Renal function decline in recipients and donors of kidney grafts: role of aortic stiffness.

BACKGROUND/AIMS: Renal function decreases over time as a result of reduction in the number of functioning nephrons with age. In recipients and donors of kidney grafts, renal function decline may be linked differently to various parameters, namely arterial stiffness. METHODS: We conducted a prospective cohort study including 101 recipients of kidney grafts and their donors aiming at determining the factors correlated to the renal function decline over time. Aortic stiffness was evaluated by the non-invasive measurement of aortic pulse wave velocity. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease (MDRD) equation and the annualized change was determined. RESULTS: Decline in renal function was estimated at 1-year post-transplantation and annually thereafter (median follow-up 8 years, range 3.6-18.3), as the mean of the annualized decrease in the glomerular filtration rate. In recipients, filtration rate decreased by 4.8 ± 19.7 ml/min/1.73 m(2) the first post-transplant year and at a yearly rate of 2.2 ± 3.8 ml/min/1.73 m(2) thereafter. The first-year decline was related to smoking and acute rejection. Later decline was significantly associated with donor age and aortic stiffness. In living donors, renal function decline after the first year corresponded to 0.7 ml/min/1.73 m(2), was significantly lower than that of recipients (p < 0.001), and was determined by donor age at nephrectomy. CONCLUSION: Recipients of kidney grafts show a glomerular filtration rate decline over time that is significantly associated with donor age and aortic stiffness after the first post-transplant year, while donors demonstrate a lower decline that is mostly determined by age at nephrectomy.

The Future of Organ Procurement.

The dream of any organ procurement organization is to achieve self-sufficiency, where the number of organs needed is met by an equal number of organs available. In 2023, we can hope to reach selfsufficiency by providing kidneys to most patients in terminal renal failure. This can be achieved by decreasing the demand since SGL2 inhibitors have shown promising results in delaying renal failure. On the other hand, progress in the development of the bioartificial kidney and advances in xenotransplantation will significantly increase the number of organs offered.

Outcome analysis of brain-death referral to NOD-Lb: A retrospective chart review of a single hospital experience over 3 years.

BACKGROUND: Organ donation shortage and in particular organ procurement is an international concern as the gap between the number of donors and recipients is steadily growing. Organ procurement is a chain of steps with donor identification and referral (ID&R) as the very first link in this chain. Failure of this step hinders the progress in the organ transplantation program. OBJECTIVES: Our study was conducted to evaluate and highlight the gap between the national system and the practice at the identification and referral (ID&R) step of the organ procurement chain in a single tertiary-care academic health center in Beirut: the Lebanese American University Medical Center-Rizk Hospital (LAUMC-RH), and to appraise the literature for challenges at this step and for possible interventions for improvement based on the international experience. MATERIALS AND METHODS: This retrospective study was a descriptive case series of ICU and ED deceased patients at a single tertiary-care university hospital in Beirut. Patients' characteristics were collected from medical records for all patients who died between 2017 and 2019 while in the ICU or the ED and shared with the National Organization for Organ and Tissue Donation and Transplantation (NOD-Lb), for each subject separately, to decide on the donor status. All data collected from the patient cohort was analyzed using R version 3.6.1. Wilcoxon signed-rank test, chi-squared, and fisher-exact tests were used to compare differences in clinical characteristics in terms of donor status when appropriate. RESULTS: This study served as 3 years audit of a single hospital experience, and it demonstrates failure to make any referrals to NOD-Lb and zero actual organ and tissue donations over the study period. The review of 295 deceased subjects' charts demonstrates 295 missed alerts to NOD-Lb and the overall missing of 5 organ and tissue donors and 24 cornea donors assuming the organ procurement chain of steps will continue uninterrupted after ID&R. CONCLUSION: The data gathered suggests the presence of an inefficient identification and referral system that is translated into a complete failure of reporting to NOD-Lb from LAUMC-RH. A systematic evidence-based approach to evaluate for the most cost-effective intervention to increase identification and referral rates is needed with a serious effort to examine and account for any inefficient implantation.

