bluuebunny/crossref_metadata_2025 huggingface dataset:
#5458 HISTOLOGICAL STUDY OF KIDNEY INJURY ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITORS COMBINED WITH CHEMOTHERAPY IN A MURINE MODEL
Authors: Tascón Javier , Casanova Alfredo G , Vicente-Vicente Laura , Pescador Moisés , Martín Ana Isabel Morales , Prieto Marta
Published: June 2023

Background and Aims

The most current lines of cancer treatment aim to increase efficacy and decrease adverse effects. In this sense, one of the main therapeutic strategies is immunotherapy. Immune checkpoint inhibitors (ICIs) constitute the most relevant immunotherapeutic pharmacological group in the clinical setting. Despite their greater safety than conventional therapies, these agents still cause adverse events. Renal effects, although rare, have been shown to worsen the prognosis of patients. In addition, immune and chemotherapy combination have been approved nowadays. Although they have improved efficacy, they have increased risk of suffering nephrotoxic side effects. Our hypothesis is that kidney damage caused by ICIs could be subclinical, and therefore, not evidenced by the classic clinical biomarkers (plasma creatinine and urea). The aim of this work was the histological evaluation of renal damage associated with anti-CTLA-4 in combination with cisplatin.

Method

An experimental model was designed in C57BL/6 mice treated with the combined therapy of cisplatin (10 mg/kg, single dose) and anti-CTLA-4 (10 or 15 mg/kg/day, for 6 days) administrated by intraperitoneal injection. In addition, groups treated with drug monotherapies and a control group were included. On the day of sacrifice (day 6) the kidneys were collected and histological sections were made and stained with hematoxylin-eosin. Histological quantification of kidney damage was performed blindly following a tissue damage quantification protocol. For this, 10 photos were taken per kidney (600X), 5 of the external cortex and 5 of the corticomedullary region. Each photo was segmented into 6 areas and a score was assigned to each area as follows. 0: no damage, 1: damage up to 1/3 of the area, 2: damage between 1/3 and 2/3 of the area, and 3: damage over 2/3 of the area. Subsequently, the mean scores of the kidneys from the same experimental group were calculated, as well as the standard error of the mean. Data was analyzed with the statistical software SPSS®.

Results

Our results showed tubular renal damage associated with cisplatin treatment. It was more pronounced in the external cortical area. However, no structural alterations associated with ICI treatment were found. Co-treatment with both drugs potenciated renal structural damage from cisplatin.

Conclusion

This potentiation was more evident in the corticomedullary region, so it seems that the drugs combination causes a deeper lesion in the kidney than cisplatin monotherapy. Our study suggests that the combined therapy of anti-CTLA-4 and cisplatin could induce generalized tubular lesions.
#5461 KIDNEY TUBULE POLYPLOIDIZATION DURING PHYSIOLOGIC AGEING IN MICE
Authors: Lazzeri Elena , Antonelli Giulia , Conte Carolina , Angelotti Maria Lucia , Mazzinghi Benedetta , Carangiolo Giulia , De Chiara Letizia , Romagnani Paola
Published: June 2023

Background and Aims

The aged population is constantly increasing, and kidney-aging is a risk factor for both acute kidney injury (AKI) and chronic kidney disease (CKD). Accordingly, CKD is a major global health problem with an increasing prevalence in older population. Therefore, there is an urgent need to understand the age-related mechanisms underpinning CKD development during ageing. Recent findings contributed to clarify the cellular and molecular mechanisms underlying CKD development and progression, posing tubular cells (TC) at the center of this process. In this regard, we have demonstrated that polyploidization of TC promotes fibrosis, CKD development and its progression in the long run. Here, we aimed to investigate TC polyploidization during physiologic ageing in mice.

Method

To investigate TC polyploidization during ageing, we took advantage of inducible Pax8/FUCCI2aR mice. In these mice, FUCCI2aR reporter is expressed by all TC after doxycycline hyclate induction. Mice were sacrificed and analyzed at 2, 5, 11 and 20 months of age. By combining DNA content with detection of FUCCI2aR fluorescent proteins, FACS analysis shows diploid (2C), tetraploid (4C) and octaploid or greater (≥8C) TC. Single cell RNA-sequencing (scRNA-seq) analysis was performed on mouse kidneys at 2 and 20 months of age to dissect the transcriptomic profile of polyploid TC and interrogate putative altered signaling pathways. Renal function parameters were assessed at 2, 5, 11 and 20 months before sacrifice. Kidneys were analyzed for senescence and interstitial fibrosis at 2, 5, 11 and 20 months of age.

