Start Of Renal Replacement Therapy Research Articles

Hyperosmolarity in children with hyperammonemia: a risk of brain herniation at the start of renal replacement therapy.

Renal replacement therapy (RRT) is used in hyperammonemia to reduce the concentration of ammonia in the blood. In the case of plasma hyperosmolarity, RRT can also rapidly decrease plasma osmolarity, which may increase cerebral edema in these patients and favor the occurrence of brain herniation. We conducted a retrospective clinical study in a tertiary care university-affiliated hospital. All patients admitted in a Pediatric Intensive Care Unit (PICU), less than 18 years old with ammonemia >150 µmol/L and who underwent RRT between January 2015 and June 2023 were included. We collected data on plasma osmolarity levels, osmolar gap and blood ammonia levels before and during RRT. Eleven patients were included (10 with acute liver failure and 1 with a urea cycle disorders). Their mean age was 36.2 months. Before RRT, the median highest measured osmolarity was 320 (305-324) mOsm/L, whereas the median calculated osmolarity was 303 (293-314) mOsm/L, corresponding to an osmolar gap of 14 mOsm/L. Ammonia blood level over 400 µmol/L are significantly associated with higher plasma osmolarity (P-Value <0.001). In one case, a patient had a brain herniation episode after a quick osmolar drop. This episode was reversed by the administration of hyperosmolar agents and the temporary suspension of RRT. This study highlights the hyperosmolarity and high osmolar gap that occur in children with hyperammonemia. A careful monitoring and control of plasma osmolarity evolution may alert clinician on the risk of occurrence of neurological complication such as brain herniation.

#1575 Cardio-renal syndrome in patients with Fabry disease on enzyme replacement therapy

Abstract Background and Aims Fabry disease (FD) is a rare X-linked lysosomal storage disorder in which mutations of the GLA gene cause a decreased or absent activity of the alpha-galactosidase A (α-Gal A) and intracellular accumulation of globotriaosylceramide and other sphingolipids [1]. FD causes a variety of symptoms, including heart and kidneys damage - cardiorenal syndrome (CRS) type 5. In patients with FD, CRS is known to increase the risk of cardiovascular events and death [2]. The aim of our study was to assess renal function and outcomes in patients with FD and CRS receiving enzyme replacement therapy (ERT). Method We performed a retrospective analysis of the medical records of 10 patients (pts) from 7 unrelated families with established diagnosis of FD and cardiac and renal involvement. Pts #1 and #3 are siblings, pt # 10 is their mother; pt #9 is mother of pt #8 (Table 1). The diagnosis was confirmed by DNA diagnostics in all plus levels of α-Gal A enzymatic activity, globotriaosylsphingosine concentrations in some patients. All the patients underwent ERT. Seven out of 10 patients received blockers of the renin-angiotensin-aldosterone system, 3 - did not receive due to contraindications. Results All 10 patients, including 3 women, had left ventricular hypertrophy - left ventricular wall thickness (LVWT) ≥ 1.2 cm. (Table 1). Average LVWT was 1.850 ± 0.097 cm. Two patients had atrial fibrillation. None of the patients had proteinuria 1 g/24 h or higher. In all еGFR was below 60 ml/min/1,73 m2: 4 patients had CKD-G3a, 4 – G3b, 1 – G4 and 1 – G5. Average еGFR was 41,111 ± 8.069 ml/min/1,73 m2 excluding hemodialysis (HD) patient. There were 4 unfavorable outcomes in our group: death occurred in 3 patients from cardiac pathology (congestive heart failure), one patient reached CKD-G5 at 25 years of age and started HD treatment. Patient on HD, brother of deceased pt #1, began receiving ERT after the start of renal replacement therapy. The death of pt #1, who had a very high Lyso-Gb3 level - 118.36 ng/ml (normal 0.05-3.0 ng/ml), appears to be related to the late diagnosis and delayed start of ERT. Conclusion Patients with FD and CRS are likely to have a high risk of cardiovascular complications, loss of kidney function and death, especially with a late start of enzyme replacement and cardio-renoprotective therapy. Early diagnosis of FD and timely initiation of treatment are important in preventing the serious complications and death.

#1982 Transcriptomic approach to predict drug targets in late-stage hypertensive nephropathy

Abstract Background and Aims Hypertensive nephropathy (HN) is a significant contributor to chronic kidney disease, yet the factors influencing the disease progression remains elusive. Notably, late-stage chronic kidney disease significantly impacts patient outcome. This project aims to unveil novel therapeutic targets for late-stage of HN using transcriptomic approach. Method A cohort of adult patients (n = 21; n = 9 females, mean age 57 years) with biopsy-confirmed HN were selected from the Norwegian Kidney Biopsy Registry (NKBR). Patients were classified as late-stage if eGFR≤45 ml/min/1.73 m2 at the time of biopsy. Patients were thereafter divided into “stable” (eGFR decline &amp;lt;3 ml/min/year) or “progressive” (eGFR decline ≥3 ml/min/year or start of renal replacement therapy) after a median follow-up of 9 years (5-15). TruSeq Exome sequencing was performed post-RNA extraction (miRNeasy FFPE kit, Qiagen) at Novogene, Cambridge, UK. R Studio (v4.2.0) and drug CTD repository in ShinyGO 0.80 facilitated data and drug interaction analysis. Results We focused on two distinct subgroups of HN patients: late stable (LS, n = 9) and late progressive (LP, n = 12). A total of n = 674 of differentially expressed genes (DEG, p-value &amp;lt; 0.05 and fold change (FC) ≥1.5) was identified in LS vs. LP. The subsequent drug interactive analysis of these DEGs unveiled 336 pathways with false discovery rate (FDR) &amp;lt; 0.05. Notably, the probenecid-related pathway demonstrated significant fold enrichment (FE=9, FDR = 1.5E-04), as depicted in Fig. 1. Particularly, key members of the SLC22 family, including SLC22A6 (FC=2.49, p-value = 0.002), SLC22A8 (FC=2.65, p-value = 0.004), SLC22A11 (FC=1.65, p-value = 0.036) and SLC22A12 (FC=1.97, p-value = 0.009) were prominently featured in this pathway. Besides their role as sole transporters, it is postulated that these proteins have central role in modulating local and systemic physiology, such as blood pressure, suggesting a potential significance of probenecid in the context of hypertensive nephropathy. Conclusion Transcriptomic profiling of kidney biopsies has strong potential to discover novel therapeutic targets, such as the probenecid-related pathway, in hypertensive nephropathy patients.

