bluuebunny/crossref_metadata_2025_split huggingface dataset:
#3440 TOCILIZUMAB INDUCTION THERAPY IN KIDNEY TRANSPLANTATION
Authors: Abdullaev Sherzod , Sharapov Olimkhon 
Published: June 2023

Abstract

Background and Aims
Antibody induction therapy is frequently used as an adjunct to the maintenance immunosuppression in adult kidney transplant recipients (KTRs). There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in KTRs. The purpose of the present study was to compare induction therapy involving tocilizumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk.

Method
In this prospective study, we randomly assigned patients to receive tocilizumab or conventional induction therapy such as basiliximab. Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 30% or more. The 102 high-risk patients received tocilizumab (one dose of 8 mg/kg, in 52 patients) or basiliximab (a total of 40 mg over 4 days, in 50 patients). The 113 low-risk patients received tocilizumab (one dose of 8 mg/kg, in 62 patients) or basiliximab (a total of 40 mg over 4 days, in 51 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 10-days glucocorticoid (prednisone) taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 2 years for safety and efficacy end points.

Results
The rate of biopsy-confirmed acute rejection was significantly lower in the tocilizumab group than in the basiliximab group at both 6 months (5.3% vs. 10.9%, P&lt;0.01) and 12 months (7.9% vs. 12.9%, P&lt;0.01). At 2 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with tocilizumab than with basiliximab (9.7% vs. 17.7%, P&lt;0.05), but among high-risk patients, no significant difference was seen between tocilizumab and basiliximab (19.2% vs. 16.0%, P = 0.68). Adverse-event rates were similar among all four treatment groups.

Conclusion
By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with tocilizumab than with conventional therapy. The apparent superiority of tocilizumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, tocilizumab and basiliximab had similar efficacy. Further randomized and controlled studies are needed to support these results.
#4139 EFFECTS OF EMPAGLIFLOZIN ON FLUID OVERLOAD IN CHRONIC KIDNEY DISEASE: AN EMPA-KIDNEY BIOIMPEDANCE SUBSTUDY
Authors: Mayne Kaitlin 
Published: June 2023

Abstract

Background and Aims
The EMPA-KIDNEY trial showed that, compared to placebo, empagliflozin 10 mg once daily reduced the risk of kidney disease progression or cardiovascular death in 6609 patients with chronic kidney disease at risk of progression. We aimed to assess effects of empagliflozin on bioimpedance-measured fluid overload and adiposity in a subset to better understand the mechanisms of cardiovascular benefits of sodium glucose co-transporter-2 inhibitors.

Method
This EMPA-KIDNEY substudy added Body Composition Monitor (BCM) measurements at randomization and the 2 and 18 month follow-up visits to the trial's main protocol-specified procedures. The primary outcome was Absolute Fluid Overload (a parameter reflecting overhydration, derived from extracellular and intracellular resistance). Pre-specified subgroup analyses of the primary outcome were by sex, diabetes status, estimated glomerular filtration rate (eGFR) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) at baseline. The key secondary analysis was a composite of death from heart failure, heart failure hospitalisation or development of new moderate (&gt;7%, ≤15%) or severe (&gt;15%) BCM-measured Relative Fluid Overload. Tertiary outcomes included weight, anthropometry, and other BCM-measurements of body water and adiposity. The primary outcome was analysed used mixed-model repeated measures (MMRM) methods. The key secondary outcome used time-to-first event methods.

Results
A total of 660 EMPA-KIDNEY participants were recruited into this substudy. Mean age was 64 years, 205 (31%) were female and 245 (37%) had diabetes. Mean (SD) eGFR was 36 (12) ml/min/1.73m2 and median (Q1-Q3) NTpro-BNP was 211 (93-581) ng/L. Mean (SD) Absolute Fluid Overload at baseline was 0.4 (1.6) L, 19% had moderate fluid overload and 5% fulfilled criteria for severe fluid overload at baseline. Compared to placebo, the mean study average absolute difference in Absolute Fluid Overload was -0.24L (95% CI -0.38, -0.11), with similar differences at 2 months and 18 months (Figure 1). This difference was similar in men and women, in people with and without diabetes, and across the spectrum of eGFR and NT-proBNP studied (Figure 2). The number of key secondary outcomes was low and there was no significant difference in the risk of this outcome between treatment groups (35/332 [10%] vs 38/328 [12%], hazard ratio 0.91 [95% CI 0.57, 1.45], p = 0.69).

