bluuebunny/crossref_metadata_2025 huggingface dataset:
MO980OUTCOMES OF RABBIT ANTI-THYMOCYTE GLOBULIN VERSUS IL-2 RECEPTOR ANTAGONIST INDUCTION THERAPIES IN 2DR MISMATCH RENAL TRANSPLANT RECIPIENTS
Authors: Ali Hatem Kaies Ibrahim Elsayed , Mohamed Mahmoud , Krishnan Nithya , Malik Shafi
Published: May 2021

Background and Aims

2DR HLA mismatch indicates high immunological risk renal transplant. Induction therapy with rabbit Anti-thymocyte Globulin (r-ATG) and IL-2 Receptor Antagonist (IL-2RA) resulted in marked reduction of acute allograft rejection rate and improved graft survival. However, the outcomes in 2DR (HLA-DR) mismatched renal transplant recipients (RTRs) in the era tacrolimus-mycophenolate mofetil maintenance immunosuppression remains understudied.

Method

This was a retrospective cohort study using data from the United States Organ Procurement and Transplantation Network, all 2 DR mismatched RTRs who were maintained on tacrolimus and mycophenolate mofetil immunotherapy between 2005 and 2015 were included. Follow up data was until September 2020. Patients who received transplants from living donors were included in the study. Collected data included recipient factors (age, sex, ethnicity, diabetes, body mass index), transplant factors (delayed graft function, cold ischemia time, number of previous transplants, panel reactive antibodies, HLA-mismatches, induction therapies, maintenance immunotherapy, and donor factors (donor type, donor age). RTRs were divided into 2 groups: based on induction therapy r-ATG and IL-2RA. Instrumental variable regression models were used to assess effect of induction therapy on acute rejection episodes at 6 months post-transplant and on graft survival. Type of induction therapy was instrumented for the transplant centre to reduce the centre effect on the choice of the induction therapy. Cox proportional hazard regression analysis was performed to assess the effect of induction therapy on graft survival. The regression models were adjusted for collected recipient, donor and transplant factors.

Results

3052 patients received IL2-RA while 5143 patients received R-ATG induction. Using instrumental variables regression models, there were no significant differences between IL2-RA versus R-ATG induction in acute rejection episodes (OR=1.49, 95% CI ranges from 0.73 to 3.05, P=0.27), or graft survival (coefficient=0.95, 95% CI: -0.18 to 2.10, P=0.10). Using Cox proportional hazards regression, there was no significant difference in graft survival between either induction therapies (HR=0.90, 95% CI: 0.74 to 1.09, P=0.29).

Conclusion

This study showed no significant difference in acute rejection episodes or graft survival when using ATG or IL-2RA in 2DR HLA mismatched renal transplant recipients in the current tacrolimus-based maintenance immunosuppression era. Therefore, IL2-RA is a safe induction therapy in this group of patients and non-inferior to R–ATG induction therapy. Moreover, this study also highlights the fact that antigen level 2DR mismatches are not a risk factor for rejection and HLA matching should be based on epitope level rather than antigen level.
MO983EFFICACY AND SAFETY OF SWITCHING TO AZATHIOPRINE FOR MYCOPHENOLATE INDUCED DIARRHEA IN RENAL TRANSPLANT RECIPIENTS
Authors: Sekmek Serhat , Yildirim Tolga , Koc Neriman Sila , Onal Ceren , Jabrayilov Jabrayil , Yilmaz Seref Rahmi , Arici Mustafa , Altun Bulent , Erdem Yunus
Published: May 2021

Background and Aims

Diarrhea is a common side effect of mycophenolate treatment in renal transplant recipients. In patients with mycophenolate induced diarrhea, one of the options is switching mycophenolate to azathioprine. In this study, we aimed to define the safety and efficacy of switching from mycophenolate to azathioprine for mycophenolate related diarrhea in renal transplant recipients.

Method

A total of 177 patients, 59 of whom were switched to azathioprine due to diarrhea and 118 of which were matched control group without diarrhea that continued mycophenolate treatment, participated in this study. We analyzed the effect of switching to azathioprine from mycophenolate on amelioration of diarrhea and graft survival.

Results

We observed that 89.8% of the patients who switched to azathioprine due to diarrhea had improved diarrhea complaints. Patients switched to azathioprine due do diarrhea had lower glomerular filtration rate (59 [15-125] vs. 74 [23-150] mL/min, p<0.001) and higher proteinuria (254 [49 – 15.500] mg/day vs. 184 [5 – 2329] mg/day, p<0.001) compared to control group before the switch. When patients switched to azathioprine were compared to a sub-group of 59 control patients who were matched to patients that switched to azathioprine in terms of baseline renal function and proteinuria in addition to demographic parameters, they had higher ten-years graft loss compared to patients that continued mycophenolate (p=0.03) (Figure 1). Particularly in patients with a glomerular filtration rate of less than 30 mL/min at the time of conversion, the risk of early graft loss was high.

Conclusion

Although switching mycophenolate to azathioprine was an effective approach to improve diarrhea, this approach is associated with increased risk of graft loss.
MO1049PROGRESSION OF CHRONIC KIDNEY DISEASE AND LONG-TERM MORTALITY IN PATIENTS HOSPITALIZED WITH TRICUSPID REGURGITATION
Authors: Elitok Saban , Haase-Fielitz Anja , Ernst Martin , Haase Michael
Published: May 2021

Background and Aims

Uremic toxins negatively affect the cardiovascular system resulting in significant morbidity and mortality. However, independent risk factors for chronic kidney disease (CKD) and that of worsening CKD have not been studied in patients with tricuspid regurgitation (TR), yet. Accordingly, in this study, we aimed to assess independent risk factors for the development of progressive CKD in patients with TR. Also, the impact of progressive CKD on long-term mortality was evaluated.

