Improving outcomes for donation after circulatory death kidney transplantation: Science of the times

The use of kidneys donated after circulatory death (DCD) remains controversial due to concerns with regard to high incidences of early graft loss, delayed graft function (DGF), and impaired graft survival. As these concerns are mainly based on data from historical cohorts, they are prone to time-related effects and may therefore not apply to the current timeframe. To assess the impact of time on outcomes, we performed a time-dependent comparative analysis of outcomes of DCD and donation after brain death (DBD) kidney transplantations. Data of all 11,415 deceased-donor kidney transplantations performed in The Netherlands between 1990-2018 were collected. Based on the incidences of early graft loss, two eras were defined (1998-2008 [n = 3,499] and 2008-2018 [n = 3,781]), and potential time-related effects on outcomes evaluated. Multivariate analyses were applied to examine associations between donor type and outcomes. Interaction tests were used to explore presence of effect modification. Results show clear time-related effects on posttransplant outcomes. The 1998-2008 interval showed compromised outcomes for DCD procedures (higher incidences of DGF and early graft loss, impaired 1-year renal function, and inferior graft survival), whereas DBD and DCD outcome equivalence was observed for the 2008-2018 interval. This occurred despite persistently high incidences of DGF in DCD grafts, and more adverse recipient and donor risk profiles (recipients were 6 years older and the KDRI increased from 1.23 to 1.39 and from 1.35 to 1.49 for DBD and DCD donors). In contrast, the median cold ischaemic period decreased from 20 to 15 hours. This national study shows major improvements in outcomes of transplanted DCD kidneys over time. The time-dependent shift underpins that kidney transplantation has come of age and DCD results are nowadays comparable to DBD transplants. It also calls for careful interpretation of conclusions based on historical cohorts, and emphasises that retrospective studies should correct for time-related effects.Transplant surger

Short- and Long-Term Results of Open Versus Laparoscopic Appendectomy

Clinical advantages of laparoscopic appendectomy have been shown in numerous trials and reviews. Most of these advantages are small and of limited clinical relevance, while laparoscopic operation costs are reported to be higher. The present study compares short- and long-term results of conventional appendectomy with or without diagnostic laparoscopy (OA), and laparoscopic appendectomy (LA). All adult patients who underwent appendectomy in our institution from 1995 to 2005 were included retrospectively. Patient data were retrieved from medical records, questionnaires sent by mail, and records of general practitioners. Primary outcome parameters were long-term complications, readmissions, and reinterventions (> 30 days postoperatively). Secondary outcome parameters were short-term complications, readmissions, and reinterventions (a parts per thousand currency sign30 days postoperatively). A total of 755 patients were included, 545 of whom underwent OA, with the remaining 210 undergoing LA. In the long term there were few complications noted, and there were no significant differences in complications between the two groups. Within 30 days postoperatively, LA was associated with a significantly higher incidence of abdominal abscesses with consequent diagnostic investigations, interventions, and readmissions. Although laparoscopic appendectomy is known to deliver clinical advantages, it is associated with a higher incidence of abdominal abscesses. Because the procedure is about to become the standard of care, future research must be directed at solving this issue. The expected lower incidence of incisional hernia and small bowel obstruction after laparoscopic appendectomy was not shown in the present stud

Clonal evolution of CD8+ T cell responses against latent viruses: relationship among phenotype, localization, and function

Human cytomegalovirus (hCMV) infection is characterized by a vast expansion of resting effector-type virus-specific T cells in the circulation. In mice, interleukin-7 receptor α (IL-7Rα)-expressing cells contain the precursors for long-lived antigen-experienced CD8(+) T cells, but it is unclear if similar mechanisms operate to maintain these pools in humans. Here, we studied whether IL-7Rα-expressing cells obtained from peripheral blood (PB) or lymph nodes (LNs) sustain the circulating effector-type hCMV-specific pool. Using flow cytometry and functional assays, we found that the IL-7Rα(+) hCMV-specific T cell population comprises cells that have a memory phenotype and lack effector features. We used next-generation sequencing of the T cell receptor to compare the clonal repertoires of IL-7Rα(+) and IL-7Rα(-) subsets. We observed limited overlap of clones between these subsets during acute infection and after 1 year. When we compared the hCMV-specific repertoire between PB and paired LNs, we found many identical clones but also clones that were exclusively found in either compartment. New clones that were found in PB during antigenic recall were only rarely identical to the unique LN clones. Thus, although PB IL-7Rα-expressing and LN hCMV-specific CD8(+) T cells show typical traits of memory-type cells, these populations do not seem to contain the precursors for the novel hCMV-specific CD8(+) T cell pool during latency or upon antigen recall. IL-7Rα(+) PB and LN hCMV-specific memory cells form separate virus-specific compartments, and precursors for these novel PB hCMV-specific CD8(+) effector-type T cells are possibly located in other secondary lymphoid tissues or are being recruited from the naive CD8(+) T cell pool. IMPORTANCE: Insight into the self-renewal properties of long-lived memory CD8(+) T cells and their location is crucial for the development of both passive and active vaccination strategies. Human CMV infection is characterized by a vast expansion of resting effector-type cells. It is, however, not known how this population is maintained. We here investigated two possible compartments for effector-type cell precursors: circulating acute-phase IL-7Rα-expressing hCMV-specific CD8(+) T cells and lymph node (LN)-residing hCMV-specific (central) memory cells. We show that new clones that appear after primary hCMV infection or during hCMV reactivation seldom originate from either compartment. Thus, although identical clones may be maintained by either memory population, the precursors of the novel clones are probably located in other (secondary) lymphoid tissues or are recruited from the naive CD8(+) T cell pool

