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BACKGROUND: In kidney patients COVID-19 is associated with severely increased morbidity and mortality. A comprehensive comparison of the immunogenicity, tolerability, and safety of COVID-19 vaccination in different cohorts of kidney patients and a control cohort is lacking.METHODS: This investigator driven, prospective, controlled multicenter study included 162 participants with chronic kidney disease (CKD) stages G4/5 (eGFR < 30 mL/min/1.73m2), 159 participants on dialysis, 288 kidney transplant recipients, and 191 controls. Participants received 2 doses of the mRNA-1273 COVID-19 vaccine (Moderna). The primary endpoint was seroconversion.RESULTS: Transplant recipients had a significantly lower seroconversion rate when compared with controls (56.9% versus 100%, P < 0.001), with especially mycophenolic acid, but also, higher age, lower lymphocyte concentration, lower eGFR, and shorter time after transplantation being associated with nonresponder state. Transplant recipients also showed significantly lower titers of neutralizing antibodies and T-cell responses when compared with controls. Although a high seroconversion rate was observed for participants with CKD G4/5 (100%) and on dialysis (99.4%), mean antibody concentrations in the CKD G4/5 cohort and dialysis cohort were lower than in controls (2405 [interquartile interval 1287-4524] and 1650 [698-3024] versus 3186 [1896-4911] BAU/mL, P = 0.06 and P < 0.001, respectively). Dialysis patients and especially kidney transplant recipients experienced less systemic vaccination related adverse events. No specific safety issues were noted.CONCLUSIONS: The immune response following vaccination in patients with CKD G4/5 and on dialysis is almost comparable to controls. In contrast, kidney transplant recipients have a poor response. In this latter, patient group development of alternative vaccination strategies are warranted.Supplemental visual abstract; http://links.lww.com/TP/C307.

Increasing numbers of elderly (>= 65 years) patients are listed for kidney transplantation. This study compares the survival outcome between living (LDK), regularly allocated (ETKAS), and Eurotransplant Senior Program (ESP) donor kidneys in elderly recipients. This is a single-center retrospective cohort study of elderly kidney transplant recipients transplanted between 2005 and 2017. Primary outcome measures were nondeath-censored graft, death-censored graft, and patient survival. In total, 348 patients were transplanted, 109 recipients (31.3%) received an LDK, 100 (28.7%) an ETKAS, and 139 (40%) an ESP kidney. 62.5% were male, and median age was 68 years. LDK recipients had significantly better 5-year nondeath-censored graft survival compared with ETKAS and ESP (resp. 71.0% vs. 66.1% vs. 55.6%, P = 0.047). Death-censored graft survival after 1 year was significantly better in LDK recipients (99.1%) (ETKAS 90.8%; ESP 87.7%, P < 0.001). After 5 years, the difference remained significant (P < 0.001) with little additional graft loss (97.7% vs. 88.1% vs. 85.6). There was no significant difference in patient survival after 5 years (71.7% vs. 67.4% vs 61.9%, P = 0.480). In elderly recipients, the patient survival benefits of an LDK are limited, but there is decreased death-censored graft loss for LDK recipients. Nevertheless, graft survival in ETKAS and ESP remains satisfactory.

Kidney international 100(4), 753-779 (2021). doi:10.1016/j.kint.2021.05.015, Published by Elsevier, New York, NY

BACKGROUND AND OBJECTIVES: High dietary acid load may accelerate a decline in kidney function. We prospectively investigated whether dietary acid load is associated with graft outcomes in kidney transplant recipients, and whether venous bicarbonate mediates this association.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used data from 642 kidney transplant recipients with a functioning graft ≥1 year after transplantation. Net endogenous acid production was estimated using food frequency questionnaires and, alternatively, 24-hour urinary urea and potassium excretion to estimate net endogenous acid production. We defined the composite kidney end point as a doubling of plasma creatinine or graft failure. Multivariable Cox regression analyses, adjusted for potential confounders, were used to study the associations of dietary acid load with the kidney end point. We evaluated potential mediation effects of venous bicarbonate, urinary bicarbonate excretion, urinary ammonium excretion, titratable acid excretion, and net acid excretion on the association between net endogenous acid production and the kidney end point.RESULTS: The median net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion were 40 (interquartile range, 35-45) and 54 (interquartile range, 44-66) mEq/day, respectively. During a median follow-up of 5.3 years (interquartile range, 4.1-6.0), 121 (19%) participants reached the kidney end point. After multivariable adjustment, net endogenous acid production using food frequency questionnaires and net endogenous acid production using urinary excretion (per SD higher) were independently associated with higher risk for kidney end point (hazard ratio, 1.33; 95% confidence interval, 1.12 to 1.57, P=0.001 and hazard ratio, 1.44; 95% confidence interval, 1.24 to 1.69, PCONCLUSIONS: Higher dietary acid load was associated with a higher risk of doubling of plasma creatinine or graft failure, and this association was partly mediated by venous bicarbonate, urinary ammonium, and net acid excretion.

The introduction of immunosuppressive therapy for ANCA-associated vasculitis (AAV) has greatly improved outcomes, though patients now accumulate damage from vasculitis activity and adverse effects of treatment. Prediction of treatment outcomes using gene variants might help reduce this damage by allowing for personalized treatment. Several studies have studied genetic polymorphisms in relation to treatment outcomes of AAV. This review gives an overview of these studies, discussing both gene polymorphisms associated with inflammatory pathways (potentially influencing disease outcomes such as activity, severity, and relapse risk) and pharmacogenetics (potentially influencing drug metabolism and/or drug response). Subsequently, potential benefits of testing genetic variants for AAV and the steps needed for its implementation in clinical practice are discussed. The conclusion of this review is that measurement of most polymorphisms is currently not indicated in clinical practice.

Contains fulltext : 245148.pdf (Publisher’s version ) (Open Access) 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

Kidney international 100(4, Supplement) S1-S276 (2021). doi:10.1016/j.kint.2021.05.021 special issue: "KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases", Published by Elsevier, New York, NY

Objectives To determine Bruton’s tyrosine kinase (BTK) protein and phosphorylation levels in B cell subsets of granulomatosis with polyangiitis (GPA) patients and to investigate the effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production. Methods BTK protein and phosphorylation levels were determined by flow cytometry in peripheral blood B cells of 29 untreated GPA patients [9 active and 20 remission GPA patients (10 ANCA– and 10 ANCA+)], 9 age- and sex-matched healthy controls (HCs) and 9 untreated active RA patients. The effect of BTK blockade on in vitro B cell cytokine production, subset distribution and (auto)antibody production was determined in the same donors in peripheral blood mononuclear cell cultures. Results BTK protein levels were significantly increased in transitional and naïve B cells of active GPA and RA patients compared with remission GPA patients and HCs. Both B cell subsets of active patients were more sensitive to B cell receptor stimulation, as BTK and phospholipase Cγ2 phosphorylation were increased in these patients. In vitro BTK blockade had profound effects on B cell cytokine production, plasma cell formation and (auto)antibody production in both GPA patients and HCs. Interestingly, the effect of BTK blockade was less pronounced in active GPA patients, possibly due to increased activation of B cells. Conclusion We show that BTK protein and phosphorylation levels are most profoundly increased in newly emerging B cells of active GPA patients compared with remission patients. BTK blockade greatly inhibits in vitro B cell effector functions in GPA patients and HCs. These promising data identify BTK as an interesting novel therapeutic target in the treatment of GPA.

