Judith A. Kal-van Gestel

High pretransplant parathyroid hormone levels increase the risk for graft failure after renal transplantation

Background. Calcium (Ca), phosphate (P), and parathyroid hormone (PTH) are important variables influencing the risk for cardiovascular disease in dialysis patients. We studied the influence of long-standing Ca-P disregulation on renal transplant survival. Methods. Pretransplant PTH, Ca, P, total protein (TP), albumin, and alkaline phosphatase (AP) values were gathered in all 407 patients that received a renal transplant in our center between January 1, 2000 and July 1, 2004. Other variables expected to influence the risks were included. Results. In the Cox proportional hazards analysis the risk for graft failure censored for death was significantly influenced by pretransplant PTH concentration (P=0.008) and donor type (P<0.001). The influence of PTH on the risk for patient death was not significant. The risk for acute rejection was studied but PTH level did not have a significant influence on this risk (P=0.055). The risk for delayed graft function was not influenced by PTH level. Conclusion. Serum PTH levels have an independent influence on the risk for graft failure censored for death. Efforts to improve calcium-phosphate-PTH homeostasis in patients on the waiting list for renal transplantation should be encouraged also to improve graft survival.

15-year follow-up of a multicenter, randomized, calcineurin inhibitor withdrawal study in kidney transplantation

Background Calcineurin inhibitors (CNIs) are essential immunosuppressive drugs after renal transplantation. Because of nephrotoxicity, withdrawal has been a challenge since their introduction. Methods A randomized multicenter trial included 212 kidney patients transplanted between 1997 and 1999. All patients were initially treated with mycophenolate mofetil (MMF), cyclosporine A (CsA), and prednisone (pred). At 6 months after transplantation, 63 patients were randomized for MMF/pred, 76 for MMF/CsA, and 73 for MMF/CsA/pred. Within 18 months after randomization 23 patients experienced a rejection episode: MMF/pred (27.0%), MMF/CsA (6.8%) and MMF/CsA/pred (1.4%) (P<0.001). Results During 15 years of follow-up, 73 patients died with a functioning graft, and 43 patients lost their graft. Ninety-six were alive with a functioning graft. Intention-to-treat analysis did not show a significant difference in patient and graft survival. In multivariate analysis, death-censored graft survival was significantly associated with serum creatinine at 6 months after transplantation and maximum PRA but not with the randomization group. CNI withdrawal did not result in a reduced incidence of or death by malignancy or cardiovascular disease. Death-censored graft survival was significantly worse in those patients randomized for CNI withdrawal that had to be reverted to CNI. Independent of randomization group, compared with no rejection, death-censored graft survival was significantly worse in 23 patients with acute rejection after randomization. Conclusion Fifteen years after conversion to a CNI free regimen, there was no benefit regarding graft and patient survival or regarding prevalence of or death by comorbidities. However, rejection shortly after CNI withdrawal was associated with decreased graft survival.

Ethnically diverse populations and their participation in living kidney donation programs

Background. The number of living donor kidney transplantations increases steeply in Europeans, whereas the non-Europeans are dependent on deceased donor transplantations. We wondered whether a low attendance or a high decline of potential non-European donors could explain this difference. Methods. This retrospective study includes all 1059 potential living kidney donors who attended our pretransplant clinic between 2000 and 2007. Potential donors were divided according to eight countries of origin: African, Dutch Antillean, European, Indonesian, Moroccan, Surinamese, Turkish, and various countries. In addition to direct living donation, alternative living donation programs are operational in our center: kidney exchange, domino paired, ABO incompatible, and anonymous donation. Results. European donors predominated in both the potential (79%) and the actual donor populations (85%). Actual donors comprised 39% of non-European and 59% of the European potential donors (P<0.001). Participation in alternative donation programs is significantly less among non-European donors in comparison with European donors (3.6% vs. 12.6%, P<0.001). In all non-European populations, genetically related donors predominated, whereas genetically related and unrelated donors were equally represented in the European potential donor population (P<0.001). Partners were under-represented in all non-European populations (P<0.001). The attitude and behavior of non-Europeans with the longest duration of stay in the Netherlands were closest to that of the Europeans. The population with the shortest stay differed the most. This could possibly be attributed to integration. Conclusion. There are less non-European donors than expected based on the population composition. Living donor characteristics are different between Europeans and non-Europeans. The reasons for the difference deserve investigation.

Accumulation of unfavorable clinical and socioeconomic factors precludes living donor kidney transplantation

Background. In the past 30 years, the number of living donor kidney transplantations has increased considerably and nowadays outnumbers the deceased donor transplantations in our center. We investigated which socioeconomic and clinical factors influence who undergoes living or deceased donor kidney transplantation. Methods. This retrospective study included all 1338 patients who received a kidney transplant between 2000 and 2011 in the Erasmus MC Rotterdam. Clinical and socioeconomic variables were combined in our study. Clinical variables were recipient age, gender, ethnicity, original disease, retransplants, ABO blood type, panel-reactive antibody, previous treatment, and transplantation year. Each recipients postcode was linked to a postcode area information data base, to extract demographic information on urbanization level, percentage non-Europeans in the area, income, and housing value. Chi-square, analysis of variance, and univariate and multivariate logistic regression analyses were performed. Results. There were significant differences between the recipients of a living versus deceased donor kidney transplantation. In multivariate logistic regression analyses, 10 variables had a significant influence on the chance of receiving living donor kidney transplantation. Clinical and socioeconomic factors had an independent influence on this chance. Patients with ABO blood type O and B have smaller chances. Highly sensitized and elderly patients have smaller chances especially when combined with a collection of other unfavorable factors. Accumulation of unfavorable factors in non-Europeans prevents their participation in living donation programs. Conclusion. Both clinical and socioeconomic factors are associated with participation in living or deceased donor kidney transplantation. This study highlights the populations that would benefit from educational intervention regarding living donor transplantation.

The functional polymorphism Ala258Ser in the innate receptor gene ficolin-2 in the donor predicts improved renal transplant outcome.

Background Innate immunity plays a role in controlling adaptive immune responses. Methods We investigated the clinical relevance of single nucleotide polymorphisms in 22 genes encoding innate, secreted, and signaling pattern recognition receptors in a total of 520 donor-recipient pairs of postmortem, human leukocyte antigen–DR-compatible kidney transplantations. Associations with rejection incidence were tested in an a priori randomized training set and validation set. Results Polymorphisms in TLR-3 (rs3775296) in the recipients and in Ficolin-2 (rs7851696; Ala258Ser) and C1qR1 (rs7492) in the donors showed the strongest association with severe rejection. In multivariate analysis, presence of the Ficolin-2 Ala258Ser variant in the donor predicted lower incidence of severe rejection (odds ratio=0.3; 95% confidence interval, 0.1–0.9; P=0.024) and of graft loss (hazard ratio=0.5; 95% confidence interval, 0.2–1.0; P=0.046) independently of clinical risk factors. Ficolin-2 messenger RNA expression was detected in pretransplantation biopsies from 69 donor grafts. Serum and tissue Ficolin-2 levels were unaffected by genotype. Ficolin-2 protein, which bound to dying cells, was detected in donor kidneys in a passenger leukocyte-like pattern. Indeed, monocytes, monocyte-derived macrophages, and peripheral blood mononuclear cells expressed Ficolin-2. Donor grafts with the Ficolin-2 Ala258Ser variant contained significantly elevated expression of interleukin 6, having ascribed cytoprotective effects. It has been described that Ala258Ser leads to increased binding capacity of Ficolin-2 to N-acetylglucosamine. Conclusions Presence of the Ficolin-2 Ala258Ser polymorphism in the donor independently predicts improved graft outcome. Based on mechanistic data, we propose that this functional polymorphism leads to more efficient handling of injured cells by phagocytozing cells, resulting in decreased intragraft exposure to danger signals and dampened alloimmune responses.

A High Comorbidity Score Should Not be a Contraindication for Kidney Transplantation.

Background Currently, potential kidney transplant patients more often suffer from comorbidities. The Charlson Comorbidity Index (CCI) was developed in 1987 and is the most used comorbidity score. We questioned to what extent number and severity of comorbidities interfere with graft and patient survival. Besides, we wondered whether the CCI was best to study the influence of comorbidity in kidney transplant patients. Methods In our center, 1728 transplants were performed between 2000 and 2013. There were 0.8% cases with missing values. Nine pretransplant comorbidity covariates were defined: cardiovascular disease, cerebrovascular accident, peripheral vascular disease, diabetes mellitus, liver disease, lung disease, malignancy, other organ transplantation, and human immunodeficiency virus positivity. The CCI used was unadjusted for recipient age. The Rotterdam Comorbidity in Kidney Transplantation score was developed, and its influence was compared to the CCI. Kaplan-Meier analysis and multivariable Cox proportional hazards analysis, corrected for variables with a known significant influence, were performed. Results We noted 325 graft failures and 215 deaths. The only comorbidity covariate that significantly influenced graft failure censored for death was peripheral vascular disease. Patient death was significantly influenced by cardiovascular disease, other organ transplantation, and the total comorbidity scores. Model fit was best with the Rotterdam Comorbidity in Kidney Transplantation score compared to separate comorbidity covariates and the CCI. In the population with the highest comorbidity score, 50% survived more than 10 years. Conclusions Despite the negative influence of comorbidity, patient survival after transplantation is remarkably good. This means that even patients with extensive comorbidity should be considered for transplantation.

Genetic variants of FOXP3 influence graft survival in kidney transplant patients.

