Chronic kidney diseases are a major worldwide societal burden. In the United States, where the prevalence of chronic kidney disease is approximately 14%,
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close to 1 million persons have end-stage ...renal disease (ESRD). Of those affected, 700,000 (70.8%) are treated with dialysis, and the remaining 300,000 (29.2%) with kidney transplantation (i.e., 56 cases per 1 million population).
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Currently, just over 100,000 U.S. patients with ESRD are on the waiting list for a kidney transplant, but every year, only 15 to 16% will receive a kidney transplant, and of those kidneys, 32 to 34% are from live donors.
3
Annual U.S. expenditures . . .
Antibody mediated rejection (ABMR) is the leading cause of immune-related allograft failure following kidney transplantation. Chronic active ABMR (CABMR) typically occurs after one-year ...post-transplant and is the most common cause of late allograft failure. This study was designed to assess common practices in Europe for post-transplant surveillance 1 year after kidney transplant, as well as the diagnosis and management of CABMR. A 15-minute online survey with 58 multiple choice or open-ended questions was completed by EU transplant nephrologists, transplant surgeons and nephrologists. Survey topics included patient caseloads, post-transplant routine screening and treatment of CABMR. The results indicated that observing clinical measures of graft function form the cornerstone of post-transplant surveillance. This may be suboptimal, leading to late diagnoses and untreatable disease. Indeed, less than half of patients who develop CABMR receive treatment beyond optimization of immune suppression. This is attributable to not only late diagnoses, but also a lack of proven efficacious therapies. Intravenous Immunoglobulin (IVIG), steroid pulse and apheresis are prescribed by the majority to treat CABMR. While biologics can feature as part of treatment, there is no single agent that is being used by more than half of physicians.
The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to ...demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.
The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.
If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.
Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
Background
A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside ...USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts.
Methods
Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed.
Results
In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of –0.6 and –3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males.
Conclusion
In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.
Graphical Abstract
Graphical Abstract
Aim
The Cockcroft‐Gault (CG) creatinine‐based equation is still used to estimate glomerular filtration rate (eGFR) for drug dosage adjustment. Incorrect eGFR may lead to hazardous over‐ or ...underdosing.
Methods
In a cross‐sectional analysis, CG was validated against measured GFR (mGFR) in 14 804 participants and compared with the Modification‐of‐Diet‐in‐Renal‐Diseases (MDRD), Chronic‐Kidney‐Disease‐Epidemiology (CKD‐EPI), Lund‐Malmö‐Revised (LMR) and European‐Kidney‐Function‐Consortium (EKFC) equations. Validation focused on bias, imprecision and accuracy (percentage of estimates within ±30% of mGFR, P30), overall and stratified for mGFR, age and body mass index at mGFR <60 mL/min, as well as classification in mGFR stages.
Results
The CG equation performed worse than the other equations, overall and in mGFR, age and BMI subgroups in terms of bias (systematic overestimation), imprecision and accuracy except for patients ≥65 years where bias and P30 were similar to MDRD and CKD‐EPI, but worse than LMR and EKFC. In subjects with mGFR <60 mL/min and at BMI 18.5‐25 kg/m2, all equations performed similarly, and for BMI < 18.5 kg/m2 CG and LMR had the best results though all equations had poor P30‐accuracy. At BMI ≥ 25 kg/m2 the bias of the CG increased with increasing BMI (+17.2 mL/min at BMI ≥ 40 kg/m2). The four more recent equations also classified mGFR stages better than CG.
Conclusions
The CG equation showed poor ability to estimate GFR overall and in analyses stratified for mGFR, age and BMI. CG was inferior to correctly classify the patients in the mGFR staging compared to more recent creatinine‐based equations.
Recommendations on the glomerular filtration rate (GFR) threshold compatible with living kidney donation are not agreed upon. The recent KDIGO guidelines suggested a reset of the conventional cutoff ...value of 80 to 90 mL/min/1.73 m2. While GFR physiologically declines with age, it is unclear whether and how age should be taken into account for selecting acceptable pre-donation GFR. In this multicenter retrospective study encompassing 2007 kidney donors in France, we evaluated the impact of age using two threshold measured GFR (mGFR)s (80 and 90 mL/min/1.73 m2). Three groups of donors were defined according to baseline mGFR: below 80, 80-89.9 and 90 mL/min/1.73 m2 or more. Thirty-two percent of donors were selected despite an mGFR below 90 mL/min/1.73 m2. Donors with the lowest mGFR were significantly older (60 ± 9 vs. 47 ± 11 years) and this applied to both male and female donors. The lifetime-standardized renal reserve, defined as the pre-donation mGFR value divided by the expected number of remaining years of life, was similar irrespective of baseline mGFR groups. Similar results were obtained when eGFR was used instead of mGFR. Finally, in a subgroup of 132 donors with repeated mGFR five years after donation, the magnitude of mGFR decrease was similar in all groups (-34.3%, -33.9%, and -34.9% respectively). Thus, the decision to accept individuals with mGFR lower than 90 mL/min/1.73 m2 for kidney donation is highly dependent on the age of the candidate. Hence, threshold values lower than 90 mL/min/1.73 m2 are reasonable for older donors. Age-calibrated mGFR may improve efficiency of the selection process.
New arylbenzo
bthiophene and arylthiophene derivatives were synthesised and evaluated as inhibitors of the NorA multidrug transporter of
Staphylococcus aureus.