BACKGROUND: ABO-incompatible and ABO-compatible kidney transplantation are equivalent in terms of short-term graft and patient survival. This is thought to be the result of ABO-incompatible graft accommodation, which occurs when anti-blood group antibodies re-occur after transplantation but somehow do not yield their detrimental effect. The underlying mechanism is unclear, but one of the hypotheses is that this is the result of complement inhibition. Since virtually all ABO-incompatible graft biopsies are C4d positive, this complement inhibition must occur somewhere in the complement cascade after the formation of C4d has already taken place, but where exactly is unclear. It is also unclear whether complement inhibition is complete. Incomplete accommodation could explain why recent studies have shown that long-term graft function in ABO-incompatible transplantation is somewhat inferior to ABO-compatible kidney transplantation.AIM: To unravel the relationship between pre-transplant anti-ABO antibodies, complement activation, and long-term graft function.METHODS: We included all 27 ABO-incompatible transplantations that were performed between 2008 and 2013 at the Academic Medical Center Amsterdam and the University Medical Center Groningen. For each ABO-incompatible transplantation, we included four ABO-compatible controls matched by age, sex, and transplantation date.RESULTS: Graft and patient survival were not significantly different. The slope of kidney function during five-year follow-up was also not significantly different, but ABO-incompatible recipients did have a lower kidney function at three months (creatinine clearance 58 vs 69 mL/min, P = 0.02, Modification of Diet in Renal Disease 46 vs 52 mL/min/1.73 m2, P = 0.08), due to a high rate of early rejection (33% vs 15%, P = 0.03), mostly T-cell mediated. Pre-transplant anti-ABO IgG titers were positively correlated with C5b-9 staining, which itself was positively correlated with the occurrence of T-cell mediated rejection. This may be the result of concurrent C5a formation, which could function as a costimulatory signal for T-cell activation.CONCLUSION: Co-stimulation of T-cell activation by ongoing complement activation by anti-ABO antibodies may be responsible for an impaired long-term graft function in ABO-incompatible kidney transplantation.

Objectives To investigate whether there is a direct relation between expanded proportions of Th17 effector memory (ThEM17) cells and regulatory B cells (Bregs) in peripheral blood of granulomatosis with polyangiitis (GPA) patients. Methods Frequencies of Bregs and ThEM17 cells, as well as ThEM1 cells, were determined by flow cytometry in blood samples from 42 GPA patients in remission and 18 matched healthy controls (HCs). The Breg frequency was defined as CD24hiCD38hiCD19+ cells. ThEM17 cells were defined as CCR6+CXCR3-CCR4+ cells and ThEM1 cells as CCR6-CXCR3+CCR4- cells within the CD3+CD4+CD45RO+CCR7- population. In addition, CD3+CD4+ Th cells from 9 GPA patients were co-cultured in vitro with either total B cells or a Breg-depleted B cell fraction. Cultured cells were stimulated with Staphylococcus Enterotoxin B (SEB) and CpG-oligodeoxynucleotides (CpG-ODN). Th17- (IL-17+) and Th1 cell (IFNγ+) frequencies were determined at baseline and day 5 upon restimulation with phorbol myristate acetate (PMA) and Ca-I. Results A decreased Breg frequency was found in treated GPA patients, whereas an increased ThEM17 cell frequency was observed in treated and untreated GPA patients compared with HCs. Additionally, a decreased ThEM1 cell frequency was seen in untreated GPA patients compared with HCs. In untreated GPA patients circulating Breg frequencies correlated negatively with ThEM17 cells (r = −0.533; P = 0.007) and positively with ThEM1 cells (r = −0.473; P = 0.015). The co-culture experiments revealed a significant increase in the frequency of IL-17+ Th cells in Breg-depleted samples (median: 3%; range: 1–7.5%) compared with Breg-undepleted samples (P = 0.002; undepleted samples median: 2.1%; range: 0.9–6.4%), whereas no difference in the frequency of IFNγ+ Th cells in Breg-depleted cultures was observed (undepleted median: 11.8%; range: 2.8–21% vs Breg-depleted median: 12.2%; range: 2.6–17.6%). Conclusion Bregs modulate ThEM17 responses in GPA patients. Future studies should elaborate on clinical and therapeutical implications of the Breg-Th17 interaction in GPA patients.

Background Previous studies have indicated decreased health-related quality of life (HRQoL) shortly after kidney donation, returning to baseline in the longer term. However, a subgroup of donors experiences persistent HRQoL problems. To identify which HRQoL aspects are impacted most by the donation and to identify at-risk donors, more specific insight into psychosocial donation consequences is needed. Methods The current study examined the HRQoL course, donor-perceived consequences of donation for donors, recipients and donor–recipient relationships, and regret up to 12 months post-donation in donors from seven Dutch transplantation centres. Kidney donor candidates (n = 588) completed self-report questionnaires early in the screening procedure, of which 361 (61%) donated their kidney. Results Data for 230 donors (64%) with complete assessments before donation and 6 and 12 months post-donation were analysed. Results indicated that donor physical HRQoL was comparable at all time points, except for an increase in fatigue that lasted up to 12 months post-donation. Mental HRQoL decreased at 6 months post-donation, but returned to baseline at 12 months. Donors reported large improvements in recipient’s functioning and a smaller influence of the recipient’s kidney disease or transplantation on the donor’s life over time. A subgroup experienced negative donation consequences with 14% experiencing regret 12 months post-donation. Predictors of regret were more negative health perceptions and worse social functioning 6 months post-donation. The strongest baseline predictors of higher fatigue levels after donation were more pre-donation fatigue, worse general physical functioning and a younger age. Conclusions Future research should examine predictors of HRQoL after donation to improve screening and to provide potential interventions in at-risk donors.

Objectives. We aimed to investigate whether five potential functional haplotypes of the glucocorticoid receptor (GR) gene and a single-nucleotide polymorphism of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) are associated with clinical outcome in ANCA-associated vasculitis.Methods. Patients diagnosed with ANCA-associated vasculitis (n=241) were genotyped for five polymorphisms of the GR gene and one polymorphism of the HSD11B1 gene. GR gene haplotypes were predicted based on genotyping results. Relapse-free survival, mortality, renal survival, metabolic adverse events and infections were compared between carriers and non-carriers of GR haplotypes and the HSD11B1 genotype.Results. Carriers of haplotype 4 (ER22/23EK + 9 beta+Tthlll1) of GR had a significantly higher 5-year mortality risk [hazard ratio (HR) 4.5 (95% CI 1.6, 12.8)] and had a higher risk of developing end-stage renal disease [HR 7.4 (95% CI 1.9, 28.7)]. Carriers of a minor variant of HSD11B1 more frequently experienced relapse [HR 2.5 (95% CI 1.5, 4.1)] except if they also carried haplotype 1 (Bcll) of GR. Homozygous carriers of haplotype 1 had a higher risk of developing dyslipidaemia [HR 4.1 (95% CI 1.8, 9.6)]. The occurrence of infections did not differ between GR haplotypes and HSD11B1 genotypes.Conclusion. Haplotypes 1 and 4 of GR and a polymorphism of the HSD11B1 gene were associated with clinically relevant inflammatory and metabolic outcomes in ANCA-associated vasculitis.