Method

This retrospective, single-center study comprised 444 consecutive patients with TR who were hospitalized between January 2010 and June 2017. We excluded patients with CKD stage 5. Demographic data, comorbidities, type of admission, medication, echocardiographic and laboratory parameters, and survival status were obtained from patient medical record from index hospital admission through discharge. For at least three years, serum creatinine concentrations and survival status were collected from outpatient medical record. We identified independent risk factors for CKD progression. Also, we assessed the impact of CKD progression and other variables on 3-year mortality using multivariable logistic regression analysis. For analysis of 3-year mortality, we grouped patients according to different combinations of their TR grade and presence or absence of CKD progression.

Results

Stage of CKD at hospital admission (odds ratio 0.34 [95% confidence interval 0.24-0.50], p < 0.001), baseline hemoglobin concentration (OR 0.72 [95% CI 0.57-0.92], p=0.006) and presence of diabetes type 2 (OR 1.81 [95% CI 1.08-3.03], p=0.024) were identified as independent risk factors for CKD progression. Progression of CKD during follow-up (OR 2.16 [95% CI 1.31-3.57], p=0.003), grade of TR and mitral regurgitation during index hospital stay and hemoglobin concentration at baseline were independent risk factors for 3-year mortality. Combination of TR grade and status of CKD progression showed a stepwise pattern for 3-year mortality (Figure 1). Patients with TR 1 and CKD progression had a similar 3-year mortality as patients with TR 2 or 3 but no CKD progression. In patients with TR 1, risk for 3-year mortality doubled if CKD progression occurred (OR 2.49 [95% CI 1.38-4.47], p=0.002).

Conclusion

Although retrospective studies cannot imply causal relationship, based on study findings, kidney follow-up especially in patients with mild TR may be advisable. If CKD progression can be prevented in patients with TR and if such kidney protection may reduce long-term mortality may be objective of future studies.
MO1050ACCESS TO DIALYSIS IN PUBLIC HOSPITALS FOR CHRONIC KIDNEY DISEASE PATIENTS: RESULTS FROM THE HEMODIALYSIS REGISTRY WAITING LIST AT ARISTIDE LE DANTEC HOSPITAL IN SENEGAL
Authors: Faye Moustapha , Keita Niakhaleen , Lemrabott Ahmed Tall , Faye Maria , Ba Bacary , Dieng Ameth , Ba Mamadou Aw , Niang Abdou , Ka Elhadji Fary
Published: May 2021

Background and Aims

The lethality and cost of chronic kidney disease (CKD) management are high in Senegal. The aim of this study was to evaluate the access in dialysis at Senegalese public’s hospitals.

Method

This was a retrospective cohort during 4 years (2014-2018) from the hemodialysis registry waiting list at Aristide Le Dantec University Hospital. This registry is composed by: a registration form (social survey and doctor's visa); a written letter addressed to hospital director and the national identity card. From this registry, telephone calls were made to collect data relating to mortality and access to dialysis.

Results

seven hundred fifty-one (751) files were collected. The mean age of the patients was 48.12 ± 15.28 years with a sex ratio of 1.02. The socioeconomic level was low in 85.40% (521/610) and average in 13.61% (83/610). The geographic origin was rural in 11.15%, semi-urban in 07.54% and urban in 81.31%. Ten patients (1.64%) had medical care coverage. On call, 49.70% (373/751) were died before accessing to public dialysis, 29.70% (223/751) had accessed public dialysis and 04.00% (30/751) didn’t yet need dialysis. Hundred twenty-one (16.10%) were unreachable and 0.50% (4/751) was unknown.

Conclusion

The lethality of CKD was high. Access to dialysis in public hospital remains problematic in Senegal despite its democratization. Additional efforts are needed for effective management of all patients at dialysis stage.
FC 046INCIDENCE OF NOSOCOMIAL ACUTE KIDNEY INJURY (AKI) IN A COHORT OF COMMUNITY-DWELLING OLDER ADULTS OVER 8 YEARS OF OBSERVATION
Authors: Ebert Natalie , Schneider Alice , Balabanova Yanina , Brobert Gunnar , Huscher Dörte , Mielke Nina , Schaeffner Elke
Published: May 2021

Background and Aims

Acute kidney injury (AKI) is amongst the most common in-hospital complications especially in old age. Epidemiological data on incidence rates (IR) of nosocomial AKI in individuals aged 70+ years, stratified by age, gender and pre-existing diseases are scarce because older adults are usually underrepresented in clinical research.

Method

We used data from the Berlin Initiative Study (BIS), a longitudinal, population-based cohort of adults aged ≥70 with biennial follow-up visits (including blood and urine tests) in combination with claims data from the AOK Nordost insurance fund to complement information on diagnoses and in-hospital procedures (based on ICD-10 and OPS coding). Nosocomial AKI was defined as documented in-hospital diagnosis (ICD-10: N17.xx) excluding cases with AKI as admission diagnosis. Incidence rates (IR) and 95% confidence intervals (CI) of the first nosocomial AKI were calculated with the number of incident cases during observation divided by the total person-years of follow-up, for AKI cases truncated at the first incidence of nosocomial AKI. IR are reported by age strata, sex and preexisting diseases (diabetes, arterial hypertension, atrial fibrillation, heart failure, angina pectoris, peripheral artery disease and impaired kidney function).

Results

In 2020 individuals (mean age 80.5 years; 52.6% women), 383 developed nosocomial AKI over the median [IQR] follow up time of 8.8 [5.9-9.3] years (Fig.1). The IR of nosocomial AKI was 26.8 (95%CI 24.1-29.6) per 1000 person years among all patients, with higher IR in men compared to women, and - when stratified by age - lowest IR in age category 70-75 versus the highest IR in age category of ≥ 90 years (Fig.1).

