The effect of additional drug therapy as metaphylaxis in patients with cystinuria: a systematic review.

INTRODUCTION: To systematically review the effect of additional drug therapy as metaphylaxis in patients with cystinuria. EVIDENCE ACQUISITION: A literature search of three databases (MEDLINE, Embase and the Cochrane Library) was performed according to the PRISMA-guidelines enclosing articles published up to May 2019. A total of 1117 articles were screened. Thirty-four publications met the inclusion criteria for this review. EVIDENCE SYNTHESIS: Male-female ratio in the studied cohorts was 49.9% - 50.1%. The majority of studies showed a positive effect in reducing stone events and/or urinary cystine excretion. D-Penicillamine showed success in 13/14 (92%) studies, whereas Tiopronin-treatment showed a reduction in all (8/8; 100%) studies. All studies on Captopril (4/4) showed a decrease, however not all significant. The same is true for studies on Thiols in combination with Captopril (2/2). Furthermore, Tiopronin showed less side effects compared to D-penicillamine, respectively 30% and 37%. Captopril showed the least adverse events, with one event in nine patients. CONCLUSIONS: The evidence on benefit of additional drug therapy in patients with cystinuria is scarce. All studied medications showed an effect on stone event and urinary cystine excretion, when used in addition to hyperhydration, alkalization and a diet low on methionine. Based on this systematic review, no drug can be preferred over another. An important aspect in the choice of drug is the risk of side effects. Therefore, the choice of additional drug should be personalized for every patient where the risk of side effects should be taken into consideration.

Impact of Cold Ischemia Time on Outcomes of Deceased Donor Kidney Transplantation: An Analysis of a National Registry.

BACKGROUND: Cold ischemia time (CIT) is known to impact kidney graft survival rates. We compare the impact of CIT on graft failure and mortality in circulatory death versus brain death donor kidneys and how it relates to donor age. METHODS: We used the prospective Dutch Organ Transplantation Registry to include 2153 adult recipients of brain death (n = 1266) and circulatory death (n = 887) donor kidneys after static cold storage from transplants performed between 2005 and 2012. CIT was modeled nonlinearly with splines. Associations and interactions between CIT, donor type, donor age, 5-year (death-censored) graft survival, and mortality were evaluated. RESULTS: The median CIT was 16.2 hours (interquartile range 12.8-20), ranging from 3.4 to 44.7 hours for brain death and 4.7 to 46.6 hours for circulatory death donor kidneys. At >12 hours of CIT, we observed an increased risk of graft failure in kidneys donated after circulatory death versus after brain death. This risk rose significantly at >22 hours of CIT (hazard ratio 1.45; 95% confidence interval, 1.01-2.49; P = 0.043). Kidneys that came from 60-year-old circulatory death donors demonstrated elevated hazard risk at 19 hours of CIT, a shorter timeline than that for kidneys that came from brain death donors of the same age (hazard ratio 1.33; 95% confidence interval, 1.00-1.78; P = 0.045). The additional harmful effects of increased CIT in kidneys from circulatory-death donors were also found for death-censored graft failure but did not affect mortality rates in any significant way. CONCLUSIONS: The findings support the hypothesis that prolonged cold ischemia is more harmful for circulatory death donor kidneys that have already been subjected to a permissible period of warm ischemia. Efforts should be made to reduce CIT, especially for older circulatory death donor kidneys.

Early Steroid Withdrawal Compared With Standard Immunosuppression in Kidney Transplantation - Interim Analysis of the Amsterdam-Leiden-Groningen Randomized Controlled Trial.