BACKGROUND: Azathioprine hypersensitivity syndrome is a rare complication of azathioprine therapy. Its symptoms resemble infection or relapse of inflammatory disease, hindering correct diagnosis. Current literature is limited to sporadic case reports and reviews.OBJECTIVE: To estimate the incidence of azathioprine hypersensitivity syndrome and describe its characteristics in the context of an observational cohort of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Also, to facilitate early recognition and awareness among clinicians.METHODS: Within a cohort of 290 patients with ANCA-associated vasculitis receiving azathioprine maintenance therapy, frequency of azathioprine hypersensitivity was described and characteristics were compared between hypersensitive and non-hypersensitive patients. Clinical picture, laboratory abnormalities, and concurrent medication of patients with azathioprine hypersensitivity were described.RESULTS: Of 290 patients, 25 (9%) experienced azathioprine hypersensitivity after a median of 14 (interquartile range [IQR] 12-18) days. Frequent symptoms were fever (100%), malaise (60%), arthralgia (36%), and rash (32%). All patients used prednisolone (median 10 mg/day, IQR 9.4-16.3 mg/day) at the time of the hypersensitivity reaction. Most patients had a rise in C-reactive protein (CRP), leukocyte counts, and neutrophil counts, but no eosinophilia. Thiopurine S-methyltransferase (TPMT) activity was significantly lower in hypersensitive patients (median 74.4 [IQR 58.0-80.1] nmol/gHb/L) compared with controls (median 81.4 [71.9-90.5] nmol/gHb/L), P = .01. Hypersensitive patients had a higher risk of relapse (hazard ratio 2.2, 95% confidence interval 1.2-4.2; P=.01).CONCLUSIONS: Azathioprine hypersensitivity syndrome is strikingly common in ANCA-associated vasculitis, might be associated with reduced TPMT activity, is accompanied by an increase in neutrophil counts, and may occur even during concomitant prednisolone therapy. Proper recognition may prevent unnecessary hospital procedures and damage to the patient. (C) 2018 American Academy of Allergy, Asthma & Immunology

Background. Early detection of renal involvement in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is of major clinical importance to allow prompt initiation of treatment and limit renal damage. Urinary soluble cluster of differentiation 163 (usCD163) has recently been identified as a potential biomarker for active renal vasculitis. However, a significant number of patients with active renal vasculitis test negative using usCD163. We therefore studied whether soluble CD25 (sCD25), a T cell activation marker, could improve the detection of renal flares in AAV.Methods. sCD25 and sCD163 levels in serum and urine were measured by enzyme-linked immunosorbent assay in 72 patients with active renal AAV, 20 with active extrarenal disease, 62 patients in remission and 18 healthy controls. Urinary and blood CD4(+) T and CD4(+) T effector memory (TEM) cell counts were measured in 22 patients with active renal vasculitis. Receiver operating characteristics (ROC) curves were generated and recursive partitioning was used to calculate whether usCD25 and serumsoluble CD25 (ssCD25) add utility to usCD163.Results. usCD25, ssCD25 and usCD163 levels were significantly higher during active renal disease and significantly decreased after induction of remission. A combination of usCD25, usCD163 and ssCD25 outperformed all individual markers (sensitivity 84.7%, specificity 95.1%). Patients positive for sCD25 but negative for usCD163 (n = 10) had significantly higher C-reactive protein levels and significantly lower serum creatinine and proteinuria levels compared with the usCD163positive patients. usCD25 correlated positively with urinary CD4(+) T and CD4(+) TEM cell numbers, whereas ssCD25 correlated negatively with circulating CD4(+) T and CD4+ TEMcells.Conclusion. Measurement of usCD25 and ssCD25 complements usCD163 in the detection of active renal vasculitis.

Item does not contain fulltext BACKGROUND: Pre-transplant donor-specific anti-human leucocyte antigen (HLA) antibodies (DSAs) are associated with impaired kidney graft survival while the clinical relevance of non-donor-specific anti-HLA antibodies (nDSAs) is more controversial. The aim of the present paired kidney graft study was to compare the clinical relevance of DSAs and nDSAs. METHODS: To eliminate donor and era-dependent factors, a post hoc paired kidney graft analysis was performed as part of a Dutch multicentre study evaluating all transplantations between 1995 and 2005 with available pre-transplant serum samples. Anti-HLA antibodies were detected with a Luminex single-antigen bead assay. RESULTS: Among 3237 deceased donor transplantations, we identified 115 recipient pairs receiving a kidney from the same donor with one recipient being DSA positive and the other without anti-HLA antibodies. Patients with pre-transplant DSAs had a significantly lower 10-year death-censored graft survival (55% versus 82%, P=0.0001). We identified 192 pairs with one recipient as nDSA positive (against Class I and/or II) and the other without anti-HLA antibodies. For the patients with nDSAs against either Class I or II, graft survival did not significantly differ compared with patients without anti-HLA antibodies (74% versus 77%, P = 0.79). Only in patients with both nDSAs Class I and II was there a trend towards a lower graft survival (58%, P = 0.06). Lastly, in a small group of 42 recipient pairs, 10-year graft survival in recipients with DSAs was 49% compared with 68% in recipients with nDSAs (P=0.11). CONCLUSION: This paired kidney analysis confirms that the presence of pre-transplant DSAs in deceased donor transplantations is a risk marker for graft loss, whereas nDSAs in general are not associated with a lower graft survival. Subgroup analysis indicated that only in broadly sensitized patients with nDSAs against Class I and II, nDSAs may be a risk marker for graft loss in the long term.

Background In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. Methods This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor 2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. Conclusions The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. Trial registration ClinicalTrials.gov: NCT03797196, registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

Organ transplantation is a life-saving treatment for patients with end-stage disease, but survival post-transplantation varies considerably. There is now increasing evidence that the gut microbiome is linked to the survival of hematopoietic cell transplant patients, yet little is known about the role of the gut microbiome in solid organ transplantation. We analyzed 1,370 fecal samples from liver and renal transplant recipients using shotgun metagenomic sequencing to assess microbial taxonomy, metabolic pathways, antibiotic resistance genes and virulence factors. To quantify taxonomic and metabolic dysbiosis, we analyzed 1,183 age-, sex- and BMI-matched subjects from the same population. A subset of patients were also followed longitudinally from pre- to post-transplantation. Our data show that transplant recipients suffer from gut dysbiosis—including lower microbial diversity, increased abundance of unhealthy microbial species, decreased abundance of important metabolic pathways, and increased prevalence and diversity of antibiotic resistant genes and virulence factors—that persist up to 20 years post-transplantation. Finally, we demonstrate that the use of immunosuppressive drugs is significantly associated with the observed dysbiosis and that the extent of dysbiosis is associated with increased post-transplant mortality.