Results

Genetic and single-cell transcriptomic approaches in mice were used to investigate TC polyploidization during ageing. Pax8/FUCCI2aR mice showed a progressive increase of polyploid TC during ageing starting from 5 months of age. ScRNA-seq analysis on kidneys of mice at 2 and 20 months of age revealed that polyploid TC were characterized by polyploidy regulators, p21 expression, accumulation of DNA damage and by acquiring senescent/fibrotic markers, demonstrating that polyploid TC rather than diploid TC accumulate DNA damage and acquire a senescent/pro-fibrotic state during physiologic ageing in vivo. In accordance with the increase of polyploid TC, mice developed interstitial fibrosis, showed a marked senescent phenotype and an age-related decline of renal function starting from 5 months of age. Collectively, these results suggest TC polyploidization is a potential trigger for CKD development and progression during physiologic kidney ageing in mice.

Conclusion

This study demonstrates the increase of TC polyploidization, which is associated with a progressive fibrosis, senescence and CKD development during physiologic kidney ageing in mice.
#5497 PREVALENCE, TREATMENT AND RECURRENCE OF STAPHYLOCOCCUS AUREUS NASAL CARRIAGE IN PATIENTS ON RENAL REPLACEMENT THERAPY
Authors: Tsikliras Nikolaos , Anagnostara Aggelina , Tsantekidou Florina , Kyrgialanis Apostolos
Published: June 2023

Background and Aims

Searching for and treating nasal carriage of staphylococcus aureus in patients undergoing renal replacement therapy (RRT) has been debated. Indeed, previous meta-analyses showed that dialysis patients who were treated with intranasal mupirocin had lower rates of staphylococcus aureus infection but significantly more infections by other microorganisms. However, given the severity of staphylococcus aureus infections, it seems reasonable to detect and treat nasal carriers among patients on RRT. The aim of our study was to estimate the prevalence of staphylococcus aureus nasal carriage in patients on RRT, to evaluate the effectiveness of intranasal mupirocin in eradication of staphylococcus aureus and to detect the recolonization rate with the above microorganism after successful treatment.

Method

It was a single center prospective observational study. In 63 patients undergoing RRT (48 on hemodialysis and 15 on peritoneal dialysis) we performed cultures of the anterior nares to identify the carriage of staphylococcus aureus. Carriers then received intranasal mupirocin twice daily for seven days (in every nostril). Thirty days later, nasal cultures were repeated in those treated with mupirocin. In patients that were decolonized, new cultures were obtained three months after initial eradication of staphylococcus aureus had been detected.

Results

Nasal carriage of staphylococcus aureus was identified in 14 out of 63 patients (rate = 22%). Female sex was related with higher rate of nasal carriage (p = 0.014). All but one patient that received mupirocin were found decolonized after thirty days (cure rate = 92.8%). Recurrence of staphylococcus aureus nasal carriage was observed in 6 out of 13 patients that had successfully been treated (recurrence rate = 46%). Sex, age, renal replacement method, primary disease or previous immunosuppression treatment didn’t seem to significantly affect the possibility of recurrence.

Conclusion

Our study found a remarkable prevalence of staphylococcus aureus nasal carriage in patients on RRT. Intranasal mupirocin was highly effective in the eradication of the above microorganism, but nearly half of the successfully treated patients experienced a recurrence of nasal carriage. Further studies are needed to detect the effect of repeated mupirocin treatment to the nasal carriage status as well as to the rate of infection in the above population.
#5525 NEPHROTOXICITY OF CHIMERIC ANTIGEN RECEPTOR T CELL (CAR-T) THERAPY: ACUTE KIDNEY INJURY AND ELECTROLYTE DISORDERS
Authors: Francés Francesc Moncho , Morales Rafael Hernani , Solis Miguel Angel , Vallejos Ana Benzaquén , Garcia Isabel Juan- , Boluda Juan Carlos Hernández , Sanchez Jose Luis Piñana , Pérez Ariadna , Teruel Jose Luis Gorriz , Maicas Isidro Antonio Torregrosa
Published: June 2023

