Clinical efficacy and safety of switching from eculizumab to ravulizumab in adult patients with aHUS- real-world data.

BACKGROUND: The complement factor 5 (C5)-inhibitor eculizumab has been established as standard-of-care for the treatment of atypical hemolytic uremic syndrome (aHUS). In 2021, the long-acting C5-inhibitor ravulizumab was approved, extending intervals of intravenous treatment from two to eight weeks resulting in improvement of quality of life for patients and lowering direct and indirect therapy associated costs. METHODS: This multicenter, retrospective data analysis of 32 adult patients with aHUS (including 10 kidney transplant recipients) treated with eculizumab for at least three months and switched to ravulizumab aims to evaluate the safety and efficacy of switching medication in the real-world setting. Hematologic parameters, kidney function, concurrent therapy and aHUS associated events were evaluated three months before and until up to 12 months after switching to ravulizumab. RESULTS: Mean age (range) at ravulizumab initiation was 41 years (19-78 years) and 59% of the patients were female. Genetic analysis was available for all patients with 72% showing a pathogenic variant. Median time (range) on eculizumab before switching was 20 months (3-120 months). No new events of TMA or worsening of renal function were reported during up to 12 months of follow-up during ravulizumab treatment. CONCLUSIONS: This is the largest, non-industry derived, multi-center retrospective analysis of adult patients with aHUS switching C5-inhibitor treatment from eculizumab to ravulizumab in the real-world setting. Switching to ravulizumab was safe and efficient resulting in sustained hematological stability and preservation of renal function.

Deceased-Donor Acute Kidney Injury and Acute Rejection in Kidney Transplant Recipients: A Multicenter Cohort.

RATIONALE & OBJECTIVE: Donor acute kidney injury (AKI) activates innate immunity, enhances HLA expression in the kidney allograft, and provokes recipient alloimmune responses. We hypothesized that injury and inflammation that manifested in deceased-donor urine biomarkers would be associated with higher rates of biopsy-proven acute rejection (BPAR) and allograft failure after transplantation. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 862 deceased donors for 1,137 kidney recipients at 13 centers. EXPOSURES: We measured concentrations of interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) in deceased donor urine. We also used the Acute Kidney Injury Network (AKIN) criteria to assess donor clinical AKI. OUTCOMES: The primary outcome was a composite of BPAR and graft failure (not from death). A secondary outcome was the composite of BPAR, graft failure, and/or de novo donor-specific antibody (DSA). Outcomes were ascertained in the first posttransplant year. ANALYTICAL APPROACH: Multivariable Fine-Gray models with death as a competing risk. RESULTS: Mean recipient age was 54 ± 13 (SD) years, and 82% received antithymocyte globulin. We found no significant associations between donor urinary IL-18, KIM-1, and NGAL and the primary outcome (subdistribution hazard ratio [HR] for highest vs lowest tertile of 0.76 [95% CI, 0.45-1.28], 1.20 [95% CI, 0.69-2.07], and 1.14 [95% CI, 0.71-1.84], respectively). In secondary analyses, we detected no significant associations between clinically defined AKI and the primary outcome or between donor biomarkers and the composite outcome of BPAR, graft failure, and/or de novo DSA. LIMITATIONS: BPAR was ascertained through for-cause biopsies, not surveillance biopsies. CONCLUSIONS: In a large cohort of kidney recipients who almost all received induction with thymoglobulin, donor injury biomarkers were associated with neither graft failure and rejection nor a secondary outcome that included de novo DSA. These findings provide some reassurance that centers can successfully manage immunological complications using deceased-donor kidneys with AKI.

[Treatment response and complications of older patients with ANCA(antineutrophil cytoplasmatic antibody)-associated vasculitis]. / Therapieansprechen und Komplikationen von älteren Patienten mit ANCA(antineutrophile cytoplasmatische Antikörper)-assoziierten Vaskulitiden.