Ischemia and reperfusion injury (IRI) is a complex pathophysiological phenomenon, inevitable in kidney transplantation and one of the most important mechanisms for non- or delayed function immediately after transplantation. Long term, it is associated with acute rejection and chronic graft dysfunction due to interstitial fibrosis and tubular atrophy. Recently, more insight has been gained in the underlying molecular pathways and signalling cascades involved, which opens the door to new therapeutic opportunities aiming to reduce IRI and improve graft survival. This review systemically discusses the specific molecular pathways involved in the pathophysiology of IRI and highlights new therapeutic strategies targeting these pathways.

Compensatory gomerular filtration rate (GFR) increase after kidney donation results in a GFR above 50% of the predonation value. The renal functional reserve (RFR) assessed by the renal response to dopamine infusion (RFRdopa) is considered to reflect functional reserve capacity and is thought to be a tool for living donor screening. However, it is unknown if the RFRdopapredicts long-term kidney function. Between 1984 and 2017, we prospectively measured GFR (125I-iothalamate) and RFR by dopamine infusion in 937 living kidney donors. We performed linear regression analysis of predonation RFRdopaand postdonation GFR. In donors with 5-yr follow-up after donation we assessed the association with long-term GFR. Mean donor age was 52 yr (SD 11); 52% were female. Mean predonation GFR was 114 ml/min (SD 22), GFRdopawas 124 ml/min (SD 24), resulting in an RFR of 9 ml/min (SD 10). Three months postdonation, GFR was 72 ml/min (SD 15) and GFRdopawas 75 ml/min (SD 15), indicating that donors still had RFRdopa[3 ml/min (SD 6), P < 0.001]. Predonation RFRdopawas not associated with predonation GFR [standardized (st.) β −0.009, P = 0.77] but was positively associated with GFR 3 mo after donation (st. β 0.12, P < 0.001). In the subgroup of donors with 5-yr follow-up data ( n = 383), RFRdopawas not associated with GFR at 5 yr postdonation (st. β 0.05, P = 0.35). In conclusion, RFRdopais a predictor of short-term GFR after living kidney donation but not of long-term kidney function. Therefore, measurement of the RFRdopais not a useful tool for donor screening. Studies investigating long-term renal adaptation are warranted to study the effects of living kidney donation and improve donor screening.

Background: Clinicians use several diagnostic modalities to recognize post-transplant complications, such as acute tubular necrosis, acute rejection, urologic and vascular complications. Currently, there is no consensus about the best procedural approach to evaluate post-transplant renal dysfunction. Renal needle-biopsy is often required, however, this is invasive and may lead to sample errors and complications, and most clinicians prefer using one of the noninvasive diagnostic modalities.Methods: A systematic literature search was performed using PubMed, EMBASE, the Cochrane Library, MEDLINE (OvidSP), Web of Science, and Google Scholar to identify relevant articles. This review provides a literature overview of the technical aspects, new developments and clinical value of renal scintigraphy (RS), after kidney transplantation. Additionally, the advantages and limitations of RS in comparison to other diagnostic modalities are addressed. The study protocol is registered with PROSPERO, protocol number CRD42017078391.Results: A total of 32 studies were included. Studies were categorized in the following groups: tracer pharmacokinetics; acute rejection and acute tubular necrosis; vascular complications; urological complications; postoperative fluid collections; early transplant outcomes; one-year transplant outcomes.Conclusions: Several studies have described the use of RS for the diagnosis of acute rejection, however, differentiating between rejection and acute tubular necrosis remains difficult. For the diagnosis of vascular complications, RS has been described as an alternative for invasive procedures. For urologic complications, studies support the use of RS in combination with routine ultrasonography (US) surveillance. For the diagnosis of postoperative fluid collections, RS provides information to differentiate lymphoceles and urinomas. Altogether, RS should be considered in case of non-acute complications, and if US provides insufficient results. (C) 2017 Elsevier Inc. All rights reserved.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases characterized by necrotizing inflammation of small- to medium-sized blood vessels, affecting primarily the lungs and kidneys. Both animal and human studies show that the balance between inflammatory- and regulatory T- and B cells determines the AAV disease pathogenesis. Recent evidence shows malfunctioning of the regulatory lymphocyte compartment in AAV. In this review we summarize the immune regulatory properties of both T- and B cells in patients with AAV and discuss how aberrations herein might contribute to the disease pathogenesis.

Background. Living kidney donor safety requires reliable long-term follow-up of renal function after donation. The current study aimed to define the precision and accuracy of post-donation estimated glomerular filtration rate (eGFR) slopes compared with measured GFR (mGFR) slopes.Methods. In 349 donors (age 51 +/- 10, 54% female), we analysed eGFR according to the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault/body surface area (CG/BSA), creatinine clearance (CrCl) and mGFR (I-125-iothalamate) changes from 3 months until 5 years post-donation.Results. Donors had a pre-donation mGFR of 116 +/- 23 mL/min, at 3 months post-donation mGFR was 73 +/- 14 mL/min and at 5 years it was 79 +/- 16 mL/min. Between 3 months and 5 years post-donation, 28% of donors had a declining mGFR (-0.82 +/- 0.79 mL/min/year), 47% were stable and 25% had an increasing mGFR. Overall, eGFR equations showed good slope estimates (bias eGFR(CKD-EPI) 0.13 +/- 2.16 mL/min/year, eGFR(MDRD) 0.19 +/- 2.10 mL/min/year, eGFR(CG/BSA) -0.08 +/- 2.06 mL/min/year, CrCl -0.12 +/- 4.75 mL/min/year), but in donors with a decreasing mGFR the slope was underestimated (bias eGFR(CKD-EPI) 1.41 +/- 2.03 mL/min/year, eGFR(MDRD) 1.51 +/- 1.96 mL/min/year, eGFR(CG/BSA) 1.20 +/- 1.87 mL/min/ year). The CrCl had a high imprecision [bias interquartile range -1.51-3.41mL/min/year].Conclusions. All eGFR equations underestimated GFR slopes in donors with a declining GFR between 3 months and 5 years post-donation. This study underlines the value of mGFR in the follow-up of donors with risk of progressive GFR loss.

The donor glomerular filtration rate (GFR) measured before kidney donation is a strong determinant of recipient graft outcome. No tubular function markers have been identified that can similarly be used in donors to predict recipient outcomes. In the present study we investigated whether the pre-donation tubular maximum reabsorption capacity of phosphate (TmP-GFR), which may be considered a functional tubular marker in healthy kidney donors, is associated with recipient GFR at 1 yr after transplantation, a key determinant of long-term outcome. We calculated the pre-donation TmP-GFR from serum and 24-h urine phosphate and creatinine levels in 165 kidney donors, and recipient125I-iothalamate GFR and eGFR (CKD-EPI) at 12 mo after transplantation. Kidney donors were 51 ± 10 yr old, 47% were men, and mean GFR was 118 ± 26 ml/min. The donor TmP-GFR was associated with recipient GFR 12 mo after transplantation (GFR 6.0 ml/min lower per 1 mg/dl decrement of TmP-GFR), which persisted after multivariable adjustment for donor age, sex, pre-donation GFR, and blood pressure and other potential confounders. Results were highly similar when eGFR at 12 mo was taken as the outcome. Tubular damage markers kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were low and not associated with recipient GFR. A lower donor TmP-GFR before donation, which may be considered to represent a functional measure of tubular phosphate reabsorption capacity, is independently associated with a lower recipient GFR 1 yr after transplantation. These data are the first to link donor tubular phosphate reabsorption with recipient GFR post-transplantation.