Cardiovascular and renal outcome in recipients of kidney grafts from living donors: role of aortic stiffness.

BACKGROUND: Cardiovascular (CV) risk remains high in renal transplant patients despite a clear improvement conferred by transplantation. This risk is attributed mostly to recipient-related risk factors. Donor vascular characteristics, such as arterial stiffness, have been poorly investigated in this regard. METHODS: Recipients of living-related (n = 75) and living-unrelated (n = 20) kidney grafts were recruited at a mean time of 107 ± 41 months after transplantation for baseline evaluation and follow-up for the occurrence of the following composite outcome: myocardial infarction, stroke, CV death, doubling of serum creatinine or development of end-stage renal disease (ESRD). At inclusion, recipients and their corresponding donors underwent complete history, physical examination, laboratory tests and non-invasive measurement of aortic pulse wave velocity (PWV). RESULTS: During a mean follow-up of 56 ± 18 months, 20 recipients doubled their serum creatinine, of whom 16 reached ESRD, and 9 suffered of a new CV event (5 of which were fatal). Cox proportional hazards regression analysis showed that, in addition to recipient-related parameters, such as the presence of CV event and the estimated glomerular filtration rate at inclusion, donor aortic PWV was a strong and independent predictor of the composite recipient outcome. CONCLUSIONS: Donor large artery stiffness may predict recipient CV and graft outcome. This finding demonstrates the tight link that exists between the vascular system and the kidneys and suggests that donor contribution to recipient outcome goes beyond simple parameters like age, gender and even familial or non-familial donor type.

The Limited Value of the Extended Criteria Donor.

The use of deceased extended criteria donors has shortened wait times for potential transplant recipients. Their use has been quite helpful in allowing elderly recipients access to transplant before the onset of intractable complications. Resorting to living extended criteria donation on the other hand represents a total disregard of the interests of the living donor and should be actively discouraged.

Outcome of 234 pregnancies in 140 renal transplant recipients from five middle eastern countries.

OBJECTIVE: To study the pregnancy and offspring outcomes in postrenal transplant recipients. METHODS: This is a retrospective case-note review study investigating the outcome of 234 pregnancies in 140 renal transplant recipients from five different Middle Eastern countries. RESULTS: Of the overall pregnancies 74.4% were successful albeit with high prevalences of preterm and Caesarean deliveries (40.8% and 53%, respectively). The mean serum creatinine did not rise significantly during pregnancy in the group as a whole but did so in patients who had serum creatinine of or above 150 micromol/L at the beginning of their pregnancies. The mean birth weight was (2,458 g) with 41.3% of the newborns being of low birth weight (<2,500 g). The prevalences of stillbirths were 7.3% and of spontaneous abortion was 19.3%. Preeclampsia and gestational diabetes were observed in 26.1% and 2% of pregnancies, respectively. CONCLUSIONS: In the presence of good allograft function, the majority of pregnancies in renal transplant recipients have a good outcome but with increased incidence of preeclampsia, reduced gestational age, and low birth weights. Patients with baseline serum creatinine of above 150 micromol/L have an increased risk of allograft dysfunction resulting from the pregnancy.

Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rγNull Mouse Model.