BACKGROUND: The optimal immunosuppressive regimen in kidney transplant recipients, delivering maximum efficacy with minimal toxicity, is unknown. METHODS: The Amsterdam, LEiden, GROningen trial is a randomized, multicenter, investigator-driven, noninferiority, open-label trial in 305 kidney transplant recipients, in which 2 immunosuppression minimization strategies-one consisting of early steroid withdrawal, the other of tacrolimus minimization 6 months after transplantation-were compared with standard immunosuppression with basiliximab, corticosteroids, tacrolimus, and mycophenolic acid. The primary endpoint was kidney function. Secondary endpoints included death, primary nonfunction, graft failure, rejection, discontinuation of study medication, and a combined endpoint of treatment failure. An interim analysis was scheduled at 6 months, that is, just before tacrolimus minimization. RESULTS: This interim analysis revealed no significant differences in Modification of Diet in Renal Disease between the early steroid withdrawal group and the standard immunosuppression groups (43.2 mL/min per 1.73 m2 vs 45.0 mL/min per 1.73 m2, P = 0.408). There were also no significant differences in the secondary endpoints of death (1.0% vs 1.5%; P = 0.737), primary nonfunction (4.1% vs 1.5%, P = 0.159), graft failure (3.1% vs 1.5%, P = 0.370), rejection (18.6% vs 13.6%, P = 0.289), and discontinuation of study medication (19.6% vs 12.6%, P = 0.348). Treatment failure, defined as a composite endpoint of these individual secondary endpoints, was more common in the early steroid withdrawal group (P = 0.027), but this group had fewer serious adverse events and a more favorable cardiovascular risk profile. CONCLUSIONS: Based on these interim results, early steroid withdrawal is a safe short-term immunosuppressive strategy. Long-term outcomes, including a comparison with tacrolimus minimization after 6 months, will be reported in the final 2-year analysis.

Long-term cardiovascular outcome of renal transplant recipients after early conversion to everolimus compared to calcineurin inhibition: results from the randomized controlled MECANO trial.

Long-term data on cardiovascular (CV) outcome of renal transplant recipients (RTR) on mTOR-i (mammalian Target Of Rapamycin-inhibitors) are scarce. In a sub-study of the MECANO trial we investigated changes in intima media thickness (IMT), CV risk profile, Major Adverse CV Events (MACE) and survival in RTR on a mTORi versus CNI based regimen. Patients (enrolled 361) were treated with (basiliximab) and triple IS (CsA-Cyclosporine A-(C), MPS (M), prednisolone (P)). At M6 patients were randomized (n = 224) to the CsA group (C, P, N = 89), MPS group (M, P, N = 39) EVL group (Everolimus, P, N = 96). At week 2, M6 and M 24, IMT measurements of the Common Carotid Artery were performed. Cardiovascular risk factors were assessed at baseline, 6 and 24 months of follow-up. Seven years survival and MACE-free survival probability were calculated by the Cardiovascular Risk Calculator for RTR. After 7 years of follow-up, incidence of cardiovascular events and patient survival were assessed. Mean IMT at baseline (N = 192), was 0.64 ± 0.14 mm. At M6 (N = 158), 0.66 ± 0.15, M24 IMT was 0.68 ± 0.15 (N = 95). No significant differences between groups concerning IMT, true CV events and mortality, CV risk profile, predicted MACE/Mortality were found between mTORi and CNI-based regimen after 7 years of follow-up.

Prediction models for delayed graft function: external validation on The Dutch Prospective Renal Transplantation Registry.

Background: Delayed graft function (DGF) is a common complication after kidney transplantation in the era of accepting an equal number of brain- and circulatory-death donor kidneys in the Netherlands. To identify those cases with an increased risk of developing DGF, various multivariable algorithms have been proposed. The objective was to validate the reproducibility of four predictive algorithms by Irish et al. (A risk prediction model for delayed graft function in the current era of deceased donor renal transplantation. Am J Transplant 2010;10:2279-2286) (USA), Jeldres et al. (Prediction of delayed graft function after renal transplantation. Can Urol Assoc J 2009;3:377-382) (Canada), Chapal et al. (A useful scoring system for the prediction and management of delayed graft function following kidney transplantation from cadaveric donors. Kidney Int 2014;86:1130-1139) (France) and Zaza et al. (Predictive model for delayed graft function based on easily available pre-renal transplant variables. Intern Emerg Med 2015;10:135-141) (Italy) according to a novel framework for external validation. Methods: We conducted a prospective observational study with data from the Dutch Organ Transplantation Registry (NOTR). Renal transplant recipients from all eight Dutch academic medical centers between 2002 and 2012 who received a deceased allograft were included (N = 3333). The four prediction algorithms were reconstructed from donor, recipient and transplantation data. Their predictive value for DGF was validated by c-statistics, calibration statistics and net benefit analysis. Case-mix (un)relatedness was investigated with a membership model and mean and standard deviation of the linear predictor. Results: The prevalence of DGF was 37%. Despite a significantly different case-mix, the US algorithm by Irish was best reproducible, with a c-index of 0.761 (range 0.756 - 0.762), and well-calibrated over the complete range of predicted probabilities of having DGF. The US model had a net benefit of 0.242 at a threshold probability of 0.25, compared with 0.089 net benefit for the same threshold in the original study, equivalent to correctly identifying DGF in 24 cases per 100 patients (true positive results) without an increase in the number of false-positive results. Conclusions: The US model by Irish et al. was generalizable and best transportable to Dutch recipients with a deceased donor kidney. The algorithm detects an increased risk of DGF after allocation and enables us to improve individual patient management.