Background Complement-fixing antibodies against donor HLA are considered a contraindication for kidney transplant. A modification of the IgG single-antigen bead (SAB) assay allows detection of anti-HLA antibodies that bind C3d. Because early humoral graft rejection is considered to be complement mediated, this SAB-based technique may provide a valuable tool in the pretransplant risk stratification of kidney transplant recipients.Methods Previously, we established that pretransplant donor-specific anti-HLA antibodies (DSAs) are associated with increased risk for long-term graft failure in complement-dependent cytotoxicity crossmatch-negative transplants. In this study, we further characterized the DSA-positive serum samples using the C3d SAB assay.Results Among 567 pretransplant DSA-positive serum samples, 97 (17%) contained at least one C3d-fixing DSA, whereas 470 (83%) had non-C3d-fixing DSA. At 10 years after transplant, patients with C3d-fixing antibodies had a death-censored, covariate-adjusted graft survival of 60%, whereas patients with non-C3d-fixing DSA had a graft survival of 64% (hazard ratio, 1.02; 95% confidence interval, 0.70 to 1.48 for C3d-fixing DSA compared with non-C3d-fixing DSA; P=0.93). Patients without DSA had a 10-year graft survival of 78%.Conclusions The C3d-fixing ability of pretransplant DSA is not associated with increased risk for graft failure.

Transplant recipients are prone to viral infections, which could affect renal transplantation outcome. Our aim was to assess the effects of early human cytomegalovirus (CMV) DNAemia on transplant renal function. A total of 264 (age 50.9 ± 13.5; male 55%) renal transplantation recipients undergoing preemptive anti-CMV therapy were retrospectively categorized based on early ( 6310 International Units/ml (IU/ml). Estimated glomerular filtration rate (eGFR) was analyzed between 1 and 36 months post-transplantation with Kruskal-Wallis test, linear regression, and a linear mixed-effects model. CMV infection was detectable in 113 (43%) recipients within 49 [38-67] days. Subjects with PVL > 6310 had statistically significant ~5-13 ml/min lower eGFR between 3 and 36 months compared to PVL ≤ 536 and PVL536-6310. eGFR declined from 46.1 to 40.7 ml/min/1.73 m2 (-12%) over 3 years, and the annual decrease for pronounced infection with high PVL was 2.0 ml/min/1.73 m2 faster than for noninfected or mildly infected subjects. In conclusion, high CMV DNAemia early after renal transplantation was associated with significant loss of renal function, from which subjects did not recover. The severity of infection (high PVL early post-transplantation), more than the infection per se, was related to irreversible and progressive loss of renal function.

Item does not contain fulltext Background.: Cognitions surrounding living organ donation, including the motivation to donate, expectations of donation and worries about donation, are relevant themes during living donor evaluation. However, there is no reliable psychometric instrument assessing all these different cognitions. This study developed and validated a questionnaire to assess pre-donation motivations, expectations and worries regarding donation, entitled the Donation Cognition Instrument (DCI). Methods.: Psychometric properties of the DCI were examined using exploratory factor analysis for scale structure and associations with validated questionnaires for construct validity assessment. Results.: From seven Dutch transplantation centres, 719 potential living kidney donors were included. The DCI distinguishes cognitions about donor benefits, recipient benefits, idealistic incentives, gratitude and worries about donation (Cronbach's alpha 0.76-0.81). Scores on pre-donation cognitions differed with regard to gender, age, marital status, religion and donation type. With regard to construct validity, the DCI was moderately correlated with expectations regarding donor's personal well-being and slightly to moderately to health-related quality of life. Conclusions.: The DCI is found to be a reliable instrument assessing cognitions surrounding living organ donation, which might add to pre-donation quality of life measures in facilitating psychosocial donor evaluation by healthcare professionals.

The clinical significance of non‐HLA antibodies on renal allograft survival is a matter of debate, due to differences in reported results and lack of large‐scale studies incorporating analysis of multiple non‐HLA antibodies simultaneously. We developed a multiplex non‐HLA antibody assay against 14 proteins highly expressed in the kidney. In this study, the presence of pretransplant non‐HLA antibodies was correlated to renal allograft survival in a nationwide cohort of 4770 recipients transplanted between 1995 and 2006. Autoantibodies against Rho GDP‐dissociation inhibitor 2 (ARHGDIB) were significantly associated with graft loss in recipients transplanted with a deceased‐donor kidney (N = 3276) but not in recipients of a living‐donor kidney (N = 1496). At 10 years after deceased‐donor transplantation, recipients with anti‐ARHGDIB antibodies (94/3276 = 2.9%) had a 13% lower death‐censored covariate‐adjusted graft survival compared to the anti‐ARHGDIB‐negative (3182/3276 = 97.1%) population (hazard ratio 1.82; 95% confidence interval, 1.32‐2.53; P = .0003). These antibodies occur independently from donor‐specific anti‐HLA antibodies (DSA) or other non‐HLA antibodies investigated. No significant relations with graft loss were found for the other 13 non‐HLA antibodies. We suggest that pretransplant risk assessment can be improved by measuring anti‐ARHGDIB antibodies in all patients awaiting deceased‐donor transplantation., From a multicenter evaluation of kidney transplants, the authors report that the pretransplant presence of autoantibodies against ARHGDIB are associated with long‐term graft loss in recipients transplanted with a deceased donor kidney, independent from donor‐specific HLA antibodies.

The pathophysiology of late kidney-allograft failure remains complex and poorly understood. Activation of filtered or locally produced complement may contribute to the progression of renal failure through tubular C5b-9 formation. This study aimed to determine urinary properdin and sC5b-9 excretion and assess their association with long-term outcome in renal transplant recipients (RTR). Methods: We measured urinary properdin and soluble C5b-9 in a well-defined cross-sectional cohort of RTR. Urinary specimens were taken from a morning urine portion, and properdin and sC5b-9 were measured using an enzyme-linked-immunosorbent assay (ELISA). Cox proportional hazard regression analyses were used to investigate prospective associations with death-censored graft failure. Results: We included 639 stable RTR at a median [interquartile range] 5.3 (1.8-12.2) years after transplantation. Urinary properdin and sC5b-9 excretion were detectable in 161 (27%) and 102 (17%) RTR, respectively, with a median properdin level of 27.6 (8.6-68.1) ng/mL and a median sC5b-9 level of 5.1 (2.8-12.8) ng/mL. In multivariable-adjusted Cox regression analyses, including adjustment for proteinuria, urinary properdin (HR, 1.12; 95% CI 1.02-1.28; P = 0.008) and sC5b-9 excretion (HR, 1.34; 95% CI 1.10-1.63; P = 0.003) were associated with an increased risk of graft failure. If both urinary properdin and sC5b-9 were detectable, the risk of graft failure was further increased (HR, 3.12; 95% CI 1.69-5.77; P < 0.001). Conclusions: Our findings point toward a potential role for urinary complement activation in the pathogenesis of chronic allograft failure. Urinary properdin and sC5b-9 might be useful biomarkers for complement activation and chronic kidney allograft deterioration, suggesting a potential role for an alternative pathway blockade in RTR.