IR per 1000 person years were higher in patients with diabetes mellitus (IR: 39.3 vs 22.7), arterial hypertension (IR: 31.1 vs 12.2), chronic heart failure (IR: 41.9 vs 22.3), angina pectoris (IR: 37.6 vs 25.7), peripheral artery disease (IR: 55.0 vs 25.1) and impaired kidney function (IR: 43.3 vs 12.4), respectively (Fig.2).

Conclusion

Nosocomial AKI is an in-hospital complication common in older adults with IRs rising continuously with age above the age of 70 years. IR of AKI are considerably higher in patients with cardiovascular comorbidities. A better understanding of the patient population at risk is of great clinical relevance when aiming to improve prevention strategies.
FC 047COMPARISON OF THE CHARACTERISTICS AND MORTALITY OF ACUTE KIDNEY INJURY IN PATIENTS WITH COVID-19 AND OTHER RESPIRATORY INFECTIONS: A PROSPECTIVE COHORT STUDY
Authors: Diebold Matthias , Zimmermann Tobias , Dickenmann Michael , Schaub Stefan , Bassetti Stefano , Siegemund Martin , Breidthardt Tobias , Twerenbold Raphael
Published: May 2021

Background and Aims

Previous studies have indicated a coherency between coronavirus disease 2019 (COVID-19) and acute kidney injury (AKI), indicating poor outcomes. However, most studies only included patients with COVID-19 and lacked a control group. Therefore, the aim of this study was to investigate the prevalence and prognostic impact of AKI in patients with COVID-19 in comparison with other respiratory tract infections.

Method

The prospective single-center observational case-control COronaVIrus surviVAl (COVIVA, clinicaltrials.gov NCT04366765) study performed at the University Hospital Basel Switzerland consecutively enrolled patients presenting to the emergency department with symptoms suggestive of COVID-19 between March 23 and May 31, 2020. The final diagnosis that led to the inclusion in the study was adjudicated by physicians after reviewing all available medical data including laboratory test results 30 days after discharge. For this analysis, we compared patients tested positive for SARS-CoV-2 with patients tested negative but with an adjudicated diagnosis of upper or lower respiratory tract infection including pneumonia. Primary outcome measure was death at 30 days, secondary outcomes were AKI incidence, renal recovery and need for renal replacement therapy. AKI was defined according to the serum creatinine criteria of the 2012 KDIGO clinical practice guideline.

Results

Of the 1086 patients included, 507 had a final adjudicated diagnosis of respiratory tract infection and were eligible for this analysis. Of those, 183 (36%) had a positive PCR swab test for SARS-CoV-2. Baseline characteristics were comparable between patients with and without COVID-19.

AKI occurred in 95 patients (19%) with a higher incidence (30%, 95%CI 24-37 versus 12%, 95%CI 9-17, p<0.001) and a higher severity (KDIGO stage 3, 22% versus 10%, p=0.003) in patients with COVID-19 as compared to controls, respectively. Need for intensive care (22% versus 6%, p<0.001) and requirement for RRT were higher in patients with COVID-19 (8 patients (4.4%) versus 2 patients (0.62%); p=0.01). Renal recovery at discharge in survivors was similar in patients with (64%) and without COVID-19 (48%, p=0.175). Survival analysis identified AKI as a predictor of 30-day mortality independent of COVID-19 status (adjusted hazard ratio (aHR) 3.44, 95% confidence interval (CI) 1.55-7.63, p=0.002), but COVID-19 patients with AKI carried the highest risk (aHR 4.24, 95%CI 1,82-9.88, p<0.001). (Figure 1)

Conclusion

AKI occurs more frequently and more severely in patients with COVID-19 compared to other respiratory tract infections. It is associated with an increased risk for death, with the highest risk observed in COVID-19 patients. This underlines the augmented burden of AKI during the COVID-19 pandemic.
FC 042IRF8 IN CDC1 IS PROTECTIVE IN POST-ISCHEMIC ACUTE KIDNEY INJURY
Authors: Na Li , Steiger Stefanie , Fei Lingyan , Li Chenyu , Shi Chongxu , Salei Natallia , Schraml Barbara U , Zheng Zhihua , Anders Hans-Joachim , Lichtnekert Julia
Published: May 2021

Background and Aims

Post-ischemic acute tubular necrosis is a common cause of acute kidney disease (AKD) and subsequent chronic kidney disease. In AKD, mononuclear phagocytes (MPCs) including conventional dendritic cells (cDCs) are present during the different phases of kidney injury, repair and regeneration. The contribution of cDCs to AKD is still poorly understood. Hence, we hypothesized that transcription factor interferon regulatory factor 8 (IRF8)-specific cDCs regulate the immune response in AKD.

Method

AKD was induced by unilateral ischemia reperfusion injury in IRF8-deficient Clec9a-specific DCs (IRF8fl/fl Clec9acre/cre or cre/wt) and wild type C57BL/6 mice. Immune phenotyping of leukocytes in kidney and spleen and mRNA expression profiling were performed, as well as kidney function evaluated. For in vitro studies, IRF8 small interfering RNA transfection technology on bone marrow-derived DCs was used.

