Background Approximately 1700 children per year with end-stage kidney disease undergo kidney transplantation in Europe and the United States of America; 30%-50% are living donor kidney transplantations. There may be immunological differences between paternal and maternal donors due to transplacental exchange of cells between the mother and fetus during pregnancy leading to microchimerism. We investigated whether the outcome of living-related kidney transplantation in young children is different after maternal compared with paternal organ donation. Methods Using the international Collaborative Transplant Study (CTS) database, we analyzed epidemiological data of 7247 children and adolescents aged In the recipient age group 1-4 years, the rate of treated rejection episodes in recipients of kidneys from maternal donors (N = 195) during the first 2 years post-transplant was significantly lower (hazard ratio HR = 0.47, p = .004) than in patients receiving kidneys from paternal donors (N = 179). This association between donor sex and risk of treated rejections was not observed in children aged 5-9 years. The 5-year death-censored graft survival in children aged 1-4 years with a maternal or paternal donor was comparable. Conclusions Maternal kidney donation in young pediatric renal transplant recipients is associated with an approximately 50% lower rate of treated rejection than paternal kidney donation. Whether this phenomenon is due to maternal microchimerism-induced donor-specific hyporesponsiveness must be evaluated in prospective mechanistic studies.

FoxP3 and Vav1 are known to be involved in the development of regulatory T cells. Two polymorphic sites in the FoxP3 promoter (rs3761548 and a (GT)(n)-dinucleotide repeat) and 2 single nucleotide polymorphisms in intron 1 of the Vav1 gene (rs2546133 and rs2617822) have been shown to correlate with gene expression levels. We investigated a potential impact of FoxP3 and Vav1 genetic variants on kidney allograft failure using samples and data of the Collaborative Transplant Study. A cohort of 384 kidney transplant patients was tested. We found no significant association of FoxP3 promoter rs3761548 or (GT)(n) repeat length with presumed immunological graft failure. The genotype frequencies of Vav1 intron polymorphisms did not significantly differ between patients with graft failure and matched controls.

Background. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) are important predictors of graft and patient survival in renal transplantation. Pulse pressure (PP), the difference between systolic and diastolic pressure, has been associated with cardiovascular and renal morbidity in nontransplant epidemiological studies and clinical trials. Methods. In this large retrospective analysis of prospectively collected data, transplant recipients from 1995 to 2015 were examined for patient and death-censored graft survival. Results. In 43 006 recipients, a higher 1-year PP was significantly associated with inferior 10-year patient and death-censored graft survival. In patients 60 years or older, SBP but not DBP was associated with 10-year survival, an effect that was pronounced in patients with a normal SBP of <140 mm Hg and an increased PP of 60 mm Hg or greater, highlighting the superior impact of PP on survival in elderly recipients. In recipients 60 years or older, higher PP was associated with increased mortality due to circulatory system diseases but not to infection or cancer. The combination of PP 60 mm Hg or greater and high SBP of 140 mm Hg or greater showed the strongest association with death-censored graft survival across all age groups. Conclusions. We found convincing evidence that PP 1-year posttransplant is predictive of patient survival, especially in elderly recipients with normal SBP. Combined analysis of SBP and PP showed that high PP confers additional predictive information for patient survival beyond that derived from analysis of SBP alone. With regard to prediction of death-censored graft survival, the combination of high SBP and high PP showed the best correlation across all age groups.

Complement-mediated humoral rejection has become the main focus of research in organ transplantation. The aim of this study was to investigate the possible association of the complement C5aR gene 450 C/T polymorphism in antibody-mediated renal allograft rejection. This polymorphism was investigated in 290 first deceased donor kidney graft recipients with well functioning grafts and no rejection treatment during the first transplant year (WFG), 265 recipients with graft failure within the first transplant year (F), and 187 healthy controls. Frequency of the 450 CT genotype was lower in the total population of 555 kidney recipients (4.7%) than in 187 healthy controls (8.6%), but the difference was not statistically significant (P = 0.065). A significantly higher frequency of CT genotype was found in F patients (CT: 6.8%) when compared to WFG patients (CT: 2.8%, P = 0.027). The CT genotype was also significantly lower in WFG patients than in healthy controls (P = 0.009). Low frequency of the C5aR 450 CT genotype, which apparently is a feature of certain kidney diseases, appears to be associated with good graft outcome in kidney transplantation and might be helpful for identifying recipients who are at low risk for graft rejection.

