In kidney transplant patients, alemtuzumab but not basiliximab/low-dose rabbit anti-thymocyte globulin induces B cell depletion and regeneration, which associates with a high incidence of de novo donor-specific anti-HLA antibody development.

In this single-center matched-cohort study, we evaluated the phenotype of repopulating B cells and its correlation with donor-specific anti-HLA Ab development and long-term graft function in 16 renal transplant recipients and 32 age- and gender-matched controls induced with alemtuzumab or basiliximab (Bas)/low-dose rabbit anti-thymocyte globulin (rATG), respectively. Alemtuzumab, but not Bas/rATG, profoundly depleted peripheral B cells in the first 2 mo posttransplantation. Early posttransplant, naive B cells were significantly depleted, whereas Ag-experienced and memory B cells were partially spared. Transitional B cells transiently increased 2 mo posttransplant. At month 6 posttransplant, pregerminal center B cells emerged, a process promoted by increased BAFF serum levels. Thereafter, B cell counts increased progressively, mainly due to expansion of naive B cells. Conversely, Bas/rATG did not modify the B cell phenotype throughout the follow-up period. Alemtuzumab was associated with a higher incidence of de novo DSA compared with Bas/rATG. DSA development was predicted by changes in the B cell compartment and correlated with worse long-term graft function. Thus, alemtuzumab-induced B cell depletion/reconstitution may promote chronic humoral responses against the graft.

Focal segmental glomerulosclerosis in children: multivariate analysis indicates that donor type does not alter recurrence risk.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS), the second leading cause of end stage renal disease in children, appears to be increasing. Moreover, posttransplantation FSGS recurrence is a major problem, and there is concern that children receiving kidneys from living donors (LD) have increased recurrence risk. METHODS: Data from the United Network for Organ Sharing from 1988 to 2008 were analyzed for number of de novo transplant recipients with a primary diagnosis of FSGS in children 1 to 20 years of age. Poisson regression was used for trend analysis. Univariate and multivariable logistic regression analyses were performed to examine the association of gender, race, human leukocyte antigen matching, age, and donor type with recurrence. RESULTS: Trend analysis of kidney transplantations for FSGS in children (n=2157) showed an increase in cases of 5.8% per year or 209% over 20 years (P<0.0001). Recurrence was reported in 327 (15%) cases overall, with a preponderance for white recipients (P<0.001) in younger age subgroups (P<0.01). Donor type was significant (P=0.02), with recurrence reported in 17% versus 14% of recipients of kidneys from LDs versus deceased donors. Using multivariate analysis, recipients' young age (P=0.02) and white race (P<0.001) were identified as significant risk factors for recurrence, whereas receiving a LD kidney became insignificant. CONCLUSIONS: FSGS as a cause of pediatric end-stage renal disease leading to transplantation is on the rise. FSGS recurrence is highest in young, white children, whereas receiving a LD kidney is not independently associated with increased risk of recurrence.

Verification of association of elevated serum IDO enzyme activity with acute rejection and low CD4-ATP levels with infection.

BACKGROUND: Both acute rejection (AR) and major infection events (MIE) can reduce long-term allograft survival. We assessed the simultaneous efficacy of serum and urine biomarker indoleamine 2,3-dioxygenase (IDO) enzyme activity and peripheral blood CD4-ATP levels for AR and MIE association, respectively. METHODS: We prospectively tested 217 blood and 167 urine serial samples, collected monthly for 12 months after transplantation from 29 consecutive children receiving a kidney transplant. The indoleamine 2,3-dioxygenase activity was assessed by mass spectrometry assays using the ratio of product L-kynurenine (kyn) to substrate tryptophan (trp). Kyn/trp ratios and blood CD4 T-cell ATP levels were correlated with AR, MIE, or stable group (no events) in the next 30 days. RESULTS: Using absolute cutoffs and allocating to samples to AR, MIE, or stable group, mean serum kyn/trp ratios were significantly elevated in the group that experienced AR (P=0.0007). Similarly, peripheral blood CD4-ATP levels were significantly lower in the group experiencing MIE (P=0.0351). Urine kyn/trp ratios and blood tacrolimus levels were not different between AR and stable groups. Within-subject analyses, accounting for repeated measures in subjects, also showed that, over time, serum kyn/trp ratios were higher before AR (P=0.031) and blood CD4-ATP levels were lower before MIE (P=0.008). CONCLUSIONS: These results from our pilot discovery group suggest that a panel of biomarkers together can predict overimmunosuppression or underimmunosuppression. Further independent validation in a multicenter cohort is suggested.

