Start Of Renal Replacement Therapy Research Articles

Thrombotic microangiopathy secondary to Capnocytophaga canimorsus bacteremia

Capnocytophaga canimorsus is an Anaerobic Gram-Negative bacterium present in the oral microbiology of cats and dogs. It can produce infections in humans, being capable of causing severe complications with the development of septic shock. There are known cases where this bacterium developed medical complications like thrombotic microangiopathy and disseminated intravascular coagulation. We have the case of 79 years old male that developed thrombotic microangiopathy and splenic infarction linked to bacteraemia by Capnocytophaga canimorsus. Due to its severity, it was necessary to start renal replacement therapy and several sessions of plasmapheresis with good evolution.

Examine the optimal multidisciplinary care teams for patients with chronic kidney disease from a nationwide cohort study.

Multidisciplinary team-based integrated care (MDC) has been recommended for patients with chronic kidney disease (CKD). However, team-based specific structured care systems are not yet established. Therefore, we investigated the efficacy of MDC system and the optimal number of professionals that make up the team for maintaining kidney function and improving prognosis. This nationwide, multicenter, observational study included 2,957 Japanese patients with CKD who received MDC from 2015 to 2019. The patients were divided into four groups according to the number of professionals in the MDC team. Groups A, B, C, and D included nephrologists and one, two, three, and four or more other professionals, respectively. Changes in the annual decline in estimated glomerular filtration rate before and after MDC were evaluated. Cox regression was utilized to estimate the correlation between each group and all-cause mortality and the start of renal replacement therapy (RRT) for 7 years. The change in eGFR significantly improved between before and at 6, 12, and 24 months after MDC in all groups (all p < 0.0001). Comparing group D to group A (reference), the hazard ratio (HR) for all-cause mortality and the start of the RRT was 0.60 (95% confidence interval, 0.48-0.73; p < 0.0001) after adjustment for multiple confounders. Lower HR in group D was confirmed in both diabetes and nondiabetes subgroups. An MDC team comprised of five or more professionals might be associated with improvements in mortality and kidney prognosis. Furthermore, MDC might be effective for treating CKD other than diabetes.

Early strategy vs. late initiation of renal replacement therapy in adult patients with acute kidney injury: an updated systematic review and meta-analysis of randomized controlled trials.

The optimal time to start renal replacement therapy (RRT) for acute kidney injury (AKI) remains controversial. We aim to compare the effects of early vs. delayed RRT initiation on clinical outcomes in adult patients with AKI. PubMed, Embase, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, ClinicalTrials.gov, and the International Clinical Trial registry platform were systematically searched from inception to 7 August 2022. The review included randomized clinical trials (RCTs) comparing early and delayed initiation of RRT in AKI patients. The selected primary outcomes were short-term and long-term mortality. Secondary outcomes included RRT dependency, intensive care unit (ICU) length of stay, hospital length of stay, mechanical ventilator-free days, vasoactive agents-free days, RRT-free days, and adverse events. Overall, 15 RCTs, including 5,625 patients, were analyzed. Early RRT showed no survival benefit when compared to the delayed therapy (28-or 30-day mortality: RR, 1.01, 95% CI: 0.94-1.08, p = 0.87; 60-day mortality: RR, 0.87, 95% CI: 0.71-1.06, p = 0.16; 90-day mortality: RR, 1.00, 95% CI: 0.88-1.13, p = 0.97; in-hospital mortality: RR, 1.05, 95% CI: 0.88-1.24, p = 0.58; ICU mortality: RR, 1.00, 95% CI: 0.91-1.10, p = 0.98). The delayed RRT did not lead to a higher risk of RRT dependency, ICU, or hospital length of stay than the early RRT. Similarly, early initiation of RRT did not lead to longer ventilator-free, vasoactive agent-free, and RRT-free days. However, early RRT initiation was associated with more adverse events. Our study suggested that early RRT initiation was not associated with survival benefits or better clinical outcomes and increased the risk of RRT-associated adverse events. Current evidence does not support the use of early RRT for AKI patients without urgent indications.