Renal transplantation represents the optimal treatment for most patients with end-stage renal failure. Although there has been an incremental reduction in the severity and frequency of acute T cell-mediated (cellular) rejection, acute and chronic antibody-mediated rejection (AMR) remain challenging 1, 2. The occurrence and severity of antibody-mediated pathology is variable, and it is likely that genetic polymorphisms that affect the magnitude of the B cell response and of the effector functions of antibody in the recipient give rise to such pathological variation. An additional unresolved challenge to long-term allograft survival is that of recipient death with a functioning graft. This occurs most frequently in the context of infection, malignancy or cardiovascular disease, all of which are influenced heavily by immunological factors. Many effector functions of antibody are mediated by a family of receptors (FcγRs) that are expressed on the majority of immune cells, including neutrophils, natural killer (NK) cells and B cells. The activating effects of immunoglobulin (Ig)G on these myeloid cells are controlled by a single inhibitory receptor, FcγRIIB (CD32B). FcγRIIB is also expressed by B cells and plasma cells, regulating B cell activation following encounter with immune-complexed antigen 3, 4. Thus, the inhibitory IgG receptor FcγRIIB plays a critical role in controlling both antibody generation and its immune activating and inflammatory effects. FcγRIIB-deficient mice are prone to inducible and spontaneous antibody-associated autoimmune disease 5, 6, but have heightened cytotoxic responses to tumours 7 and are protected from some infections 8, 9. In murine cardiac allograft models FcγRIIB had no effect on acute allograft rejection, but chronic arteriopathy and autoantibody production were increased in FcγRIIB-deficient recipients 10. In humans, a single nucleotide polymorphism (SNP, rs1050501) has been identified in the FCGR2B gene that encodes an amino acid substitution (a threonine for an isoleucine at position 232) within the transmembrane domain of the receptor. FcγRIIB-T232 is associated with receptor dysfunction 11, 12 and is found at increased frequency in patients with systemic lupus erythematosus (SLE) 13. The prevalence of this polymorphism shows considerable racial variation (7–13% of Africans are homozygous for FcγRIIB-T232 but only 1–2% of Caucasians 13), which may have arisen due to enhanced protective immune responses to some pathogens in FcγRIIB-T232 homozygotes 9, 11, 13. We sought to determine the effect of the FCGR2B SNP on outcomes in renal transplantation 14. The FCGR2B SNP rs1050501 was genotyped in three cohorts of renal transplant recipients enrolled into the Collaborative Transplant Study; cohort A comprised 2851 Caucasian patients; cohort B, 570 African Caribbean patients; and cohort C, 236 patients with a primary diagnosis of SLE to determine whether rs1050501 affected allograft or patient survival. In cohort A the frequency of FcγRIIB-T232 homozygotes was 2·2% and in cohort B was 6·8% (Table 1), consistent with published data for Caucasian and African control populations 13. In cohort A, the proportion of patients with a pre-transplant panel-reactive antibody (PRA) of > 10% was highest in the FcγRIIB-T/T232 genotype group (31·1%) versus 24·2 and 23·9% in the subjects with the FcγRIIB-T/I232 and FcγRIIB-I/I232 genotypes, respectively, but this did not reach statistical significance. The frequency of treatment for rejection was also highest in FcγRIIB-T/T232 patients [29% (Table 1)] but, again, this was not statistically significant. Death-censored