Mining the human urine proteome for monitoring renal transplant injury.

The human urinary proteome provides an assessment of kidney injury with specific biomarkers for different kidney injury phenotypes. In an effort to fully map and decipher changes in the urine proteome and peptidome after kidney transplantation, renal allograft biopsy matched urine samples were collected from 396 kidney transplant recipients. Centralized and blinded histology data from paired graft biopsies was used to classify urine samples into diagnostic categories of acute rejection, chronic allograft nephropathy, BK virus nephritis, and stable graft.

A Three-Gene Assay for Monitoring Immune Quiescence in Kidney Transplantation.

Organ transplant recipients face life-long immunosuppression and consequently are at high risk of comorbidities. Occasionally, kidney transplant recipients develop a state of targeted immune quiescence (operational tolerance) against an HLA-mismatched graft, allowing them to withdraw all immunosuppression and retain stable graft function while resuming immune responses to third-party antigens. Methods to better understand and monitor this state of alloimmune quiescence by transcriptional profiling may reveal a gene signature that identifies patients for whom immunosuppression could be titrated to reduce patient and graft morbidities.

The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study.

Background: Development of noninvasive molecular assays to improve disease diagnosis and patient monitoring is a critical need. In renal transplantation, acute rejection (AR) increases the risk for chronic graft injury and failure. Noninvasive diagnostic assays to improve current late and nonspecific diagnosis of rejection are needed.

A rapid noninvasive assay for the detection of renal transplant injury.

Background: The copy number of donor-derived cell-free DNA (dd-cfDNA) in blood correlates with acute rejection (AR) in heart transplantation. We analyzed urinary dd-cfDNA as a surrogate marker of kidney transplant injury.

Methods: Sixty-three biopsy-matched urine samples (41 stable and 22 allograft injury) were analyzed from female recipients of male donors for chromosome Y (donor)-specific dd-cfDNA.

The clinical impact of humoral immunity in pediatric renal transplantation.

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months.

Progressive histological damage in renal allografts is associated with expression of innate and adaptive immunity genes.

The degree of progressive chronic histological damage is associated with long-term renal allograft survival. In order to identify promising molecular targets for timely intervention, we examined renal allograft protocol and indication biopsies from 120 low-risk pediatric and adolescent recipients by whole-genome microarray expression profiling. In data-driven analysis, we found a highly regulated pattern of adaptive and innate immune gene expression that correlated with established or ongoing histological chronic injury, and also with development of future chronic histological damage, even in histologically pristine kidneys.

Pediatric kidney recipients with small capacity, defunctionalized urinary bladders receiving adult-sized kidney without prior bladder augmentation.

Background: Children with small capacity, defunctionalized urinary bladders present unique operative challenges. Thus, traditional practice has included pretransplant bladder augmentation, but this has several adverse consequences.

Methods: A single-institutional, retrospective review from January 1, 2004 to December 31, 2008 was conducted.

Efficacy and safety of thymoglobulin induction as an alternative approach for steroid-free maintenance immunosuppression in pediatric renal transplantation.

Background: Given the recent withdrawal of daclizumab (DAC), the safety and efficacy of thymoglobulin (TMG) was tested as an alternative induction agent for steroid-free (SF) immunosuppression in pediatric kidney transplant recipients.

Methods: Thirteen pediatric renal transplant recipients meeting defined high-risk criteria at transplantation were offered TMG induction and SF immunosuppression with maintenance mycophenolate mofetil and tacrolimus between October 2008 and January 2010. Patients were closely monitored at baseline, 3, 6, 9, and 12 months posttransplant for protocol biopsy and clinical outcomes.

Kidney transplantation at UCSF: 8,300 transplants and onward.

Overall, the kidney transplant experience at UCSF has been highly successful. The program has made significant contributions to the field of kidney transplantation with advancements in organ allocation, crossmatching, clinical trials, pediatric transplantation, organ preservation and transplantation in HIV-positive recipients, to name a few. The program was built on the shoulders of giants in kidney transplantation but continues to be innovative and bold and does not rely on past success to pave the future.

Steroid-free immunosuppression in pediatric renal transplantation: rationale for and [corrected] outcomes following conversion to steroid based therapy.

Background: Short-term outcomes using steroid-free immunosuppression after renal transplantation have been promising. No studies have examined the incidence of and reasons for steroid-avoidance protocol failures.

Methods: We present a single-center analysis of steroid-free immunosuppression failures among 129 pediatric renal transplant recipients with mean follow-up of 5 years.

Expression of complement components differs between kidney allografts from living and deceased donors.

A disparity remains between graft survival of renal allografts from deceased donors and from living donors. A better understanding of the molecular mechanisms that underlie this disparity may allow the development of targeted therapies to enhance graft survival. Here, we used microarrays to examine whole genome expression profiles using tissue from 53 human renal allograft protocol biopsies obtained both at implantation and after transplantation.

Standardizing resistive indices in healthy pediatric transplant recipients of adult-sized kidneys.

Small pediatric recipients of an adult-sized kidney have insufficient renal blood flow early after transplantation, with secondary chronic hypoperfusion and irreversible histological damage of the tubulo-interstitial compartment. It is unknown whether this is reflected by renal resistive indices. We measured renal graft resistive indices and volumes of 47 healthy pediatric kidney transplant recipients of an adult-sized kidney in a prospective study for six months post-transplant.

Extended daclizumab monotherapy for rejection-free survival in non-adherent adolescent recipients of renal allografts.