Background and Aims

Chimeric antigen receptor T cell therapy (CAR-T) has improved the prognosis of patients with refractory hematologic malignancies. The most important toxicities are the cytokine release syndrome (CRS), where interleukin 6 (IL-6) plays a major role, and the immune effector cell-associated neurotoxicity syndrome (ICANS). A low incidence of acute kidney injury (AKI) with a high frequency of electrolyte imbalance has been described with CAR-T therapy. The aim of our study is to describe the nephrotoxicity of CAR-T therapy and to focus on AKI and the physiopathology of hypophosphatemia.

Method

A prospective single-center case series was performed which included all patients undergoing CAR-T therapy between 2020 and 2022. Clinical data included medical history, previous chemotherapy treatments, concomitant treatments, and clinical evolution. Daily monitoring of renal function, electrolytes and IL-6 was obtained after infusion of CAR-T. A urine sample was obtained on days 0, +7 and +14 with parathyroid hormone (PTH) and 25-OH vitamin D. AKI was classified according to the KDIGO criteria.

Results

40 patients received CAR-T therapy during the follow-up period. The median age was 62 years. The same number of men as women were included. The most frequent comorbidities were hypertension (27.5%), followed by diabetes (12.5%) and chronic kidney disease (12.5%). 12 patients presented AKI. Baseline serum creatinine (SCr) in patients with AKI was 0.9 mg/dL (0.68-1.04) with a SCr peak of 1.27 mg/dL (1.1-1.7). The time from CAR-T therapy infusion to SCr peak was 6.5 days (4-10). Of these 12 patients, 8 presented stage 1, 3 stage 2, and 1 stage 3 AKI. There were no differences between the AKI and non-AKI group in baseline characteristics, inflammatory markers, CRS, ICANS or hospital length stay. Hypophosphatemia was the most frequent electrolyte imbalance, occurring in 36 patients (90 %), 22 (61 %) patients experienced moderate hypophosphatemia (phosphorus < 2 mg/dL) while 14 (39 %) patients experienced mild hypophosphatemia. 29 patients (72 %) presented hypokalemia and 25 patients (62.5 %) hyponatremia. Patients with moderate hypophosphatemia had a significantly higher elevation of IL-6 but there were no differences in PTH or vitamin D (Table 1). Although there were no significant differences in fractional excretion of filtered phosphate (FEPO4), patients with moderate hypophosphatemia trend to have higher FEPO4 values.

Conclusion

Electrolyte disturbances are common in CAR-T therapy, with hypophosphatemia being the most frequent. There is probably a mechanism for renal phosphorus loss related to systemic inflammation. AKI is less frequent and has mild characteristics in these patients.
#5541 EVALUATION OF PROTEIN MALNUTRITION IN CKD PATIENTS ON LOW-PROTEIN DIET
Authors: Bologna Arianna , Pisoni Matteo Brambilla , Avino Monica , Giambo Federica , Arcidiacono Teresa , Vezzoli Giuseppe
Published: June 2023

Background and Aims

Low-protein diet is considered crucial in patients with chronic kidney disease to slow down kidney function deterioration and control metabolic variables such as serum phosphate, urea and bicarbonate. However, low-protein diet may result in malnutrition if patients do not respect nutritional prescription. Thus, the present study examined the risk of protein malnutrition in CKD patients who started a low-protein diet.

Method

We analysed anthropometric variables, nutrient intake and body composition in 27 patients with CKD stage 4-5 (M/F 15/12; 69±15 years; 72±18 kg; BMI 27.3±7 kg/m2; serum creatinine 4.9±1.9 mg/dl; GFR 11±4 ml/min; 10 diabetic patients) before and after 3-months of low-protein diet (0.6 g/kg). We estimated nutrient intake with a food frequency questionnaire composed of 37 items and administered by a nutritionist who also prescribed the low-protein diet. We also measured body fat mass (FM) and free-fat mass (FFM) and appendicular skeletal muscle mass using bioimpedentiometry analysis (Akern, Florence). Patients having a protein intake lower than 0.6 g/kg at the nutritional survey was defined as malnourished.