Results

In the healthy kidney and lymphoid organ (e.g., spleen and kidney draining lymph node), we identified four MPC subsets according to the diverse expression patterns of CD11b and CD11c. Of which, IRF8 was specifically expressed in the CD11blow CD11chigh R4 subset (containing mainly cDC1). During AKD, IRF8 deficiency in cDCs reduced the number of MHCII+ DCs accumulating among tubulointerstium space without affecting cDC2 or CD64+ DCs, while completely abolished cDC1 in post-ischemic kidney (See Figure). This was accompanied with a decrease in the surface expression of chemokine receptor CCR7 and CCR9, reduction in the number of kidney CD4- CD8+ T cells and Tregs, but a moderate increase in TH1-related and pro-inflammatory cytokines and infiltrating neutrophils in the kidney of mice with IRF8-deficient cDCs. This was in line with reduced kidney function, marked by aggravated GFR loss, elevated plasma BUN level, kidney atrophy, pathological tubular injury and living proximal tubule loss. In vitro, bone marrow-derived IRF8-deficient DCs showed an impaired ability to repair “artificially injured” tubular epithelial cells (TECs), accompanied with less phagocytosis capacity and maturation capacity under necrotic TECs soup or histone stimulation.

Conclusion

Our data show that the restricted depletion of IRF8 in cDCs reduces the number of infiltrating kidney cDC1, which drives tissue inflammation and damage, and ultimately aggravates post-ischemic AKD. Thus, cDC1s are having a protective role in AKD.
FC 029PODOCYTE AND GLOMERULAR ENDOTHELIAL CELL DERIVED MICRORNAS REGULATE PODOCYTE NEPHRONECTIN IN MEMBRANOUS GLOMERULONEPHRITIS
Authors: Müller-Deile Janina , Sopel Nina , Ohs Alexandra , Kotb Ahmed , Marwin Groener , Daniel Christoph , Amann Kerstin , Schiffer Mario
Published: May 2021

Background and Aims

Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier is normally size selective and impermeable for antibodies.

Method

Kidney biopsies from patients with MGN, cell culture, zebrafish and mice models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the glomerular filtration barrier.

Results

We found that endothelial cell-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in patients with anti-phospholipase A2 receptor antibody positive (PLA2R-ab+) iMGN and regulate glomerular NPNT expression (Fig. 1). Overexpression of miR-378a-3p and miR-192-5p as well as morpholino mediated npnt knockdown in zebrafish induced edema, proteinuria, loss of podocyte markers and podocyte effacement. The most prominent phenotype however were structural changes of the glomerular basement membrane (GBM) with increased lucidity, slicing and lamellation especially of the lamina rara interna (Fig. 2, Fig. 3). The phenotype was comparable to ultrastructural findings seen in iMGN. IgG sized nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte specific Npnt knockout mice (Fig. 4).

Conclusion

Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by podocyte and glomerular endothelial cell derived miRs. We hypothesize that loss of NPNT in the GBM is part of the pathophysiology of iMGN and enables subepithelial immune complex deposition in iMGN.
FC 030CONTACTIN-1 IS A NOVEL ANTIGEN IN IDIOPATHIC MEMBRANOUS GLOMERULONEPHRITIS AND IN CIDP- ASSOCIATED GLOMERULONEPHRITIS
Authors: Salama Alan , Fehmi Janev , Antonelou Marilina , Barratt Jonathan , Ashman Neil , Carr Aisling , Reilly Mary , Keddie Stephen , Querol Luis , Pikkuoeura Sonja , Cortese Andrea , Delmont Emilien , Persson Staffan , Radunovic Aleksandar , Roberts Ian Simon David , Davies Alexander , Rinaldi Simon
Published: May 2021

Background and Aims

Recently a number of antigens have been identified as pathogenic antibody targets in cases of primary membranous glomerulonephritis(MGN), including phospholipase A2 receptor (PLA2R), thrombospondin type 1 domain containing 7A(THSD7A), and NELL-1, while exostosin is found in secondary (lupus associated) MGN. However, other as yet undiscovered antigens are thought to exist. Although rare, there is a recognised association between chronic inflammatory demyelinating polyneuriopathy (CIDP) and nephrotic syndrome.

Method

We investigated the link between CICP and MGN and the associations with Contactin-1(CNTN1), a node of Ranvier neuronal protein, as a potential common autoantigen, by immunohistochemistry, RT-PCR and proteomic analysis of isolated glomeruli. We tested sera from 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 210 disease controls, for CNTN1 antibodies.

Results

We describe a series of 16 patients, all presenting with CIDP, nephrotic syndrome due to MGN, and with circulating and deposited anti-contactin-1 (CNTN1) antibodies (IgG4 predominant in those tested) in the kidney. The onset and resolution of both disorders had a close temporal relationship, and the majority of cases were resistant to first-line therapies typically employed for inflammatory neuropathies, but achieved a good outcome with non-standard treatment. Importantly, four (1.4%) further patients with isolated MGN identified from a serum bank of 295 idiopathic MGN patients with no CIDP were also positive for anti-CNTN1 antibodies. CNTN1 protein was detected by mass spectroscopy within glomeruli from patients with CNTN1 antibodies, but not in healthy kidney or anti-PLA2R associated MGN. CNTN1 mRNA was found in renal cortical tissue.

Conclusion

These data provide evidence that CNTN1 antibodies precipitate both autoimmune neuropathy and MGN. The temporal correlation of these disorders, as well as the presence of CNTN1 protein and antibodies in both peripheral nerve and diseased glomeruli, supports a common antibody-mediated pathological process, and defines a new antigenic target in MGN. CNTN1 antibodies have diagnostic and therapeutic relevance, and may additionally serve as a means of monitoring disease activity in both conditions. Other factors may explain presentation with isolated neurological disease or MGN.
FC 031LARGE SCALE VALIDATION OF THE NEW INTERNATIONAL PROGNOSTIC SCORE OF IGA NEPHROPATHY ON A FRENCH COHORT WITH PROLONGED FOLLOW-UP
Authors: Bon Grégoire , Jullien Perrine , Mariat Christophe , Alamartine Eric , Maillard Nicolas
Published: May 2021

Background and Aims

IgA Nephropathy is the most frequent primary glomerulonephritis worldwide, with a progression to End Stage Renal Disease in up to 30% of cases within 20 years after diagnosis. The severity of this disease is nevertheless extremely heterogenous with a majority of slow progression to late stages of Chronic Kidney Disease. The early stratification of risk to progress to ESRD is crucial. In this aim, International IgA Nephropathy Network recently developped a risk prediction tool (IINN tool) to allow an estimation of the probability to progress. The objective of our study was to validate this prediction tool (i) in our French Caucasien retrospective cohort (ii) on long term prognosis.

Method

All biopsy-proven IgA Nephropathy patients from Saint Etienne retrospective cohort for whom proteinuria, mean arterial pressure, CKD-EPI based GFR estimate and adequate Oxford classification at diagnosis were available have been included for analysis. For each patient the estimate of risk to progress to ESRD and/or 50% GFR decline was computed at 5, 10 and 15 years according to the IINN tool. For each time of follow-up, risks were grouped and ranked by deciles, and the median observed rate of event was compared to the median of predicted risk by decile, at 5, 10 and 15 years of follow-up. Correlation between observed and predicted risk was expressed as a Pearson correlation coefficient. A R²>0.8 was considered adequate to validate the prognosis tool.

Results

A total of 468 patients have been included for analysis, with a median age of 38.9 years old, a median proteinuria of 0.5g/day, a mean CKD-EPI of 81,6 mL/min/1,73m² and mean arterial pressure of 96.9mmHg at diagnosis. The cumulative number of events at 5,10, 15 years were respectively of 34, 54, 68. The median follow-up was 12 years. The correlations between observed/predicted risks were R² =0,990 [0,959 ; 0,998] at 5 years, R² = 0,984 [0,930 ;0,996] at 10 years and 0,964 [0,851 ;0,992] at 15 years after diagnosis.

Conclusion

In our study we validated the IINN tool to predict the risk to progress to ESRD and/or 50% eGFR decline (i) in a French Caucasian cohort and (ii) even after 5, 10 and 15 years after diagnosis, allowed by a particularly long follow-up.
FC 035VOCLOSPORIN INCREASES RENAL RESPONSE AT COMMONLY USED UPCR THRESHOLDS IN PATIENTS WITH LUPUS NEPHRITIS
Authors: Dall'Era Maria , Mina-Osorio Paola , Birardi Vanessa , Randhawa Simrat
Published: May 2021

Background and Aims

Voclosporin is a novel calcineurin inhibitor with a favorable metabolic profile and a consistent dose-concentration relationship, potentially eliminating the need for therapeutic drug monitoring.

We have previously reported the primary endpoint of the Phase 3 AURORA trial showing the addition of voclosporin to mycophenolate mofetil (MMF) and a low-dose glucocorticoid regimen results in significantly higher renal response (RR) rates at one year of treatment compared to MMF and low-dose glucocorticoids alone in patients with lupus nephritis (LN). For the primary endpoint, RR was defined as ≤0.5 mg/mg UPCR with stable renal function in the presence of low-dose glucocorticoids and no use of rescue medication.

Several studies have demonstrated that proteinuria represents the best single predictor for long-term renal outcomes.1,2 Given the efficacy of voclosporin in terms of proteinuria reduction, we conducted a sensitivity analysis evaluating RR with additional UPCR targets.

Method

A total of 179 participants in the voclosporin (23.7 mg BID) arm and 178 participants in the control arm from the AURORA trial were included in this analysis. All participants received MMF (target 1 g BID) and low-dose oral glucocorticoids (initiated at 20-25 mg/day and tapered to 2.5 mg/day at 16 weeks).

For this post hoc analysis, the UPCR component of RR was revised to include UPCR targets at 0.2 mg/mg intervals above and below the original ≤0.5 target used for the primary endpoint in AURORA (i.e., ≤0.7 mg/mg or ≤0.3 mg/mg, respectively). Odds ratios for RR at six months and one year of treatment were analyzed using a logistic regression model with terms for treatment, baseline UPCR, biopsy class, and MMF use at baseline and region.

Results

RR with UPCR ≤0.7 mg/mg was achieved by 46.9% of participants in the voclosporin arm vs 32.0% of participants in the control arm at one year of treatment (OR 2.07, p<0.0014) and 39.1% of participants in the voclosporin arm vs 24.7% of participants in the control arm at six months of treatment (OR 2.10, p=0.0020). RR with UPCR ≤0.3 mg/mg was achieved by 28.5% of participants in the voclosporin arm vs 15.7% of participants in the control arm at one year (OR 2.27, p=0.0023 and 22.9% of participants in the voclosporin arm vs 14.0% of participants in the control arm at six months of treatment (OR 1.90, p=0.0238; Table 1).

Conclusion

Participants treated with voclosporin in addition to MMF and low-dose glucocorticoids achieved statistically significantly increased renal response rates regardless of the level of UPCR used, including at an even more stringent ≤0.3 mg/mg target. This analysis further supports the efficacy observed with voclosporin in the Phase 3 AURORA and the prior Phase 2 AURA-LV global trials.
FC 068QUALITY OF LIFE OVER TIME IN OLDER MEN AND WOMEN WITH ADVANCED CKD - RESULTS FROM THE EQUAL STUDY
Authors: Chesnaye Nicholas , Meuleman Yvette , De Rooij Esther , Dekker Friedo W , Evans Marie , Caskey Fergus , Torino Claudia , Szymczak Maciej , Drechsler Christiane , Wanner Christoph , Jager Kitty J
Published: May 2021

Background and Aims

Differences between the sexes are apparent in the epidemiology of CKD. Cross-sectional studies show that women consistently report a poorer health-related quality of life (QoL) than men, however, longitudinal studies are lacking. Here we investigate the sex-specific evolution of QoL over time in advanced CKD. As a secondary aim, we explore the sex-specific determinants of QoL.