#3067 ALPORT SYNDROME NATURAL HISTORY FROM THE RADAR REGISTRY: ASSOCIATIONS WITH GENE, VARIANT TYPE AND SEX

Abstract Background and Aims Alport Syndrome (AS) is caused by pathogenic variants in COL4A3, COL4A4 &amp; COL4A5 genes. The clinical course of AS can be highly variable, depending on gene affected, mutation type and Male (M) or Female (F) sex. Proteinuria is associated with worse prognosis. Previous genotype-phenotype correlation studies have shown protein length altering variants are associated with a more severe phenotype in males with COL4A5 variants, however studies in females have shown contradicting results. This study aims to describe demographics and investigate renal outcomes associated with pathogenic variant type in M vs F AS patients, using longitudinal data from the National Registry of Rare Kidney Diseases (RaDaR) which recruits patients at 108 UK renal clinics. Method RaDaR is linked to Regional Genetics hubs for clinical genetic reports, renal IT systems for routine test results and the UK Renal Registry for Renal Replacement Therapy (RRT) initiation data. eGFR was calculated using CKD-EPI Cr equation (2021) or Schwartz equation for those ≤ 16 yrs. eGFR slope was calculated over the last 3 years (or 3 years prior to End Stage Kidney Disease (ESKD)/death for patients who reached those outcomes), with patients required to have a minimum of 4 values over 2 years. For genotype data, variants classified in clinically issued reports as “Pathogenic” or “Likely Pathogenic” were included and classed as: 1. Protein Length Altering and 2. Missense variants. Where both protein length altering and missense variants in the same gene were identified in an individual, the missense variant was used. Data are presented as percentages for categorical variables and mean ± SD for continuous variables. Kaplan Meier analysis and the log rank statistic were used to compare age at RRT start, stratified by gender and variant types. Lower quartile (LQ) (25%) estimates are presented where too few events have occurred to calculate a median (50%) estimate. Results Between Jan 2013–Jul 2022, 920 AS patients were recruited; 53% M vs. 47% F. Genetic test reports were available for 343/920 (37%) patients. 294/343 (86%) reported a pathogenic or likely pathogenic variant, 140 protein length altering and 154 missense. Individuals with 2x COL4A3/COL4A4 variants were youngest at RRT start, whilst females with COL4A5 variants were oldest (LQ 20.1 vs 60.9 yrs, log-rank p&amp;lt;0.0001) (Figure 1a). COL4A5 variants Males with protein length altering COL4A5 variants were younger at ESKD compared with missense variants (median age 30.2 vs 52.1 yrs, p = 0.01). Conversely 0/36 females with protein length altering COL4A5 variants had started RRT, compared with 6/37 with missense variants (p = 0.01) (Figure 1bi-ii). COL4A3 or COL4A4 variants Whilst females with heterozygous protein length altering COL4A3/4 variants were younger at RRT start vs. those with missense variants (LQ 47.1 vs 64.9 yrs, p = 0.05), age at RRT start did not differ by mutation type for males with COL4A3/4 heterozygous variants (Figure 1b iii-iv). However, males with homozygous or 2x protein length altering COL4A3/4 variants were younger at RRT start than those with missense variants (median age 20.1 vs 24.3 yrs, P = 0.05), whilst no difference was observed by variant type for females with 2x COL4A3/4 variants (Figure 1b v-vi). Proteinuria and eGFR slope were generally correlated with age at ESKD. Conclusion The observed effect of pathogenic variant type on renal outcomes varied by gene affected, number of mutations and sex. The relatively reduced severity among females harbouring a protein length altering COL4A5 variant may represent an effect of skewed X-inactivation or a missense gain-of-function mechanism. RaDaR recruits patients with a clinical diagnosis of Alport syndrome or Thin Basement Membrane Nephropathy; ascertainment of individuals with a single COL4A3 or COL4A4 variant is therefore likely to favour those with more severe kidney disease. Linkage of the RaDaR AS cohort with genetic report data is ongoing; further correlations may be observed with larger numbers.

#6448 IMPACT OF PRE-DIALYSIS FOLLOW-UP ON OUTCOMES IN DIALYSIS PATIENTS

Abstract Background and Aims Pre-dialysis care aims to slow down the decline in kidney function and to prepare patients for their potential start of renal replacement therapy. Patients who received attention earlier showed reduced mortality and hospitalization, better uptake of peritoneal dialysis, and earlier placement of arteriovenous fistula for hemodialysis. The objective of this study is to analyze the impact of pre-dialysis care in dialysis patients from Fresenius Medical Care Latin America (FME LatAm). Method Patients incident to dialysis that started treatment at FME LatAm between January 2019 and December 2022 were included in this retrospective observational study. They were classified according to whether they received pre-dialysis care or not as CKD (more than 10 days of follow up;) or No CKD (less than 10 days). CKD group was subclassified regarding the length of stay in pre-dialysis care in 10 to 45 days (10-45), 45 to 90 days (45–90), and more than 90 days (&amp;gt;90). Demographic variables, vascular access, and lab variables were compared between CKD and No CKD, and within subgroups during the observation period. Values are expressed in mean ± SD. Values compared using Student t-test or ANOVA accordingly. Results CKD patients were older than No CKD (CKD: 61.5 ± 16.6 vs NoCKD: 60.6 ± 17.2; p = 0.02), with lower male prevalence (CKD: 57.5% vs NoCKD: 60.2%; p=0.001). No significative differences in prevalence of diabetes were found. Patients under pre-dialysis treatment showed a higher rate of PD referrals (CKD: 44.6% vs NoCKD: 7.3%; p &amp;lt;0.0001). Regarding vascular access, a higher percentage of CKD patients started dialysis with definitive access (AVF or AVG) (CKD: 47.9% vs NoCKD: 31.5%; p &amp;lt;0.0001). In the same way, prevalence of definitive accesses was higher in patients with longer CKD stay (10-45: 38.4%, 45-90: 57.3%, &amp;gt;90: 50.2%; p&amp;lt;0.0001). Within patients who started treatment with a catheter, a higher percentage of CKD patients already had a fistula or graft performed at treatment start (CKD: 7.3% vs NoCKD: 2.7%; p &amp;lt;0.0001). EPO prescription was higher as the time of follow-up was longer (10-45: 3.3%, 45-90: 7%, &amp;gt;90: 14.9%; p&amp;lt;0.0001). As expected for CKD patients haemoglobin was higher and ferritin was lower (Table 1). Though TSAT, Calcium, and Albumin were significative different between CKD and No CKD, the difference was not clinically relevant. Phosphorus and iPTH was higher in CKD patients and creatitine clearence calculated by MDRD was lower in those patients, opposite of expected (Table 1). Conclusion Older and male patients are more likely to have CKD follow-up. Pre-dialysis treatment has a deep impact on PD referral, EPO prescription, type of vascular access at admission, and ready-made vascular access at treatment start. Some laboratory results were not as expected, maybe due to non proper medication accessibility or inadequate financial support at predialysis stages. Even though, CKD follow-up is crucial to prepare patients for a better start of renal replacement therapy.