Conclusion
In patients with chronic kidney disease, empagliflozin reduced bioimpedance-measured fluid overload irrespective of diabetes status or level of eGFR. This effect persisted for at least 18 months with no evidence of attenuation over time.

Funding
Boehringer Ingelheim, Eli Lilly and others; Clinicaltrials.gov:NCT03594110.
#4572 EFFECTS OF EMPAGLIFLOZIN ON KIDNEY AND CARDIAC MRI MEASURES IN PATIENTS WITH CHRONIC KIDNEY DISEASE
Authors: Judge Parminder , EMPA-KIDNEY collaborative group on behalf of the 
Published: June 2023

Abstract

Background and Aims
EMPA-KIDNEY demonstrated empagliflozin reduced the risk of kidney disease progression or cardiovascular death in patients with CKD at risk of progression, but the mechanisms of benefit are uncertain. MRI was used to assess whether empagliflozin modified the structure and function of the kidneys and heart at around 18 months after randomization.

Method
Randomized participants from 8 sites in UK and Germany without a contraindication to MRI scanning, were eligible and invited to participate in this substudy. MRI scans were performed using a standardized protocol. Renal T1 mapping (MOLLI 5[3]3 scheme which measures fibrosis and inflammation) was computed by first segmenting MOLLI data using a U-net and then applying the masks to both kidneys. Cardiac MRI included cine steady-state free precession imaging to assess biventricular volumes, mass and function, and T1 mapping to assess myocardial inflammation and fibrosis. The primary outcome was kidney cortical T1 mapping measured by MOLLI. Secondary outcomes included LV ejection fraction, myocardial T1 MOLLI and LV mass index. Differences in MRI measurements between treatment groups were analysed using linear regression adjusted for baseline age, sex, eGFR, UACR and diabetes status. 172 participants were required to provide 90% power at 2p = 0.05 to detect a 50 ms difference in T1.

Results
172 participants had an MRI scan around 18 months after randomization. 93 (54%) were allocated empagliflozin and 79 (46%) placebo. Mean (SD) age was 60 (15) years, 26% were female and 23% had diabetes. Mean eGFR was 37 (13) mL/min/1.73m2 and geometric mean (95% CI) UACR was 242 (182-322) mg/g (Table 1). Adjusted mean (SE) cortical T1 mapping by MOLLI was 1623 (10) ms in those allocated empagliflozin versus 1634 (11) ms in those allocated placebo, difference in means (95% CI) −11 (−41 to 18), P = 0.45 (Table 2). Medullary T1 MOLLI scores were similar. Empagliflozin had no significant effect on cardiac MRI measures: difference (95% CI) in LV ejection fraction 1% (−1 to 4); myocardial T1 MOLLI −3 ms (−16 to 10); LV mass index −3 g/m2 (−5 to 0) (Table 2).

Conclusion
Empagliflozin had no significant effect on MRI-based measures of fibrosis within the kidney cortex or myocardium in people with CKD at risk of progression. There was no effect of treatment on measures of cardiac structure or function. Further MRI measures will be available for presentation by the time of the ERA congress.

Funding
Boehringer Ingelheim, Eli Lilly and others; Clinicaltrials.gov:NCT03594110.
#4989 FIRST INTERIM ANALYSIS OF THE INTERNATIONAL DISTAL RENAL TUBULAR ACIDOSIS REGISTRY
Authors: Giaccari Marta , Haffner Dieter , Schaefer Franz , Ariceta Gema , Bockenhauer Detlef , Emma Francesco 
Published: June 2023

Abstract

Background and Aims
Primary Distal Renal Tubular Acidosis (dRTA) is a rare genetic condition characterized by impaired capacity of A-type intercalated cells to excrete excess of H+ ions. The disease is caused primarily by pathogenic variants in the SLC4A1 gene encoding for the basolateral anion exchanger 1 (AE1) or the ATP6V1B1 and ATP6V0A4 genes encoding for two subunits of the apical proton ATPase. The latter also cause variable degrees of sensorineural hearing loss (SNHL). Additional genes include WDR72 that is associated with amelogenesis imperfecta and FOXI1 that also causes SNHL. To understand better the impact of alkali treatment on the natural history of dRTA, a European prospective registry has been created in collaboration with the ERKNet European Reference Network.

Method
We present a first interim descriptive analysis of first 182 patients that have been collected from 2019 to 2022. Treatment data are under analysis and are not included.