The lack of preclinical models able to faithfully predict the immune responses which are later obtained in the clinic is a major hurdle for vaccines development as it increases markedly the delays and the costs required to perform clinical studies. We developed and evaluated the relevance to human immune responses of a novel humanized mouse model, humanized-spleen cells-NOD-SCID-gamma null (Hu-SPL-NSG), in which we grafted human spleen cells in immunodeficient NOD-SCID-IL-2rγnull (NSG) mice. We selected the malaria vaccine candidate, Liver Stage Antigen 3-Full Length, because we had previously observed a major discrepancy between preclinical and clinical results, and compared its immunogenicity with that of a shorter form of the molecule, LSA3-729. NSG mice engrafted with human spleen lymphocytes were immunized with either LSA3-FL or LSA3-729, both adjuvanted with montanide ISA720. We found that the shorter LSA3-729 triggered the production of human antibodies and a T-helper-type 1 cellular immune response associated with protection whereas LSA3-FL did not. Results were consistent in five groups receiving lymphocytes from five distinct human donors. We identified antigenic regions in the full-length molecule, but not in the shorter version, which induced T-regulatory type of cellular responses. These regions had failed to be predicted by previous preclinical experiments in a wide range of animal models, including primates. Results were reproducible using spleen cells from all five human donors. The findings in the Hu-SPL-NSG model were similar to the results obtained using LSA3-FL in the clinic and hence could have been used to predict them. The model does not present graft versus host reaction, low survival of engrafted B lymphocytes and difficulty to raise primary immune responses, all limitations previously reported in humanized immune-compromised mice. Results also point to the shorter construct, LSA3-729 as a more efficient vaccine candidate. In summary, our findings indicate that the Hu-SPL-NSG model could be a relevant and cost-saving choice for early selection of vaccine candidates before clinical development, and deserves being further evaluated.

Ethical aspects of organ donation activities.

Renal transplant remains the treatment of choice for patients with end-stage renal disease. Human organs can be harvested from 2 main sources: living and deceased donors. Preference should be given to deceased-donor transplants since they represent the only source of organs for several nonrenal solid-organ transplants and the only modality where there is no risk to the donor. Unfortunately, even the most well-developed deceased-donor program (eg, the Spanish program) can barely cover 50% of its waiting list because the demand for deceased-donor organs far exceeds supply. The success of transplant surgery has created a waiting list dilemma. Despite all efforts, deceased-donor donation cannot meet current needs and therefore, living donation demands serious consideration. This is supported by the fact that the risk to live donors is minimal, graft survival is significantly better than that of deceased-donor kidneys regardless of HLA matching, and professional ethical philosophers have fewer difficulties with voluntary living donations than with the removal of an organ from a cadaver. This is especially true in our region. Living-related donation has always been acceptable ethically. It is, however, limited by the number of willing and qualified donors, the high incidence of familial renal diseases, and donor coercion (especially in our area). Living-unrelated donation increases the availability of donors, decreases the chances of coercion, and eliminates the problem of consanguinity. It raises, however, the ethical issues of commercialism, transplant tourism, and organ trafficking. The arguments for and against living-unrelated donation are innumerable. They have been the subject of several international forums and have raised endless discussions. We have set long ago a series of rules and regulations that are in close agreement with the recent Amsterdam and Kuwait resolutions. We have been continually modifying them over the last 15 years to try to implement our ideal, which is to protect the interest of the living donor and avoid commercialism.

A novel approach in clinical immunosuppression monitoring: drug lymphocyte level.

Like others, we have shown a weak correlation between drug blood levels and clinical outcome and immune response. We recently established that in contrast to blood levels, drug lymphocyte levels are strongly associated with therapeutic efficacy. The discordance between the 2 methodologies regarding clinical outcome and immune response is related mainly to the weak association between drug blood level and target-cell content. This weak association explains the intra- and interindividual variabilities of the therapeutic response. These variations are related mainly to genetic and environmental factors including age, sex, body mass index, organ function, food and subsequent drug absorption, drug interactions, and the availability of extra-target-cell binding sites. These factors seem to influence the modes of action of immunosuppressive agents including drug absorption, metabolism, elimination, transport, extra-target-cell sites, as well as target-cell receptor expression and its binding affinity and specific enzyme baseline activity. Therefore, the cellular fraction of a drug at a fixed dosage is the result of the integration of out-fluxing and in-fluxing forces that are affected by genetic and environmental factors. Any redistribution of the drug between the different binding sites will ultimately affect its bioactivity with no change to its extracellular bioavailability (which is currently determined by pharmacokinetic measurements). Compared with whole-blood or plasma-level measurements, monitoring immunosuppression therapy at the site of action appears to be not only more clinically and immunologically relevant (since it measures the free fraction of the drug at its effector site), but this method also bypasses the potentially complex extracellular factors that affect bioactivity. Since the intracellular content of a drug strongly correlates with its biological effect, monitoring immunosuppression therapy at the site of action is comparable to pharmacodynamic monitoring. It is cost effective and easy to perform in clinical practice and could be used for all immunosuppressive drugs. Since it allows maximal reduction of adverse effects through dosage reduction while maintaining an optimal level of immunosuppression, it should offer a new alternative for immunosuppressive therapy monitoring and tailoring to the individual patient.