BACKGROUND: ANCA (antineutrophil cytoplasmatic antibody)-associated vasculitis (AAV) mainly affects elderley people but adjusted therapy concepts for this patient group are lacking. AIM: The aim of this study was therefore to analyze differences in course and outcome of patients with AAV with respect to age. MATERIALS AND METHODS: 62 patients were analyzed for treatment response, of whom 53 (85%) experienced adverse events (AE and SAE) that could be evaluated. Older (> 65 yrs.) versus younger (< 65 yrs.) patients were compared. Treatment response was assessed at 6 months, complications were assessed over 18 months. RESULTS: Treatment response was not seen to differ by age groups. In multiple logistic regression, pulmonary involvement (OR = 6,9; CI = 1,7-27,8, p < 0,01) and ΔGFR [ml/min] (OR = 0,93; CI = 0,89-0,97, p < 0,01) were predictors of SAE. 14 patients had more than 1 SAE. Again, pulmonary involvement (28,2% vs. 78,6%, p < 0,01) was a risk factor and older patients (78,6% vs. 43,6%, p = 0,025) were more frequently affected. Patients with multiple SAEs received glucocorticoids of more than 5 mg/d for longer periods of time (171 ± 65 days vs. 120 ± 70 days, p = 0,03). DISCUSSION: No differences were found between older and younger patients with regard to treatment response. Multiple SAEs occurred more frequently in elderly patients. There was a correlation between pulmonary manifestation and duration of glucocorticoid therapy with a complicated course. The most frequent SAEs were infections requiring hospitalisation. CONCLUSION: Therapy for elderly patients should be individualized with the goal of a fast reduction of glucocorticoids. Special monitoring is indicated for elderly patients, especially those with pulmonary involvement.

Diverse molecular causes of unsolved autosomal dominant tubulointerstitial kidney diseases.

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.

Contemporary incidence and risk factors of post transplant Erythrocytosis in deceased donor kidney transplantation.

BACKGROUND: Post-Transplant erythrocytosis (PTE) has not been studied in large recent cohorts. In this study, we evaluated the incidence, risk factors, and outcome of PTE with current transplant practices using the present World Health Organization criteria to define erythrocytosis. We also tested the hypothesis that the risk of PTE is greater with higher-quality kidneys. METHODS: We utilized the Deceased Donor Study which is an ongoing, multicenter, observational study of deceased donors and their kidney recipients that were transplanted between 2010 and 2013 across 13 centers. Eryrthocytosis is defined by hemoglobin> 16.5 g/dL in men and> 16 g/dL in women. Kidney quality is measured by Kidney Donor Profile Index (KDPI). RESULTS: Of the 1123 recipients qualified to be in this study, PTE was observed at a median of 18 months in 75 (6.6%) recipients. Compared to recipients without PTE, those with PTE were younger [mean 48±11 vs 54±13 years, p < 0.001], more likely to have polycystic kidney disease [17% vs 6%, p < 0.001], have received kidneys from younger donors [36 ±13 vs 41±15 years], and be on RAAS inhibitors [35% vs 22%, p < 0.001]. Recipients with PTE were less likely to have received kidneys from donors with hypertension [16% vs 32%, p = 0.004], diabetes [1% vs 11%, p = 0.008], and cerebrovascular event (24% vs 36%, p = 0.036). Higher KDPI was associated with decreased PTE risk [HR 0.98 (95% CI: 0.97-0.99)]. Over 60 months of follow-up, only 17 (36%) recipients had sustained PTE. There was no association between PTE and graft failure or mortality, CONCLUSIONS: The incidence of PTE was low in our study and PTE resolved in majority of patients. Lower KDPI increases risk of PTE. The underutilization of RAAS inhibitors in PTE patients raises the possibility of under-recognition of this phenomenon and should be explored in future studies.

[Frailty in renal diseases]. / "Frailty" bei nephrologischen Erkrankungen.

