Perioperative Minimal Induction Therapy: A Further Step toward More Effective Immunosuppression in Transplantation

Dual induction with low doses of rabbit anti-human thymoglobulin (RATG) and basiliximab effectively and safely prevented allograft rejection in high-risk renal transplant recipients. To assess whether treatment timing affects efficacy and tolerability, in this single-center, matched-cohort study, we compared posttransplant outcomes in 25 patients and 50 gender-, age-, and treatment-matched reference patients induced with the same course of 7 daily RATG infusions (0.5 mg/kg/day) started before or after engraftment, respectively. All subjects received basiliximab (20 mg) before and 4 days after transplantation, withdrew steroids within 6 days after surgery, and were maintained on steroid-free immunosuppression with cyclosporine and mycophenolate mofetil or azathioprine. Over 12 months after transplant, 1 patient (4%) and 13 reference patients (26%) had acute rejection episodes. One patient and 5 reference-patients required dialysis therapy because of delayed graft function. In all patients circulating CD4+ and CD8+ T lymphocytes were fully depleted before engraftment. Both treatments were well tolerated. In kidney transplantation, perioperative RATG infusion enhances the protective effect of low-dose RATG and basiliximab induction against graft rejection and delayed function, possibly because of more effective inhibition of early interactions between circulating T cells and graft antigens

Autologous Mesenchymal Stromal Cells and Kidney Transplantation: A Pilot Study of Safety and Clinical Feasibility

Background and objectives: Mesenchymal stromal cells (MSCs) abrogate alloimmune response in vitro, suggesting a novel cell-based approach in transplantation. Moving this concept toward clinical application in organ transplantation should be critically assessed. Design, setting, participants & measurements: A safety and clinical feasibility study (ClinicalTrials.gov, NCT00752479) of autologous MSC infusion was conducted in two recipients of kidneys from living-related donors. Patients were given T cell - depleting induction therapy and maintenance immunosuppression with cyclosporine and mycophenolate mofetil. On day 7 posttransplant, MSCs were administered intravenously. Clinical and immunomonitoring of MSC-treated patients was performed up to day 360 postsurgery. Results: Serum creatinine levels increased 7 to 14 days after cell infusion in both MSC-treated patients. A graft biopsy in patient 2 excluded acute graft rejection, but showed a focal inflammatory infiltrate, mostly granulocytes. In patient 1 protocol biopsy at 1-year posttransplant showed a normal graft. Both MSCtreated patients are in good health with stable graft function. A progressive increase of the percentage of CD4+CD25highFoxP3+CD127- Treg and a marked inhibition of memory CD45RO+RA-CD8+ T cell expansion were observed posttransplant. Patient T cells showed a profound reduction of CD8+ T cell activity. Conclusions: Findings from this study in the two patients show that MSC infusion in kidney transplant recipients is feasible, allows enlargement of Treg in the peripheral blood, and controls memory CD8+ T cell function. Future clinical trials with MSCs to look with the greatest care for unwanted side effects is advised

The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome

The copy number variation landscape of congenital anomalies of the kidney and urinary tract.

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome

The copy number variation landscape of congenital anomalies of the kidney and urinary tract

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome