Lower extremity joints and their contributions to whole limb extension.

Lower extremity multi-joint strength curves tend not to evaluate individual joint contributions to endpoint force in maximum effort isometric whole limb extension. Therefore, the purpose of this study was to measure the contribution of the hip, knee, and ankle to vertical ground reaction force in maximum effort isometric whole limb extension at various postures. An effect of posture on the contributions of the hip, knee, and ankle to vertical ground reaction force was found (F(3,96) = 85.31, p < 0.0001; F(3,96) = 21.32, p < 0.0001; F(3,96) = 130.61, p < 0.0001 for the hip, knee, and ankle, respectively). The hip and knee contributed most to vertical endpoint force when the lower limb was in a flexed posture, and their contributions decreased when posture was extended. Conversely, the ankle contributed least when the limb was flexed, but its contribution increased as posture was changed from flexed to more extended. In comparison to recent research involving induced acceleration analysis, it appears that the hip, knee, and ankle utilize the same force allocation strategy in multi-joint maximum effort isometric leg extensions and activities of daily living.

[Proposal for an anonymous reporting code organ trafficking: how transplant professionals can play a role in preventing this trafficking]. / Voorstel voor een anoniem meldpunt orgaanhandel.

Patients travel worldwide to undergo kidney transplantations. Care providers in the Netherlands encounter these patients, both before and after the transplantation. We present the results of a survey that was distributed among Dutch transplant professionals about their experiences with patients who have undergone a kidney transplantation abroad. We propose that care providers should report illegal transplantations. Of the 241 surveyed professionals, 100 treated patients who travelled to a country outside the European Union for a kidney transplant. Thirty-one professionals were certain that patients purchased their kidney, and sixty-five had suspicions that it had been purchased. The majority reported a conflict of duties. Professionals can help prevent organ purchase by detecting and disclosing information about organ trafficking networks. The aim of reporting is two-fold. Firstly, such disclosure can lead to increased knowledge and information about organ trafficking. Secondly, it can support the police and law enforcement agencies to investigate if networks are involved in facilitation of these transplantations. In this manner, those who facilitate organ trafficking can be prosecuted and exploitation of donors can be prevented.

Multivariate Analysis of Health-related Quality of Life in Donors After Live Kidney Donation.

BACKGROUND: Live-kidney donation has a low mortality rate. Evidence suggests that live-kidney donors experience a quality of life (QoL) comparable to or even superior to that of the general population. There is limited information on factors associated with a decrease in QoL in particular for baseline factors, which would improve information to the donor, donor selection, and convalescence. METHODS: QoL data on 501 live donors included in three prospective studies between 2001 and 2010 were used. The 36-item short form health survey (SF-36) was used to measure QoL up to 1 year after the procedure. Longitudinal effects on both the mental (MCS) and physical component scales (PCS) were analyzed with multilevel linear regression analyses. Baseline variables were age, gender, body mass index (BMI), pain, operation type, and comorbidity. Other covariates were loss of the graft, glomerular filtration rate, and recipient complications. RESULTS: After 1 year we observed a small decrease in PCS (effect size = -0.24), whereas the MCS increased (effect size = 0.32). Both PCS and MCS were still well above the norm of the general Dutch population. Factors associated with a change in PCS were BMI (Cohen's d = -0.17 for 5 BMI points) and age (d = -0.13 for each 10 years older). CONCLUSIONS: Overall, QoL after live-donor nephrectomy is excellent. A lowered PCS is related to age and body weight. Expectations towards a decreased postoperative QoL at 1 year are unjustified. However, one should keep in mind that older and obese donors may develop a reduced physical QoL after live-kidney donation.

Conversion from tacrolimus to everolimus with complete and early glucocorticoid withdrawal after kidney transplantation: a randomised trial.

BACKGROUND: While conversion from cyclosporine to everolimus is well documented, conversion from tacrolimus has been poorly studied. In this randomised, controlled trial the safety and tolerability of switching from tacrolimus to everolimus with glucocorticoid withdrawal after living-donor kidney transplantation was studied. METHODS: A total of 194 patients were planned to be randomised 1:1 to either continue tacrolimus or to convert to everolimus at month 3 after transplantation. At randomisation, all patients received tacrolimus, mycophenolate mofetil and prednisolone. Everolimus was started in a dose of 1.5 mg twice daily, aiming for predose concentrations of 4-7 ng/ml. Prednisolone was gradually withdrawn in both groups. RESULTS: The trial was stopped prematurely after the inclusion of 60 patients. The interim analysis showed an unacceptably high rejection rate in the everolimus group as compared with the control group: 30.0% vs. 6.7% (95% CI: 0.047-0.420; p = 0.045). An additional 8 patients stopped everolimus because of toxicity. At the end of follow-up (month 12) only 12 (40%) patients assigned to everolimus were still on the study drug. CONCLUSIONS: Conversion from tacrolimus to everolimusbased immunosuppression with withdrawal of prednisolone three months after kidney transplantation results in an unacceptably high risk of acute rejection and causes considerable toxicity. Based on our findings, such a switch strategy cannot be recommended.

