Alkaline phosphatase treatment of acute kidney injury - an update.

Through improved insight in the increasing incidence and detrimental effects of acute kidney injury (AKI), its clinical relevance has become more and more apparent. Although treatment strategies for AKI have also somewhat improved, an adequate remedy still does not exist. Finding one is complicated by a multifactorial pathophysiology and by heterogeneity in the patient population. Alkaline phosphatase (AP) has been suggested as a therapy for sepsis-associated AKI because of its protective effects against lipopolysaccharide (LPS) induced inflammation and kidney injury in animals. However, translation of these protective effects into tangible clinical benefit has proven difficult. Because the anti-inflammatory properties of AP are likely not reliant on a direct effect on LPS itself, we postulate that other pathways are much more important in explaining the renoprotective properties ascribed to AP. The reevaluation of which properties of the AP enzyme are responsible for the benefit seen in the lab, is an important step to determine where the true potential of AP as a treatment strategy for AKI in the clinic lies. In this review, we will discuss how AP can prevent activation of harmful pro-inflammatory receptors, redirect cell-cell signaling, and protect barrier tissues, which together form the basis for current knowledge of the role of AP in the kidney. With this knowledge in mind and by analyzing currently available clinical evidence, we propose directions for new research that can determine whether AP as a treatment strategy for AKI has a future in the clinical field.

Antibody and T-Cell Responses 6 Months After Coronavirus Disease 2019 Messenger RNA-1273 Vaccination in Patients With Chronic Kidney Disease, on Dialysis, or Living With a Kidney Transplant.

BACKGROUND: The immune response to COVID-19 vaccination is inferior in kidney transplant recipients (KTRs) and to a lesser extent in patients on dialysis or with chronic kidney disease (CKD). We assessed the immune response 6 months after mRNA-1273 vaccination in kidney patients and compared this to controls. METHODS: A total of 152 participants with CKD stages G4/5 (eGFR <30 mL/min/1.73 m2), 145 participants on dialysis, 267 KTRs, and 181 controls were included. SARS-CoV-2 Spike S1 specific IgG antibodies were measured using fluorescent bead-based multiplex-immunoassay, neutralizing antibodies to ancestral, Delta, and Omicron (BA.1) variants by plaque reduction, and T-cell responses by interferon-γ release assay. RESULTS: At 6 months after vaccination, S1-specific antibodies were detected in 100% of controls, 98.7% of CKD G4/5 patients, 95.1% of dialysis patients, and 56.6% of KTRs. These figures were comparable to the response rates at 28 days, but antibody levels waned significantly. Neutralization of the ancestral and Delta variants was detected in most participants, whereas neutralization of Omicron was mostly absent. S-specific T-cell responses were detected at 6 months in 75.0% of controls, 69.4% of CKD G4/5 patients, 52.6% of dialysis patients, and 12.9% of KTRs. T-cell responses at 6 months were significantly lower than responses at 28 days. CONCLUSIONS: Although seropositivity rates at 6 months were comparable to rates at 28 days after vaccination, significantly decreased antibody levels and T-cell responses were observed. The combination of low antibody levels, reduced T-cell responses, and absent neutralization of the newly emerging variants indicates the need for additional boosts or alternative vaccination strategies in KTRs. CLINICAL TRIALS REGISTRATION: NCT04741386.

The role of interleukin-21 in COVID-19 vaccine-induced B cell-mediated immune responses in patients with kidney disease and kidney transplant recipients.