Results
To date, mostly paediatric patients (79%) have been included in the registry. A genetic diagnosis was available in 111/182 (61%) of patients and showed the following distribution of underlying genes: ATP6V0A4: 45%, ATP6V1B1: 41%, SLC4A1: 14%. Variants in WDR72 and FOXI1 were reported in one patient each. Overall, we observed no major differences in blood pressure and in urinary/blood parameters, when comparing children vs adults or proton ATPase vs AE1 defects (partially shown in tables 1 and 2). Adult patients were on average diagnosed later, had more frequently nephrolithiasis and higher BMI. In part, differences may reflect selections biases that will be assessed with the collection of longitudinal data. As expected, patients with proton pump defects were diagnosed earlier and had more frequently SNHL. The degree of nephrocalcinosis and the estimated glomerular filtration rates were similar when comparing all groups. None of the patients had developed end stage kidney disease.

Conclusion
This first report demonstrates successful enrolment of a cohort of patients with dRTA. Enrolment is still ongoing. Longitudinal data will allow assessing the impact of alkali therapy on the long-term outcome.
#5419 INVESTIGATING THE ROLE OF CFH VARIANTS AND HAPLOTYPES AS A RISK FACTOR OF IGA NEPHROPATHY IN A FRENCH COHORT
Authors: Duval Anna , Maillard Nicolas , Limou Sophie , Mariat Christophe , Ohlmann Sophie , Bacchi Veronique Fremeaux 
Published: June 2023

Abstract

Background and Aims
Excessive complement activation is particularly important in the pathogenesis of IgAN nephropathy (IgAN). The relationship of complement CFH gene genetics and IgAN phenotype has not been clearly established in IgAN.

Method
We performed a genetic analysis of 234 French IgAN patients by next generation sequencing and Sanger. CFH polymorphisms were combined into haplotypes using the Michigan imputation Server1. CFH rare variants (MAF&lt;0.1%) and haplotypes frequencies were compared to the 1k genome population of European ancestry. Recombinant full-length FH rare variants were produced and studied functionally in vitro.

Results
Genetic analysis revealed an enrichment in CFH non synonymous rare variants in IgAN patients (n = 234) compared to the reference population (n = 503) (5.1 versus 1.8%, p = 0.010). Interestingly, the identified variants preferentially located in FH functional domains. In vitro functional studies based on new functional Luminex® assays showed a decrease in C3b-binding, C3bBb decay-accelerating activity and/or FI-cofactor activity for 4 variants, classifying a newly identified variant as a pathogenic variant. CFH haplotypes distribution differed between the IgAN patients and controls (p&lt;0.001), with a higher prevalence of the H3 haplotype (rs80029 c.184G&gt;A, rs1061170 c.1204T&gt;C, rs7542235 chr1:196854483 A&gt;G, GTA) in IgAN patients (28.2 versus 21.1%, p = 0.0029), but this haplotype was not associated with renal survival.

Conclusion
In our series of French IgAN patients, CFH rare variants and haplotypes are associated with disease's susceptibility. Our results support the hypothesis of a complement dysregulation underlying the IgAN pathogenesis.
#5773 URINARY OROSOMUCOID IS ASSOCIATED WITH ALL-CAUSE MORTALITY IN THE GENERAL POPULATION
Authors: Andreassen Runa Marie , Brobak Karl Marius , Melsom Toralf , Eriksen Bjørn Odvar , Solbu Marit Dahl 
Published: June 2023

Abstract

Background and Aims
Urinary albumin excretion (UAE) is considered a risk factor for cardiovascular (CV) disease and all-cause mortality, but the pathophysiological mechanisms are not known, and studies are not consistent with regards to the effect of pharmacological UAE reduction on endpoints. Another protein, orosomucoid (41-43kDa), is a non-specific acute inflammatory protein and is a part of the glycolax that covers the endothelium. Under normal conditions the concentration in urine is low, but a marked increase is demonstrated under both acute and chronic inflammation and in cardiovascular disease. In patients with diabetes urinary orosomucoid excretion (UOE), was an independent predictor of all-cause and cardiovascular mortality even in normoalbuminuric patients. In this longitudinal study, our aim was to study both UAE and UOE in a middle-aged cohort from the general population. We hypothesized that UOE, but not UAE, is an independent predictor for all-cause mortality.

Method
The Tromsø Study is a population-based, prospective study with repeated health surveys of inhabitants of Tromsø (Northern Norway), and the first took place in 1974. From the sixth wave (Tromsø6, 2007/2008) we included all participants with urinary samples. Follow-up time was assigned from the attendance date of Tromsø6 until 31.08.2022. The associations between urinary markers and all-cause mortality were assessed by Cox regression analysis.