[Waiting list registration for kidney transplants must improve]. / Wachtlijstregistratie niertransplantatie moet beter.

OBJECTIVE: To investigate how the composition of the waiting list for postmortem kidney transplant has developed, and whether the waiting list reflects actual demand. DESIGN: Retrospective research and cohort study. METHOD: We used data from the period 2000-2014 from the Dutch Transplant Foundation, 'RENINE' and Eurotransplant. This concerned data on postmortem kidney donation, live donor transplants, the waiting list and kidney transplantation. RESULTS: The postmortem kidney transplant waiting list included transplantable (T) and non-transplantable (NT) patients. The number of T-patients declined from 1271 in 2000 to 650 in 2014, and the median waiting time between the start of dialysis and postmortem kidney transplant decreased from 4.1 years in 2006 to 3.1 years in 2014. The total number of patients on the waiting list, however, increased from 2263 in 2000 to 2560 in 2014 and in the same period the number of new patient registrations increased from 772 to 1212. In about 80% of the NT-patients the reason for their NT status was not registered. A cohort analysis showed that NT-patients have a 2-times lower chance of a postmortem kidney transplant and a 2-times higher chance of leaving the waiting list without transplantation or of live-donor transplantation. CONCLUSION: The demand for donor kidneys remains high. The increased number of transplants resulted in a declining waiting list for T-patients while the total waiting list is getting longer. Waiting list registration and maintenance need to be improved, to give better insight into the real demand.

Kidney transplantation in patients declined by other centres.

BACKGROUND: Transplant centres show considerable disagreement in the acceptance of transplant candidates with relative contraindications. The aim of this study is to investigate the outcomes of our patients who had been refused at other centres prior to transplantation at our centre. METHODS: We included patients who had been excluded from transplantation or wait-listing at other centres before referral to our centre. We scored the reasons for refusal at other centres, the type of transplantation procedure, postoperative and long-term complications, patient and graft survival and how these patients experienced the transplantation and quality of life at our centre. All regular patients transplanted in 2010 functioned as a control group for outcome parameters. RESULTS: We identified 23 patients in the period from January 2000 until March 2013. The most frequent reason for the refusal at other centres was obesity. Twenty of the 23 patients (87%) were alive and 19 had a functioning graft (83%) after a median follow-up of 21.0 months after transplantation (range 11.0-48.9). There were significantly more wound-related problems in the study group as compared with the control group (p = 0.029), but their kidney function at one year after transplantation was not significantly different. The patients indicated an improvement of quality of life after transplantation and in general were satisfied with the transplantation. CONCLUSIONS: Patients who had previously had been denied transplantation at other centres generally did well after kidney transplantation with an increased risk of wound complications but a satisfactory graft and patient survival.

Interviews With Patients Who Traveled From Macedonia/Kosovo, The Netherlands, and Sweden for Paid Kidney Transplantations.

BACKGROUND: Patients travel worldwide for paid kidney transplants. Although transplantations abroad are not always illegal, they are commonly perceived to be illegal and unethical involving risks. AIM: We aimed to describe the motivations and experiences of patients who traveled abroad for paid kidney transplantations and to examine how these transplantations were facilitated. METHODS: We interviewed 22 patients who traveled from Macedonia/Kosovo, the Netherlands, and Sweden for paid kidney transplantations between years 2000 and 2009. RESULTS: Patients traveled because of inadequate transplant activity in their domestic countries and dialysis-related complaints. However, 6 patients underwent preemptive transplantations. Cultural factors such as patients' affinity with destination countries, feelings of being discriminated against by the health-care system, and family ties also help explain why patients travel abroad. Seven of the 22 patients went to their country of origin. They were able to organize their transplantations by arranging help from family and friends abroad who provided contacts of caregivers there and who helped cover the costs of their transplants. The costs varied from €5000 to €45 000 (US$6800-US$61 200). Seven patients paid the hospital, 5 paid their doctor, 4 paid a broker, and 6 paid their donors. CONCLUSION: Research should include interviews with brokers, transplant professionals, and other facilitators to achieve a full picture of illegally performed transplantations.