Tolerance induction: hematopoietic chimerism.

PURPOSE OF REVIEW: Although numerous experimental models to induce allograft tolerance have been reported, it has been difficult to translate these basic studies to clinical transplantation. However, successful induction of tolerance in HLA-mismatched kidney transplantation has recently been reported. In this review, recent progress in tolerance induction in preclinical (nonhuman primates) and clinical transplantation is summarized. RECENT FINDINGS: Among many clinical trials to induce renal allograft tolerance, success has so far been achieved only by combining donor bone marrow with organ transplantation. Induction of renal allograft tolerance by transient or durable mixed chimerism has been reported in HLA-matched or mismatched kidney transplant recipients. More recently, renal allograft tolerance by induction of full donor chimerism has also been reported using a more intensified preparative conditioning regimen. SUMMARY: Durable allograft tolerance has been achieved by induction of hematopoietic chimerism in clinical kidney transplantation, with outstanding long-term results in successful cases. However, these approaches have been associated with higher early complications than are seen following transplantation with conventional immunosuppression. Improvements in the consistency and safety of tolerance induction and extension of successful protocols to other organs will be the next steps in bringing tolerance to a wider range of clinical applications.

Biomarkers of tolerance.

PURPOSE OF REVIEW: As the induction and maintenance of donor-specific tolerance is a central aim in solid organ transplantation, it is essential that clinicians are able to identify and monitor tolerance accurately and reliably. This review highlights recent advances in defining sets of biomarkers in noninvasive samples that may guide minimization and withdrawal of immunosuppression in tolerant recipients. RECENT FINDINGS: Recent studies in liver and kidney transplant recipients have identified distinct biomarker profiles that are associated with operational tolerance. Although there is some heterogeneity in the findings of these studies, these have suggested novel cellular mechanisms for the development of tolerance. SUMMARY: Multiple platforms such as microarray gene expression analysis, flow cytometry, and immune cell functional assays have been used to discover and validate composite sets of biomarkers, which identify recipients with operational tolerance both in liver and kidney transplantation. These studies suggest that distinct cellular and molecular mechanisms lead to the development of tolerance in different transplanted organs. These putative biomarker profiles now need to be validated prospectively in trials of immunosuppression withdrawal and in novel approaches to induce transplant tolerance.

Physiological and therapeutic complement regulators in kidney transplantation.

PURPOSE OF REVIEW: This review will summarize the key contribution of complement regulators in the immune response to an allograft. RECENT FINDINGS: Over the past 10 years, compelling evidences have been accumulated in support of a critical role of complement in the pathological phenomena related to organ transplantation. In addition to recurrence of complement-mediated disease after graft, complement is involved in situations as diverse as brain death induced tissue damages, ischaemia-reperfusion and antibody-mediated rejections. This complement activation is counterbalanced by various regulatory mechanisms. SUMMARY: We discuss the role of physiological and therapeutic complement regulators that are designed to overcome the impact of complement overactivation with the aim of improving long-term transplant outcomes. We will focus primarily on renal allograft, but the discussed mechanisms take place to a different degree in any kind of organ transplantation.

Current role of human leukocyte antigen matching in kidney transplantation.

PURPOSE OF REVIEW: With graft survival rates steadily improving during the recent years, there is debate whether donor kidneys should still be allocated according to compatibility for human leukocyte antigens (HLA). RECENT FINDINGS: Recent studies argue for continued kidney exchange efforts for achieving better HLA compatibility. In this modern era of immunosuppression, better HLA matching is associated not only with better graft survival, but also with the administration of lower dosages of immunosuppressive agents, a lower incidence of side-effects of immunosuppression such as non-Hodgkin lymphoma, hip fractures, and death from infection, and a lower grade of sensitization if a patient has lost a kidney graft and is relisted for a retransplant. SUMMARY: Despite the overall improved graft survival rates in the recent years, the data continue to support organ sharing based on HLA matching in kidney transplantation.