Results

In the whole sample, after a 3-month diet protein intake decreased from 0.87±0.23 to 0.69±0.18 g/kg (p<0.001; Wilcoxon test). Protein intake was positively correlated with 24-h urine excretion of phosphate at baseline (r = 0.69, p = 0.012) and after 3-monts of diet (r = 0.62, p = 0.02). The diet induced a decrease in body weight (72±18 to 70±17 kg; p = 0.001), BMI (27.3±7 to 26.7±6.8 kg/m2; p = 0.001), FM (24±11 to 21±11 kg; p = 0.006), serum phosphate (1.68±0.33 to 1.52±0.32 mmol/l; p = 0.033) and urea (166±53 to 133±42 mg/dl; p<0.001), whereas FFM, expressed as percentage of body weight, significantly increased (69±9 to 73±8%; p = 0.011). Six patients (22%; 3 diabetic patients) had a protein intake lower than 0.6 g/kg after 3-months of diet. Their protein intake was significantly lower than that in the other 21 patients with protein intake above 0.6 g/kg (0.43±0.1 vs 0.77±0.12 g/kg; p<0.001). These patients had lower FM (14±2 vs 26±11 kg; p = 0.03) and protein intake before starting the low-protein diet than the other 21 patients (0.64±0.06 vs 0.94±21 g/kg; p = 0.003). Patients with protein intake lower than 0.6 g/kg slightly decreased FFM after 3 months of diet compared to the value at baseline (52±7 to 50±7 kg; p = 0.07); conversely the other 21 patients did not change FFM (51±10 to 53±11 kg; p = 0.17), but significantly decreased FM (26±11 to 23±12 kg; p<0.001).

Conclusion

In conclusion, protein malnutrition may occur during a low-protein diet in CKD patients with a low consumption of proteins before starting this diet. Nutritional analysis is necessary to identify CKD patients at risk of protein malnutrition and to adequately follow up CKD patients on low protein diet.
#5554 ROLE OF THE TUBULAR EPITHELIAL CELL NLRP3 INFLAMMASOME DURING HYPERGLYCEMIA AND GLUCOSURIA IN DIABETES
Authors: Honda Tamisa , Marschner Julian , Zhao Danyang , Anders Hans-Joachim
Published: June 2023

Background and Aims

Diabetes is a prominent risk factor for the progression of CKD because hyperglycemia and glucose filtration increase the hemodynamic and metabolic workload to the nephrons, which imposes adaptive mechanisms. Tubules adapt to diabetes by enlargement and epithelial cell hypertrophy but an exceeding metabolic workload promotes oxidative stress, cytokine signaling and tubular epithelial (TEC) cell demise leading to tubular atrophy and interstitial fibrosis. Several studies propose a role of the NLRP3 inflammasome in tubulointerstitial inflammation in diabetic and non-diabetic kidney disease. The NLRP3 inflammasome is a sensor of cellular damage responsible for regulate the IL-1β and IL-18 production, playing important role during the progression of CKD. However, the role of NLRP3 in diabetes-induced tubular adaptation is unknown.

Method

scRNAseq analysis showed previously that the TECs do not express NLRP3 or inflammasome components. However, a group of patients diagnosed with Cryopyrin-Associated Autoinflammatory Syndromes, have a mutation that overexpress NLRP3, which is associated with chronic and systemic inflammation. To investigate the role of NLRP3 on tubular cells under diabetes conditions, we generated a mouse line by crossing mice bearing LoxP-target A350V allele with Pax8-driven Cre transgenic mice. Animals carrying the A350V allele have overexpression of NLRP3 in tubular cells. The combination of unilateral nephrectomy and treatment with multiple low doses of streptozotocin (60 mg/Kg) accelerate the kidney injury caused by hyperglycaemia. Kidney function, histology and gene expression were evaluated at the end of 16 weeks of diabetes. In vitro experiments carried out using TECs isolated from Pax8-A350V, and stimulated with LPS (1µg/ml) and/or ATP (20 mM).