On Patients Who Purchase Organ Transplants Abroad.

The international transplant community portrays organ trade as a growing and serious crime involving large numbers of traveling patients who purchase organs. We present a systematic review about the published number of patients who purchased organs. With this information, we discuss whether the scientific literature reflects a substantial practice of organ purchase. Between 2000 and 2015, 86 studies were published. Seventy-six of these presented patients who traveled and 42 stated that the transplants were commercial. Only 11 studies reported that patients paid, and eight described to what or whom patients paid. In total, during a period of 42 years, 6002 patients have been reported to travel for transplantation. Of these, only 1238 were reported to have paid for their transplants. An additional unknown number of patients paid for their transplants in their native countries. We conclude that the scientific literature does not reflect a large number of patients buying organs. Organ purchases were more often assumed than determined. A reporting code for transplant professionals to report organ trafficking networks is a potential strategy to collect and quantify cases.

Kidney transplant patients' attitudes towards self-management support: A Q-methodological study.

OBJECTIVE: Kidney transplant recipients face many self-management challenges. We aimed to identify profiles of attitudes towards self-management support (SMS) shortly after kidney transplantation. METHODS: Profiles were generated using Q-methodology: In face-to-face interviews participants rank-ordered opinion statements on aspects of SMS according to agreement. Socio-demographic and medical characteristics were assessed using a questionnaire. By-person factor analysis was used to analyze the rankings and qualitative data was used to support choice of profiles. The resulting factors represent clusters of patients with similar attitudes towards SMS. RESULTS: Forty-three patients (mean age=56; 77% male) participated. Four profiles were identified: (A) transplant-focused and obedient; (B) holistic and collaborative; (C) life-focused and self-determined; and (D) was bipolar. The positive pole (D+) minimalizing and disengaged and the negative pole (D-) coping-focused and needy represent opposing viewpoints within the same profile. Socio-demographic and medical characteristics were not related to profile membership. DISCUSSION: Each profile represents a specific attitude on post-transplant life, responsibility for health and decision-making, SMS needs, and preferences for SMS. PRACTICAL IMPLICATIONS: Patients vary in their attitude, needs and preferences for SMS indicating the necessity of providing personalized support after kidney transplantation. Health professionals should explore patients' SMS needs and adapt support accordingly.

A Randomized Controlled Trial Comparing the Efficacy of Cyp3a5 Genotype-Based With Body-Weight-Based Tacrolimus Dosing After Living Donor Kidney Transplantation.

Patients expressing the cytochrome P450 (CYP) 3A5 gene require a higher tacrolimus dose to achieve therapeutic exposure compared with nonexpressers. This randomized-controlled study investigated whether adaptation of the tacrolimus starting dose according to CYP3A5 genotype increases the proportion of kidney transplant recipients being within the target tacrolimus predose concentration range (10-15 ng/mL) at first steady-state. Two hundred forty living-donor, renal transplant recipients were assigned to either receive a standard, body-weight-based or a CYP3A5 genotype-based tacrolimus starting dose. At day 3, no difference in the proportion of patients having a tacrolimus exposure within the target range was observed between the standard-dose and genotype-based groups: 37.4% versus 35.6%, respectively; p = 0.79. The proportion of patients with a subtherapeutic (i.e. <10 ng/mL) or a supratherapeutic (i.e. >15 ng/mL) Tac predose concentration in the two groups was also not significantly different. The incidence of acute rejection was comparable between both groups (p = 0.82). Pharmacogenetic adaptation of the tacrolimus starting dose does not increase the number of patients having therapeutic tacrolimus exposure early after transplantation and does not lead to improved clinical outcome in a low immunological risk population.

Reporting Organ Trafficking Networks: A Survey-Based Plea to Breach the Secrecy Oath.

Patients travel worldwide to purchase kidneys. Transplant professionals can play a role in identifying kidney purchase. However, due to the tension between their rights and obligations, a lack of understanding and knowledge exists on how to prevent and report purchase. We present the results of a national survey that describes transplant professionals' experiences, attitudes, behaviors, conflicts of duties, legal knowledge and needs for guidelines toward patients who purchase kidneys abroad. Second, we clarify professionals' rights and obligations regarding organ purchase and propose actions that they can take to report purchase. Of the 100/241 (42%) professionals who treated patients who traveled to a country outside the European Union for a kidney transplant, 31 (31%) were certain that patients purchased kidneys. Sixty-five (65%) had suspicions that patients had bought kidneys. The majority reported a conflict of duties. Eighty percent reported a need for guidelines. Professionals can help prevent organ purchase by disclosing information about organ trafficking networks to law enforcement. Such disclosure can support the investigation and prosecution of networks. We offer key components for guidelines on disclosure of these networks.