T-cell-mediated help to B cells is required for the development of humoral responses, in which the cytokine interleukin (IL)-21 is key. Here, we studied the mRNA-1273 vaccine-induced SARS-CoV-2-specific memory T-cell IL-21 response, memory B cell response, and immunoglobulin (Ig)G antibody levels in peripheral blood at 28 days after the second vaccination by ELISpot and the fluorescent bead-based multiplex immunoassay, respectively. We included 40 patients with chronic kidney disease (CKD), 34 patients on dialysis, 63 kidney transplant recipients (KTR), and 47 controls. We found that KTR, but not patients with CKD and those receiving dialysis, showed a significantly lower number of SARS-CoV-2-specific IL-21 producing T cells than controls (P < .001). KTR and patients with CKD showed lower numbers of SARS-CoV-2-specific IgG-producing memory B cells when compared with controls (P < .001 and P = .01, respectively). The T-cell IL-21 response was positively associated with the SARS-CoV-2-specific B cell response and the SARS-CoV-2 spike S1-specific IgG antibody levels (both Pearson r = 0.5; P < .001). In addition, SARS-CoV-2-specific B cell responses were shown to be IL-21 dependent. Taken together, we show that IL-21 signaling is important in eliciting robust B cell-mediated immune responses in patients with kidney disease and KTR.

Disease activity in patients with immune-mediated inflammatory diseases after SARS-CoV-2 vaccinations.

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity.

Prophylactic and early outpatient treatment of COVID-19 in patients with kidney disease: considerations from the Immunonephrology Working Group of the European Renal Association (ERA-IWG).

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic led to rapid vaccine development and large global vaccination schemes. However, patients with immune-mediated kidney disease, chronic kidney diseases and kidney transplant recipients show high non-response rates to vaccination despite more than three vaccinations and, consequently, reduced viral clearance capacity when infected while receiving certain immunosuppressants, carrying an elevated risk for coronavirus disease 2019 (COVID-19)-related morbidity and mortality. SARS-CoV-2 evolution has been characterized by the emergence of novel variants and spike mutations contributing to waning efficacy of neutralizing antibodies. To this end, the therapeutic field expands from vaccination towards a combined approach of immunization, pre-exposure prophylaxis and early post-exposure treatment using direct-acting antivirals and neutralizing monoclonal antibodies to treat early in the disease course and avoid hospitalization. This expert opinion paper from the Immunonephrology Working Group of the European Renal Association (ERA-IWG) summarizes available prophylactic and/or early treatment options (i.e. neutralizing monoclonal antibodies and direct-acting antivirals) of SARS-CoV-2-infected patients with immune-mediated kidney disease, chronic kidney disease and kidney transplant recipients.

Alkaline phosphatase to treat ischaemia-reperfusion injury in living-donor kidney transplantation: APhIRI I feasibility pilot study.

AIMS: Ischemia-reperfusion injury (IRI) during kidney transplant procedures is associated with adverse outcome. Alkaline phosphatase (AP) is an enzyme that has the potential to dampen IRI. Prior to this study, it had not been tested in the setting of kidney transplantation. This study aimed to evaluate the safety and feasibility of peri-procedural AP administration in living donor kidney transplantation. METHODS: In this double blind, randomized, placebo-controlled, single-center pilot study, all eligible recipients of living donor kidneys were asked to give informed consent. AP (bRESCAP) or a placebo was administered intravenously over 24 hours after the transplantation procedure. The primary outcome-graft function at 1 year-was represented by iohexol measured glomerular filtration rate (mGFR). Serum and urine biomarkers within seven days after surgery were used as surrogate markers of kidney function and injury. RESULTS: Eleven patients were enrolled of whom five were treated with bRESCAP and six with placebo. After 1 year, mGFR was not different between groups. No specific adverse events were observed in the bRESCAP group. Urine expression of injury biomarkers CCL14, NGAL and Cystatin C was lower in the bRESCAP group at day seven. This was statistically significant. CONCLUSION: This study illustrates that bRESCAP treatment is feasible in kidney transplantation, might have a dampening effect on IRI induced renal inflammation, and raises no safety concerns. Future research will evaluate the effects of bRESCAP treatment in donation after circulatory death kidney transplantation where IRI is more pronounced.

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity.

BACKGROUND: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. METHODS: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. RESULTS: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%). CONCLUSION: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. TRIAL REGISTRATION: NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020.

Risk factors for neurocognitive impairment and the relation with structural brain abnormality in children and young adults with severe chronic kidney disease.