#2245 ECYSCO, a European cystinosis cohort

Abstract Background and Aims Cystinosis is a rare multisystem lysosomal storage disease due to variants in the CTNS gene, coding for the carrier protein cystinosin, a lysosome membrane transporter, causing cystine accumulation. Specific treatment by cysteamine decreases renal and extrarenal complications frequency in cystinosis patients but data on long-term manifestations of the disease are lacking. The aim of the ECYSCO cohort is to describe the natural history of the disease and the effect of treatments. Methods 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 177 patients (50.8% male) were analyzed. Median age at diagnosis was 1.3 years [IQ 0.9; 1.8], with earlier diagnosis since the 1980s, but no further improvement in the 2000s. Genetic analysis was available for 158 patients: 46 (31.9%) presented with homozygous 57kb deletion in the CTNS gene, 57 (39.6%) 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 7 patients were treated with cysteamine. Sixty-seven patients received immediate release formulation (Cystagon®) and 103 received extended release formulation (Procysbi®). Median white blood cell cystine level was 1.2 nmol ½ cystine/mg protein (IQ 0.6; 2.2). The median duration of treatment was 21.5 years [IQ 11.7; 31.1]. 165 (93,2%) patients also received cysteamine ocular gel, Cystadrops®. Median age at inclusion was 18.4 years (IQ 10.4; 30.6). At that time, 104 patients (57.8%) had reached kidney failure (KF). There was no impact of genotype on age at KF. Median age at KF 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 29 (16.4%) patients, diabetes mellitus in 15 (8.4%), skeletal manifestations in 89 (53.6%), myopathy in 28 (17.9%), and neurological disorders in 21 (13.5%). Skeletal manifestations involved patients before dialysis/transplantation in 46% of cases. The main complications in these patients were genu valgum (62.9%), genu varum (11.1%), kyphosis (21.2%), fractures (20.4%), and 12.6% required surgery. Patients with myopathy were dialysed or transplanted in 58.8% of cases. 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 kidney failure 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.

Occupational particle exposure and chronic kidney disease: a cohort study in Swedish construction workers

ObjectivesIncreasing epidemiological and experimental evidence suggests that particle exposure is an environmental risk factor for chronic kidney disease (CKD). However, only a few case–control studies have investigated this association in...

HYPERTENSIVE NEPHROPATHY: TRANSCRIPTOMICS OF KIDNEY BIOPSIES PREDICTS LONG TERM OUTCOME AND IDENTIFIES THERAPEUTIC TARGETS

Objective: Hypertensive nephropathy (HN) represents a major cause of chronic kidney disease, but it is incompletely understood why some patients show disease progression. Our project aim is to identify potential markers of disease progression and novel therapeutic targets. Design and method: Adult patients (n=43; n=16 females, mean age 53 years) with biopsy-verified HN were categorized as ’early’ (estimated glomerular filtration rate (eGFR) &gt;45 ml/min/1.73m2) or ’late’ disease (eGFR &lt;45 ml/min/1.73m2) at the time of biopsy. Patients were further divided into “stable” (eGFR decline &lt;3 ml/min/year) or “progressive” (eGFR decline &gt;3 ml/min/year or start of renal replacement therapy) after median follow-up of 10 years (5-22). TruSeq Exome sequencing was executed after RNA extraction (miRNeasy FFPE kit, Qiagen) at Novogene, Cambridge, UK. Quality control and data analysis was performed using R Studio (v4.2.0) and QIAGEN Ingenuity Pathway Analysis. Results: We analyzed the following subgroups of HN patients: early stable (ES, n=11), early progressive (EP, n=11), late stable (LS, n=9) and late progressive (LP, n=12). Differentially expressed genes (DEG, fold change (FC) &gt;1.5 and p-value &lt; 0.05) were identified, with n=265 in ES vs. EP, and n=674 in LS vs. LP. Principal component analysis (PCA) showed separation of ES vs. EP and LS vs. LP, as depicted in Figure 1A and B. K-nearest neighbour (KNN) analysis of DEG identified a 6-gene classifier in LS vs. LP (19/21 samples correctly classified), while IER5L and CNTNAP5 were the top 2-gene classifier in ES vs. EP (20/21 samples). These classifiers, as well as other DEGs such as PER1, YB1, TIMP3, ADAMTS4, IGFBP5 and EGF could represent novel targets to inhibit disease progression. Differentially regulated pathways were associated with regulation of TP53 activity and circadian rhythm involving melatonin metabolism in ES vs. EP, and metabolic processes related to water-soluble vitamins, glutathione and sphingolipids in LS vs. LP. Conclusions: Transcriptomic profiling from diagnostic kidney biopsies with HN can distinguish future disease progression from non-progression and may identify novel therapeutic targets.

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.