Mental health among living kidney donors: a prospective comparison with matched controls from the general population.

The impact of living kidney donation on donors' mental health has not been sufficiently nor comprehensively studied. Earlier studies demonstrated that mental health did not change in the majority of donors, however they often lacked a suitable control group and/or had other methodological limitations. Consequently, it remains unclear whether changes in mental health found among a minority of donors reflect normal fluctuations. In this study we matched 135 donors with individuals from the general Dutch population on gender and baseline mental health and compared changes in mental health over time. Mental health was measured using the Brief Symptom Inventory and Mental Health Continuum Short Form. Primary analyses compared baseline and 6 months follow-up. Secondary analyses compared baseline and 9 (controls) or 15 months (donors) follow-up. Primary multilevel regression analyses showed that there was no change in psychological complaints (p = 0.20) and wellbeing (p = 0.10) over time and donors and controls did not differ from one another in changes in psychological complaints (p = 0.48) and wellbeing (p = 0.85). Secondary analyses also revealed no difference in changes between the groups. We concluded that changes in mental health in the short term after donation do not significantly differ from normal fluctuations found in the Dutch general population.

Follicular T helper cells and humoral reactivity in kidney transplant patients.

Memory B cells play a pivotal role in alloreactivity in kidney transplantation. Follicular T helper (Tfh) cells play an important role in the differentiation of B cells into immunoglobulin-producing plasmablasts [through interleukin (IL)-21]. It is unclear to what extent this T cell subset regulates humoral alloreactivity in kidney transplant patients, therefore we investigated the absolute numbers and function of peripheral Tfh cells (CD4(POS) CXCR5(POS) T cells) in patients before and after transplantation. In addition, we studied their relationship with the presence of donor-specific anti-human leucocyte antigen (HLA) antibodies (DSA), and the presence of Tfh cells in rejection biopsies. After transplantation peripheral Tfh cell numbers remained stable, while their IL-21-producing capacity decreased under immunosuppression. When isolated after transplantation, peripheral Tfh cells still had the capacity to induce B cell differentiation and immunoglobulin production, which could be inhibited by an IL-21-receptor-antagonist. After transplantation the quantity of Tfh cells was the highest in patients with pre-existent DSA. In kidney biopsies taken during rejection, Tfh cells co-localized with B cells and immunoglobulins in follicular-like structures. Our data on Tfh cells in kidney transplantation demonstrate that Tfh cells may mediate humoral alloreactivity, which is also seen in the immunosuppressed milieu.

Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells.

Mesenchymal or stromal stem cells (MSC) interact with cells of the immune system in multiple ways. Modulation of the immune system by MSC is believed to be a therapeutic option for autoimmune disease and transplant rejection. In recent years, B cells have moved into the focus of the attention as targets for the treatment of immune disorders. Current B-cell targeting treatment is based on the indiscriminate depletion of B cells. The aim of this study was to examine whether human adipose tissue-derived MSC (ASC) interact with B cells to affect their proliferation, differentiation, and immune function. ASC supported the survival of quiescent B cells predominantly via contact-dependent mechanisms. Coculture of B cells with activated T helper cells led to proliferation and differentiation of B cells into CD19(+) CD27(high) CD38(high) antibody-producing plasmablasts. ASC inhibited the proliferation of B cells and this effect was dependent on the presence of T cells. In contrast, ASC directly targeted B-cell differentiation, independently of T cells. In the presence of ASC, plasmablast formation was reduced and IL-10-producing CD19(+) CD24(high) CD38(high) B cells, known as regulatory B cells, were induced. These results demonstrate that ASC affect B cell biology in vitro, suggesting that they can be a tool for the modulation of the B-cell response in immune disease.

Human renal tubular epithelial cells suppress alloreactive T cell proliferation.