Results

In silico analysis showed TECs do not express NLRP3 or inflammasome components. A350V-TECs under inflammasome activation did not produce IL-1β or IL-18. However, the Nlrp3 overexpression upregulated kidney injury markers, as well IL-6 and TNF. Moreover, the increase in kidney inflammation was associated with significative upregulation of fibrosis markers (Tgfb1, Asma, and Fn1) and extracellular molecules (Ctgf, AnxaII, and Chd2). Diabetic mice carrying the A350V mutation did not have significative differences in blood glucose, albuminuria, or body weight when compared with diabetic control mice. The overexpression of NLRP3 in tubular cells was associated with significative reduction in GFR and BUN when compared with controls mice, even though no differences in tubular injury markers observed. Furthermore, Pax8-A350V diabetic mice expressed significantly more Nlrp3 and Il1b than control group. Although, no differences observed in cryopyrin staining.

Conclusion

Our data suggest the NLRP3-associated damage in tubular epithelial cells occurs in a non-canonical manner.
#5564 OUTCOMES OF PERITONEAL DIALYSIS AFTER KIDNEY TRANSPLANT FAILURE: A SINGLE-CENTER EXPERIENCE
Authors: Kumru Gizem , Eren Sayeste Akkan , Aktar Merve , Ateş Kenan , Keven Kenan
Published: June 2023

Background and Aims

There is a hesitation in returning peritoneal dialysis (PD) after kidney transplant (KTx) failure. Studies in larger multicentre matched cohorts are missing.

Method

We conducted a retrospective study about 19 patients who started PD after KTx failure (PDpostTx group) between January 2010 and August 2022 in Ankara University School of Medicine who were compared with 70 never-transplanted patients having started PD during the same period (PDnoTx group). Patients’ clinical data and PD technique survival as well as peritonitis episodes were analysed.

Results

Mean age was 51 years and continuous ambulatory PD was the treatment of choice (59.6%) (Table 1). Even the mean time on PD was similar between groups (45.4 months in PDpostTx vs 51.7 months in PDnoTx, p = 0.525), transfer to HD was more common in PDpostTx patients (36.8% vs 10.0%, p = 0.015). The main cause of transfer to HD was ultrafiltration failure, which was significantly higher in PDpostTx group (p = 0.002). Diuresis at baseline was similar between groups, but decreased significantly in PDpostTx group at first year and final follow-up (p < 0.001, and p = 0.001, respectively). Peritonitis was more common in PDpostTx group (68.4% vs 30.0%, p = 0.002). Diabetes mellitus was a risk factor for peritonitis episode (p = 0.012), but we didn’t observe any effect of immunosuppressive therapy on peritonitis and reduction of the diuresis. In multivariate analysis, KTx failure (p = 0.014), peritonitis episodes (p = 0.011) and ultrafiltration failure (p < 0.001) were associated with a higher risk of transfer to HD. Over the study period, patients’ survival was similar between groups (p = 0.766).

Conclusion

We reported similar patient survival, but higher peritonitis rates and PD technique failure in the PDpostTx group, when compared to patients who started PD for other reasons. Considering these findings, taking precautions against peritonitis is more important for patients who started PD after KTx failure.
#5571 THERAPY WITH BUROSUMAB IN ADULT PATIENTS WITH X-LINKED HYPOPHOSPHATEMIA: A YEAR OF FOLLOW-UP
Authors: Rotondi Silverio , Tartaglione Lida , Perrotta Adolfo , Carroccia Nadia , Pasquali Marzia , Mazzaferro Sandro
Published: June 2023

Background and Aims

X-linked hypophosphatemic rickets (XLH) is a genetic disorder secondary to the mutation of the PHEX gene that results in increased circulating levels of FGF23. Increased FGF23 causes hypophosphatemia secondary to renal phosphate loss. Clinically, the disease is characterized by reduced growth, bone alterations, weakness, chronic pain and reduced mobility. From a biochemical point of view, patients have hypophosphatemia, increased values of alkaline phosphatase, increased fraction excretion of phosphate (FEP). Recently, therapy with Burosumab, a monoclonal antibody against FGF23, has been introduced. Burosumab by reducing the receptor availability of circulating FGF23 reduces its activity. This leads to a normalization of serum phosphate and in paediatric patients an improvement of the clinical phenotype. In adult patients, the effectiveness of therapy in improving the clinical outcome and quality of life is being investigated. The purpose of the study was to evaluate the efficacy in improving the biochemical, bone and clinical picture of adult patients with XLH in therapy with Burosumab for one year.