Method

EQUAL is an observational prospective cohort study in stages 4 and 5 CKD patients ≥65 years not on dialysis with an incident estimated glomerular filtration rate (eGFR) < 20 ml/min/1.73m². Data on QoL (measured using the RAND-36), clinical and demographic patient characteristics were collected between April 2012 and September 2020. QoL trajectories were modelled by sex using linear mixed models, and joint models were applied to deal with informative censoring. We followed patients until death or dialysis initiation.

Results

We included 5151 QoL measurements in 1416 patients over a total of 1986 person years of follow-up. Overall, the physical component summary (PCS) declined with 2.0 (95% CI 1.4-2.6) points and the mental component summary (MCS) by 2.4 (95% CI 1.8-3.0) points per year. Although women had overall lower QoL scores, figure 1 demonstrates that PCS and MCS declined more than twice as fast in men (PCS: 2.4 per year, 95% CI 1.7 – 3.1, MCS: 2.9 per year, 95% CI 2.2 – 3.6) compared with women (PCS: 1.1 per year, 95% CI -0.2 – 2.0, MCS: 1.5 per year, 95% CI 0.5 – 2.4). We identified a non-linear interaction effect between sex and eGFR levels on QoL, demonstrating a stronger negative effect of decreased eGFR on both PCS (p=0.02) and MCS (p=0.04) in men compared with women. Subsequent adjustment for renal decline attenuated the difference in rate of QoL decline between men and women (difference after adjustment; PCS: 1.1, 95% CI -0.1 – 2.2, MCS: 1.2, 95% 0.0 – 2.3). In univariable analyses, higher serum haemoglobin was more beneficial to QoL in men compared to women (p-value for interaction; PCS: p=0.03, MCS: p=0.01). Higher serum phosphate had a strong harmful effect on both PCS and MCS in men, but not in women (PCS & MCS: p<0.001). The presence of pre-existing diabetes had a negative effect on PCS and MCS in men, but to a lesser extent in women (PCS: p=0.02, MCS: p=0.01).

Conclusion

Despite the higher overall QoL reported by men, both their physical and mental QoL declined approximately twice as fast compared with women. The faster decline in men was mediated in part by their lower levels of renal function, which had a stronger impact on their QoL as compared with women. Furthermore, in exploratory analyses we identified that high levels of phosphate, low levels of haemoglobin, and pre-existing diabetes were more detrimental to QoL in men than in women.
FC 069CHRONIC KIDNEY DISEASE AND ATRIAL FIBRILLATION: A DANGEROUS COMBINATION
Authors: Ocak Gurbey , Khairoun Meriem , Khairoun Othman , Bos Willem Jan , Fu Edouard , Cramer Maarten J , Westerink Jan , Verhaar Marianne , Visseren Frank L J
Published: May 2021

Background and Aims

Chronic kidney disease (CKD) and atrial fibrillation (AF) are both risk factors for bleeding, stroke and mortality. Whether the combination of CKD and AF leads to higher risks of bleeding, stroke and mortality than CKD or AF alone is not known. The aim of our study was to investigate the interaction between CKD and AF and outcomes.

Method

We included 12,394 subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2018f for an out-patient visit with classical risk factors for arterial disease or with symptomatic arterial disease (Utrecht Cardiovascular Cohort Second Manifestation of Arterial disease (UCC-SMART) cohort). Hazard ratios (HRs) with 95% confidence intervals (CIs) for bleeding, ischemic stroke or mortality were calculated with Cox proportional hazards analyses. Presence of additive interaction between AF and CKD was examined by calculating the relative excess risk due to interaction (RERI), the attributable proportion (AP) due to interaction and the synergy index (S).

Results

Of the 12,394 patients, 699 patients had AF, 2,752 patients had CKD and 325 patients had both AF and CKD. Overall, 382 patients developed a first bleeding event, 421 patients had a first ischemic stroke and 2203 patients died. Patients with both CKD and AF had a 3.0-fold (95% CI 2.0-4.4) increased risk for bleeding, a 4.2-fold (95% CI 3.0-6.0) increased ischemic stroke risk and a 2.2-fold (95% CI 1.9-2.6) increased mortality risk after adjustment as compared with subjects without AF and CKD (Table 1). Although bleeding and mortality risks were highest for the combination of AF and CKD, we did not find interaction between AF and CKD. However, we found an interaction between AF and CKD for ischemic stroke risk (RERI 1.88 (95% CI 0.31-3.46), AP 0.45 (95% CI 0.17-0.72) and S 2.40 (95% CI 1.08-5.32)) (Table 1).

Conclusion

The combination of CKD and AF is associated with high risks for bleeding, ischemic stroke and mortality. There is a positive interaction between AF and CKD for ischemic stroke risk, but not for bleeding or mortality.
FC 076DIAGNOSTIC ACCURACY OF BONE TURNOVER MARKERS IN RENAL OSTEODYSTROPHY
Authors: Jørgensen Hanne Skou , Behets Geert , Cavalier Etienne , D'Haese Patrick , Evenepoel Pieter
Published: May 2021

Background and Aims

A transiliac bone biopsy is the gold standard for diagnosing renal osteodystrophy, but is not recommended as part of routine clinical workup due to its invasive nature. Suitable non-invasive alternatives have yet to be established. The aim of this study was to investigate the diagnostic accuracy novel biochemical markers of bone remodeling compared to that of biointact parathyroid hormone (PTH) for bone turnover as evaluated by histomorphometry.

Method

Protocolled bone biopsies were performed in end-stage kidney disease patients (ESKD, n = 80) and kidney transplant recipients (n = 119). Full-length (1-84) PTH, bone-specific alkaline phosphatase (BsAP), intact N-terminal propeptide of type I collagen (P1NP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) were measured. Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC). Optimal diagnostic cutoffs were established in an exploration cohort (n=100), and subsequently validated in a separate subset of patients (n=99).