allograft survival did not differ significantly between FCGR2B genotypes either at 1 year (93·6, 92·9 and 91·1% in those with FcγRIIB-T/T232, FcγRIIB-T/I232 and FcγRIIB-I/I232 genotypes, respectively), 5 years (79·2, 85·5 and 81·5%, respectively) or 10 years (73·8, 69·2 and 69·3%, respectively) post-transplant. Patient survival was similar in all FcγRIIB-I/T232 genotype groups (Table 1). In cohort B (African Caribbean transplant recipients) there was no significant difference in death-censored allograft survival, the frequency of treatment for rejection in the first year post-transplant or in patient survival between the individuals with different FCGR2B genotype (Table 1). There is an increasing appreciation that the deleterious effects of alloantibody on renal transplants may occur via complement-independent pathways, as evidenced by the existence of C4d-negative AMR. Such complement-independent effects would probably be mediated via FcγRs expressed on effector cells such as neutrophils and NK cells. Of note, FcγRIIB regulates IgG-mediated activation of neutrophils, a cell type observed within the capillaries of biopsies with AMR. There is also increasing evidence that donor-specific antibodies (DSAs) activate NK cells (presumably via activating FcγRs) causing chronic allograft pathology 15, 16. In this study we did not detect any statistically significant increase in early or late graft survival in individuals with the FCGR2B genotype associated with receptor dysfunction. This is in contrast to the murine data available 10, and emphasizes the limitations of mouse models and the importance of human studies to confirm the relevance of such experimental observations. It may also have implications for our understanding of the pathogenesis of chronic antibody-mediated graft damage; NK cells express only activating FcγR and do not normally express FcγRIIB. Therefore, although the de-functioning FCGR2B SNP would affect neutrophil, macrophage, dendritic and B cell activation, it would not normally influence NK cell-mediated allograft damage. Thus, our results support a role for NK cells in mediating the non-complement dependent effects of antibody on the allograft. There are a number of caveats worth noting when interpreting our data; a failure to detect an association between FCGR2B genotype and allograft or patient survival may be due to the fact that the effect size of this SNP is smaller than estimated by our power calculations, and therefore we were under-powered to detect any differences. Larger studies with an increased number of patients may reveal such associations. In addition, the phenotypical data available on this cohort did not include detailed information on humoral alloimmune responses, such as the development of donor-specific antibody post-transplant or the presence of transplant glomerulopathy on biopsy. Therefore, we cannot exclude that the FCGR2B genotype might affect more specific aspects of antibody-mediated alloimmunity. In summary, in two cohorts of Caucasian and African renal transplant recipients, we found no effect of FCGR2B genotype on pre-transplant PRA, acute rejection rates and graft function at 1 year, nor on 10-year transplant or patient survival. This work was supported by a Wellcome Trust Intermediate Fellowship (WT081020) to MRC, by a grant from the Roche Organ Transplant Research Fund, and by the National Institute for Health Research Cambridge Biomedical Research Centre. K. G. C. S. was funded by a Wellcome Trust (Program Grant Number 083650/Z/07/Z). M. R. C., R. M., B. D., L. W., G. O. and K. G. C. S. have no conflicts of interest to disclose.