Method

We enrolled patients with XLH naive for Burosumab therapy. In all we evaluated the biochemical aspects (phospahatemia, alkaline phosphatase, FEP), bone Radiographic Global Impression of Change score and clinical improvements (six-minute walk test, UP and go timed test, WOMAC Index) pre therapy and after a year of therapy. Burosumab was administered monthly at a dose of 1 mg/Kg.

Results

We enrolled 5 patients (45 ± 10 year old, weight 60 ± 10 Kg, Burosumab dose 60 ±10 mg) with genetic diagnosis of XLH. The comparison between pre therapy and post-one-year therapy showed in all patients: increase in average phosphatemia (pre 1.9± 0.5 mg/dl vs post 3.4 ±0.6 mg/dl p = 0.003), reduction in FEP (pre 50 ±15% vs 20 ±10% p = 0.004), reduction of UP and go timed test (pre 20± 5 sec vs post 11 ±5 sec p = 0.005) increase of the distance in the six minutes’ walk test (pre 150 ± 30 meters vs post 250 ± 50 meters p = 0.01), improvement of the WOMAC test (pre 15± 3 vs post 5± 2; p = 0.008) and reduction of the Radiographic Global Impression of Change score (pre -2 ±0.5 and post 2± 0.4; p = 0.001). The serum value of alkaline phosphate was high and it did not change with the Burosumab therapy (pre 200±50 UI/L vs post 220±60 UI/L; p: n.s. n.v. 33–98 UI/L). No patients had significant complications during the first year of treatment.

Conclusion

The therapy with Burosumab was well tolerated by patients. It resulted in a marked improvement in the biochemical picture associated with a better quality of life identified by increased strength (improved walk test and UP and go timed test) reduction of pain (best WOMAC test) and bone damage score. In conclusion, Burosumab may be a good and safe therapy option for adults’ patients with XLH.
#5602 DEPRESSION AND ANXIETY IN FAMILY CAREGIVERS OF END STAGE KIDNEY DISEASE PATIENTS IN GREECE: A COMPARISON BETWEEN DIALYSIS AND KIDNEY TRANSPLANTATION
Authors: Vovlianou Stavroula , Koutlas Vasileios , Papoulidou Fani , Tsigaras George , Skapinakis Petros , Milionis Haralampos , Ntounousi Evangelia
Published: June 2023

Background and Aims

Chronic kidney disease (CKD) is considered a high-stress disease because of its chronicity, co-morbidity, and lifelong treatment. Family members are often the main caregivers of end stage kidney disease (ESKD) patients and they are involved in various roles. Caregivers of ESKD patients experience emotional stress, anxiety and depression as they support their family members throughout the disease and treatment. This cross-sectional study aimed to assess depression and anxiety in caregivers of ESKD patients and to compare these disorders between caregivers of hemodialysis (HD) patients’ and kidney transplant recipients (KTR), as well as to investigate potential social-demographic parameters associated with caregivers’ depression and anxiety.

Method

A total of 342 participants (171 couples of patients and caregivers) were recruited. Structured interviews and self-completed questionnaires were obtained from HD patients, KTR (138 HD patients and 33 KTR) and their caregivers. The Beck Depression Inventory and the Generalized Anxiety Disorder-2 scales were used as screening tools. Depression scores were classified into four levels based on the level of severity (low, mild, moderate, severe). The collected data were encoded and analyzed using ΙΒΜ SPSS version 25 and R Statistical Software.

Results

Mean age of caregivers was 58 years and the majority were females (67.2%). Total anxiety score was high (Mdn = 3) with a mildly increased score of depression (Mdn = 9.5). Caregivers’ anxiety and depressive symptoms were significantly associated with gender, duration of caregiving, educational level, financial status, and caregivers’ age (p<0.01 for all). Caregivers’ depression and anxiety were also, related to the type of patients’ treatment (Table 1). HD caregivers reported significantly higher anxiety scores (Mdn = 3(2-5)) in comparison to KTR caregivers (Mdn = 2(2-4)) (p = 0.048) (Table 2). Moreover, HD caregivers revealed higher (Mdn = 11(0-46)) levels of depression than the KTR group (Mdn = 6 (0-25)) (p = 0.049) (Table 3).