The synthesis based on palladium ...catalytic coupling of 38 new-arylated benzo
bthiophenes or thiophenes is described in a few steps. We also report the direct arylation of the position 3 of the benzo
bthiophenic structure, a ‘one pot’ 2,5-heterodiarylation of thiophenes as well as the synthesis of precursors of amino-acids with a 2-arylated benzo
bthiophene core. These compounds were evaluated on bacteria strains: most of them did not exhibit any antibiotic activity but were found to selectively inhibit the NorA multidrug transporter of
Staphylococcus aureus. As such, they restored the activity of the NorA substrates ciprofloxacin against a resistant
S. aureus strain in which this efflux pump is over-expressed.
BACKGROUNDTreatment decisions in kidney transplantation requires patients and clinicians to weigh the benefits and harms of a broad range of medical and surgical interventions, but the heterogeneity ...and lack of patient-relevant outcomes across trials in transplantation makes these trade-offs uncertain, thus, the need for a core outcome set that reflects stakeholder priorities.
METHODSWe convened 2 international Standardized Outcomes in Nephrology-Kidney Transplantation stakeholder consensus workshops in Boston (17 patients/caregivers; 52 health professionals) and Hong Kong (10 patients/caregivers; 45 health professionals). In facilitated breakout groups, participants discussed the development and implementation of core outcome domains for trials in kidney transplantation.
RESULTSSeven themes were identified. Reinforcing the paramount importance of graft outcomes encompassed the prevailing dread of dialysis, distilling the meaning of graft function, and acknowledging the terrifying and ambiguous terminology of rejection. Reflecting critical trade-offs between graft health and medical comorbidities was fundamental. Contextualizing mortality explained discrepancies in the prioritization of death among stakeholders—inevitability of death (patients), preventing premature death (clinicians), and ensuring safety (regulators). Imperative to capture patient-reported outcomes was driven by making explicit patient priorities, fulfilling regulatory requirements, and addressing life participation. Specificity to transplant; feasibility and pragmatism (long-term impacts and responsiveness to interventions); and recognizing gradients of severity within outcome domains were raised as considerations.
CONCLUSIONSStakeholders support the inclusion of graft health, mortality, cardiovascular disease, infection, cancer, and patient-reported outcomes (ie, life participation) in a core outcomes set. Addressing ambiguous terminology and feasibility is needed in establishing these core outcome domains for trials in kidney transplantation.
The Chronic Kidney Disease in Children Study (CKiD) equation for children and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for adults are recommended serum creatinine ...(SCr)-based calculations for estimating glomerular filtration rate (GFR). However, these equations, as well as their combination, have limitations, notably the problem of implausible changes in GFR during the transition from adolescence to adulthood and overestimation of GFR in young adults. The full age spectrum (FAS) equation addresses these issues but overestimates GFR when SCr levels are low.
To develop and validate a modified FAS SCr-based equation combining design features of the FAS and CKD-EPI equations.
Cross-sectional analysis with separate pooled data sets for development and validation.
Research and clinical studies (
= 13) with measured GFR available.
11 251 participants in 7 studies (development and internal validation data sets) and 8378 participants in 6 studies (external validation data set).
Clearance of an exogenous marker (reference method), SCr level, age, sex, and height were used to develop a new equation to estimate GFR.
The new European Kidney Function Consortium (EKFC) equation is a FAS equation with low bias (-1.2 mL/min/1.73 m
95% CI, -2.7 to 0.0 mL/min/1.73 m
in children and -0.9 mL/min/1.73 m
CI, -1.2 to -0.5 mL/min/1.73 m
in adults) across the FAS (2 to 90 years) and SCr range (40 to 490 µmol/L 0.45 to 5.54 mg/dL) and with fewer estimation errors exceeding 30% (6.5% CI, 3.8% to 9.1% in children and 3.1% CI, 2.5% to 3.6% in adults) compared with the CKiD and CKD-EPI equations.
No Black patients were included.
The new EKFC equation shows improved accuracy and precision compared with commonly used equations for estimating GFR from SCr levels.
Swedish Research Council (Vetenskapsrådet).
BACKGROUNDInconsistencies in outcome reporting and frequent omission of patient-centered outcomes can diminish the value of trials in treatment decision making. We identified critically important ...outcome domains in kidney transplantation based on the shared priorities of patients/caregivers and health professionals.
METHODSIn a 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcome domains for trials in kidney transplantation on a 9-point Likert scale and provided comments. During rounds 2 and 3, participants rerated the outcomes after reviewing their own score, the distribution of the respondentsʼ scores, and comments. We calculated the median, mean, and proportion rating 7 to 9 (critically important), and analyzed comments thematically.
RESULTSOne thousand eighteen participants (461 45% patients/caregivers and 557 55% health professionals) from 79 countries completed round 1, and 779 (77%) completed round 3. The top 8 outcomes that met the consensus criteria in round 3 (mean, ≥7.5; median, ≥8; proportion, >85%) in both groups were graft loss, graft function, chronic rejection, acute rejection, mortality, infection, cancer (excluding skin), and cardiovascular disease. Compared with health professionals, patients/caregivers gave higher priority to 6 outcomes (mean difference of 0.5 or more)skin cancer, surgical complications, cognition, blood pressure, depression, and ability to work. We identified 5 themescapacity to control and inevitability, personal relevance, debilitating repercussions, gaining awareness of risks, and addressing knowledge gaps.
CONCLUSIONSGraft complications and severe comorbidities were critically important for both stakeholder groups. These stakeholder-prioritized outcomes will inform the core outcome set to improve the consistency and relevance of trials in kidney transplantation.
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