#5827 MYCOPHENOLATE MOFETIL AS IMMUNOSUPPRESSIVE THERAPY IN IGA NEPHROPATHY

Abstract Background and Aims IgA Nephropathy is the commonest cause of primary Glomerulonephritis in developed countries. It is characterised by IgA-dominant deposits in the mesangium on renal biopsy. Classically presenting with asymptomatic non-visible haematuria or episodic visible haematuria 24-48 hours after an upper respiratory tract infection, raised BP and Proteinuria. End-stage renal disease (ESRD) can occur in up to 20-50% of patients. Treatment with ACEI/ARB has strong evidence in managing IgA. If there is evidence of progression, steroids and immunosuppression are recommended. Mycophenolate Mofetil's effectiveness in IgA nephropathy is controversial. KGIGO guidelines authors suggest not to use it. In this work, we reviewed immunosuppression with mycophenolate Mofetil (MMF) retrospectively in IgA nephropathy patients managed at Sussex Kidney unit – Brighton -UK. Method We retrospectively reviewed 25 patients who had a diagnosis of IgA nephropathy and were treated with mycophenolate mofetil as immunosuppression for IgA nephropathy under the care of the Sussex Renal Unit at University Hospitals Sussex. Patients reviewed, had been diagnosed between 2011-2020. Data collected from our department's electronic system, including laboratory results, histopathology reports, clinic letters and medications. Data were collected until January 2023 for patients who had renal survival. For patients who started on renal replacement therapy (RRT), data were collected until the start of RRT. The work aimed at looking at MMF efficacy in IgA nephropathy. The primary measures were renal survival without the need for RRT and proteinuria reduction to &amp;gt; 50% of the baseline at diagnosis. Results We reviewed 25 patients, 13 male and 12 female. Twenty-four patients (96%) were of white Caucasian ethnicity while one patient (4%) was Asian. The mean age was 42.4± 16 years. All the patients were diagnosed with both clinical pictures and renal biopsies. Oxford classification score showed M1 (21) patients, E (5 patients), S (19 patients), T (1 = 10 patients, 2 = 4 patients), and C (1 = 15 patients, 2 = 4 patients). On presentation, 5 patients presented with a sore throat, 8 with skin rash and 7 with macroscopic haematuria. Seventeen patients (60%) presented with AKI. Eleven patients (44%) had nephrotic range proteinuria on presentation. The average duration of the disease was 6.1 years at the time of assessment. MMF was used in the 25 patients, five of them had prednisolone and cyclophosphamide for 3 months followed by MMF maintenance. Twenty patients were treated with MMF alone or in combination with steroids (17 patients) from the start. The average duration of treatment was 2 years, and the average dose was 1 gm twice daily. Five patients (20%) progressed to ESRD and three of them had renal transplantation while twenty patients (80%) maintained renal survival. For the 80% who maintained renal survival the mean eGFR at diagnosis was 45.6± 34.1 and at the time of assessment was 56.1±26.6. Of the 17 patients presented with AKI, five patients (29.4%) recovered to normal renal function, five patients had ESRD (29.4%) and four had improvements of eGFR while three patients showed a decrease of eGFR (Mean 45.6± 1.1 ml/min) to eGFR (Mean 32± 8.2 ml/min). In total, 70.6% of AKI patients recovered either to normal or to CKD level and 80% of the total patients had renal survival without RRT during the time of review. Twenty patients (80%) achieved more than 50% reduction of proteinuria, with five patients (20%) having proteinuria less than 0.3 g/24 hours and 9 (36%) patients less than 0.5 g/24 hours. Comparison between the proteinuria at diagnosis and at the time of assessment was significant (P&amp;lt;0.001). Conclusion Mycophenolate mofetil was effective in maintaining renal survival and improving proteinuria in IgA nephropathy patients who were indicated for immunosuppression based on histopathology and risk of progression. It was well tolerated by patients. A randomised controlled trial is needed to compare the MMF effect in comparison with currently available therapies.

#4346 SERUM NONSKELETAL ALKALINE PHOSPHATASE AS A MARKER OF METABOLIC ENDOTOXINEMIA AND PREDICTOR OF ADVERSE OUTCOME IN PATIENTS WITH CKD

Abstract Background and Aims Elevated alkaline phosphatase (ALP) levels are widely recognized as a marker of poor outcomes in chronic kidney disease (CKD). This association remains poorly understood, with arguments pointing to the skeletal and non-skeletal isozyme fractions as being decisive factors. The liver and intestinal isoenzymes of ALP are able to dephosphorylate and thus inactivate a number of substrates which have been implicated in the promotion of inflammation, including the bacterial endotoxin lipopolysaccharide (LPS). Present study aimed to test the hypothesis whether association of total ALP with all-cause mortality is mainly driven by non-skeletal ALP and its link with metabolic endotoxemia and inflammation. Method Laboratory parameters of mineral and bone disease, inflammation (C-reactive protein, CRP), and metabolic endotoxemia (Lipopolysaccharide binding protein, LBP) were assessed in 431 CKD patients enrolled in the Leuven Mild-to-Moderate CKD Study between Nov 2005 and Sept 2006. Non-skeletal ALP levels were estimated as residuals of the linear regression of log transformed total and bone-specific ALP. Spearman correlation, multivariate regression, and Cox proportional hazard analyses were performed to investigate the associations between skeletal and non-skeletal ALP, LBP, CRP and mortality. Data were censored at start of renal replacement therapy. Results Median age was 63 years, 54% were men, 19% had diabetes, 31% had established cardiovascular disease. At baseline, non-skeletal ALP was associated with inflammatory parameters (CRP: rho = 0.33, P&amp;lt;0.001) and with metabolic endotoxemia (LBP: rho = 0.32, P&amp;lt;0.001). Non-skeletal ALP was a significant predictor of elevated CRP (&amp;gt;3 mg/dL) in multivariate models (odds ratio (OR) per standard deviation (SD) increase 1.97; 95% CI 1.21-3.21; P = 0.006). This association was attenuated by further adjustment for LBP (OR 1.40; 95% CI 0.69-2.80; P = 0.3). During a median follow-up of 8.0 (interquartile range, 2.6-14.7) years 131 patients died. High non-skeletal ALP associated with increased risk of all-cause mortality, even after adjusting for demographics, Framingham risk factors and comorbidities (Hazard ratio (HR) per SD increase 1.28; 95% CI 1.05 – 1.56; P = 0.016). This association was attenuated by further adjustment for LBP (HR 1.22; 95% CI 1.00-1.50; P = 0.051). High bone-specific ALP was not associated with increased risk of all-cause mortality. Conclusion In patients with CKD not yet on dialysis, increased non-skeletal ALP (as opposed to skeletal ALP) is associated with inflammation and increased risk of all-cause mortality. These associations are at least partly driven by metabolic endotoxemia.