Validation of the Prognostic Kidney Donor Risk Index Scoring System of Deceased Donors for Renal Transplantation in the Netherlands.

BACKGROUND: The prognostic Kidney Donor Risk Index (KDRI)-developed and internally validated in the United States-is a widely used tool to predict transplant outcome of a deceased donor kidney. The KDRI is currently used for longevity matching between donors and recipients in the United States. METHODS: We aimed to externally validate the KDRIdonor-only and KDRIfull as proposed by Rao et al (2009). KDRIdonor-only consist of 10 donor factors, and KDRIfull with an additional 4 transplant factors. We used the Dutch Organ Transplantation Registry to include 3201 adult recipients transplanted from 2002 to 2012. RESULTS: The median Dutch KDRI was 1.21 and comparable with the year 2012 in the United States (median of 1.24). The calibration-slope was 0.98 and 0.96 for the KDRIfull and KDRIdonor-only, respectively, indicating that predictions of graft failure were on average similar. The discriminative ability (Harrell C) of the KDRIfull and the KDRIdonor-only at 5 years was 0.63 (95% confidence interval [CI], 0.62-0.64), and 0.62 (95% CI, 0.61-0.63), respectively. We found misspecification of 3 KDRI factors: age (P = 0.002), weight (P = 0.017), and cold ischemia time (P < 0.001). Adding the use of inotropic drugs before donation (P = 0.040) and the interaction between circulatory-death donor kidneys and prolonged cold ischemic time (>24 hours vs 12 hours; P = 0.059) could improve predictive ability. CONCLUSIONS: The KDRI performs equal in the Dutch population. Discriminative ability of the KDRI indicates limited clinical use for adequate individualized decisions. An updated KDRI may contribute to a standardized policy meeting the growing demand of donor kidneys in the Eurotransplant region.

Incidence and outcome of BK polyomavirus infection in a multicenter randomized controlled trial with renal transplant patients receiving cyclosporine-, mycophenolate sodium-, or everolimus-based low-dose immunosuppressive therapy.

BACKGROUND: It remains unclear whether overall degree of immunosuppression or specific effects of individual immunosuppressive agents are causal for increased occurrence of BK polyomavirus (BKPyV) infection in renal transplant recipients (RTR). METHODS: A prospective, multicenter, open-label randomized controlled trial in 361 de novo RTR was performed. A total of 224 RTR were randomized at 6 months into three treatment groups with dual therapy consisting of prednisolone (Pred) plus either cyclosporine (CsA), mycophenolate sodium (MPS), or everolimus (EVL). Primary outcomes were incidence of BK viruria, BK viremia, and BKPyV-associated nephropathy (BKVAN). RESULTS: From 6 months, incidence of BK viruria in the MPS group (43.6%) was significantly higher than in the other groups (CsA: 16.9%, EVL: 19.8%) (P=.003). BKVAN was diagnosed in 3 patients, all treated with MPS (7.8%, P=.001). Longitudinal data analysis showed a lower BKPyV load and a significantly faster clearance of BK viruria in the CsA group compared to the MPS group (P=.03). CONCLUSIONS: Treatment with MPS was associated with an increased incidence of BK viruria. Dual immunosuppressive therapy with CsA and Pred was associated with the lowest rate of BKPyV replication and the fastest clearance of the virus.

Changes of perceived control after kidney transplantation: a prospective study.