Results

Mean age was 55±13 years, two-thirds were men (67%), and 23% had diabetes mellitus. Post-transplant eGFR was 49 [IQR 39, 59] ml/min/1.73m². Bone turnover was low in 47 (24%), normal in 119 (60%), and high in 33 (17%) patients. All biomarkers differed significantly across categories of bone turnover (p < 0.001). The AUC of biointact PTH for high turnover was 0.82 (0.73, 0.91), which was not significantly different from AUC values for BsAP, Intact P1NP, and TRAP5b (0.87, 0.90, and 0.86, respectively). AUC of biointact PTH for low turnover was 0.71 (0.63, 0.78), which was significantly lower than the values for BsAP, Intact P1NP, and TRAP5b (0.79, 0.83, and 0.79, respectively; p < 0.05, all). Calculated optimal diagnostic cutoffs in the exploration cohort are shown in Table 1. Applying these cutoffs in the validation cohort revealed high negative predictive values for both high (92 - 96%) and low (82 - 90%) bone turnover. Positive predictive values were consistently low.

Conclusion

The diagnostic accuracies of BsAP, Intact P1NP and TRAP5b are sufficient to rule out both high and low bone turnover in CKD. Biointact PTH shows inferior performance, particularly in kidney transplant recipients.
FC 077LONG-TERM SAFETY OF TENAPANOR FOR THE CONTROL OF SERUM PHOSPHORUS IN PATIENTS WITH CKD ON DIALYSIS
Authors: Weiner Daniel , Fishbane Steven , Lynn Robert , Yang Yang , Rosenbaum David
Published: May 2021

Background and Aims

Tenapanor, a first-in-class, phosphate absorption inhibitor blocks the paracellular absorption of phosphate in the GI tract by local inhibition of the sodium-hydrogen exchanger (NHE3). It therefore provides a novel, non-binder approach for managing hyperphosphatemia. Tenapanor is dosed as one small pill twice daily. In three pivotal trials, tenapanor met its primary phosphorus-lowering outcome. This report evaluates long-term safety data from the longest of these trials.

Method

This 52-week study consisted of a 26-week, open-label, randomized treatment period with a 12-week placebo-controlled randomized withdrawal period, followed by a 14-week open label safety extension period. Maintenance dialysis patients with serum phosphorus ≥ 6.0 mg/dL and a 1.5 mg/dL increase in serum phosphorus following phosphate binder washout were randomized 3:1 to receive tenapanor 30 mg twice daily or sevelamer carbonate, dosed per package insert. At end of the randomized treatment period all patients in the tenapanor arm were re-randomized 1:1 to either tenapanor or placebo for the randomized withdrawal period followed by tenapanor for the safety extension period. Sevelamer was used as a safety control for comparisons of serious adverse events/hospitalizations to tenapanor.

Results

Tenapanor was generally well tolerated, with diarrhea the only adverse event reported by >5% of patients during the randomized treatment period. Diarrhea was typically mild-to-moderate in severity, transient, and occurred more commonly during the randomized treatment period than the randomized withdrawal or safety extension periods. Rates of serious adverse events leading to hospitalization were higher in patients treated with sevelamer than tenapanor (35.8% vs 24.6%). The highest reported percentages of serious adverse events were infections and infestations (16.1% vs 9.3%) cardiac disorders (8.0% vs 5.7%), respiratory, thoracic and mediastinal disorders (8.8% vs 5.5%), and metabolism and nutritional disorders (7.3% vs 3.6%) for sevelamer and tenapanor, respectively. Adverse events leading to death were higher in patients treated with sevelamer than tenapanor (3.6% vs 2.9%).

Conclusion

Among maintenance dialysis patients with hyperphosphatemia, tenapanor, a novel, non-binder, phosphate absorption inhibitor that blocks paracellular absorption of phosphorus with a one tablet twice daily dose, has an acceptable safety profile, and, if approved, may offer a new approach to the treatment of hyperphosphatemia.
FC 080VARIABILITY IN SERUM PHOSPHATE ASSESSED BY DIRECTIONAL CHANGE IS ASSOCIATED WITH INCREASED MORTALITY
Authors: Ye Xiaoling (Janice) , Ter Meulen Karlien , Usvyat Len A , Van Der Sande Frank , Konings Constantijn , Kooman Jeroen , Kotanko Peter , Maddux Frank
Published: May 2021

Background and Aims

Prior studies showed that there is a wide variability between serial pre-dialysis measurements of serum phosphate (P). Serum P vary can be due to changes in nutritional intake, underlying bone disorders, medication use or inflammation. Various variability markers have been investigated to study the association between P variability and its association with outcomes, however, the directional trends have not been studied in depth. We aimed to study directional changes and investigated its association with outcomes.

Method

All adult incident HD patients treated in Fresenius Medical Care North America (FMCNA) clinics between 01/2010 and 10/2018 were included in this retrospective cohort study. Serum P levels were averaged from month 1 to 6 after the initiation of dialysis (baseline). Baseline absolute and directional range (DR) of serum P were calculated. DR of P was calculated as: P min/max (t2) – P max/min (t1), with P (t1) and P (t2) represents the timepoint when either the min P value or max P value was measured, whichever comes first, and with t2 happened after t1. It is positive when the minimum antedates the maximum, otherwise negative. All-cause mortality was recorded between months 7 and 18. Cox proportional hazards models with spline terms were applied to explore the association between absolute and DR of P and all-cause mortality. Additionally, tensor product smoothing splines were computed to study the interactions of P with absolute P and DR of P and their joint associations with outcomes, respectably.