BACKGROUND: Severe chronic kidney disease (CKD) in children and young adults has shown to be associated with abnormal brain development, which may contribute to neurocognitive impairments. We aimed to investigate risk factors for neurocognitive impairment and investigate the relation with structural brain abnormalities in young severe CKD patients. METHODS: This cross-sectional study includes 28 patients with severe CKD (eGFR < 30), aged 8-30 years (median 18.5 years), on different treatment modalities (pre-dialysis [n = 8], dialysis [n = 8], transplanted [n = 12]). We assessed neurocognitive functioning using a comprehensive test battery and brain structure by magnetic resonance imaging metrics of brain volume and white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD] measured with diffusion tensor imaging). Multivariate regression and mediation analyses were performed between clinical CKD parameters, brain structure, and neurocognitive outcome. RESULTS: A combination of risk factors (e.g., longer time since kidney transplantation, longer dialysis duration and late CKD onset) was significantly associated with lower intelligence and/or worse processing speed and working memory. Lower FA in a cluster of white matter tracts was associated with lower intelligence and mediated the relation between clinical risk factors and lower intelligence. CONCLUSIONS: Young severe CKD patients with a prolonged duration of kidney replacement therapy, either dialysis or transplantation are at particular risk for impairments in intelligence, processing speed, and working memory. Disrupted white matter integrity may importantly contribute to these neurocognitive impairments. Prospective, longitudinal studies are needed to elucidate the mechanisms involved in CKD and treatment that affect white matter integrity and neurocognitive outcome in young patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Human CXCR5+ PD-1+ CD8 T cells in healthy individuals and patients with hematologic malignancies.

Immune checkpoint blockade (ICB) has revolutionized cancer therapy, but varying response rates illustrate the need for biomarkers of response. Studies in mice have identified a subset of CD8 T cells that is essential for response to PD-1 ICB. These CD8 T cells co-express CXCR5, PD-1 and Tcf1, and provide effector T cells upon PD-1 ICB. It is unknown whether similar T cells play a role in PD-1 ICB in humans. We studied human peripheral blood and lymph nodes (LNs) for the frequency, phenotype, and functionality of CXCR5+ PD-1+ CD8 T cells. We find that CXCR5+ PD-1+ CD8 T cells are memory-like cells, express Tcf1, and lack expression of effector molecules. CXCR5+ PD-1+ CD8 T cells produce cytokines upon stimulation, but have limited proliferative capacity. We studied patients with hematologic malignancies with varying response rates to PD-1 ICB. Specifically in chronic lymphocytic leukemia, in which PD-1 ICB does not induce clinical responses, CXCR5+ PD-1+ CD8 T cells show loss of the memory phenotype and increased effector differentiation. In conclusion, we identified CXCR5+ PD-1+ CD8 T cells in human peripheral blood and LN, which could play a similar role during PD-1 ICB. Future studies should analyze CXCR5+ PD-1+ CD8 T cells during PD-1 ICB and their importance for therapeutic response.

Risk factors associated with short-term adverse events after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases.

BACKGROUND: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). METHODS: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. RESULTS: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93). CONCLUSIONS: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. TRIAL REGISTRATION: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020.

Work status and work ability of patients receiving kidney replacement therapy: results from a European survey.

BACKGROUND: Employment is important for the quality of life and financial security of patients of working age receiving kidney replacement therapy (KRT). We aimed to examine self-reported work status and general, physical and mental work ability and to determine associations between demographic, disease-related, work-related and macroeconomic factors and employment. . METHODS: Europeans from 37 countries, ages 19-65 years, treated with dialysis or kidney transplantation, filled out the web-based or paper-based cross-sectional EDITH kidney patient survey between November 2017 and January 2019. We performed descriptive analyses and multivariable generalized logistic mixed models. RESULTS: Of the 3544 patients, 36.5% were employed and working [25.8% of dialysis patients, 53.9% of kidney transplant recipients (KTRs)]. The mean general work ability was 5.5 out of 10 (dialysis: 4.8, KTRs: 6.5). Non-working patients (all: 4.1, dialysis: 3.9, KTRs: 4.7) scored lower than working patients (all: 7.7, dialysis 7.3, KTRs: 8.0). Working dialysis patients scored lower on physical and mental work ability (7.1 and 8.1) than working KTRs (8.0 and 8.4; P < 0.001). Impaired physical work ability (42.7%) was more prevalent than impaired mental work ability (26.7%). Male sex, age 40-49 years, higher education, home dialysis or kidney transplantation as current treatment, treatment history including kidney transplantation, absence of diabetes mellitus, better general work ability and higher country gross domestic product were positively associated with employment (P < 0.05). CONCLUSIONS: Low employment rates and impaired work ability were prevalent among European patients receiving KRT. Demographic, disease-related, work-related and macro-economic factors were associated with employment.