FOXP3(+) regulatory T cells (Treg) play a role in controlling alloreactivity. It has been shown that short (GT)n dinucleotide repeats (≤(GT)15; S) in the promoter region of the FOXP3 gene enhance the promoter activity when compared to long (GT)n repeats (≥(GT)16; L). The present study retrospectively investigated the influence of this (GT)n FOXP3 gene polymorphism on renal allograft survival. A total of 599 consecutive first-time kidney transplant patients (median follow-up time 7.7 years) were subdivided according to their FOXP3 genotype into the S-genotype group (SG) and the L-genotype group (LG). The SG was superior to the LG in both general graft survival censored for death (logrank test, p=0.013) and graft survival following acute rejection (p=0.021). Multivariate analysis defined the (GT)n FOXP3 dinucleotide repeat polymorphism as an independent factor and confirmed an advantage for the SG in renal allograft survival (HR=0.67, 95% CI 0.48-0.94, p=0.02). This gene association study identified a beneficial effect of FOXP3 genetic variants on graft survival in kidney transplant patients.

Understanding the influence of ethnicity and socioeconomic factors on graft and patient survival after kidney transplantation.

Background Studies on the influence of socioeconomic factors and ethnicity on the results of kidney transplantation have led to various outcomes. In this study, we analyzed the influence of a combination of these factors on graft and patient survival in a population of kidney transplant recipients. Methods This retrospective study included all 1,338 patients who received a kidney transplant between 2000 and 2011 (825 living, 513 deceased donor transplantations). Both clinical and socioeconomic variables were studied. Clinical variables were recipient age, gender, ethnicity, original disease, maximum and current panel reactive antibodies, ABO blood type, retransplants, pretreatment, time on dialysis, comorbidity, transplant year, total number of HLA mismatches, donor type (living or deceased), age and gender, and calcineurin inhibitor treatment. Each recipient’s postal code was linked to a postal code area information database to extract information on housing value, income, percentage non-Europeans in the area, and urbanization level. Results In multivariable analysis, graft survival censored for death was significantly influenced by recipient age, maximum panel reactive antibodies, HLA mismatches, donor type, donor age, and calcineurin inhibitor treatment. Patient survival was significantly influenced by recipient age, comorbidity, transplant year, and donor type. Socioeconomic factors and ethnicity did not have a significant influence on graft and patient survival. Conclusions Though ethnicity and socioeconomic factors do not influence survival after kidney transplantation, the favorable influence of living donor type is of paramount importance. As non-Europeans and patients with unfavorable socioeconomic variables less often receive a living donor kidney transplant, their survival may be unfavorable after all.

Transplantation results of completely HLA-mismatched living and completely HLA-matched deceased-donor kidneys are comparable.

Background Human leukocyte antigen (HLA) mismatches are known to influence graft survival in deceased-donor kidney transplantation. We studied the effect of HLA mismatches in a population of recipients of deceased-donor or living-donor kidney transplantations. Methods All 1998 transplantations performed in our center between 1990 and 2011 were included in this retrospective cohort study. Four different multivariable Cox proportional hazard analyses were performed with HLA mismatches as continuous variable, as categorical variable (total number of HLA mismatches), as binary variable (zero vs. nonzero HLA mismatches), and HLA-A, -B, and -DR mismatches included separately. Results Nine hundred ninety-one patients received a deceased-donor kidney and 1007 received a living-donor kidney. In multivariable Cox analysis, HLA mismatches, recipient age, current panel-reactive antibodies, transplant year, donor age, calcineurin inhibitor treatment, and donor type were found to have a significant and independent influence on the risk of graft failure, censored for death. Variables representing the total number of HLA-A, -B, and -DR mismatches had a significant and comparable influence in all analyses. Conclusions The influence of HLA mismatches on death-censored graft survival holds true for both deceased- and living-donor kidney transplantation. However, the relative risk of death-censored graft failure of a 2-2-2 mismatched living-donor kidney is comparable with that of a 0-0-0 mismatched deceased-donor kidney.

Alternative Living Kidney Donation Programs Boost Genetically Unrelated Donation

Donor-recipient ABO and/or HLA incompatibility used to lead to donor decline. Development of alternative transplantation programs enabled transplantation of incompatible couples. How did that influence couple characteristics? Between 2000 and 2014, 1232 living donor transplantations have been performed. In conventional and ABO-incompatible transplantation the willing donor becomes an actual donor for the intended recipient. In kidney-exchange and domino-donation the donor donates indirectly to the intended recipient. The relationship between the donor and intended recipient was studied. There were 935 conventional and 297 alternative program transplantations. There were 66 ABO-incompatible, 68 domino-paired, 62 kidney-exchange, and 104 altruistic donor transplantations. Waiting list recipients (n = 101) were excluded as they did not bring a living donor. 1131 couples remained of whom 196 participated in alternative programs. Genetically unrelated donors (486) were primarily partners. Genetically related donors (645) were siblings, parents, children, and others. Compared to genetically related couples, almost three times as many genetically unrelated couples were incompatible and participated in alternative programs (P < 0.001). 62% of couples were genetically related in the conventional donation program versus 32% in alternative programs (P < 0.001). Patient and graft survival were not significantly different between recipient programs. Alternative donation programs increase the number of transplantations by enabling genetically unrelated donors to donate.