The term frailty describes a complex syndrome of reduced resistance to stress factors as a consequence of age-related degeneration in various organ systems.In the general population frailty is associated with poor clinical outcomes, including an increased risk of falls, hospitalization, functional impairment and mortality. Frailty occurs earlier and its prevalence is higher in patients with chronic kidney disease (CKD) compared to the general population. Frail patients with CKD, on dialysis or not, have reduced quality of life and increased hospitalization and mortality rates, regardless of age, sex or comorbidities.The identification of frailty in patients with CKD can lead to the detection of important and potentially modifiable risk factors. Early nephrological evaluation coupled with an interdisciplinary approach including primary care physicians, geriatricians, physiotherapists, occupational therapists and nutritionists, is fundamental in the prevention of frailty as well as in the management of frail patients with CKD.Several instruments have been developed to screen for and assess the degree of frailty; however, there is currently no recommendation as to which should be used in nephrology and how to manage frail patients with CKD. In this article we suggest an approach based on a multidimensional, interdisciplinary evaluation aimed at the early identification and management of frail CKD patients independent of the clinical setting of admission; however, more important than the method used is the need to identify and follow-up on frail CKD patients.

Peritransplant eculizumab does not prevent delayed graft function in deceased donor kidney transplant recipients: Results of two randomized controlled pilot trials.

Animal models and observational human data indicate that complement, including C5a, pathogenically participates in ischemia reperfusion (IR) injury that manifests as delayed graft function (DGF) following deceased donor kidney transplantation. We report on the safety/efficacy of anti-C5 monoclonal antibody eculizumab (Ecu) administered in the operating room prior to reperfusion, to prevent DGF in recipients of deceased donor kidney transplants in two related, investigator-sponsored, randomized controlled trials. Eight recipients from a single center were enrolled in a pilot study that led to a 19-subject multicenter trial. Together, 27 deceased donor kidney transplant recipients, 16 Ecu-treated and 11 controls, were treated with rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil with or without glucocorticoids, and followed for 6 months. Data analysis showed no epidemiological or transplant-related differences between study arms. Ecu was well tolerated with a similar severe adverse event incidence between groups. The DGF rate did not differ between Ecu-treated (44%) and control (45%, P = 1.0) subjects. Serum creatinine reduction in the first week after transplantation, and graft function up to 180-days post-transplant, were also similar. Ecu administration was safe but did not reduce the rate of DGF in a high-risk population of deceased donor recipients.

Deceased-donor acute kidney injury is not associated with kidney allograft failure.

Deceased-donor acute kidney injury (AKI) is associated with organ discard and delayed graft function, but data on longer-term allograft survival are limited. We performed a multicenter study to determine associations between donor AKI (from none to severe based on AKI Network stages) and all-cause graft failure, adjusting for donor, transplant, and recipient factors. We examined whether any of the following factors modified the relationship between donor AKI and graft survival: kidney donor profile index, cold ischemia time, donation after cardiac death, expanded-criteria donation, kidney machine perfusion, donor-recipient gender combinations, or delayed graft function. We also evaluated the association between donor AKI and a 3-year composite outcome of all-cause graft failure or estimated glomerular filtration rate ≤ 20 mL/min/1.73 m2 in a subcohort of 30% of recipients. Among 2,430 kidneys transplanted from 1,298 deceased donors, 585 (24%) were from donors with AKI. Over a median follow-up of 4.0 years, there were no significant differences in graft survival by donor AKI stage. We found no evidence that pre-specified variables modified the effect of donor AKI on graft survival. In the subcohort, donor AKI was not associated with the 3-year composite outcome. Donor AKI was not associated with graft failure in this well-phenotyped cohort. Given the organ shortage, the transplant community should consider measures to increase utilization of kidneys from deceased donors with AKI.

Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response.