Employment and ability to work after kidney transplantation in the Netherlands: The impact of preemptive versus non-preemptive kidney transplantation.

BACKGROUND: Work can have a major positive impact on health and wellbeing. Employment of kidney transplant recipients (KTR) of working age is much lower than in the general population. The first aim of this study was to examine the impact of a preemptive kidney transplantation (PKT) on employment, in addition to other possible influencing factors. The second aim was to explore differences in work ability, absenteeism and work performance among employed KTR with different types of transplantations. METHODS: A cross-sectional survey study was conducted between 2018 and 2019 in nine Dutch hospitals. PKT as potential predictor of employment was examined. Furthermore, work ability, absenteeism and loss of work performance were compared between employed preemptive recipients with a living donor (L-PKT) and non-preemptive recipients with a living donor (L-nPKT) and with a deceased donor (D-nPKT). RESULTS: Two hundred and twenty four KTR participated; 71% reported having paid work. Paid work was more common among PKT recipients (82% vs. 65% in L-nPKT and 55% in D-nPKT) and recipients who were younger (OR .950, 95%CI .913-.989), had no comorbidities (1 comorbidity: OR .397, 95%CI .167-.942; 2 comorbidities: OR .347, 95%CI .142-.844), had less fatigue (OR .974, 95%CI .962-.987) and had mentally demanding work tasks (only in comparison with physically demanding tasks, OR .342, 95%CI .145-.806). If recipients were employed, D-nPKT recipients worked fewer hours (mean 24.6±11.3 vs. PKT 31.1±9.6, L-nPKT 30.1±9.5) and D-nPKT and L-nPKT recipients received more often supplemental disability benefits (32 and 33.3%, respectively) compared to PKT recipients (9.9%). No differences were found for self-reported ability to work, sick leave (absenteeism) and loss of work performance with the exception of limitations in functioning at work. CONCLUSIONS: Preemptive kidney transplantation recipients with a kidney from a living donor are employed more often, work more hours per week (only in comparison with D-nPKT) and have a partial disability benefit less often than nPKT recipients. More knowledge regarding treatments supporting sustainable participation in the labor force is needed as work has a positive impact on recipients' health and wellbeing and is also beneficial for society as a whole.

Structural brain abnormalities in children and young adults with severe chronic kidney disease.

BACKGROUND: The pathophysiology of neurological dysfunction in severe chronic kidney disease (CKD) in children and young adults is largely unknown. We aimed to investigate brain volumes and white matter integrity in this population and explore brain structure under different treatment modalities. METHODS: This cross-sectional study includes 24 patients with severe CKD (eGFR < 30) aged 8-30 years (median = 18.5, range = 9.1-30.5) on different therapy modalities (pre-dialysis, n = 7; dialysis, n = 7; transplanted, n = 10) and 21 healthy controls matched for age, sex, and parental educational level. Neuroimaging targeted brain volume using volumetric analysis on T1 scans and white matter integrity with tract-based spatial statistics and voxel-wise regression on diffusion tensor imaging (DTI) data. RESULTS: CKD patients had lower white matter integrity in a widespread cluster of primarily distal white matter tracts compared to healthy controls. Furthermore, CKD patients had smaller volume of the nucleus accumbens relative to healthy controls, while no evidence was found for abnormal volumes of gray and white matter or other subcortical structures. Longer time since successful transplantation was related to lower white matter integrity. Exploratory analyses comparing treatment subgroups suggest lower white matter integrity and smaller volume of the nucleus accumbens in dialysis and transplanted patients relative to healthy controls. CONCLUSIONS: Young CKD patients seem at risk for widespread disruption of white matter integrity and to some extent smaller subcortical volume (i.e., nucleus accumbens). Especially patients on dialysis therapy and patients who received a kidney transplant may be at risk for disruption of white matter integrity and smaller volume of the nucleus accumbens.