Whereas regular allocation avoids unacceptable mismatches on the donor organ, allocation to highly sensitized patients within the Eurotransplant Acceptable Mismatch (AM) program is based on the patient's HLA phenotype plus acceptable antigens. These are HLA antigens to which the patient never made antibodies, as determined by extensive laboratory testing. AM patients have superior long‐term graft survival compared with highly sensitized patients in regular allocation. Here, we questioned whether the AM program also results in lower rejection rates. From the PROCARE cohort, consisting of all Dutch kidney transplants in 1995‐2005, we selected deceased donor single transplants with a minimum of 1 HLA mismatch and determined the cumulative 6‐month rejection incidence for patients in AM or regular allocation. Additionally, we determined the effect of minimal matching criteria of 1 HLA‐B plus 1 HLA‐DR, or 2 HLA‐DR antigens on rejection incidence. AM patients showed significantly lower rejection rates than highly immunized patients in regular allocation, comparable to nonsensitized patients, independent of other risk factors for rejection. In contrast to highly sensitized patients in regular allocation, minimal matching criteria did not affect rejection rates in AM patients. Allocation based on acceptable antigens leads to relatively low‐risk transplants for highly sensitized patients with rejection rates similar to those of nonimmunized individuals., The authors show that kidney allocation to highly sensitized patients based on proven acceptable HLA antigens results in a significantly lower incidence of rejection episodes when compared to allocation based on the avoidance of unacceptable HLA antigens only.

Background and objectives Cyclophosphamide has been the mainstay of treatment of ANCA-associated vasculitis. However, cyclophosphamide has unfavorable side effects and alternatives are needed. Evidence suggests that mycophenolate mofetil can induce sustained remission in nonlife-threatening disease. The purpose of this study was to compare the efficacy and safety of mycophenolate mofetil versus cyclophosphamide for the induction treatment of nonlife-threatening relapses of proteinase 3-ANCA– and myeloperoxidase-ANCA–associated vasculitis. Design, setting, participants, & measurements We conducted a multicenter randomized, controlled trial. Participants with a first or second relapse of ANCA-associated vasculitis were randomized to induction treatment with cyclophosphamide or mycophenolate mofetil both in combination with glucocorticoids. Maintenance therapy consisted of azathioprine in both arms. Primary outcome was remission at 6 months, and secondary outcomes included disease-free survival at 2 and 4 years. Results Eighty-four participants were enrolled, of whom 41 received mycophenolate mofetil and 43 received cyclophosphamide. Eighty-nine percent of participants were proteinase 3-ANCA positive. At 6 months, 27 (66%) mycophenolate mofetil–treated participants versus 35 (81%) cyclophosphamide-treated participants were in remission (P=0.11). Disease-free survival rates at 2 and 4 years were 61% and 39% for cyclophosphamide, respectively, and 43% and 32% for mycophenolate mofetil, respectively (at 4 years, log rank test, P=0.17). Conclusions We did not demonstrate mycophenolate mofetil to be similarly effective as cyclophosphamide in inducing remission of relapsed ANCA-associated vasculitis. However, mycophenolate mofetil might be an alternative to cyclophosphamide for the treatment of selected patients with nonlife-threatening relapses.

Supplemental Digital Content is available in the text., Background. There is no consensus in the literature on the interpretation of single-antigen bead positive for a specific HLA antibody. Methods. To inform the debate, we studied the relationship between various single-antigen bead positivity algorithms and the impact of resulting donor-specific HLA antibody (DSA) positivity on long-term kidney graft survival in 3237 deceased-donor transplants. Results. First, we showed that the interassay variability can be greatly reduced when working with signal-to-background ratios instead of absolute median fluorescence intensities (MFIs). Next, we determined pretransplant DSA using various MFI cutoffs, signal-to-background ratios, and combinations thereof. The impact of the various cutoffs was studied by comparing the graft survival between the DSA-positive and DSA-negative groups. We did not observe a strong impact of various cutoff levels on 10-year graft survival. A stronger relationship between the cutoff level and 1-year graft survival for DSA-positive transplants was found when using signal-to-background ratios, most pronounced for the bead of the same HLA locus with lowest MFI taken as background. Conclusions. With respect to pretransplant risk stratification, we propose a signal-to-background ratio-6 (using the bead of the same HLA-locus with lowest MFI as background) cutoff of 15 combined with an MFI cutoff of 500, resulting in 8% and 21% lower 1- and 10-year graft survivals, respectively, for 8% DSA-positive transplants.

OBJECTIVE:Physical quality of life is reduced in ANCA-associated vasculitis (AAV). This study aims to investigate whether this may be explained by reduced muscle strength and physical activity resulting from disease damage and steroid myopathy. METHODS:Forty-eight AAV patients were sequentially included from the outpatient clinic. Patients in different stages of disease and treatment underwent measurements of muscle strength and anthropometric parameters. Patients filled in physical activity (Baecke) and quality of life questionnaires (RAND-36) and carried an accelerometer for a week. Muscle strength and physical activity were compared to quality of life, prednisolone use and disease duration. RESULTS:Most AAV patients had lower knee extension (76%) and elbow flexion (67%) forces than expected based on healthy norms. Also, physical (P

Background Few studies have evaluated the effect of different immunosuppressive strategies on long-term kidney transplant outcomes. Moreover, as they were usually based on historical data, it was not possible to account for the presence of pretransplant donor-specific human-leukocyte antigen antibodies (DSA), a currently recognized risk marker for impaired graft survival. The aim of this study was to evaluate to what extent frequently used initial immunosuppressive therapies increase graft survival in immunological low-risk patients. Methods We performed an analysis on the PROCARE cohort, a Dutch multicentre study including all transplantations performed in the Netherlands between 1995 and 2005 with available pretransplant serum (n = 4724). All sera were assessed for the presence of DSA by a luminex single-antigen bead assay. Patients with a previous kidney transplantation, pretransplant DSA or receiving induction therapy were excluded from the analysis. Results Three regimes were used in over 200 patients: cyclosporine (CsA)/prednisolone (Pred) (n = 542), CsA/mycophenolate mofetil (MMF)/Pred (n = 857) and tacrolimus (TAC)/MMF/Pred (n = 811). Covariate-adjusted analysis revealed no significant differences in 10-year death-censored graft survival between patients on TAC/MMF/Pred therapy (79%) compared with patients on CsA/MMF/Pred (82%, P = 0.88) or CsA/Pred (79%, P = 0.21). However, 1-year rejection-free survival censored for death and failure unrelated to rejection was significantly higher for TAC/MMF/Pred (81%) when compared with CsA/MMF/Pred (67%, P Conclusion These results suggest that in immunological low-risk patients excellent long-term kidney graft survival can be achieved irrespective of the type of initial immunosuppressive therapy (CsA or TAC; with or without MMF), despite differences in 1-year rejection-free survival.