To determine the site and mechanism of suppression by regulatory T (Treg) cells, we investigated their migration and function in an islet allograft model. Treg cells first migrated from blood to the inflamed allograft where they were essential for the suppression of alloimmunity. This process was dependent on the chemokine receptors CCR2, CCR4, and CCR5 and P- and E-selectin ligands. In the allograft, Treg cells were activated and subsequently migrated to the draining lymph nodes (dLNs) in a CCR2, CCR5, and CCR7 fashion; this movement was essential for optimal suppression. Treg cells inhibited dendritic cell migration in a TGF-beta and IL-10 dependent fashion and suppressed antigen-specific T effector cell migration, accumulation, and proliferation in dLNs and allografts. These results showed that sequential migration from blood to the target tissue and to dLNs is required for Treg cells to differentiate and execute fully their suppressive function.

The association of discharge decisions after deceased donor kidney transplantation with the risk of early readmission: Results from the deceased donor study.

BACKGROUND: Kidney transplant (KT) recipients experience high rates of early (≤30 days) hospital readmission (EHR) after KT, and existing studies provide limited data on modifiable discharge factors that may mitigate EHR risk. METHODS: We performed a retrospective cohort study of 468 adult deceased donor KT recipients transplanted between 4/2010 and 11/2013 at 5 United States transplant centers. We fit multivariable mixed effects models to assess the association of two potentially modifiable discharge factors with the probability of EHR after KT: (i) weekend discharge and (ii) days to first scheduled follow-up. RESULTS: Among 468 KT recipients, 38% (n = 178) experienced EHR after KT. In fully adjusted analyses, compared to weekday discharges, KT recipients discharged on the weekend had a 29% lower risk of EHR (adjusted odds ratio [aOR] 0.71, 95% confidence interval [CI] 0.41-0.94). Compared to follow-up within 2 days of discharge, KT recipients with follow-up within 3 to 6 days had a 28% higher probability of EHR (aOR 1.28, 95% CI 1.13-1.45). CONCLUSIONS: These findings suggest that clinical decisions related to the timing of discharge and follow-up modify EHR risk after KT, independent of traditional risk factors.

Reliability of deceased-donor procurement kidney biopsy images uploaded in United Network for Organ Sharing.

Prior studies demonstrate poor agreement among pathologists' interpretation of kidney biopsy slides. Reliability of representative images of these slides uploaded to the United Network of Organ Sharing (UNOS) web portal for clinician review has not been studied. We hypothesized high agreement among pathologists' image interpretation, since static images eliminate variation induced by viewing different areas of movable slides. To test our hypothesis, we compared the assessments of UNOS-uploaded images recorded in standardized forms by three pathologists. We selected 100 image sets, each having at least two images from kidneys of deceased donors. Weighted Cohen's kappa was used for inter-rater agreement. Mean (SD) donor age was 50 (13). Acute tubular injury had kappas of 0.12, 0.14, and 0.19; arteriolar hyalinosis 0.16, 0.27, and 0.38; interstitial inflammation 0.30, 0.33, and 0.49; interstitial fibrosis 0.28, 0.32, and 0.67; arterial intimal fibrosis 0.34, 0.42, and 0.59; tubular atrophy 0.35, 0.41, and 0.52; glomeruli thrombi 0.32, 0.53, and 0.85; and global glomerulosclerosis 0.68, 0.70, and 0.77. Pathologists' agreement demonstrated kappas of 0.12 to 0.77. The lower values raise concern about the reliability of using images. Although further research is needed to understand how uploaded images are used clinically, the field may consider higher-quality standards for biopsy photomicrographs.

YKL-40 Associates with Renal Recovery in Deceased Donor Kidney Transplantation.