AIMS: The aim of this study was to determine if kidney transplantation is associated with increases of perceived control and how changes of perceived control affect the course of psychological distress until 1 year after transplantation. BACKGROUND: Low levels of perceived control are associated with reduced well-being among dialysis patients. DESIGN: Prospective longitudinal cohort study. METHODS: Perceived control (Mastery Scale) and psychological distress (GHQ-12) were prospectively assessed before (T0; n = 470) and three (T1; n = 197), six (T2; n = 210) and twelve (T3; n = 183) months after transplantation. Differences between T1 and T0 perceived control were used to stratify the sample into three groups (control gain, stable control and control loss). Socio-demographic and clinical variables, including complications, were examined as potential correlates and the course of psychological was distress compared across groups. Data were collected between July 2008 - July 2013. RESULTS: Perceived control showed a small increase overall, with 35·1%, 50·0% and 14·9% reporting gain, stable level and loss respectively. Patients with secondary schooling were overrepresented in the control loss group. The course of psychological distress varied across perceived control change groups, with patients in the control gain group experiencing a significant reduction in psychological distress. CONCLUSION: A considerable number of patients report increased levels of perceived control after transplantation that are associated with a subsequent decrease in psychological distress. Results emphasize the importance of perceived control and could inform interventions to facilitate well-being after kidney transplantation.

Similar 5-Year Estimated Glomerular Filtration Rate Between Kidney Transplants From Uncontrolled and Controlled Donors After Circulatory Death-A Dutch Cohort Study.

BACKGROUND: Organ shortage persists despite a high rate of donation after circulatory death (DCD) in the Netherlands. The median waiting time for a deceased donor kidney in 2013 was 3.5 years. Most DCD kidneys are from controlled DCD (cDCD; Maastricht category III). Experience with uncontrolled donors after cardiac death (uDCD), that is, donors with an unexpected and irreversible cardiac arrest (Maastricht categories I and II), is increasing; and its effect on transplant outcomes needs evaluation. METHODS: We used the Dutch Organ Transplantation Registry to include recipients (≥18 years old) from all Dutch centers who received transplants from 2002 to 2012 with a first DCD kidney. We compared transplant outcome in uDCD (n = 97) and cDCD (n = 1441). RESULTS: Primary nonfunction in uDCD was higher than in the cDCD (19.6% vs 9.6%, P < 0.001, respectively). Delayed graft function was also higher in uDCD than in cDCD, but not significantly (73.7% vs 63.3%, P = .074, respectively). If censored for primary nonfunction, estimated glomerular filtration rates after 1 year and 5 years were comparable between uDCD and cDCD (1 year: uDCD, 44.3 (23.4) mL/min/m and cDCD, 45.8 (24.1) mL/min/m; P = 0.621; 5 years: uDCD, 49.1 (25.6) mL/min/m and cDCD, 47.7 (21.7) mL/min/m; P = 0.686). The differences in primary nonfunction between kidneys from uDCD and cDCD were explained by differences in the first warm ischemic period, cold ischemic time, and donor age. CONCLUSIONS: We conclude that uDCD kidneys have potential for excellent function and can constitute a valuable extension of the donor pool. However, further efforts are necessary to address the high rate of primary nonfunction.

Stretching the Limits of Renal Transplantation in Elderly Recipients of Grafts from Elderly Deceased Donors.

An increasing number of elderly patients (≥65 years) receive a donor kidney from elderly donors after brain death (DBD) or after circulatory death (DCD). These organs are allocated within the Eurotransplant Senior Program, but outcomes must be evaluated. From the Dutch Organ Transplantation Registry, we selected 3597 recipients (≥18 years) who received a first DBD or DCD kidney during 2002-2012, and categorized them as young or elderly recipients receiving a graft from either a young or elderly donor, stratified by donor type. In multiple logistic regression analysis, elderly recipients of elderly DCD kidneys experienced more delayed graft function and acute rejection than did elderly recipients of young DBD kidneys (odds ratios 10.43 [95% confidence interval (95% CI), 5.75 to 18.91] and 2.78 [95% CI, 1.35 to 5.73], respectively). In Cox regression analysis, elderly recipients of elderly DCD kidneys had a 5-year mortality risk higher than that of elderly recipients of young DBD kidneys (hazard ratio, 1.86; 95% CI, 1.15 to 3.02). Elderly recipients of elderly kidneys had a 5-year mortality rate comparable to that of waitlisted elderly patients remaining on dialysis. Among elderly recipients, 63.8% of those who received elderly DCD kidneys, 45.5% of those who received elderly DBD kidneys, and approximately 26% of those who received young DBD or DCD kidneys had an eGFR<30 ml/min per 1.73 m2 (including primary nonfunction) after 1 year. In conclusion, improving donor selection and preservation is warranted if the allocation of elderly DCD grafts to elderly recipients is to be expanded.

Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients.

AIMS: This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR). METHODS: Adult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model. RESULTS: Fourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6-month biopsy (13% vs. 50%). CONCLUSIONS: Transplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies.

Towards a standardised informed consent procedure for live donor nephrectomy: the PRINCE (Process of Informed Consent Evaluation) project-study protocol for a nationwide prospective cohort study.

INTRODUCTION: Informed consent is mandatory for all (surgical) procedures, but it is even more important when it comes to living kidney donors undergoing surgery for the benefit of others. Donor education, leading to informed consent, needs to be carried out according to certain standards. Informed consent procedures for live donor nephrectomy vary per centre, and even per individual healthcare professional. The basis for a standardised, uniform surgical informed consent procedure for live donor nephrectomy can be created by assessing what information donors need to hear to prepare them for the operation and convalescence. METHODS AND ANALYSIS: The PRINCE (Process of Informed Consent Evaluation) project is a prospective, multicentre cohort study, to be carried out in all eight Dutch kidney transplant centres. Donor knowledge of the procedure and postoperative course will be evaluated by means of pop quizzes. A baseline cohort (prior to receiving any information from a member of the transplant team in one of the transplant centres) will be compared with a control group, the members of which receive the pop quiz on the day of admission for donor nephrectomy. Donor satisfaction will be evaluated for all donors who completed the admission pop-quiz. The primary end point is donor knowledge. In addition, those elements that have to be included in the standardised format informed consent procedure will be identified. Secondary end points are donor satisfaction, current informed consent practices in the different centres (eg, how many visits, which personnel, what kind of information is disclosed, in which format, etc) and correlation of donor knowledge with surgeons' estimation thereof. ETHICS AND DISSEMINATION: Approval for this study was obtained from the medical ethical committee of the Erasmus MC, University Medical Center, Rotterdam, on 18 February 2015. Secondary approval has been obtained from the local ethics committees in six participating centres. Approval in the last centre has been sought. RESULTS: Outcome will be published in a scientific journal. TRIAL REGISTRATION NUMBER: NTR5374; Pre-results.

Role of the vascular wall in sodium homeostasis and salt sensitivity.

Excessive sodium intake is associated with both hypertension and an increased risk of cardiovascular events, presumably because of an increase in extracellular volume. The extent to which sodium intake affects extracellular volume and BP varies considerably among individuals, discriminating subjects who are salt-sensitive from those who are salt-resistant. Recent experiments have shown that, other than regulation by the kidney, sodium homeostasis is also regulated by negatively charged glycosaminoglycans in the skin interstitium, where sodium is bound to glycosaminoglycans without commensurate effects on extracellular volume. The endothelial surface layer is a dynamic layer on the luminal side of the endothelium that is in continuous exchange with flowing blood. Because negatively charged glycosaminoglycans are abundantly present in this layer, it may act as an intravascular buffer compartment that allows sodium to be transiently stored. This review focuses on the putative role of the endothelial surface layer as a contributor to salt sensitivity, the consequences of a perturbed endothelial surface layer on sodium homeostasis, and the endothelial surface layer as a possible target for the treatment of hypertension and an expanded extracellular volume.

Great expectations? Pre-transplant quality of life expectations and distress after kidney transplantation: a prospective study.

OBJECTIVES: Previous research suggests that prior to kidney transplantation, patients overestimate their post-transplant quality of life (QoL). The current study aimed to corroborate these findings, identify determinants of QoL overestimation, examine its association with subsequent distress, and clarify the role of optimism. DESIGN: Prospective observational study. METHODS: Physical, psychological, and social QoL expectations, actual QoL, and distress (GHQ-12) of participants (56% male) were prospectively assessed before (T0; n = 228) and 3 (T1; n = 149), 6 (T2; n = 146), and 12 (T3; n = 114) months after successful transplantation. RESULTS: Patients who were treated with haemodialysis before transplantation reported greater physical QoL overestimation than those who received treatment with peritoneal dialysis. Neither physical nor social QoL overestimation at T1 was prospectively associated with increased distress at T2 or T3. The interaction between optimism and social QoL overestimation at T1 (ß = -.56, p < .001) for distress at T2 was significant, with patients low in optimism experiencing more distress after QoL overestimation. CONCLUSIONS: QoL overestimation is not associated with subsequent distress. Findings suggest that patients low in optimism are more vulnerable to distress following QoL overestimation. STATEMENT OF CONTRIBUTION: What is already known on this subject? Kidney transplantation improves patients' quality of life. Prior to kidney transplantation, patients overestimate the scale of this improvement. What does this study add? Quality of life overestimation is not associated with subsequent distress. When optimism is low, kidney transplant recipients experience higher distress following quality of life overestimation.