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

OBJECTIVE: One of the side effects of cyclophosphamide is earlier menopause and primary ovarian insufficiency. This study was undertaken to investigate the onset of menopause and the incidence of primary ovarian insufficiency in women with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), especially after treatment with orally administered cyclophosphamide. METHODS: We retrospectively studied the onset of menopause and the influence of cyclophosphamide in women diagnosed as having AAV in our center between 1970 and 2012. RESULTS: Ninety-four premenopausal women diagnosed as having AAV were included. Sixty-seven patients received cyclophosphamide, and 27 received other, mostly immunosuppressive, medication. Forty-six cyclophosphamide-treated women developed menopause, 22 of whom were considered to have primary ovarian insufficiency. None of the patients who were not treated with cyclophosphamide developed primary ovarian insufficiency. There was a significant association between a cumulative cyclophosphamide dose of >16.6 gm, versus a cumulative dose of

The PRO-C6 assay, a reflection of collagen type VI synthesis, has been proposed as a non-invasive early biomarker of kidney fibrosis. We aimed to investigate cross-sectional and longitudinal associations between plasma and urine PRO-C6 and proven histological changes after kidney transplantation. The current study is a post-hoc analysis of 94 participants of the MECANO trial, a 24-month prospective, multicenter, open-label, randomized, controlled trial aimed at comparing everolimus-based vs. cyclosporine-based immunosuppression. PRO-C6 was measured in plasma and urine samples collected 6 and 24 months post-transplantation. Fibrosis was evaluated in biopsies collected at the same time points by Banff interstitial fibrosis/tubular atrophy (IF/TA) scoring and collagen staining (Picro Sirius Red, PSR), inflammation was evaluated by the tubulo-interstitial inflammation score (ti-score). Linear regression analyses were performed. Six-month plasma PRO-C6 was cross-sectionally associated with IF/TA score (Std. &beta, = 0.34), and prospectively with 24-month IF/TA score and ti-score (Std. &beta, = 0.24 and 0.23, respectively) (p &lt, 0.05 for all). No significant associations were found between urine PRO-C6 and any of the biopsy findings. Fibrotic changes and urine PRO-C6 behaved differentially over time according to immunosuppressive therapy. These results are a first step towards non-invasive fibrosis detection after kidney transplantation by means of collagen VI synthesis measurement, and further research is required.

Objective: We studied whether in ANCA-associated vasculitis patients, duration of AZA maintenance influenced relapse rate during long-term follow-up.Methods: Three hundred and eighty newly diagnosed ANCA-associated vasculitis patients from six European multicentre studies treated with AZA maintenance were included; 58% were male, median age at diagnosis 59.4 years (interquartile range: 48.3-68.2 years); granulomatosis with polyangiitis, n = 236; microscopic polyangiitis, n = 132; or renal limited vasculitis, n = 12. Patients were grouped according to the duration of AZA maintenance after remission induction: ⩽18 months, ⩽24 months, ⩽36 months, ⩽48 months or > 48 months. Primary outcome was relapse-free survival at 60 months.Results: During follow-up, 84 first relapses occurred during AZA-maintenance therapy (1 relapse per 117 patient months) and 71 after withdrawal of AZA (1 relapse/113 months). During the first 12 months after withdrawal, 20 relapses occurred (1 relapse/119 months) and 29 relapses >12 months after withdrawal (1 relapse/186 months). Relapse-free survival at 60 months was 65.3% for patients receiving AZA maintenance >18 months after diagnosis vs 55% for those who discontinued maintenance ⩽18 months (P = 0.11). Relapse-free survival was associated with induction therapy (i.v. vs oral) and ANCA specificity (PR3-ANCA vs MPO-ANCA/negative).Conclusion: Post hoc analysis of combined trial data suggest that stopping AZA maintenance therapy does not lead to a significant increase in relapse rate and AZA maintenance for more than 18 months after diagnosis does not significantly influence relapse-free survival. ANCA specificity has more effect on relapse-free survival than duration of maintenance therapy and should be used to tailor therapy individually.

A recently published article in the Lancet (AMACING trial) challenges a long-standing clinical consensus: intravenous (i.v.) volume expansion with isotonic saline as a prophylactic measure for iodinated contrast-induced nephropathy (CIN) [1]. The randomized trial showed that - in patients with an estimated glomerular filtration rate (eGFR) of 30-59 mL/min/1.73m², undergoing an elective procedure - as compared to i.v. hydration, no prophylaxis is non-inferior in preventing CIN.

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

Background High doses of exogenous glucocorticoids (e.g., prednisolone) are a standard part of treatment for ANCA-associated vasculitis.1 Efficacy and toxicity of glucocorticoid treatment differ widely between individuals.2 We hypothesised that this can be partly explained by genetic polymorphisms of the glucocorticoid receptor (GR) and 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) that influence glucocorticoid sensitivity. Objectives To investigate whether five haplotypes of the Glucocorticoid Receptor gene (NR3C1) and a single nucleotide polymorphism of 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) are associated with treatment efficacy and toxicity in ANCA associated vasculitis. Methods A total of 241 ANCA associated vasculitis patients were genotyped for five polymorphisms of the glucocorticoid receptor gene and one polymorphism of the HSD11B1 gene. Glucocorticoid receptor gene haplotypes were predicted based on genotyping results. Relapse free survival, mortality, renal survival, metabolic adverse events and infections were compared between carriers and non-carriers of glucocorticoid receptor haplotypes and the HSD11B1 genotype. Results Carriers of the ER22/23EK haplotype of the glucocorticoid receptor had a significantly higher risk of 10 year mortality (Hazard Ratio (HR) 3.0, 95% confidence interval, CI: 1.2 to 7.3), more frequently required plasmapheresis treatment (p=0.04) and had a higher risk of developing end-stage renal disease (HR 7.4, 95% CI: 1.9 to 28.7). Carriers of a minor variant of HSD11B1 more frequently experienced relapse (HR 2.5, 95% CI: 1.5 to 4.1), except if they also carried the BclI haplotype of the glucocorticoid receptor. Homozygous carriers of the BclI haplotype had a higher risk of developing hypertension (HR 2.7, 95% CI: 1.2 to 5.7) and dyslipidemia (HR 4.1, 95% CI: 1.8 to 9.6). Occurrence of infections neither differed between GR haplotypes, nor between HSD11B1 genotypes. Conclusions The ER22/23EK and BclI haplotype of the glucocorticoid receptor and a polymorphism of the gene for HSD11B1 are associated with clinically relevant inflammatory and metabolic outcomes in ANCA associated vasculitis. References [1] Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis2016Sep;75(9):1583–1594. [2] Quax RA, Manenschijn L, Koper JW, Hazes JM, Lamberts SW, van Rossum EF, et al. Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol2013Nov;9(11):670–686. Disclosure of Interest None declared