#4432 ECYSCO: A EUROPEAN COHORT DEDICATED TO CYSTINOSIS

Abstract Background and Aims Cystinosis is a rare multisystem lysosomal storage disease due to variants in the CTNS gene, coding for the carrier protein cystinosine, a lysosome membrane transporter causing cystine accumulation with a reported incidence of 1:180,000 live births. Specific treatment by cysteamine decreases renal and extrarenal complications frequency and increases life expectancy. Recently, new treatments for cystinosis entered into the European market with an extended-release formulation of cysteamine and a new formulation of eye drops. The aim of this project is to describe the natural history of the disease and long-term clinical manifestations. Method We set up a European, multi-centre, longitudinal, non-interventional cohort, ECYSCO, that uses observational study methods to collect uniform data. 243 patients with a confirmed diagnosis of cystinosis and followed in 25 French and 5 European centers (Belgium, Italy, Spain and Germany) were included. Data are collected on the secure RaDiCo platform, via an e-CRF (REDCap). Results Data from 180 patients (50.0% male) were analyzed. Median age at diagnosis was 1.3 years [IQ 0.8; 1.9], with earlier diagnosis since the 1980s, but no further improvement in the 2000s. Genetic analysis was available for 174 patients: 57 (32.8%) presented with homozygous 57kb deletion in the CTNS gene, 71 (40.8%) with heterozygous 57kb deletion associated with another variant and 46 (26.4%) with other variants. The type of variant had no impact on the age at diagnosis. Median age at cysteamine start was 1,6 years (IQ 1.0-3.0). An improvement on age at treatment start was observed after the 1990s. All but 6 patients were treated with cysteamine. 71 patients received immediate release formulation (Cystagon®) and 103 received extended release formulation (Procysbi®). Median white blood cell cystine level was correct at 1.2 nmol ½ cystine/mg protein (IQ 0.59; 2.20). The median duration of treatment was 21.5 years [IQ 11.7; 31.1]. 167 (95,9%) patients also received cysteamine ocular gel, Cystadrops®. Median age at inclusion was 19.08 years (IQ 10.43; 31.41). At that time, 104 patients (57.8%) had reached end-stage renal disease (ESRD). There was no impact of genotype on age at ESRD. Median age at ESRD was 12.9 years [IQ 9.9; 18.0]. A 5-year gain in renal survival was observed after the 1990s. 102 patients (56.7%) received a kidney transplant. Among these transplanted patients: 76 (74.5%) received 1 transplant, 23 (22.5%) received 2 consecutive transplants, and 3 (2.9%) received 3. Median eGFR in the remaining patients was 58.9 ml/min [IQ 40.4; 82.2]. Extrarenal manifestations included hypothyroidism in 61 (33.9%) patients, diabetes mellitus in 11 (6.1%), skeletal manifestations in 73 (40.5%), myopathy in 32 (17.8%), and neurological disorders in 22 (12.2%). At inclusion, 36 patients had no ESRD and no extra-renal complication. Conclusion Cystinosis is a good example of a pediatric disease with multiorgan involvement extending into adult care. More than half of patients are adults and have reached ESRD even if age at renal replacement therapy start has increased. The high frequency of extra-renal manifestations demonstrates the importance of a multidisciplinary follow up of these patients.

Improving Kidney Outcomes in Patients With Nondiabetic Chronic Kidney Disease Through an Artificial Intelligence-Based Health Coaching Mobile App: Retrospective Cohort Study.