Plasma Exchange Therapy Using Solvent Detergent-Treated Plasma: An Observational Pilot Study on Complement, Neutrophil and Endothelial Cell Activation in a Case Series of Patients Suffering from Atypical Hemolytic Uremic Syndrome.

Introduction: Plasma exchange therapy (PEX) was standard treatment for thrombotic microangiopathy before eculizumab was available and is still widely applied. However, most PEX patients still ultimately progress to end-stage renal disease (ESRD). It has been suggested that infusion of plasma that contains active complement may induce additional complement activation with subsequent activation of neutrophils and endothelial cells, leading to exacerbation of organ damage and deterioration of renal function. Objective: This observational pilot study examines the effect of hemodialysis, eculizumab and PEX before and after treatment in plasma of aHUS patients on complement-, neutrophil and endothelial cell activation. Methods: Eleven patients were included in this pilot study. Six patients were treated with hemodialysis, 2 patients received regular infusions of eculizumab, and 3 patients were on a regular schedule for PEX. Patients were followed during 3 consecutive treatments. Blood samples were taken before and after patients received their treatment. Results: Complement activation products increased in plasma of patients after PEX, as opposed to patients treated with hemodialysis or eculizumab. Increased levels of complement activation products were detected in omniplasma used for PEX. Additionally, activation of neutrophils and endothelial cells was observed in patients after hemodialysis and PEX, but not in patients receiving eculizumab treatment. Conclusion: In this pilot study we observed that PEX induced complement and neutrophil activation, and that omniplasma contains significant amounts of complement activation products. Additionally, we demonstrate that hemodialysis induces activation of neutrophils and endothelial cells. Complement activation with subsequent neutrophil activation may contribute to the deterioration of organ function and may result in ESRD. Further randomized controlled studies are warranted to investigate the effect of PEX on complement- and neutrophil activation in patients with thrombotic microangiopathy.

Tissue-resident mucosal-associated invariant T (MAIT) cells in the human kidney represent a functionally distinct subset.

Mucosal-associated invariant T (MAIT) cells are innate-like T-cells that recognize bacterial riboflavin metabolites. They are present in human blood but are abundant at barrier sites, including the liver, lungs, and kidneys, where they possess a CD69+ /CD103+/- tissue-resident phenotype. In renal tissue, MAIT cells likely defend against the ascending uropathogens responsible for urinary tract infections (UTIs), which are common, especially among renal transplant recipients (RTRs). Nevertheless, the functional role for MAIT cells in renal tissue and the influence of renal transplantation on MAIT cells remains unclear. Using multiparameter flow cytometry and the MR1-tetramer, we characterized MAIT cell phenotype and function in healthy renal tissue (n = 6), renal transplants explanted after allograft failure (n = 14) and in blood from healthy controls (n = 20) and RTRs before and 1-year after transplantation (n = 21). MAIT cells in renal tissue constitute a distinct CD69+ CD103+/- population that displays typical phenotypic features of tissue-resident T-cells and is skewed toward IL-2, GM-CSF, and IL-17A production upon stimulation. The circulating MAIT cell population was not decreased in number in RTRs pre- or post-transplantation. Tissue-resident MAIT cells in the kidney represent a functionally distinct population. This shows how MAIT cells in the kidney may be involved in the protection against microorganisms.

ABO-incompatible kidney transplantation in perspective of deceased donor transplantation and induction strategies: a propensity-matched analysis.