Background Circulating regulatory T cells (Tregs) in anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) are frequently functionally deficient. The mechanism behind their impaired function is however unknown. Small non-coding microRNA (miR) are post-transcriptional regulators of protein synthesis and previous studies have shown that differently expressed miRs in T cells are associated with auto immunity. Objectives To investigate whether the dysfunctionality of Tregs in AAV is due to altered microRNA (miR) expression. Methods Tregs (CD4+CD45RO+CD25+CD127-) of healthy controls (HC) and AAV patients in remission without treatment (AAV-REM) were FACS-sorted, and total RNA was isolated. Samples from 8 HCs and 8 AAV-REMs were subjected to miRNA microarray analysis. Based on relative expression and fold change, 5 differentially expressed miRs were validated in an independent cohort using qRT-PCR and a database and literature search was performed to identify potential targets. Results Nineteen miRs differentially expressed were detected by microarray analysis, of which Let-7g, miR-20a-5p, miR-26a-5p, miR-142–3 p, miR-146a-5p were validated in an independent cohort. Of these, miR-142–3 p was confirmed to be significantly upregulated (2-fold, p=0.03) in Tregs from AAV-REM patients compared to HC Tregs (n=23, n=22). To study the functional impact of miR-142–3 p overexpression, HC Tregs were transfected using either a mimic-miR-142–3 p or a scrambled (SCR)-control. After transfection, live Tregs were co-cultured with T effectors (CD4+CD25-) in a suppression assay to test their suppressive capacity. Transfection with mimic-miR-142–3 p significantly increased the miR-142–3 p levels (2.4 fold, p=0.03) and reduced the suppressive capacity compared to SCR-transduced Tregs (1.9 fold reduction, p=0.02). Moreover, miR-142–3 p levels tended to correlate to the suppressive function of Tregs (p=0.06, rho=−0.591). A database and literature search identified adenylyl cyclase 9 (AC9) as a promising target of miR-142–3 p. mRNA levels of AC9 tended to be lower in AAV-REM patients compared to HC (3.8 fold, p=0.07). In addition, cAMP levels, which are partly produced by AC9, were significantly lower in Tregs from AAV-REM patients after 48 hour of stimulation with anti-CD3 and anti-CD28 (1.7 fold, p=0.003). Conclusions Increased expression of miR-142–3 p in Tregs of AAV-REM patients is associated with their functional impairment, potentially by targeting the AC9/cAMP mediated suppression. Disclosure of Interest G. Dekkema: None declared, T. Bijma: None declared, W. Abdulahad Grant/research support from: European Union’s Horizon 2020 research and innovation program under grant No 6 68 036., P. Jellema: None declared, A. Van Den Berg: None declared, B. J. Kroesen: None declared, C. Stegeman: None declared, P. Heeringa Grant/research support from: European Union’s Horizon 2020 research and innovation program under grant No 6 68 036., J.-S. Sanders Grant/research support from: Nierfonds grant no. 13OKJ39

The presence of donor‐specific anti‐HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long‐term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement‐dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10‐year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10‐year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10‐year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence., Via a retrospective multicenter study, the authors investigate the impact of pretransplant donor‐specific HLA antibodies on long‐term graft survival in deceased and living donor kidney transplantations.

Giant cell arteritis (GCA) is an autoimmune vasculitis affecting large and medium-sized arteries. Ample evidence indicates that GCA is a heterogeneous disease in terms of symptoms, immune pathology, and response to treatment. In the current review, we discuss the evidence for disease subsets in GCA. We describe clinical and immunologic characteristics that may impact the risk of cranial ischemic symptoms, relapse rates, and long-term glucocorticoid requirements in patients with GCA. In addition, we discuss both proven and putative immunologic targets for therapy in patients with GCA who have an unfavorable prognosis. Finally, we provide recommendations for further research on disease subsets in GCA.

OBJECTIVE: Azathioprine is a widely used immunosuppressive drug. Genetic polymorphisms and activity of the enzyme thiopurine methyltransferase (TPMT) have been associated with azathioprine efficacy and toxicity in several populations. We investigated whether these associations also exist for ANCA associated vasculitis (AAV) patients, who receive azathioprine maintenance therapy after remission induction with cyclophosphamide.METHODS: 207 AAV patients treated with cyclophosphamide induction and azathioprine maintenance therapy were included and followed for 60 months. TPMT genotype and tertiles of TPMT activity were compared to relapse free survival and occurrence of adverse events, particularly leukopenia. Multivariable regression was performed to account for confounders.RESULTS: In univariable analysis, relapse free survival was not significantly associated with TPMT genotype (P = 0.41) or TPMT activity (P = 0.07), although it tended to be longer in lower tertiles of TPMT activity. There was no significant association of TPMT genotype and activity with occurrence of any adverse event. In multiple regression, leukocyte counts at the end of cyclophosphamide induction were related to risk of leukopenia during azathioprine therapy [PCONCLUSION: TPMT genotype and activity were not independent predictors of relapse, and could not predict leukopenia or other adverse effects from azathioprine. Leukocyte counts after cyclophosphamide induction were related to both outcomes, implying a greater influence of cyclophosphamide response compared to azathioprine and TPMT in AAV patients.

BACKGROUND: Smoking is a risk factor for poor late outcomes in renal transplant recipients (RTR). Smoking exposure can be assessed by self-report and cotinine measurements. We investigated whether use of cotinine as a biomarker for smoking exposure can serve as an alternative for self-report and to compare associations of smoking exposure by self-report and cotinine with outcomes in RTR and assess dose dependency.METHODS: Renal transplant recipients were classified as never, former, light (≤10 cigarettes/day), and heavy smokers (>10 cigarettes/day) according to self-report and analogous categories for urine and plasma cotinine. First, we assessed agreement of self-reported smoking exposure with smoking exposure according urine and plasma cotinine. Second, we compared the associations with graft failure and mortality.RESULTS: Of 603 RTR (age 51.5 ± 12.1 years, 55% men), 36.0% RTR were never, 42.3% former, 10.6% light, and 11.1% heavy smokers according to self-report. The majority (98.6%) of never smokers had nondetectable cotinine. However, 14 and 13 RTR reporting no active smoking had respective urine or plasma cotinine consistent with active smoking. Cotinine-based measurements were dose-dependently associated with mortality and graft failure.CONCLUSIONS: Plasma and urine cotinine can serve as an alternative to self-report and were dose-dependently associated with poor late outcomes in RTR.

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are severe chronic auto-immune diseases in which the small vessels are inflamed. Nowadays, in the majority of patients disease can be brought into remission with cyclophosphamide and corticosteroids. However, depending upon disease characteristics patients with AAV have a risk of 29-60% to experience relapses of disease within 5 years despite maintenance therapy after induction of remission with less toxic agents, such as azathioprine, methotrexate or mycophenolate mofetil. More recently, rituximab has been found effective in both induction and maintenance of remission in AAV. This review discusses the different aspects of maintenance therapy in AAV based on reported cohorts and studies, including the different agents, therapy duration, efficacy or lack thereof and future directions. Finally, recommendations are made who to treat and for how long.