Background. Recipient death is a leading cause for renal allograft loss. Cardiovascular mortality is the most important cause of death among this patient group. Single nucleotide polymorphisms (SNPs) in a noncoding region close to the CDKN2a/b senescence genes have been associated with higher cardiovascular morbidity and mortality in nontransplant populations.Methods. We selected 2064 renal transplant recipients: 688 with a known cardiovascular cause of death and 1376 matched controls. DNA specimens were genotyped for the three SNPs with known risk allele (rs10757274, rs2383206, and rs10757278) and one SNP without risk allele (rs518394). Genotyping results were analyzed according to the frequency of risk alleles in the two groups.Results. The risk allele for three SNPs was detected significantly more often in patients with a known cardiovascular cause of death than in matched controls (all P<0.05). Diabetes and time on dialysis were modifiers of this effect with the presence of high-risk alleles having a stronger impact in diabetic patients and those with longer dialysis time. There was no difference between groups for the investigated SNP without risk allele.Conclusions. Our results support data from large cohort studies in normal nontransplant populations, which suggested a higher risk for cardiovascular events in individuals carrying certain SNPs in senescence-associated genes. Notably, this finding was obtained in a population known to be at increased risk of cardiovascular death.

Background. Reliable markers for assessing the biological effect of immunosuppressive drugs and identification of transplant recipients at risk of developing rejection are not available. Methods. In a prospective multicenter study, we investigated whether posttransplant measurement of the T-cell activation marker soluble CD30 (sCD30) can be used for estimating the risk of graft loss in kidney transplant recipients. Pre- and posttransplant sera of 2322 adult deceased-donor kidney recipients were tested for serum sCD30 content using a commercial enzyme-linked immunosorbent assay. Results. sCD30 decreased posttransplant and reached a nadir on day 30. Patients with a high sCD30 of more than or equal to 40 U/mL on day 30 showed a subsequent graft survival rate after 3 years of 78.3±4.1%, significantly lower than the 90.3±1.0% rate in recipients with a low sCD30 on day 30 of less than 40 U/mL (log-rank P<0.001; Cox hazard ratio 2.02, P<0.001). Although an association was found between pre- and posttransplant sCD30 levels, patients with high sCD30 on posttransplant day 30 demonstrated significantly lower 3-year graft survival irrespective of the pretransplant level. Conclusions. Our data suggest that posttransplant measurement of sCD30 on day 30 is a predictor of subsequent graft loss in kidney transplant recipients and that sCD30 may potentially serve as an indicator for adjustment of immunosuppressive medication.

Süsal, C.; Mahmoud, K.; Ovens, J.; Ruhenstroth, A.; Döhler, B.; Scherer, S.; Opelz, G. Author Information

Renin-angiotensin system blockade retards the progression of diabetic and non-diabetic chronic kidney disease of the native kidneys. Though most patients suffer from a significant renal insufficiency (Chronic kidney disease stage III) and a concomitant heart disease after renal transplantation, there is Up to now no evidence supporting the use of inhibitors of the renin-angiotensin system in these patients. We wish to summarize the available evidence on the use of inhibitors of the renin-angiotensin system after renal transplantation. We specifically discuss potential beneficial as well as adverse effects of a renin-angiotensin system blockade. In addition, we review their influence on morphologic and biochemical markers as well as on renal function, graft and patient survival after renal transplantation.

The outcome of simultaneous pancreas–kidney (SPK) transplantation in type 1 diabetes has dramatically improved in recent years because of optimized surgical techniques and new immunosuppressive drug regimens. Normoglycemia is followed by stabilization or even regression of diabetic lesions, i.e., of heart and kidneys. However, these effects are only visible after more than five yr of normoglycemia (achieved by a functioning allograft). This is also a likely explanation for the conflicting results of studies that investigated patient or kidney graft survival in SPK transplantation compared to kidney transplantation alone. Most studies had too short follow‐up periods, i.e., less than five yr, to compare effectively different transplant strategies in patients with type 1 diabetes and therefore failed to discover a survival benefit in favor of simultaneously transplanted patients. Recent data now indicate that, with a longer follow‐up, there is an increasing survival benefit for simultaneously transplanted patients compared to patients who received a single kidney transplant. This is paralleled by the comparison of simultaneously transplanted patients to patients who received a single kidney transplant from a living donor. A survival benefit for the combined procedure was here visible after 10 yr of follow‐up. We give a short overview on SPK transplantation, with a focus on the effects of this procedure on diabetic complications as well as patient and kidney graft survival.

In hematopoietic stem cell transplantation (HSCT), disparities between recipients and donors for minor histocompatibility antigens (mHags) have been shown to be related to graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. We investigated the effect of mHag mismatches on kidney allograft survival. Out of 33 785 kidney transplants on which DNA and clinical data were available to the Collaborative Transplant Study (CTS), 702 recipient/donor pairs could be identified as HLA-A, -B and -DRB1 matched first transplants of Caucasian origin. These pairs were typed for genetic polymorphisms of the mHags HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1 and UGT2B17. Because mHags are presented in an HLA-restricted manner, only HLA-A*02 positive pairs were included in the analysis of HA-1, HA-2 and HA-8. Similarly, only HLA-A*01, HLA-B*44 and HLA-A*24 positive pairs were considered for the evaluation of HA-3, HB-1 and ACC-1, respectively, whereas UGT2B17 compatible transplants were assessed in HLA-A*29 and HLA-B*44 positive pairs. None of the mHag disparities showed a statistically significant effect on death-censored 5-year graft survival. This report represents the first large-scale study on the relevance of mHags in kidney transplantation.

Immunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplant-related AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selective proliferation of MMR-defective, azathioprine-resistant myeloid cells may contribute significantly to the development of AML/MDS in patients who have received organ transplants. Identifying azathioprine as a risk factor for AML/MDS suggests that discontinuing the use of azathioprine as an immunosuppressant might reduce the incidence of posttransplantation AML/MDS.