The Biobank of Nephrological Diseases in the Netherlands cohort: the String of Pearls Initiative collaboration on chronic kidney disease in the university medical centers in the Netherlands.

Despite advances in preventive therapy, prognosis in chronic kidney disease (CKD) is still grim. Clinical cohorts of CKD patients provide a strategic resource to identify factors that drive progression in the context of clinical care and to provide a basis for improvement of outcome. The combination with biobanking, moreover, provides a resource for fundamental and translational studies. In 2007, the Dutch government initiated and funded the String of Pearls Initiative (PSI), a strategic effort to establish infrastructure for disease-based biobanking in the University Medical Centres (UMCs) in the Netherlands, in a 4-year start-up period. CKD was among the conditions selected for biobanking, and this resulted in the establishment of the Biobank of Nephrological Diseases-NL (BIND-NL) cohort. Patients with CKD Stages 1-4 are eligible. The data architecture is designed to reflect routine care, with specific issues added for enrichment, e.g. questionnaires. Thus, the collected clinical and biochemical data are those required by prevailing guidelines for routine nephrology care, with a minimal dataset for all patients, and diagnosis-specific data for the diagnostic categories of primary and secondary glomerular disorders and adult dominant polycystic kidney disease, respectively. The dataset is supplemented by a biobank, containing serum, plasma, urine and DNA. The cohort will be longitudinally monitored, with yearly follow-up for clinical outcome. Future linking of the data to those from the national registries for renal replacement therapy is foreseen to follow the patients' lifeline throughout the different phases of renal disease and different treatment modalities. In the design of the data architecture, care was taken to ensure future exchangeability of data with other CKD cohorts by applying the data harmonization format of the Renal DataSHaPER, with a dataset based upon standardized indicator sets to facilitate collaboration with other CKD cohorts. Enrolment started in 2010, and over 2200 eligible patients have been enrolled in the different UMCs. Follow-up of enrolled patients has started, and enrolment will continue at a slower rate. The aggregation and standardization of clinical data and biosamples from large numbers of CKD patients will be a strategic resource not only for clinical and translational research, but also by its basis in routine clinical care for clinical governance and quality improvement projects.

Nonesterified fatty acids and development of graft failure in renal transplant recipients.

BACKGROUND: Chronic transplant dysfunction is the most common cause of graft failure on the long term. Proteinuria is one of the cardinal clinical signs of chronic transplant dysfunction. Albumin-bound fatty acids (FA) have been hypothesized to be instrumental in the etiology of renal damage induced by proteinuria. We therefore questioned whether high circulating FA could be associated with an increased risk for future development of graft failure in renal transplant recipients (RTR). To this end, we prospectively investigated the association of fasting concentrations of circulating nonesterified FA (NEFA) with the development of graft failure in RTR. METHODS: Baseline measurements were performed between 2001 and 2003 in outpatient RTR with a functioning graft of more than 1 year. Follow-up was recorded until May 19, 2009. Graft failure was defined as return to dialysis or retransplantation. RESULTS: We included 461 RTR at a median (interquartile range [IQR]) of 6.1 (3.3-11.3) years after transplantation. Median (IQR) fasting concentrations of NEFA were 373 (270-521) µM/L. Median (IQR) follow-up for graft failure beyond baseline was 7.1 (6.1-7.5) years. Graft failure occurred in 23 (15%), 14 (9%), and 9 (6%) of RTR across increasing gender-specific tertiles of NEFA (P=0.04). In a gender-adjusted Cox-regression analysis, log-transformed NEFA level was inversely associated with the development of graft failure (hazard ratio, 0.61; 95% confidence interval, 0.47-0.81; P<0.001). CONCLUSIONS: In this prospective cohort study in RTR, we found an inverse association between fasting NEFA concentrations and risk for development of graft failure. This association suggests a renoprotective rather than a tubulotoxic effect of NEFA. Further studies on the role of different types of NEFA in the progression of renal disease are warranted.