Acute rejection episodes are almost inevitable in the face of immunosuppression non-adherence and a known risk factor for developing chronic allograft nephropathy and accelerated graft loss. Daclizumab, a humanized monoclonal antibody directed against the alpha chain of the IL-2 receptor, is an important advance for induction therapy in renal transplant immunosuppression, reducing early acute graft rejection without affecting the tolerability of standard immunosuppression, for both steroid-based and steroid-free immunosuppressive protocols, in children and adults. In the absence of depot immunosuppression for maintenance therapy, we explored extended daclizumab therapy as temporary maintenance immunosuppression for acute rejection prophylaxis in two patients with recalcitrant immunosuppression non-adherence.

Renal transplantation in children with thrombosis of the inferior vena cava requires careful assessment and planning.

Children with end-stage renal disease and inferior vena cava (IVC) thrombosis are rare, and their condition is complex and high risk for renal transplantation. Detailed imaging studies of the recipient's abdominal vasculature should be carried out prior to transplantation, followed by careful pre-operative joint planning by the pediatric transplant surgeon and nephrologist. Critical decisions need to be made as to whether a deceased child's kidney or an adult-sized kidney is to be used, and if the latter, whether it should be from a deceased or living donor.

Patient selection critical for calcineurin inhibitor withdrawal in pediatric kidney transplantation.

CNI withdrawal may be employed as a "rescue" strategy for patients with established renal allograft injury and/or declining allograft function, with the aim at eliminating CNI-associated nephrotoxic effects. This analysis reviews outcomes in a pediatric population and identifies risk factors for adverse events post-CNI withdrawal. We performed a retrospective analysis of 17 pediatric renal transplants who underwent CNI withdrawal, with conversion to sirolimus and MMF.

Characterization of intra-graft B cells during renal allograft rejection.

Intra-graft CD20(+) B-cell clusters are found during acute rejection of renal allografts and correlate with graft recovery following rejection injury. Here using archived kidney tissue we conducted immunohistochemical studies to measure specific subsets of pathogenic B cells during graft rejection. Cluster-forming CD20(+) B cells in the rejected graft are likely derived from the recipient and are composed of mature B cells.

Maturation of dose-corrected tacrolimus predose trough levels in pediatric kidney allograft recipients.

Background: In contrast to adult kidney recipients, in whom the long-term evolution and clinical determinants of tacrolimus pharmacokinetics are well studied, less is known about the long-term evolution of tacrolimus pharmacokinetics in pediatric kidney transplant recipients.

Methods: One-hundred and five pediatric recipients of a kidney allograft, all treated with a corticosteroid-free immunosuppressive protocol, were included. The evolution of tacrolimus doses and predose trough (C0) levels was recorded at 3, 6, 9, 12, 18, and 24 months after transplantation, as well as all C0 levels obtained in the first 2 years after transplantation.

Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance.

Long-term allograft survival generally requires lifelong immunosuppression (IS). Rarely, recipients display spontaneous "operational tolerance" with stable graft function in the absence of IS. The lack of biological markers of this phenomenon precludes identification of potentially tolerant patients in which IS could be tapered and hinders the development of new tolerance-inducing strategies.

Transplant reno-vascular stenoses associated with early erythropoietin use.

Background And Objectives: This report describes an unusual presentation of severe hypertension (HTN) in a subset of pediatric kidney recipients treated with a steroid avoidance pediatric renal transplantation protocol. The HTN was secondary to atypical, reno-vascular abnormalities (RVA) of the transplanted vasculature, temporally associated with erythropoietin (EPO) use.

Design, Setting, Participants, And Measurements: To investigate the clinical significance underlying this event, a retrospective clinical study of 100 pediatric renal transplants was undertaken (50 steroid-free and 50 matched steroid-based controls), with peripheral blood transcriptional analysis of four RVA patients and controls.

A novel, semiquantitative, clinically correlated calcineurin inhibitor toxicity score for renal allograft biopsies.

Calcineurin inhibitor toxicity (CNIT) is an important cause of chronic allograft nephropathy (CAN), but clinically relevant, diagnostic pathologic criteria remain to be defined. A semiquantitative, clinically correlative CNIT scoring system was developed and validated by pathologic analyses of 254 renal transplant biopsies that were obtained from 50 consecutive pediatric renal transplant recipients. Differentially weighted pathologic criteria (glomerulosclerosis, tubular atrophy, arteriolar medial hyaline, and tubular isometric vacuolization) contributed to the composite CNIT model score.

Optimizing outcomes for neonatal ARPKD.

A retrospective analysis was conducted on 10 consecutive cases of neonatal ARPKD, 9 of whom received kidney transplants (KT). All were diagnosed antenatally (n = 6) or at birth. In the first month of life 70% required ventilatory support.

Subclinical cytomegalovirus and Epstein-Barr virus viremia are associated with adverse outcomes in pediatric renal transplantation.

Post-transplant clinical disease with cytomegalovirus (CMV) and Epstein-Barr virus (EBV) is a known risk factor for graft dysfunction and lymphoproliferation. We postulate that subclinical, asymptomatic viremia also adversely impacts outcomes, and may warrant re-assessment of current monitoring and antiviral prophylaxis protocols. A single-center study was conducted on 102 pediatric (51 steroid-free and 51 matched steroid-based historical controls).

Successful renal transplantation in high-risk small children with a completely thrombosed inferior vena cava.

Background: Inferior vena cava (IVC) thrombosis is generally a contraindication to renal transplantation in small children because of the technical difficulty and limitations in allograft venous outflow drainage that risk graft thrombosis.

Methods: The records of six consecutive children (9.9-27.