Organ Shortage: Can We Decrease the Demand?

The shortage of organs for transplant is a universal problem. The World Health Organization is urging every nation to seek self-sufficiency regarding their organ procurement program. Reaching self-sufficiency inevitably requires the provision of a well-developed deceased-donor organ procurement program. Most countries represented by the Middle East Society for Organ Transplantation still rely on living-donor organ donations. Some of these countries have been relatively successful in promoting deceased-donor donation as well. In our region, deceased-donor organs are recovered exclusively from patients who have been declared brain dead. However, with improvements in preventive and therapeutic interventions, the pool of potential brain dead donors is rapidly shrinking. This should, therefore, stimulate our interest in developing a program for recovering organs after cardiac death. However, increasing the pool of donors, even to optimal levels, may still not be enough to meet the growing demand. More resources must be invested in reducing the demand for organs. This is especially true in our region, where primary care programs aimed at slowing or containing disease progression that may lead to organ failure are lacking. This problem is compounded by limited access to such programs and, for that matter, limited access to even the most basic primary care. Continued efforts to increase the supply of donor organs must be pursued. At the same time, we must work to more effectively treat the diseases that could lead to end-stage renal disease and the increased demand for donor organs. A comprehensive approach to the problem of donor organ shortages in countries in the Middle East also must consider the relatively limited financial resources that are available.

Vitamin K2 supplementation and arterial stiffness among renal transplant recipients-a single-arm, single-center clinical trial.

Subclinical vitamin K deficiency is prevalent among renal transplant recipients and is associated with an increased risk of cardiovascular disease. However, the association between vitamin K supplementation and improvement of arterial stiffness has not been explored in the renal transplant population. The KING trial (vitamin K2 In reNal Graft) is a single-arm study that evaluated the association between the change in vitamin K status and indices of arterial stiffness following 8 weeks of menaquinone-7 (vitamin K2) supplementation (360 µg once daily) among renal transplant recipients (n = 60). Arterial stiffness was measured using carotid-femoral pulse wave velocity (cfPWV). Subclinical vitamin K deficiency was defined as plasma concentration of dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP) >500 pmol/L.At baseline, 53.3% of the study subjects had subclinical vitamin K deficiency. Supplementation was associated with a 14.2% reduction in mean cfPWV at 8 weeks (cfPWV pre-vitamin K2 = 9.8 ± 2.2 m/s vs. cfPWV post-vitamin K2 = 8.4 ± 1.5 m/s; P < .001). Mean dp-ucMGP concentrations were also significantly reduced by 55.1% following menaquinone-7 supplementation with a reduction in the prevalence of subclinical deficiency by 40% (P = .001). When controlled for age, durations of hemodialysis and transplantation, and the change in 24-hour mean arterial pressure, the improvement in arterial stiffness was independently associated with the reduction in dp-ucMGP concentration (P = .014).Among renal transplant recipients with stable graft function, vitamin K2 supplementation was associated with improvement in subclinical vitamin K deficiency and arterial stiffness. (Clinicaltrials.gov: NCT02517580).

Cyclosporine lymphocyte maximum level: a new alternative for cyclosporine monitoring in kidney transplantation.