Renal tubular epithelial cells (TECs) are one of the main targets of alloreactive T cells during acute rejection. We hypothesize that TECs modulate the outcome of alloimmunity by executing immunosuppressive effects in order to dampen the local inflammation. We studied whether TECs possess immunosuppressive capacities and if indoleamine 2,3-dioxygenase (IDO) might play a role in suppressing T cell alloreactivity. Next, we studied the role of programmed death ligand 1 (PD-L1) and intercellular adhesion molecule-1 (ICAM-1 with regard to TEC-related immunomodulatory effects. CD3/CD28 and alloactivated peripheral blood mononuclear cells were co-cultured with activated TECs. We analysed CD4(+) and CD8(+) T cell proliferation and apoptosis in the absence or presence of IDO inhibitor 1-methyl-L-tryptophan (1-L-MT), anti-PD-L1 and anti-ICAM-1. Further, we examined whether inhibition of T cell proliferation was cell-cell contact-dependent. We found that TECs dose-dependently inhibited CD4(+) and CD8(+) T cell proliferation (P<0.05). Activated TECs showed significantly increased IDO activity and up-regulated PD-L1 and ICAM-1 expression. Suppressed CD4(+) and CD8(+) T cell proliferation was only partially restored or failed to restore using 1-L-MT. Activated TECs increased early and late apoptosis of proliferating CD4(+) and CD8(+) T cells; only CD4(+) T cell apoptosis was statistically affected by 1-L-MT. Transwell experiments revealed that TEC-mediated immunosuppression is cell-cell contact-dependent. We found that anti-ICAM-1 affected only CD4(+) T cell apoptosis and not T cell proliferation. Our data show that TECs suppress both CD4(+) and CD8(+) T cell proliferation contact dependently. Interestingly, inhibition of proliferation and enhancement of apoptosis of T cell subsets is differentially regulated by indoleamine 2,3-dioxygenase and ICAM-1, with no evidence for the involvement of PD-L1 in our system.

Home-based family intervention increases knowledge, communication and living donation rates: a randomized controlled trial.

Our aim was to develop and test an educational program to support well-informed decision making among patients and their social network regarding living donor kidney transplantation (LDKT). One hundred sixty-three patients who were unable to find a living donor were randomized to standard care or standard care plus home-based education. In the education condition, patients and members of their social network participated in home-based educational meetings and discussed renal replacement therapy options. Patients and invitees completed pre-post self-report questionnaires measuring knowledge, risk perception, communication, self-efficacy and subjective norm. LDKT activities were observed for 6 months postintervention. Patients in the experimental group showed significantly more improvements in knowledge (p < 0.001) and communication (p = 0.012) compared with the control group. The invitees showed pre-post increases in knowledge (p < 0.001), attitude toward discussing renal replacement therapies (p = 0.020), attitude toward donating a kidney (p = 0.023) and willingness to donate a kidney (p = 0.039) and a decrease in risk perception (p = 0.003). Finally, there were significantly more inquiries (29/39 vs. 13/41, p < 0.001), evaluations (25/39 vs. 7/41, p < 0.001) and actual LDKTs (17/39 vs. 4/41, p = 0.003) in the experimental group compared with the control group. Home-based family education supports well-informed decision making and promotes access to LDKT.

The protein kinase C inhibitor sotrastaurin allows regulatory T cell function.

The novel immunosuppressant sotrastaurin is a selective inhibitor of protein kinase C isoforms that are critical in signalling pathways downstream of the T cell receptor. Sotrastaurin inhibits nuclear factor (NF)-κB, which directly promotes the transcription of forkhead box protein 3 (FoxP3), the key regulator for the development and function of regulatory T cells (Tregs). Our center participated in a randomized trial comparing sotrastaurin (n = 14) and the calcineurin inhibitor Neoral (n = 7) in renal transplant recipients. We conducted ex vivo mixed lymphocyte reaction (MLR) and flow cytometry studies on these patient samples, as well as in vitro studies on samples of blood bank volunteers (n = 38). Treg numbers remained stable after transplantation and correlated with higher trough levels of sotrastaurin (r = 0·68, P = 0·03). A dose-dependent effect of sotrastaurin on alloresponsiveness was observed: the half maximal inhibitory concentration (IC50 ) to inhibit alloactivated T cell proliferation was 45 ng/ml (90 nM). In contrast, Treg function was not affected by sotrastaurin: in the presence of in vitro-added sotrastaurin (50 ng/ml) Tregs suppressed the proliferation of alloactivated T effector cells at a 1:5 ratio by 35 versus 47% in the absence of the drug (P = 0·33). Signal transducer and activator of transcription 5 (STAT)-5 phosphorylation in Tregs remained intact after incubation with sotrastaurin. This potent Treg function was also found in cells of patients treated with sotrastaurin: Tregs inhibited the anti-donor response in MLR by 67% at month 6, which was comparable to pretransplantation (82%). Sotrastaurin is a potent inhibitor of alloreactivity in vitro, while it did not affect Treg function in patients after kidney transplantation.