Chronic kidney disease (CKD) is a global health burden. However, the efficacy of different modes of eHealth care in facilitating self-management for patients with CKD is unclear. The aim of this study was to evaluate the effectiveness of a mobile app-based intelligent care system in improving the kidney outcomes of patients with CKD. Our study was a retrospective analysis based on the KidneyOnline intelligent system developed in China. Patients with CKD but not dependent on dialysis who registered on the KidneyOnline app between January 2017 and January 2021 were screened. Patients in the the KidneyOnline intelligent system group and those in the conventional care group were 1:1 matched according to their baseline characteristics. The intervention group received center-based follow-up combined with the KidneyOnline intelligent patient care system, which was a nurse-led, patient-oriented collaborative management system. Health-related data uploaded by the patients were integrated using deep learning optical character recognition (OCR). Artificial intelligence (AI)-generated personalized recipes, lifestyle intervention suggestions, early warnings, real-time questions and answers, and personalized follow-up plans were also provided. Patients in the conventional group could get professional suggestions from the nephrologists through regular clinical visits, but they did not have access to the service provided by AI and the health coach team. Patients were followed for at least 3 months after recruitment or until death or start of renal replacement therapy. A total of 2060 eligible patients who registered on the KidneyOnline app from 2017 to 2021 were enrolled for the analysis. Of those, 902 (43.8%) patients were assessed for survival analysis after propensity score matching, with 451(50%) patients in the KidneyOnline intelligent patient care system group and 451(50%) patients in the conventional care group. After a mean follow-up period of 15.8 (SD 9.5) months, the primary composite kidney outcome occurred in 28 (6%) participants in the KidneyOnline intelligent patient care system group and 32 (7%) in the conventional care group, with a hazard ratio of 0.391 (95% CI 0.231-0.660; P<.001). Subgroup survival analysis demonstrated that the KidneyOnline care system significantly reduced the risk of composite kidney outcome, irrespective of age, sex, baseline estimated glomerular filtration rate (eGFR), and proteinuria. In addition, the mean arterial pressure (MAP) significantly decreased from 88.9 (SD 10.5) mmHg at baseline to 85.6 (SD 7.9) mmHg at 6 months (P<.001) in the KidneyOnline intelligent patient care system group and from 89.3 (SD 11.1) mmHg to 87.5 (SD 8.2) mmHg (P=.002) in the conventional CKD care group. The utilization of the KidneyOnline intelligent care system was associated with reduced risk of unfavorable kidney outcomes in nondiabetic patients with CKD.

Indications and timing of renal replacement therapy

The management of patients with acute kidney injury is mainly supportive in nature, with no available proven therapeutic modalities to treat the condition. Renal replacement therapy (RRT) is indicated in patients with severe kidney injury, or increased volume or metabolic demands. In the absence of clinically significant uremic symptoms or specific indications such as severe electrolyte abnormalities or volume overload, the optimal timing of RRT initiation is controversial. Randomized, controlled trials that have compared strategies of early versus delayed initiation of RRT in the absence of obvious indications have yielded conflicting results. The implementation of decision support systems is challenging but could provide clinicians a framework with specific recommendations for interventions. Recently, some algorithms have been proposed to guide physicians in the decision to initiate, and their application in clinical practice may reduce variations across physicians and centers. The decision on the appropriate time to start RRT is complex, integrating numerous variables, and should largely be individualized, however the lack of definitive parameters to define early or late initiation reveals a great need to continue research on this field. Such evidence is important for reducing variations in the clinical practice of RRT prescription and improving patient outcomes.

Timing of dialysis in acute kidney injury using routinely collected data and dynamic treatment regimes

Background and objectivesDefining the optimal moment to start renal replacement therapy (RRT) in acute kidney injury (AKI) remains challenging. Multiple randomized controlled trials (RCTs) addressed this question whilst using absolute criteria such as pH or serum potassium. However, there is a need for identification of the most optimal cut-offs of these criteria. We conducted a causal analysis on routinely collected data (RCD) to compare the impact of different pre-specified dynamic treatment regimes (DTRs) for RRT initiation based on time-updated levels of potassium, pH, and urinary output on 30-day ICU mortality.Design, setting, participants, and measurementsPatients in the ICU of Ghent University Hospital were included at the time they met KDIGO-AKI-stage ≥ 2. We applied inverse-probability-of-censoring-weighted Aalen–Johansen estimators to evaluate 30-day survival under 81 DTRs prescribing RRT initiation under different thresholds of potassium, pH, or persisting oliguria.ResultsOut of 13,403 eligible patients (60.8 ± 16.8 years, SOFA 7.0 ± 4.1), 5622 (63.4 ± 15.3 years, SOFA 8.2 ± 4.2) met KDIGO-AKI-stage ≥ 2. The DTR that delayed RRT until potassium ≥ 7 mmol/l, persisting oliguria for 24–36 h, and/or pH < 7.0 (non-oliguric) or < 7.2 (oliguric) despite maximal conservative treatment resulted in a reduced 30-day ICU mortality (from 12.7% [95% CI 11.9–13.6%] under current standard of care to 10.5% [95% CI 9.5–11.7%]; risk difference 2.2% [95% CI 1.3–3.8%]) with no increase in patients starting RRT (from 471 [95% CI 430–511] to 475 [95% CI 342–572]). The fivefold cross-validation benchmark for the optimal DTR resulted in 30-day ICU mortality of 10.7%.ConclusionsOur causal analysis of RCD to compare RRT initiation at different thresholds of refractory low pH, high potassium, and persisting oliguria identified a DTR that resulted in a decrease in 30-day ICU mortality without increase in number of RRTs. Our results suggest that the current criteria to start RRT as implemented in most RCTs may be suboptimal. However, as our analysis is hypothesis generating, this optimal DTR should ideally be validated in a multicentric RCT.

Pre-emptive vs. classic criteria for initiation of dialysis in critically ill patients with acute kidney injury (AKI) - A retrospective real-world study.