Results
The cohort included 7180 subjects (4094 women and 3086 men) with a mean (SD) age 63.5 (±9.2) years. Median urinary orosomucoid to creatinine ratio (UOCR) was 0.44 g/g, median albumin to creatinine ratio (UACR) was 0.36 mg/mmol, mean (SD) eGFR was 88.1 (±14.0) ml/min/1.73m² and 1689 died during follow-up. UOCR was independently associated with all-cause mortality (hazard ratio (HR) per g/g increase 1.02, 95% CI 1.01,1.03, p&lt;0.001) adjusted for sex, age, UACR, eGFR and CV risk factors (diabetes, hypertension, smoke, cholesterol, BMI). The HR for UOCR above vs. below median adjusted for the same variables was 1.13 (95% CI 1.01, 1.27, p = 0.032). UACR above median with the same adjustments was not associated to all-cause mortality (hazard ratio 1.04, 95%CI 0.93, 1.15, p = 0.484).

Conclusion
In this study, we showed for the first time that UOE, but not UAE, was an independent predictor of all-cause mortality in a large cohort from the general population. Thus, UOE may be an earlier marker of vascular damage than UAE. Whether UOE is clinically useful as an early marker of CV disease should be further studied.
#6402 IMPACT OF DARATUMUMAB AND BELATACEPT ON HLA ANTIBODIES IN KIDNEY TRANSPLANT CANDIDATES WITH 100% CPRA: EARLY RESULTS OF ATTAIN (ITN090ST)
Authors: Vincenti Flavio , Chandran Sindhu , Raja Rajalingam , Mason Kristen , Mall Shreya , Maruthamuthu Stalinraja , Martin Thomas , Breeden Cynthia , Silva Juliete 
Published: June 2023

Abstract

Background and Aims
Despite high allocation priority, &lt;10% of kidney transplant candidates with cPRA 100% can find a compatible donor. Current desensitization strategies are ineffective due to antibody rebound. Adding costimulation blockade to plasma cell (PC) depletion prevents antibody rebound in nonhuman primates by countering nodal B cell and Tfh expansion.

Method
ATTAIN is a pilot, phase I/II trial of daratumumab, a CD38 mAb used in multiple myeloma, plus belatacept, a high affinity CTLA4-Ig, to desensitize kidney transplant candidates with cPRA ≥99.9%. Enrolled subjects receive daratumumab (6 doses: 8 mg/kg) and belatacept (4 doses: 10 mg/kg) over 10 weeks with bone marrow and blood assessments pre-and post-treatment. The primary efficacy endpoint (PE) is a composite of (1) elimination of ≥1 HLA antibody specificity, (2) ≥50% reduction in the MFI of ≥3 HLA antibody specificities, or (3) kidney transplant from a previously incompatible donor. Target accrual is 15, enrolled in 2 cohorts (5+10).

Results
Cohort 1 (n = 5, mean age 44, 60% with previous transplant) has been enrolled and treated, with 5-31 weeks follow-up to date. The treatment was tolerated well in all 5 patients who showed a significant reduction in most HLA antibodies after treatment without manifestation of rebound. 3 of 5 participants reached the PE and 5 of 5 had &gt;50% bone marrow (BM) PC depletion. One patient received a kidney transplant from a previously incompatible deceased donor and is doing well at 7 months post-transplant without rejection or rebound of HLA antibody. Treatment was temporarily paused in 3 subjects due to AEs (acute cholecystitis and COVID, upper GI bleed, fevers); no cases of opportunistic infection or malignancy occurred.

Conclusion
A novel HLA desensitization regimen consisting of PC depletion with Daratumumab and costimulatory blockade with Belatacept appears safe and successful in the ongoing ATTAIN clinical trial. In the initial subject, this regimen led to transplant without HLA antibody rebound or acute rejection. Longer follow-up and additional subjects are needed to confirm these promising results. ATTAIN (NCT04827979) is a trial conducted by the Immune Tolerance Network and sponsored by NIAID (award UM1AI109565).
#3248 COMPARATIVE EFFECTIVENESS OF DIURETICS AND CALCIUM CHANNEL BLOCKERS ON TOP OF RASI ON CKD PROGRESSION AND MORTALITY: A NATIONWIDE COHORT STUDY
Authors: Faucon Anne-Laure , Fu Edouard , Stengel Benedicte , Mazhar Faizan , Evans Marie , Carrero Juan Jesus 
Published: June 2023

Abstract

Background and Aims
It is unknown whether initiating diuretics on top of renin-angiotensin system inhibitors (RASi) is superior to alternative antihypertensive agents such as calcium channel blockers (CCBs) in persons with CKD.