Conclusion

Based on the findings of this study, the type of ESKD treatment displayed an important role in caregivers’ anxiety and depression symptoms, with KTR caregivers having the best scores. In particular, KTR caregivers appeared to have lower levels of depression and anxiety than caregivers of HD patients.
#5603 HYPERKALAEMIA MAY LIMIT POTENTIAL RENAL INTERVENTIONS IN PATIENTS WITH LOW GFR AND SIGNIFICANT PROTEINURIA
Authors: Koo Hyewon Nina , Thoren Fredrik , Greasley Peter , Chandankhede Shardul , Khayyam Afrah , Ambery Philip
Published: June 2023

Background and Aims

Evidence-based therapies including ACE inhibitors, ARBs and mineralocorticoid receptor antagonists (MRA) can significantly delay progression of CKD, yet their use is potentially limited by hyperkalaemia risk. In this study, we describe hyperkalaemia events among CKD patients to provide a better understanding of the current unmet need.

Method

This was a retrospective secondary data analysis from electronic medical records (EMR) in the US TriNetX analytics data CKD subset from Jan 2015-Dec 2019. Patients with ≥1 uACR measure were included, whereby the first date of the uACR measure was considered the index date. The study cohort included patients aged > 18 years with a) two consecutive estimated glomerular filtration rate (eGFR) values between 20 and 90 mL/min/1.73m2 recorded 91–730 days apart prior to the index date, or, b) at least one CKD diagnosis code before the index date. Patient demographics, ACE/ARB, MRA and SGLT2i treatments on index were described. The frequency of HK (defined as serum potassium >5.5 mmol/L or a diagnosis code) during a 1-year baseline period and 1-year follow-up period was described by uACR (>700mg/g, 300–700mg/g, <300mg/g) and eGFR (<20mL/min/1.73m2, 20–45mL/min/1.73m2, 45–60mL/min/1.73m2, 60–90mL/min/1.73m2 and >90mL/min/1.73m2) categories.

Results

Baseline characteristics of the included patients are described in the table below. During the 1-year follow-up period, HK events were more frequently recorded for patients with uACR>700mg/g (15.3%), eGFR<60ml/min/1.73m2 (9.3%) and combined uACR>700mg/g and eGFR<60ml/min/<1.73m2 (18.3%).

Conclusion

The preliminary results of this analysis shows that HK occurs more frequently among patients with low eGFR and/or high uACR. Despite guidelines, uACR testing is not done frequently in clinical practice and likely performed more frequently among patients with high uACR. Further analyses and more conservative study definitions will be applied to more comprehensively clarify the unmet need among patients at risk of HK. Of particular interest are the patients who discontinued RAASi treatment after a hyperkalemia event during baseline and were not on renoprotective treatment, yet who had recurrent hyperkalemia. Adequate treatment options for these patients are currently limited, and there is a need for more renoprotective treatments with limited hyperkalemia risk.
#5630 SCREENING AND DIAGNOSIS STRATEGY FOR FABRY DISEASE IN TAIWANESE PATIENTS WITH CHRONIC KIDNEY DISEASE
Authors: Wu Mlng-Ju , Wu Chih-Jen , Lin Cheng-Jui , Yang Feng-Jung , Wu Mai-Szu
Published: June 2023

Background and Aims

Fabry disease (FD) is not uncommon in patients with chronic kidney disease (CKD) who are on dialysis or have stroke at a young age, left ventricular hypertrophy (LVH) or hypertrophic obstructive cardiomyopathy (HOCM). However, FD is easily overlooked by physicians due to the heterogeneity of clinical manifestations. Therefore, an expert consensus meeting was held to establish a screening algorithm for FD in patients with CKD.

Method

The first meeting was held in Taiwan in August 2022. The screening criteria for FD with respect to age, sex, family history, cardiac involvement and signs and symptoms were discussed. The findings of meeting and the consensus opinion of the expert group were summarized.