Results

We studied 353,142 patients. The average age was 62.7 years, 58% were male, 64% were diabetic. Baseline P was 4.98 mg/dL, median absolute range was 2.40 mg/dL, median DR was 1.1 mg/dL. Across different levels of P, both higher levels of absolute range and DR of P were associated with higher risk of mortality (Figure 1, Figure 2). The associations even seemed stronger in patients with lower levels of serum P and with negative DR (Figure 1).

Conclusion

Lower levels of serum P are independently associated with an increased risk of all-cause mortality. Whereas both a positive and negative DR of P are in general associated with increased mortality, the effects of an increase are most predominant in patients with higher levels of serum P, whereas a negative directional range are most predominant in patients with low serum P. This could be explained by the fact that patients with lower levels of P are generally malnourished or inflamed, where a further reduction indicates nutritional deterioration.
FC 008INTERDEPENDENT REGULATION OF POLYCYSTIN EXPRESSION INFLUENCES STARVATION-INDUCED AUTOPHAGY AND CELL DEATH
Authors: Decuypere Jean-Paul , Van Giel Dorien , Janssens Peter , Dong Ke , Somlo Stefan , Cai Yiqiang , Mekahli Djalila , Vennekens Rudi
Published: May 2021

Background and Aims

Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations in either PKD1 (ca. 78%) or PKD2 (ca. 15%), encoding for the proteins polycystin-1 (PC1) or polycystin-2 (PC2), respectively. Mutations in PKD1 generally lead to a more severe disease progression compared to PKD2 patients. The exact function of the polycystins in cyst formation remains unclear, but it is clear that the levels of PC1 and PC2 are inversely correlated to cyst formation. Moreover, renal stress has been proposed to enhance cystogenesis. We therefore aimed to investigate the cellular response towards nutritional stress in mouse inner medullary collecting duct cells (mIMCDs), either wild-type (WT) or lacking PC1 or PC2 (PC1KO or PC2KO), and unique human urine-derived proximal tubular epithelial cells (PTECs) of early-stage ADPKD patients with truncating PKD1 mutations versus healthy individuals, with a focus on cell survival (autophagy) and cell death.

Method

Cell death was assessed with Cytotox green-based live cell imaging in the Incucyte, by trypane blue exclusion and by analyzing the levels of cleaved Caspase 3. Autophagy was measured by LC3 immunoblotting and by counting GFP-LC3 punctae. Autophagy was blocked with Bafilomycin A1. To modulate the levels of PC1 and PC2, transient overexpression of human PC1 or siRNA-mediated knockdown of PC2 was performed.

Results

During chronic starvation, cell death was reduced and autophagy was increased in mouse PC1- and PC2-deficient mIMCDs. This was validated in human cells from early-stage ADPKD patients. Autophagy inhibition restored cell death resistance in KO cells, implying that decrease in cell death was caused by autophagy upregulation in PC1- and PC2KO cells. Interestingly, PC2 expression was increased in PC1KO cells, while PC2KO displayed a downregulation of PC1. Although PC2 is known to regulate autophagy, PC2 knockdown did not reduce autophagy in PC1KO cells, while the effect in PC2KO could be reversed by overexpression of PC1.

Conclusion

These findings indicate that PC1 levels determine the transition from renal cell survival to death, leading to enhanced survival of ADPKD cells during nutritional stress. Moreover, PC1 also indirectly influences this process by regulating PC1 levels during starvation. Our findings imply that in early stage ADPKD, cells with the lowest polycystin levels (which are most prone to form cysts) are more resistant to stress by autophagy upregulation. This is important, as renal stress is inherent to the cystic environment and has been proposed as an additional trigger in cystogenesis.
FC 0104-WEEK ANTIBIOTIC THERAPY PREVENTS RECURRENT RENAL CYST INFECTIONS IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
Authors: Dang Julien , Knebelmann Bertrand , Charlier Caroline
Published: May 2021

Background and Aims

Renal cyst infection (CI) is a major complication of autosomal dominant polycystic kidney disease (ADPKD), associated with frequent hospitalization, worsening of kidney function and significant mortality. Data regarding treatment are scarce and recommendations only expert-based, with low level of evidence. Prolonged treatment duration and use of lipid-soluble antibiotics may increase antibiotic concentration in infected kidney cysts. However, benefits of this strategy have never been investigated in clinical practice.

Method

We undertook a monocentric retrospective study of CI in ADPKD patients from 2000 to 2018. CI were classified as “definite” (microbiologically proven), “probable” (clinical/biological and radiological signs) or possible (clinical/biological signs). Determinants of treatment failure and recurrences were studied.

Results

139 CI (11 “definite”, 74 “probable”, 54 “possible”) were compiled among 90 patients. Median age was 53 years. 28/90 (31%) were kidney transplant recipients. Escherichia coli was identified in 89/106 (84%) episodes. Treatment failure was reported in 22/139 (16%), and found associated with cyst diameter >5cm (80% vs 36%, P<0.01), cyst wall thickening (53% vs 12%, P<0.001), cyst septations (18% vs 1%, P<0.01), intracystic gas (18% vs 1%, P<0.01), kidney abscess (35% vs 1%, P<0.001), higher C-reactive protein level (210 [140-358] vs 145 [99-213] mg/L, P<0.01) or documentation of Staphylococcus aureus and lugdunensis (P<0.001). Recurrence was reported in 20/139 (14%) cases within 1-year follow-up. Recurrence rate was lower in patients treated with lipid soluble antibiotics than with non-lipid soluble antibiotics (HR=0.34 [0.12-0.97], p=0.045). Most importantly, cases with definite and probable CI experienced significantly fewer recurrences when treated with longer treatment duration: 81% for treatment <21 days, 47% for 21-27 days, but only 2% for ≥28 days (p<0.0001).

Conclusion

Treatment of kidney CI should last ≥28 days and include when possible lipid soluble antibiotics.