Method
We emulated a target trial in the Swedish Renal Registry 2007–2022, enrolling patients with moderate-advanced CKD under nephrology care who had good adherence to RASi and initiated antihypertensive therapy with either diuretics or CCB. Using propensity score-weighted cause-specific Cox regression, we compared risks of major adverse renal events (MAKE, including kidney replacement therapy [KRT], ≥40% decline in eGFR, eGFR&lt;15 mL/min per 1.73 m²), major cardiovascular events (MACE, including CV death, myocardial infarction, stroke) and death.

Results
We identified 5875 patients (median age 71 years, 64% men, eGFR 26 mL/min per 1.73 m²), of whom 3165 started diuretics and 2710 CCB. After a median follow-up of 6.3 [3.2-9.7] years, 2558 MAKE and 1178 MACE occurred, and 2299 deaths (Figure). Compared to CCB, diuretic use was associated with a lower risk of MAKE (adjusted HR: 0.87 [95%CI: 0.77-0.97]), consistent across single components (KRT: 0.77[0.67-0.88], ≥40% eGFR decline: 0.81[0.72-0.91], and eGFR &lt;15mL/min/1.73 m²: 0.85[0.75-0.97]). The risks of MACE (1.15 [0.96-1.36]), all-cause (1.07 [0.94-1.22]), CV- (1.20 [0.95-1.51]) and non-CV death (1.01 [0.86-1.19]) did not differ between therapies. Results were consistent across subgroups and robust to competing risks.

Conclusion
Our findings provide evidence from real-world clinical practice that in patients with moderate-advanced CKD, add-on antihypertensive therapy to RASi with diuretics may confer further kidney benefits and similar cardioprotection compared with CCBs.
#3682 THE KETONE BODY BETA-HYDROXYBUTYRATE IS ASSOCIATED WITH BETTER KIDNEY FUNCTION OUTCOME IN PATIENTS WITH ADPKD: RESULTS OF THE DIPAK COHORT
Authors: Knol Martine , Bais Thomas , Geertsema Paul , Connelly Margery A , Bakker Stephan J L , Gansevoort Ron T , Van Gastel Maatje 
Published: June 2023

Abstract

Background and Aims
A dysregulated energy metabolism is a key feature of Autosomal Dominant Polycystic Kidney Disease (ADPKD), characterized by cystic cells being dependent on glucose and poorly able to use other energy sources such as ketone bodies. Besides providing energy, ketone bodies, especially beta-hydroxybutyrate, can act as signaling metabolites and reduce inflammation and oxidative stress. In experimental studies, raising ketone body concentration reduced disease progression. Therefore, we hypothesized that higher endogenous serum beta-hydroxybutyrate concentration reduces disease progression in patients with ADPKD.

Method
We analyzed data from the DIPAK cohort, a prospective observational cohort study that included 670 patients with ADPKD. Beta-hydroxybutyrate was measured at baseline using nuclear magnetic resonance spectroscopy. We excluded participants with type 2 diabetes, who used disease-modifying drugs (e.g., tolvaptan, somatostatin analogs), were not fasting, or had missing beta-hydroxybutyrate, leaving 521 participants for the analyses. Linear regression analyses were used to study cross-sectional associations and linear mixed-effect modeling for longitudinal associations.

Results
The median concentration of beta-hydroxybutyrate was 94 (IQR 68–147) μmol/L. Of the participants, 61% were female, the mean age was 47.3 ± 11.8 years, and the mean estimated glomerular filtration rate (eGFR) was 63.3 ± 28.9 mL/min/1.73 m2. Cross-sectionally, beta-hydroxybutyrate was neither associated with eGFR nor with kidney volume. Longitudinally, beta-hydroxybutyrate was positively associated with the eGFR slope (B = 0.37 (95% CI 0.11 to 0.62), p = 0.005) but not with kidney growth. After adjustment for potential confounders, every doubling in beta-hydroxybutyrate concentration reduced the annual rate of eGFR loss by 0.34 (95% CI 0.10 to 0.58, p = 0.005) ml/min/1.73 m2.

Conclusion
These analyses support the hypothesis that raising the beta-hydroxybutyrate concentration, one of the ketone bodies, reduces the rate of kidney function decline in patients with ADPKD.