Deceased donor kidneys with AKI are often discarded for fear of poor transplant outcomes. Donor biomarkers that predict post-transplant renal recovery could improve organ selection and reduce discard. We tested whether higher levels of donor urinary YKL-40, a repair phase protein, associate with improved recipient outcomes in a prospective cohort study involving deceased kidney donors from five organ procurement organizations. We measured urinary YKL-40 concentration in 1301 donors (111 had AKI, defined as doubling of serum creatinine) and ascertained outcomes in the corresponding 2435 recipients, 756 of whom experienced delayed graft function (DGF). Donors with AKI had higher urinary YKL-40 concentration (P<0.001) and acute tubular necrosis on procurement biopsies (P=0.05). In fully adjusted analyses, elevated donor urinary YKL-40 concentration associated with reduced risk of DGF in both recipients of AKI donor kidneys (adjusted relative risk, 0.51 [95% confidence interval (95% CI), 0.32 to 0.80] for highest versus lowest YKL-40 tertile) and recipients of non-AKI donor kidneys (adjusted relative risk, 0.79 [95% CI, 0.65 to 0.97]). Furthermore, in the event of DGF, elevated donor urinary YKL-40 concentration associated with higher 6-month eGFR (6.75 [95% CI, 1.49 to 12.02] ml/min per 1.73 m2) and lower risk of graft failure (adjusted hazard ratio, 0.50 [95% CI, 0.27 to 0.94]). These findings suggest that YKL-40 is produced in response to tubular injury and is independently associated with recovery from AKI and DGF. If ultimately validated as a prognostic biomarker, urinary YKL-40 should be considered in determining the suitability of donor kidneys for transplant.

Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective study.

BACKGROUND: Chronic injury in kidney transplants remains a major cause of allograft loss. The aim of this study was to identify a gene set capable of predicting renal allografts at risk of progressive injury due to fibrosis. METHODS: This Genomics of Chronic Allograft Rejection (GoCAR) study is a prospective, multicentre study. We prospectively collected biopsies from renal allograft recipients (n=204) with stable renal function 3 months after transplantation. We used microarray analysis to investigate gene expression in 159 of these tissue samples. We aimed to identify genes that correlated with the Chronic Allograft Damage Index (CADI) score at 12 months, but not fibrosis at the time of the biopsy. We applied a penalised regression model in combination with permutation-based approach to derive an optimal gene set to predict allograft fibrosis. The GoCAR study is registered with ClinicalTrials.gov, number NCT00611702. FINDINGS: We identified a set of 13 genes that was independently predictive for the development of fibrosis at 1 year (ie, CADI-12 ≥2). The gene set had high predictive capacity (area under the curve [AUC] 0·967), which was superior to that of baseline clinical variables (AUC 0·706) and clinical and pathological variables (AUC 0·806). Furthermore routine pathological variables were unable to identify which histologically normal allografts would progress to fibrosis (AUC 0·754), whereas the predictive gene set accurately discriminated between transplants at high and low risk of progression (AUC 0·916). The 13 genes also accurately predicted early allograft loss (AUC 0·842 at 2 years and 0·844 at 3 years). We validated the predictive value of this gene set in an independent cohort from the GoCAR study (n=45, AUC 0·866) and two independent, publically available expression datasets (n=282, AUC 0·831 and n=24, AUC 0·972). INTERPRETATION: Our results suggest that this set of 13 genes could be used to identify kidney transplant recipients at risk of allograft loss before the development of irreversible damage, thus allowing therapy to be modified to prevent progression to fibrosis. FUNDING: National Institutes of Health.

Detection of Hot-Spot Mutations in Circulating Cell-Free DNA From Patients With Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Intraductal papillary mucinous neoplasms (IPMNs) are the most frequent cystic pancreatic tumors. Little is known about their molecular alterations, but mutations in GNAS have been reported to promote IPMN formation. A tumor-derived fraction of circulating cell-free DNA (cfDNA), isolated from blood samples, contains many of the same mutations as the primary tumor, and could be a tool for noninvasive disease monitoring. We found that the total amount of cfDNA can discriminate between individuals without pancreatic lesions (controls) and patients with Fukuoka-negative branch-duct IPMN or pancreatic cancer. Furthermore, we detected GNAS mutations in cfDNA from patients with IPMN, but not in patients with serous cystadenoma or controls. Analyses of cfDNA might therefore be used in the diagnosis of patients with IPMN or in monitoring disease progression.

Performance of Serum Creatinine and Kidney Injury Biomarkers for Diagnosing Histologic Acute Tubular Injury.

