 and June 1999 were considered. Exclusion criteria were insufficient sample, unknown HCV serological status at time of biopsy and final diagnosis of acute rejection. Light microscopy and immunofluorescence studies were performed on all biopsies. According to a predefined protocol, electron microscopy was carried out. Of 138 eligible renal allograft biopsies, 42 fulfilled at least one exclusion criterion. Of 96 biopsies selected for the study, 44 (45.8%) were from HCV-positive and 52 from HCV-negative recipients. Renal biopsy was performed 74 ± 55 and 60 ± 39 months after transplantation in HCV-positive and HCV-negative groups, respectively (p = 0.12). Of 44 HCV-positive biopsies, 20 (45.4%) showed membranoproliferative glomerulonephritis (MPGN) (16 type I and 4 type III). Conversely, in HCV-negative biopsies there were only three cases of MPGN (2 type I and 1 type III). De novo membranous GN (MGN) was diagnosed in 8/44 (18.2%) HCV-positive and in 4/52 (7.7%) HCV-negative cases. The prevalence of chronic transplant glomerulopathy was similar in HCV-positive and HCV-negative groups (11.4% and 11.5%, respectively). The prognosis of de novo GN (either MPGN or MGN) was worse in HCV-positive than in HCV-negative recipients (relative risk 4.89; 95% confidence interval, 1.15–20.69; p = 0.03). By multivariate analysis, HCV-positive serology infection was the only independent predictor of graft loss (relative risk 2.64; 95% confidence interval, 1.35–5.17; p = 0.005). In diagnostic renal allograft biopsies the presence of de novo immune-mediated glomerulonephritis, especially type I MPGN, is strongly associated with HCV infection and results in accelerated loss of the graft.