Guidelines recommend starting renal replacement therapy (RRT) in critically ill acute kidney injury (AKI) patients according to classic criteria for the initiation of dialysis (CCID). However, comparative data on the presence or absence of CCID in patients receiving continuous veno-venous hemodialysis (CVVHD) or intermittent hemodialysis (IHD) as the initial modality are scarce. Altogether 733 critically ill AKI patients receiving CVVHD or IHD at the research hospital between 2010 and 2019 were screened for this real-world study. All patients on maintenance dialysis were excluded. Patient survival was studied in 662 patients and adverse renal outcomes in 375 surviving patients at 90 days follow-up. The adverse renal outcome was defined as RRT requirement and the secondary outcome was estimated glomerular filtration rate (eGFR) at 90 days follow-up. Altogether 472 (71.3%) patients received CVVHD and 190 (28.7%) IHD, and CCID was present at the time of RRT initiation in 250 (37.8%). The CCID was independently associated with mortality in a multivariable logistic regression analysis (odds ratio [OR] 2.226, 95% confidence interval [CI] 1.455-3.407, p < 0.001) adjusted for age, sex, baseline eGFR, disease severity, RRT modality, hypertension, and diabetes. The presence of CCID at the start of RRT was not associated with adverse renal outcome (OR 0.548, 95% CI 0.230-1.305, p=1.74) nor eGFR (β=0.155, p=0.066) at 90 days follow-up. However, starting RRT in the presence of CCID was independently associated with eGFR at 90 days follow-up in a multivariable ordinal regression analysis (β=0.930, p=0.018) after adjusting for age, sex, baseline eGFR, disease severity markers, hypertension, and diabetes in patients receiving CVVHD but not IHD as the initial modality. The presence of CCID at the initiation of RRT was associated with mortality but not adverse renal outcomes in this large real-world study on critically ill AKI patients requiring RRT. Initiating RRT in the presence of CCID was associated with improved eGFR at 90 days follow-up in patients receiving CVVHD as the initial modality.

The Usefulness of Calcium/Magnesium Ratio in the Risk Stratification of Early Onset of Renal Replacement Therapy.

Background: A growing number of studies have reported a close relationship between high serum calcium (Ca)/low serum magnesium (Mg) and vascular calcification. Endothelial dysfunction and vascular inflammation seem plausible risk factors for the enhanced progression of kidney disease. The aim of this study was to evaluate the role of the Ca/Mg ratio as a predictor of the early onset of renal replacement therapy (RRT). Methods: This was a prospective study conducted in an outpatient low-clearance nephrology clinic, enrolling 693 patients with stages 4–5 of CKD. Patients were divided into two groups according to the start of renal replacement therapy (RRT). Results: The kidney’s survival at 120 months was 60% for a Ca–Mg ratio < 6 and 40% for a Ca–Mg ratio ≥ 6 (p = 0.000). Patients who started RRT had lower levels of Hb, Ca, Mg, albumin, and cholesterol and higher values of phosphorus, the Ca/Mg ratio, and PTH. High values of phosphorus and the Ca/Mg ratio and low levels of Mg and GFR were independent predictors of entry into RRT. A high Ca/Mg ratio, high phosphorus levels, and low levels of GFR were associated with a cumulative risk for initiation of RRT. Conclusions: In our population, the Ca/Mg ratio is an independent predictive factor for the initiation of a depurative technique.

On estimation and cross-validation of dynamic treatment regimes with competing risks.

The optimal moment to start renal replacement therapy in a patient with acute kidney injury (AKI) remains a challenging problem in intensive care nephrology. Multiple randomized controlled trials have tried to answer this question, but these contrast only a limited number of treatment initiation strategies. In view of this, we use routinely collected observational data from the Ghent University Hospital intensive care units (ICUs) to investigate different prespecified timing strategies for renal replacement therapy initiation based on time-updated levels of serum potassium, pH, and fluid balance in critically ill patients with AKI with the aim to minimize 30-day ICU mortality. For this purpose, we apply statistical techniques for evaluating the impact of specific dynamic treatment regimes in the presence of ICU discharge as a competing event. We discuss two approaches, a nonparametric one - using an inverse probability weighted Aalen-Johansen estimator - and a semiparametric one - using dynamic-regime marginal structural models. Furthermore, we suggest an easy to implement cross-validation technique to assess the out-of-sample performance of the optimal dynamic treatment regime. Our work illustrates the potential of data-driven medical decision support based on routinely collected observational data.

Intravenous amino acid therapy for kidney protection in cardiac surgery a protocol for a multi-centre randomized blinded placebo controlled clinical trial. The PROTECTION trial

BackgroundPostoperative acute kidney injury (AKI) is frequent in cardiac surgery patients. Its pathophysiology is complex and involves decreased renal perfusion. Preliminary clinical evidence in critically ill patients shows that amino acids infusion increases renal blood flow and may decrease the incidence and severity of AKI. We designed a study to evaluate the effectiveness of perioperative continuous infusion of amino acids in decreasing AKI. MethodsThis is a phase III, multi-center, randomized, double-blind, placebo-controlled trial. Adults undergoing cardiac surgery with cardiopulmonary bypass (CPB) are included. Patients are randomly assigned to receive either continuous infusion of a balanced mixture of amino acids in a dose of 2 g/kg ideal body weight/day or placebo (balanced crystalloid solution) from the operating room up to start of renal replacement therapy (RRT), or ICU discharge, or 72 h after the first dose. The primary outcome is the incidence of AKI during hospital stay defined by KDIGO (Kidney Disease: Improving Global Outcomes). Secondary outcomes include the need for, and duration of, RRT, mechanical ventilation; ICU and hospital length of stay; all-cause mortality at ICU, hospital discharge, 30, 90, and 180 days after randomization; quality of life at 180 days. Data will be analyzed in 3500 patients on an intention-to-treat basis. DiscussionThe trial is ongoing and currently recruiting. It will be one of the first randomized controlled studies to assess the relationship between amino acids use and kidney injury in cardiac surgery. If our hypothesis is confirmed, this practice could reduce morbidity in the studied population. Study registrationThis trial was registered on ClinicalTrials.gov with the trial identification NCT03709264 in October 2018.