BACKGROUND: The diagnosis of acute kidney injury (AKI), which is currently defined as an increase in serum creatinine (Scr) concentration, provides little information on the condition's actual cause. To improve phenotyping of AKI, many urinary biomarkers of tubular injury are being investigated. Because AKI cases are not frequently biopsied, the diagnostic accuracy of concentrations of Scr and urinary biomarkers for histologic acute tubular injury is unknown. STUDY DESIGN: Cross-sectional analysis from multicenter prospective cohort. SETTINGS & PARTICIPANTS: Hospitalized deceased kidney donors on whom kidney biopsies were performed at the time of organ procurement for histologic evaluation. PREDICTORS: (1) AKI diagnosed by change in Scr concentration during donor hospitalization and (2) concentrations of urinary biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], liver-type fatty acid-binding protein [L-FABP], interleukin 18 [IL-18], and kidney injury molecule 1 [KIM-1]) measured at organ procurement. OUTCOME: Histologic acute tubular injury. RESULTS: Of 581 donors, 98 (17%) had mild acute tubular injury and 57 (10%) had severe acute tubular injury. Overall, Scr-based AKI had poor diagnostic performance for identifying histologic acute tubular injury and 49% of donors with severe acute tubular injury did not have AKI. The area under the receiver operating characteristic curve (AUROC) of change in Scr concentration for diagnosing severe acute tubular injury was 0.58 (95% CI, 0.49-0.67) and for any acute tubular injury was 0.52 (95% CI, 0.45-0.58). Compared with Scr concentration, NGAL concentration demonstrated higher AUROC for diagnosing both severe acute tubular injury (0.67; 95% CI, 0.60-0.74; P=0.03) and any acute tubular injury (0.60; 95% CI, 0.55-0.66; P=0.005). In donors who did not have Scr-based AKI, NGAL concentrations were higher with increasing severities of acute tubular injury (subclinical AKI). However, compared with Scr concentration, AUROCs for acute tubular injury diagnosis were not significantly higher for urinary L-FABP, IL-18, or KIM-1. LIMITATIONS: The spectrum of AKI cause in deceased donors may be different from that of a general hospitalized population. CONCLUSIONS: Concentrations of Scr and kidney injury biomarkers (L-FABP, IL-18, and KIM-1) lack accuracy for diagnosing acute tubular injury in hospitalized deceased donors. Although urinary NGAL concentration had slightly higher discrimination for acute tubular injury than did Scr concentration, its overall AUROC was still modest.

Correlation between pharmacokinetics of tacrolimus and pharmacodynamics on NFAT-regulated gene expression in stable kidney transplant recipients
.