Impact of depression on long-term outcome after renal transplantation: a prospective cohort study.

BACKGROUND: Renal transplantation is the treatment of choice for end stage renal disease. Although there is more depression in wait-listed versus transplant patients, depression persists after transplantation. We investigated the determinants of depression in renal transplantation recipients (RTRs) and the association with cardiovascular (CV) and all-cause-mortality and graft failure. METHODS: RTR were investigated between 2001 and 2003. Depression was assessed using the Depression Subscale of the Symptom Checklist (SCL-90). Mortality and graft failure were recorded until May 2009. RESULTS: A total of 527 RTR (age, 51±12 years; 55% men) were studied; 31% of the RTR were indicated with depression. Independent variables associated with depression were medically unfit for work, proteinuria, lower physical activity level, and longer dialysis duration. During follow-up for 7.0 (6.2-7.5) years, 114 RTR (59 CV) died. In Cox regression analyses, depression was strongly associated with increased risk for CV (HR=2.12 [1.27-3.53], P=0.004) and all-cause mortality (HR=1.96 [1.36-2.84], P<0.001). Adjustments for confounders did not materially change these associations. The association with graft failure (HR=1.77 [1.01-3.10]. P=0.047) disappeared after adjustment for kidney function (P=0.6). CONCLUSIONS: Although our study has several limitations, including the lack of pretransplant depression status, we identified medically unfit for work, proteinuria, lower physical activity level, and longer dialysis duration as independent variables associated with depression. We furthermore found that depression is associated with CV and all-cause mortality in RTR.

The role of personal characteristics in the relationship between health and psychological distress among kidney transplant recipients.

Although kidney transplantation improves overall quality of life and physical functioning, improvements of psychological distress are often modest. However, apparent stressors such as comorbidity are only weakly associated with psychological distress and their impact differs considerably between patients. Wilson and Cleary proposed a theoretical model to explain these relationships. This model has been supported by research, but has never been applied in a population of kidney transplant recipients. Findings of the current study are based on a cross-sectional study carried out in 2008 in the northern Netherlands. An elaborated version of Wilson and Cleary's model specifying hypothesized relationships of objective health, functional status, subjective health, personal characteristics and psychological distress was evaluated with structural equation modelling. After elimination of non-significant paths the final model provided a good fit for the data, X(2) (2)=4.23, p=0.12; RMSEA=0.047, CI(RMSEA) (0; 0.11); ECVI=0.060, ECVI(sat)=0.059. Results suggest that objective health has an indirect effect on psychological distress, in size comparable to the effects exerted by functional status and subjective health. Personal characteristics are the strongest determinant of psychological distress, but are directly and indirectly affected by objective health. Results indicate that poor health might cause psychological distress by increasing coping demands while simultaneously decreasing coping resources.

Plasma bilirubin and late graft failure in renal transplant recipients.

Exogenous bilirubin has been shown to protect against oxidative stress in ischemia-reperfusion injury. Oxidative stress has been implicated in the pathophysiology of chronic transplant dysfunction leading to late graft failure after renal transplantation. We prospectively investigated whether high endogenous bilirubin is protective against development of late graft failure in renal transplant recipients (RTR). Baseline data were collected between August 2001 and July 2003 in nonicteric outpatient RTR with a functioning graft for >1 year. At baseline, bilirubin and liver enzymes were measured using routine assays on a Merck Mega analyzer. Graft failure was prospectively recorded until May 19 2009. During follow-up for 7.1 [6.2-7.2] years, 55 RTR developed graft failure. We found that circulating levels of bilirubin are inversely associated with late graft failure in RTR (HR = 0.29 [95% CI: 0.16-0.52], P < 0.001). This association was independent of potential confounders, including creatinine clearance, urinary protein excretion, calcineurin inhibitors, and gender (HR = 0.31 [95% CI: 0.15-0.62] P = 0.001). Our findings are consistent with a protective effect of increased endogenous bilirubin against development of late graft failure in RTR. If our findings are confirmed by other studies, intervention with endogenous or exogenous bilirubin may be of interest for long-term preservation of renal function in RTR.