OBJECTIVES: To determine the relationship between clinical outcome, lymphocyte count (LC), and cyclosporine (CsA) lymphocyte maximum level (LT(m)L) in kidney transplant recipients. MATERIALS AND METHODS: CsA LT(m)L was determined in patients with biopsy-proven graft dysfunction and in patients with normal graft function. Clinical outcome was compared according to CsA LT(m)L, dosage, blood trough (C(0)) and maximum (C(max)) levels, hematocrit level, and LC. RESULTS: Rejecting patients had significantly lower LT(m)L than did those with normal graft function (27 -/+ 11 pg/Lc vs 71 -/+ 79 pg/Lc; P < 0.01) and similar LTmL to those with nephrotoxicity (27 -/+ 8 pg/Lc). Patients with normal graft function exhibited significantly lower LC (0.001292 -/+ 696 x 10(9)/L) and serum creatinine levels (88.4 -/+ 35 micromol/L) when compared with rejecting patients (0.001717 -/+ 364 x 10(9)/L, 132.6 -/+ 8.8 micromol/L) and those with nephrotoxicity (0.001884 -/+ 582 x 10(9)/L, 123.7 -/+ 8.8 micromol/L) (P < 0.03, P < 0.001). No significant difference was observed among the 3 groups with regard to CsA dosage, C(0), C(max), mycophenolate mofetil (MMF) dosage, and mycophenolic acid (MPA) plasma levels. CsA LT(m)L closely correlated in an exponential (R(2) = 0.98) and linear (R(2) = 0.35) fashion with LC and hematocrit level, respectively. Conversely, CsA C(max) failed to correlate with C(0) and these 2 latter parameters. Weak correlations were observed between CsA C(max) and its corresponding LT(m)L. CONCLUSIONS: CsA LT(m)L appears to correlate better than CsA C(max) with rejection-free outcome and LC. An increase in hematocrit appears to have an adverse effect on CsA lymphocyte binding. CsA LT(m)L may offer a new alternative for CsA monitoring in kidney transplantation.

Organ procurement: should we teach undergraduate medical and nursing students?

Organ procurement and transplant improve health outcomes among patients with organ failure. Although many strategies have been developed to overcome the organ shortage, the worldwide rates of organ donation remain suboptimal. The lack of commitment to the health care mission of organ donation and the limited expertise of health care professionals reflect 2 major barriers to organ procurement and raise the need to teach organ procurement to health care professionals early during their undergraduate education. To accommodate the various available curricular models and to develop a homogeneous and equitable teaching methodology irrespective of the adopted design, an early step is to set clear goals and objectives for an organ procurement program. Outcomes should be matched to different academic levels and tailored to the duration of each medical and nursing curriculum. In all cases, hands-on experience leads to a better understanding of the topic, especially with the advent of simulation techniques that may be useful for training as well as testing purposes. An effective program finally requires that attainment of objectives and outcomes are systematically tested using proper evaluation tools that adequately pair with the curricular design. In conclusion, organ procurement teaching should adopt a systematic evidence-based approach that simultaneously contributes to medical and nursing education and improves organ donation rates.

Middle East Society for Organ Transplantation (MESOT) Transplant Registry.