Kidney transplant candidates are blood group incompatible with roughly one out of three potential living donors. We compared outcomes after ABO-incompatible (ABOi) kidney transplantation with matched ABO-compatible (ABOc) living and deceased donor transplantation and analyzed different induction regimens. We performed a retrospective study with propensity matching and compared patient and death-censored graft survival after ABOi versus ABOc living donor and deceased donor kidney transplantation in a nationwide registry from 2006 till 2019. 296 ABOi were compared with 1184 center and propensity-matched ABOc living donor and 1184 deceased donor recipients (matching: recipient age, sex, blood group, and PRA). Patient survival was better compared with deceased donor [hazard ratio (HR) for death of HR 0.69 (0.49-0.96)] and non-significantly different from ABOc living donor recipients [HR 1.28 (0.90-1.81)]. Rate of graft failure was higher compared with ABOc living donor transplantation [HR 2.63 (1.72-4.01)]. Rejection occurred in 47% of 140 rituximab versus 22% of 50 rituximab/basiliximab, and 4% of 92 alemtuzumab-treated recipients (P < 0.001). ABOi kidney transplantation is superior to deceased donor transplantation. Rejection rate and graft failure are higher compared with matched ABOc living donor transplantation, underscoring the need for further studies into risk stratification and induction therapy [NTR7587, www.trialregister.nl].

A nationwide evaluation of deceased donor kidney transplantation indicates detrimental consequences of early graft loss.

Early graft loss (EGL) is a feared outcome of kidney transplantation. Consequently, kidneys with an anticipated risk of EGL are declined for transplantation. In the most favorable scenario, with optimal use of available donor kidneys, the donor pool size is balanced by the risk of EGL, with a tradeoff dictated by the consequences of EGL. To gauge the consequence of EGL we systematically evaluated its impact in an observational study that included all 10,307 deceased-donor kidney transplantations performed in The Netherlands between 1990 and 2018. Incidence of EGL, defined as graft loss within 90 days, in primary transplantation was 8.2% (699/8,511). The main causes were graft rejection (30%), primary nonfunction (25%), and thrombosis or infarction (20%). EGL profoundly impacted short- and long-term patient survival (adjusted hazard ratio; 95% confidence interval: 8.2; 5.1-13.2 and 1.7; 1.3-2.1, respectively). Of the EGL recipients who survived 90 days after transplantation (617/699) only 440 of the 617 were relisted for re-transplantation. Of those relisted, only 298 were ultimately re-transplanted leading to an actual re-transplantation rate of 43%. Noticeably, re-transplantation was associated with a doubled incidence of EGL, but similar long-term graft survival (adjusted hazard ratio 1.1; 0.6-1.8). Thus, EGL after kidney transplantation is a medical catastrophe with high mortality rates, low relisting rates, and increased risk of recurrent EGL following re-transplantation. This implies that detrimental outcomes also involve convergence of risk factors in recipients with EGL. The 8.2% incidence of EGL minimally impacted population mortality, indicating this incidence is acceptable.

Urinary mitochondrial DNA associates with delayed graft function following renal transplantation.

BACKGROUND: Ischaemia-reperfusion (IR) injury is an important determinant of delayed graft function (DGF) affecting allograft function. Mitochondrial DNA (mtDNA) is released upon cell death and platelet activation into the extracellular environment and has been suggested to be a biomarker in several diseases. Whether extracellular mtDNA accumulates in plasma and/or urine upon renal IR and predisposes DGF is unknown. METHODS: C57BL/6J wild-type mice were subjected to renal IR. In addition, an observational case-control study was set up enrolling 43 patients who underwent kidney transplantation. One day post-IR in mice and a few days following renal transplantation in human, blood and urine were collected. Patients were stratified into DGF and non-DGF groups. RESULTS: mtDNA-encoded genes accumulate in urine and plasma in both mice subjected to renal IR injury and in humans following renal transplantation. In human renal transplant recipients, cold ischaemia time and renal function correlate with urinary mtDNA levels. Urinary mtDNA levels but not urinary nuclear DNA levels were significantly higher in the DGF group compared with the non-DGF group. Multiple receiver operating characteristic curves revealed significant diagnostic performance for mtDNA-encoded genes cytochrome c oxidase III (COXIII); nicotinamide adenine dinucleotide hydrogen subunit 1 (NADH-deh); mitochondrially encoded, mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 2 (MT-ND2) with an area under the curve of, respectively, 0.71 [P = 0.03; 95% confidence interval (CI) 0.54-0.89], 0.75 (P = 0.01; 95% CI 0.58-0.91) and 0.74 (P = 0.02; 95% CI 0.58-0.89). CONCLUSIONS: These data suggest that renal ischaemia time determines the level of mtDNA accumulation in urine, which associates with renal allograft function and the diagnosis of DGF following renal transplantation.