Butyrate production in patients with end-stage renal disease

Matty L Terpstra,1–3 Marjan J Sinnige,1,3 Floor Hugenholtz,4 Hessel Peters-Sengers,4 Ester BM Remmerswaal,1,3 Suzanne E Geerlings,2 Frederike J Bemelman11Department of Internal Medicine, Division of Nephrology, Renal Transplant Unit, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands; 2Department of Internal Medicine, Division of Infectious Diseases, Amsterdam Infection & Immunity Institute (AI&II), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; 3Department of Experimental Immunology, Amsterdam Infection & Immunity Institute (AI&II), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; 4Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsBackground: Chronic kidney disease (CKD) is associated with a decreased intestinal barrier function, causing bacterial translocation over the intestinal wall and triggering a systemic inflammatory response. Butyrate, a short-chain fatty acid produced by certain bacterial strains, is considered instrumental to keep the intestinal barrier intact. There are indications that a decreased amount of these specific bacterial species is part of the cause of the decreased intestinal barrier function in CKD. The aim of this study is (i) to determine if Dutch patients with end-stage renal disease (ESRD) have a decreased amount of butyrate-producing species and butyrate-producing capacity and (ii) whether this correlates with systemic inflammation.Methods: We used qPCR to evaluate the most abundant butyrate-producing species F. prauznitzii, E. rectale and Roseburia spp. and the BCoAT gene, which reflects the butyrogenic capacity of the intestinal microbiota. Fecal samples were collected from healthy kidney donors (n=15), preemptive renal transplant recipients (n=4) and dialysis patients (n=31). Markers of inflammation (CRP and IL-6) and intestinal permeability (D-lactate) were measured in plasma.Results: Patients with ESRD did not have a significantly decreased amount F. prauznitzii, E. rectale and Roseburia spp. or the BCoAT gene. Neither was there a significant correlation with CRP, IL-6 or D-lactate. On the individual level, there were some patients with decreased BCoAT levels and increased levels of CRP, IL-6 and D-lactate.Conclusions: Patients with ESRD do not have a decreased amount of the most abundant butyrate-producing species nor a decreased butyrate-producing capacity.Keywords: renal failure, intestinal barrier function, butyrate, intestinal microbiota, inflammatio

Validation of the prognostic Kidney Donor Risk Index (KDRI) 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 US—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 US. METHODS: We aimed to externally validate the KDRI as proposed by Rao et al, (2009) containing 10 donor factors (KDRIdonor-only) and 1 with 4 additional transplant factors (KDRIfull), with stratification on recipient age and diabetes. 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 US (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’s C) of the KDRIfull and the KDRIdonor-only at 5 years was 0.63 (95%CI 0.62-0.64), and 0.62 (95%CI 0.61-0.63), respectively. We found misspecification of 3 KDRI factors: age (p=.002), weight (p=.017), and cold ischemia time (p andlt; 0.001). Adding the use of inotropic drugs prior to donation (p=.040), and the interaction between circulatory-death donor kidneys and prolonged cold ischemic time ( andgt; 24h vs 12h, p=.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.</p

Validation of the prognostic Kidney Donor Risk Index (KDRI) 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 US—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 US. METHODS: We aimed to externally validate the KDRI as proposed by Rao et al, (2009) containing 10 donor factors (KDRIdonor-only) and 1 with 4 additional transplant factors (KDRIfull), with stratification on recipient age and diabetes. 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 US (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’s C) of the KDRIfull and the KDRIdonor-only at 5 years was 0.63 (95%CI 0.62-0.64), and 0.62 (95%CI 0.61-0.63), respectively. We found misspecification of 3 KDRI factors: age (p=.002), weight (p=.017), and cold ischemia time (p &lt; 0.001). Adding the use of inotropic drugs prior to donation (p=.040), and the interaction between circulatory-death donor kidneys and prolonged cold ischemic time ( &gt; 24h vs 12h, p=.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.</p