Gene expression regulated by the transcription factor NFAT (nuclear factor of activated T-cells) has been proposed for monitoring the pharmacodynamic effect of calcineurin inhibitors. We aimed to correlate the pharmacokinetics of tacrolimus with the suppression of NFAT-regulated gene expression. Tacrolimus trough (Ctrough) and peak concentrations (Cpeak) were measured by LC-MS. The effect on NFAT-regulated gene expression at trough (Etrough) and at peak levels (Epeak) were determined by qRT-PCR. The pharmacodynamic concentration producing the half-maximum effect (CE50) and the Hill coefficient (H) were estimated from Etrough and from Epeak. Ten stable kidney transplant recipients on triple immunosuppression with prednisolone, mycophenolate, and tacrolimus were analyzed. Median age was 58 years, median time since transplant was 84 months, and median serum creatinine was 249 µmol/L. The immunosuppressive effect on NFAT-regulated genes at trough concentrations was 38% (Etrough), and the effect at peak concentrations was 59% (Epeak) of maximum immunosuppression (Emax). The pharmacodynamic parameters of the action of tacrolimus were estimated with the Hill coefficient H at 1.5 and the CE50 at 6.7 ng/mL. Accordingly, the pharmacodynamic threshold concentration was estimated at 0.9 ng/mL and the ceiling concentration at 48 ng/mL, indicating a wide span between target trough and peak levels. The low Hill coefficient indicates concentration-dependent pharmacodynamics of tacrolimus on NFAT transcripts. Therefore, the extension of the administration interval to 24 hours is not likely to jeopardize the immunosuppressive effect of the prolonged-release tacrolimus preparations. 
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Survey among nephrologists in Germany: current practice and management of pregnant women on dialysis
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BACKGROUND: To assess the experience and practice patterns of nephrologists in Germany with regard to the care of pregnant women on dialysis. METHODS: The 26-item internet survey sent by email asked for demographic information, subjective proficiency, maternal and fetal complications, treatment approaches and goals. RESULTS: Of the 2,015 surveys sent out, 200 (10%) were available for evaluation. 38% of respondents never provided care, whereas 62% treated at least one pregnant patient on dialysis. In 306 total reported cases of pregnant women on dialysis, 58% became pregnant while on maintenance dialysis, and 42% developed dialysis-dependent renal failure in the course of pregnancy. For women on peritoneal dialysis (PD), only 22% of the nephrologists would continue PD until delivery, while 78% would convert to hemodialysis either immediately or shortly before delivery. 40% of the respondents reported complications in either mother or child. 45% of the respondents routinely provided prenatal counseling, and 2/3 of the nephrologists did not routinely perform fetal monitoring. While we found a significant difference in self-reported proficiency between nephrologists having and those not having treated pregnant women on dialysis, only 40% of all physicians felt confident in treating pregnant women on dialysis. CONCLUSIONS: Our survey demonstrates that the practice of nephrologists in treating pregnant women on dialysis differs significantly. These findings highlight the need for European guidelines to standardize the care of pregnant dialysis patients.
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Associations between Deceased-Donor Urine Injury Biomarkers and Kidney Transplant Outcomes.

Assessment of deceased-donor organ quality is integral to transplant allocation practices, but tools to more precisely measure donor kidney injury and better predict outcomes are needed. In this study, we assessed associations between injury biomarkers in deceased-donor urine and the following outcomes: donor AKI (stage 2 or greater), recipient delayed graft function (defined as dialysis in first week post-transplant), and recipient 6-month eGFR. We measured urinary concentrations of microalbumin, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), IL-18, and liver-type fatty acid binding protein (L-FABP) from 1304 deceased donors at organ procurement, among whom 112 (9%) had AKI. Each biomarker strongly associated with AKI in adjusted analyses. Among 2441 kidney transplant recipients, 31% experienced delayed graft function, and mean±SD 6-month eGFR was 55.7±23.5 ml/min per 1.73 m(2) In analyses adjusted for donor and recipient characteristics, higher donor urinary NGAL concentrations associated with recipient delayed graft function (highest versus lowest NGAL tertile relative risk, 1.21; 95% confidence interval, 1.02 to 1.43). Linear regression analyses of 6-month recipient renal function demonstrated that higher urinary NGAL and L-FABP concentrations associated with slightly lower 6-month eGFR only among recipients without delayed graft function. In summary, donor urine injury biomarkers strongly associate with donor AKI but provide limited value in predicting delayed graft function or early allograft function after transplant.

Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.

Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.

Delayed kidney graft function: from mechanism to translation.

In as many as 50% of cases the immediate post-kidney transplant course is complicated by delayed graft function that is most commonly related to ischemia and reperfusion injury. In addition to the acute complications related to renal failure and the associated economic impact of prolonged hospitalization, the development of delayed graft function is associated with an increased risk of chronic allograft nephropathy and shortened allograft survival. Challenges in understanding its mechanisms include the complexity, as contributors are derived from both the donor and the recipient. This acute kidney injury is modulated and caused by a complex interplay of events that lead to hypoxic and ischemic injury as well as to altered repair mechanisms. New therapies primarily seek to suppress the inflammatory homing of adaptive immune cells to the kidney, limit cell death, and/or interrupt detrimental signaling of necrosis. Although there are several promising novel targets and innovative therapeutics available, many challenges remain in their translation from bench to bedside. Identifying organs at risk and clearly defined end points will be critical in designing interventional trials.