Retrospective case-control study exploring pretransplant predictors for loss of kidney transplant function or death among indigenous kidney transplant recipients.

The factors affecting the outcomes among Indigenous kidney transplant recipients is not fully understood. We conducted a retrospective case control study to identify risk factors beyond those explained by the ANZDATA registry. To identify the risk factors for loss of kidney transplant function or death among Indigenous kidney transplant recipients. Cases were defined as all Indigenous Australian kidney transplant recipients from 1 January 2005 to 31 December 2015 from the major hospitals in the Northern Territory (NT) and South Australia (SA) who experienced graft loss (including patient death) up to 2-years post-transplant. Controls (matched 4:1) were defined as all indigenous kidney transplant recipients during the same period with functioning transplants at 2-years post-transplant operation. Matching was done on gender and diabetes status. Regression analysis adjusted for age was used for comparing cases and controls. There were 17 cases and 68 matched controls. Among cases, the odds ratio for more than one hospital admission episode (compared with ≤1 episode) in the 2-year pretransplant period was 6.2 (95% confidence interval, 1.2-32.5). However, there were no significant differences in the frequency of comorbidities at renal replacement therapy start, cardiovascular intervention pretransplant, pretransplant infection screening, age and gender of the donors, frequency of admission episodes where an infection was documented, the total length of inpatient stay or admission to intensive care unit during pretransplant hospital admission between cases and controls. Early graft loss was associated with a higher frequency of hospital admissions in the 2-years pretransplant period. In contrast, other measured factors in the pretransplant period did not predict these adverse outcomes.

An algorithm for identifying chronic kidney disease in the French national health insurance claims database

BackgroundPublished algorithms for identifying chronic kidney disease in healthcare claims databases have poor performance except in patients with renal replacement therapy. We propose and describe an algorithm to identify all stage chronic kidney disease in a French healthcare claims databases and assessed its performance by using data from the Renal Epidemiology and Information Network registry and the French Childhood Cancer Survivor Study cohort. MethodsA group of experts met several times to define a list of items and combinations of items that could be related to chronic kidney disease. For the French Childhood Cancer Survivor Study cohort, information on confirmed chronic kidney disease cases extracted from medical records was considered the gold standard (KDIGO definition). Sensitivity, specificity, and positive and negative predictive value and kappa coefficients were estimated. The contribution of each component of the algorithm was assessed for 1 and 2 years before the start of renal replacement therapy for confirmed end-stage kidney disease in the Renal Epidemiology and Information Network registry. ResultsThe algorithm's sensitivity was 78%, specificity 97.4%, negative predictive value 98.4% and positive predictive value 68.7% in French Childhood Cancer Survivor Study cohort and the kappa coefficient was 0.79 for agreement with the gold standard. The algorithm 93.6% and 55.1% of confirmed incident end-stage kidney disease cases from the Renal Epidemiology and Information Network registry when considering 1 year and 2 years, respectively, before renal replacement therapy start. ConclusionsThe algorithm showed good performance among younger patients and those with end-stage kidney disease in the twol last years prior to renal replacement therapy. Future research will address the ability of the algorithm to detect early chronic kidney disease stages and to classify the severity of chronic kidney disease.

Uso de dieta muy baja en proteínas con keto análogos comparado con dieta baja en proteínas en pacientes con enfermedad renal crónica pre diálisis

Introduction It has been proposed that a very low protein diet supplemented with keto analogues in pre-dialysis chronic kidney disease patients can slow the progression to a terminal disease and delay the start of renal replacement therapy, without a malnutrition risk. However, its common use has not yet been implemented due to the uncertainty of its efficacy and safety. Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. Results and conclusions We identified eight systematic reviews including 14 studies overall, of which 12 were randomized trials. We concluded that a very low protein diet supplemented with keto analogues delays the progression to end-stage kidney disease, probably reduces the fall or deterioration of renal function, could reduce mortality by any cause y result in little or no difference in malnutrition risk, but the certainty of the evidence is low for these last two results.

MO363: Target Trial Emulation on Timing of Start of Renal Replacement Therapy in Acute Kidney Injury: Lessons Learned