Clinical consequences of primary CMV infection after renal transplantation: a case-control study.

The impact of primary cytomegalovirus infection (pCMV) on renal allograft function and histology is controversial. We evaluated the influence on incidence of acute rejection, allograft loss, allograft function and interstitial fibrosis/tubular atrophy (IF/TA). Retrospective case-control study, recipients transplanted between 2000 and 2014. Risk of acute rejection and allograft loss for those who experienced pCMV infection compared with those who did not, within an exposure period of two months after transplantation. Besides, its influence on allograft function and histology at one to three years after transplantation. Of 113 recipients experienced pCMV infection, 306 remained CMV seronegative. pCMV infection in the exposure period could not be proven as increasing the risk for acute rejection [HR = 2.18 (95% CI 0.80-5.97) P = 0.13] or allograft loss [HR = 1.11 (95%CI 0.33-3.72) P = 0.87]. Combination of pCMV infection and acute rejection posed higher hazard for allograft loss than acute rejection alone [HR = 3.69 (95% CI 1.21-11.29) P = 0.02]. eGFR(MDRD) values did not significantly differ at years one [46 vs. 50], two [46 vs. 51] and three [46 vs. 52]. No association between pCMV infection and IF/TA could be demonstrated [OR = 2.15 (95%CI 0.73-6.29) P = 0.16]. pCMV infection was not proven to increase the risk for acute rejection or allograft loss. However, it increased the risk for rejection-associated allograft loss. In remaining functioning allografts, it was not significantly associated with decline in function nor with presence of IF/TA.

The Use of the Oxygenated AirdriveTM Machine Perfusion System in Kidney Graft Preservation: A Clinical Pilot Study.

BACKGROUND: The shortage of donor kidneys has led to the use of marginal donors, e.g., those whose kidneys are donated after circulatory death. Preservation of the graft by hypothermic machine perfusion (HMP) provides a viable solution to reduce warm ischemic damage. This pilot study was undertaken to assess the feasibility and patient safety of the AirdriveTM HMP system in clinical kidney transplantation. METHODS: Five deceased-donor kidneys were preserved using the oxygenated Airdrive HMP system between arrival at the recipient center (Amsterdam UMC) and implantation in the patient. The main study end-points were adverse effects due to the use of Airdrive HMP. Secondary end-points were clinical outcomes and perfusion parameters. All events occurring during the transplantation procedure or within 1 month of follow-up were monitored. RESULTS: Five patients were included in this pilot study. No technical failures were observed during the preservation period using the Airdrive HMP. Mean perfusion parameters were: duration 8.5 h (3-15 h), pressure 25 mm Hg (18-25 mm Hg), flow 49.77 mL/min (19-58 mL/min), resistance 0.57 mm Hg/min/mL (0.34-1.3 mm Hg/min/mL), and temperature 8.2 °C (2-13°C). Mean cold ischemia time (CIT) was 20.2 h (11-29.5 h). No adverse events or technical failures were observed during preservation and transplantation or during the 1-month follow-up. CONCLUSIONS: This pilot study showed the feasibility of the use of the Airdrive HMP system with no adverse events in clinical kidney transplantation.