During the seventies, sporadic renal transplants were performed in few MESOT-region countries, mainly Turkey, Iran, Egypt, and Lebanon. Since the introduction of cyclosporine in the early eighties, transplantation has become the preferred therapeutic modality for end-stage renal failure. In 1986, the Islamic theologians (Al Aloma) issued what became known as the Amman declaration, in which they accepted brain death and retrieval and transplantation of organs from living and cadaveric donors. Based on this and similar declarations, all Middle Eastern countries except Egypt passed laws that allow cadaveric transplantation and regulate live donations. Iran, Turkey, Saudi Arabia, Kuwait, Tunisia, Jordan, and Lebanon all have current active cadaveric programs and perform liver, heart, pancreas, and lung transplants. More than 5088 renal transplants/year are performed in the region with Iran leading with 1600. The cumulative number of renal transplant patients is now nearly 60,000. With a 2003 population of 600,682,175, the rate/million for renal transplantation in the MESOT region is a mere 9/million. Rates of renal transplantation range from 31/million in some countries to 0 in others. The major obstacle in establishing an accurate number of transplants is "tourist transplantation," in which the same transplanted patients are registered in different countries. Although cadaveric programs have been active for more than 10 years, live-related and nonrelated transplants account for nearly 85% of the total transplants. The data presented were collected from MESOT representatives in the region and from publications. For proper compilation of the registry, a format is being proposed that will be presented at the Congress for review and adaptation. Even with the limited resources in the region, immunosuppressive drugs for induction and maintenance therapy are available and are used. Costs for transplantation and immunosuppressive therapy are either totally or heavily supported by governmental agencies.

Aortic stiffness, living donors, and renal transplantation.

In subjects with renal disease, reduced renal function and increased arterial stiffness are significantly associated in cross-sectional studies. The relationship is independent of age, blood pressure (BP), and atherosclerosis. Because both variables are independent predictors of cardiovascular risk, time-dependent relationships between them are important to determine. Aortic pulse wave velocity was measured noninvasively by comparison with healthy volunteers in 101 living kidney donors and their 101 corresponding recipients. Healthy volunteers were divided into 2 groups: one was recipient related through familial links and the other was nonrecipient related. Independently of age, gender, and BP, pulse wave velocity was significantly elevated in donors and recipients by comparison with the 2 groups of healthy volunteers. Pulse wave velocity was significantly higher in the recipient-related than in the nonrecipient-related group. Whereas in healthy volunteers, pulse wave velocity was exclusively related to age, gender, and BP, in donors and recipients, it was rather associated with a cluster of cardiovascular risk factors, including smoking habits and plasma glucose. Major factors related to pulse wave velocity were renal: time since nephrectomy (donation date) in donors, in whom pulse pressure was specifically associated with proteinuria, and renal rejection in recipients. Plasma creatinine doubling secondary to chronic allograft nephropathy was significantly associated with renal rejection and donor pulse wave velocity, independent of age. Our findings strongly suggest consistent interactions (including familial factors) between kidney function and arterial stiffness. Assessment of cause-effect relationships and implication of biochemical and/or genetic factors warrant additional studies.

Aortic pulse wave velocity in renal transplant patients.

BACKGROUND: In subjects with end-stage renal disease (ESRD) undergoing hemodialysis, aortic pulse wave velocity (PWV) is increased independently of blood pressure level and mostly is a strong predictor of cardiovascular risk. Few studies on this subject have been performed in renal transplant patients. METHODS: Aortic PWV was determined noninvasively in 106 patients with kidney transplantation and treated using a standard immunosuppression protocol. Mean age was 43 +/- 14 years. During the follow-up period (mean duration 54.3 +/- 28.9 months), the following parameters were studied: characteristics of the renal graft, degree of renal insufficiency, number of acute rejections, cardiovascular risk factors, drug medications, and cardiovascular complications. RESULTS: Aortic PWV was increased in subjects with renal transplants independently of age and mean blood pressure. Acute renal rejection and smoking habits were the principal factors modulating together: the increase of aortic PWV and the reduction of the glomerular filtration rate (GFR). The latter renal parameter was also influenced by the donor age. Two main parameters were predictors of cardiovascular events: a past history of cardiovascular disease and the pulse pressure x heart rate product, the major mechanical consequence of increased PWV. CONCLUSION: In renal transplant subjects, tobacco consumption and mostly acute renal rejection modulate both aortic stiffness and chronic renal failure independent of blood pressure level and donor characteristics. Pulsatile stress mediates cardiovascular complications and predicts cardiovascular risk, particularly in the presence of increased heart rate.