Abstract BACKGROUND AND AIMS Routinely collected data (RCD) are readily available at most ICUs. Their secondary analysis is expected to improve medical decision-making by providing expedited answers to clinical questions that would otherwise require conducting costly and less generalizable RCTs. However, doubts remain whether RCD can produce sound answers to comparative effectiveness questions. Trial emulation studies based on RCD closely mimic trial protocols, limit the risk of avoidable biases and could therefore be a powerful tool to expand our evidence base on patient management. We assess whether such an emulation of the ELAIN trial[1] can replicate results of this landmark study comparing timing strategies for initiating renal replacement therapy (RRT) in ICU patients with acute kidney injury (AKI). METHOD Using serum creatinine and urine output measures, we identified patients admitted to the Ghent University Hospital ICUs (2013–2017) who developed KDIGO stage 2 AKI. Other eligibility criteria from the ELAIN trial available from our linked databases were applied to obtain a final sample that matches the trial population. Based on time from study inclusion to RRT and/or progression to stage 3 AKI or reaching an absolute indication for RRT, we identified patients with a treatment history compatible with assignment either to the early RRT arm, the delayed RRT arm, or both. To avoid immortal time bias, patients who died or were discharged without RRT within the grace period for initiating RRT were also considered compatible with the respective RRT strategies. To avoid selection bias, more weight was given to compatible patients less likely to remain compatible through follow-up (inverse probability weighting). The number of patients receiving RRT and ICU mortality were compared between RRT groups (ad hoc approach) and emulated trial arms (emulation approach). RESULTS Finally, 2756 out of 16 434 patients (16.8%) would have been eligible for the ELAIN trial (Fig. 1). Of these, 2565 (93.1%) did not receive RRT at any time (Fig. 1: bottom, white boxes); 9.6% and 1.7% of patients compatible with assignment to early and delayed RRT, respectively, actually received RRT (Fig. 1: bottom, grey boxes). The majority of patients were discharged without RRT, did not progress to stage 3 AKI or did not reach an absolute indication for RRT. In contrast to the ELAIN trial, there was no evidence that early (versus delayed) RRT reduces mortality, neither using the ad hoc approach (59 versus 51%), or the emulation approach (6.4 versus 8%) (Fig. 2). Furthermore, mortality was comparable to that observed in the ELAIN trial using the ad hoc approach in the delayed arm but was &amp;gt;5 times lower using the emulation approach. CONCLUSION Our observational emulation of the ELAIN trial did not reproduce certain key aspects of the benchmark trial. In each of the emulated trial arms &amp;lt;10% of patients received RRT. Along with the much lower mortality (compared with the ELAIN trial), this may in part be due to too broad patient inclusion into the emulation, e.g. because of failure to emulate eligibility criteria unavailable in RCD or an implicit application of undocumented selection criteria in the ELAIN trial. Considering ICU mortality only in patients who did receive RRT (ad hoc approach) may conceal these discrepancies and lead to a false sense of comparability in terms of baseline risk. Although our bias corrections may better signal this issue, final mortality estimates cannot directly be compared head-to-head due to unadjusted confounding. In sum, emulation of even basic protocol components such as eligibility criteria and allocation to treatment strategies can be cumbersome if the available RCD does not contain sufficient information. Future emulations may therefore need to consider careful selection of available proxies of unavailable eligibility criteria and need to rely on adequate adjustment for confounding.

MO336: Renal Recovery After Acute Kidney Injury Associated to COVID Requiring CRRT During ICU Hospitalization

BACKGROUND AND AIMSRenal recovery (RR) after AKI is a determinant outcome of future comorbidity and mortality in critical care patients. Related predictive factors remain uncertain.METHODWe retrospectively analyzed patients admitted to ICU between January 2020 and February 2021 from our critical nephrology database.We analyzed adult patients with diagnosis of AKI (KDIGO criteria) treated with renal replacement therapy (RRT) during ICU hospitalization. We excluded patients with dialysis support previous to the admission.The main outcomes we evaluated were(1) RR (successful suspension of RRT without hyperkalemia, increase in serum creatinine (SCr), hypervolemia or acidemia after 1 week without RRT, with urine volume > 500 mL/d without diuretic treatment or > 2000 mL/d with diuretics).(2) Mortality during hospitalization.RESULTSWe found 1442 patients were admitted to ICU, 418 presented AKI (29.8%), of them, 178 patients (64% male) required RRT (AKI-RRTd) in ICU during follow-up, with mean age of 66 year old (52.8% >65 year). Main comorbidity and demographic data are in Table 1. Mean time in ICU was 19 days (RIC 11–35). The most frequent admission cause was non-surgical pathologies (93%), 53% of admitted patients had COVID-19 as main diagnosis (95 patients). There was need of vasoactive support in 73.6%, ventilatory support (82.6) and 67.2% of patients had fluid overload.The indication of dialysis was determined by a nephrologist: mainly oliguria, acidosis, hyperkalemia, fluid overload and increase SCr. Mean SCR at admission was 2.5 mg/dL. There were missing data in 48% of basal SCr (known SCr between 1 and 12 months prior to admission). Total mortality in AKI-RRTd was 70.8% (126 patients). In COVID patients, was 77.9% (74 patients).We found renal recovery in 63.4% of total survivors (33/52 patients). When analyzing COVID, there were 21 survivors, and we found renal recovery in 80.9% of patients.Patients who did not achieved renal recovery had longer ICU stay (median: 20 days, RIC: 4–26) and inhospitalization (median: 41 days, RIC: 29–58). Those patients were older, and had higher morbidity (diabetes), higher SCr at ICU admission and lower urine output. Their fluid balance was higher at 48 h after CRRT initiation (OR 3.05, 95% CI 1.39–6.65, P <.01). In COVID population without renal recovery, there were more urgent dialysis onset (OR 8.33, 95% confidence interval (95% CI) 1.04–66.2; P = .04), age > 65 year (OR 6.48, 95% CI 1.94–21.6; P < .01), positive fluid balance at 48 h after RRT (OR 3.25; 95% CI 1.09–9.69; P = .03).The risk factors for mortality, were age > 65 year (OR 4.14, 95% CI 2.05–8.35; P < .01), mechanical ventilation (OR 3.28, 95% CI 1.48–7.30; P < .01), haemodynamic support (OR 4.37, 95% CI 2.14–8.92; P < .01). Otherwise, lower SCr at admission (OR 0.82, 95% CI 0.71–0.93; P < .01) and at instauration of RRT (OR 0.75, 95% CI 0.065–0.88; P < .01) were associated to lower mortality.In COVID patients, fluid overload at RRT initiation (OR 10.83, 95% CI 1.37–85.36; P = .02), age > 65 year old (OR 8.85, 95% CI 2.68–29.1; P < .01) and FiO2 > 50% at RRT start (OR 2.77, 95% CI 1.02–7.50; P = .04) were associated to higher mortality.CONCLUSIONIn ICU patients with AKI-RRT dependence, negative fluid balance at 48 h after RRT onset and in COVID patients, age < 65 year old, negative fluid balance at 48 h after RRT onset and non-urgent onset of RRT were related with renal recovery.