Results

The screening algorithm was shown in Figure 1. It is recommended to screen for FD regardless of age. Screening for FD is recommended for CKD patients with family history of FD, stroke at young age (<55 years) or typical signs and symptoms including angiokeratoma, hypohidrosis, neuropathic pain, heat/cold and exercise intolerance, hearing loss and cornea verticillata. If CKD patients have one of the cardiac symptoms including dyspnea, palpitation and chest pain, it is recommended to check the cardiac-related red flags including LVH and HOCM using echocardiogram, short PQ interval, atrioventricular block and prolonged QRS interval using electrocardiogram, and low native T1 and posterolateral late gadolinium enhancement using magnetic resonance imaging. If cardiac-related red flags are present, screening for FD is recommended. Screening can also be performed in patients with CKD who do not have any typical symptoms but have a high suspicion of FD. In males, screening can be performed by measuring α-galactosidase A enzyme activity. If the enzyme activity is reduced or absent, assessment of globotriaosylsphingosine (lyso-Gb3) levels in plasma and genetic analysis are recommended. In female, assessment of lyso-Gb3 levels in plasma and genetic analysis are recommended.

Conclusion

FD is an underrecognized and not so rare disease. Physicians should maintain a skeptical attitude in clinical practice in order to make diagnosis in time and help patients and their entire families avoid life-threatening diseases at a young age. There are still more issues to be addressed, including whether to inform patients of the screening results, how to interact and communicate with patients, etc.
#5632 THE CLINICAL AND ECONOMIC BURDEN OF CHRONIC KIDNEY DISEASE IN GREECE
Authors: Stafylas Panos , Sarafidis Pantelis , Tychala Christiana , Pella Eva , Karaiskou Marianthi , Valsami Renata , Stergiou George , Boletis Ioannis
Published: June 2023

Background and Aims

Chronic Kidney Disease (CKD) is a progressive disorder with a substantial clinical and economic burden. This burden is expected to grow, mainly because of the ageing population, and the increasing incidence of diabetes mellitus and arterial hypertension. The objective of this study is to provide insights into the clinical and economic burden of CKD in Greece.

Method

A cost of illness (COI) study has been performed to approximate the burden of CKD in Greece from the perspective of EOPYY (National Organization for Health Care Services Provision), with reference year 2022. The COI model employs a prevalence-based approach using national and international sources and approximates the annual direct cost of CKD. The direct costs included in this analysis are categorized into primary care, medication, hospitalization and renal replacement therapy (RRT) costs.

Results

It has been estimated that there about 1,115,991 patients with CKD (stages 1–5) in Greece, most of them in stage 3 (about 534,694), and about 15,337 receiving RRT or having received a kidney transplant. In 2032 this population is expected to increase to approximately 1,249,475 patients. The total annual direct cost of CKD was estimated at €845,936,094. The main cost driver was RRT, which accounted for roughly 49% (417 millions) of total cost of care, followed by hospitalizations 29% (246 millions) and medications 17% (143 millions). The progression of the disease is strongly correlated with an increase in the annual management cost. About 1.4% of the CKD population (RRT group) spent about half of the total CKD budget or more than 4% of the total public health expenditure, higher than other European countries.

Conclusion

CKD is creating a high and growing clinical and economic burden, largely driven by the RRT cost. There is an urgent need for public health strategies aiming at early detection and management of CKD.
#5649 HEPARANASE OVEREXPRESSION MODIFIES PODOCYTE MOTILITY
Authors: Lensky Aviya , Suleiman Hanan Abu-Tayeh , Vlodavsky Israel , Ilan Neta , Assady Suheir
Published: June 2023

Background and Aims

Heparanase is an endo-β-d-glucuronidase that degrades heparan sulfate side chains, which are essential components of extracellular matrices and cell surfaces, including in the kidney filtration apparatus, the glomerulus. Upregulation of heparanase in glomerular diseases (GDs) was demonstrated in experimental models of GDs and in humans. Using transgenic mice overexpressing the human heparanase gene, we recently showed that heparanase reduced proteinuria and preserved the glomerular filtration barrier (GFB) after Adriamycin-induced injury. Furthermore, heparanase improved survival of key GFB cells, the podocytes and enhanced their autophagic flux both in vitro and in vivo. Here, we aimed to study the potential role of heparanase on podocyte locomotion and adhesion.

Methods

We utilized immortalized human podocyte cell line AB8/13 (a kind gift of Prof. Moin Saleem, Bristol, UK) as an experimental platform. Cells were infected with pLenti6/V5-DEST carrying the heparanase gene construct (H) or control empty vector (V) and were allowed to differentiate for 14 days. To induce injury, differentiated podocytes were treated with Adriamycin (0.5 μg/mL), mimicking Adriamycin nephropathy, an established experimental model for progressive proteinuric GDs. For readouts, we used scratch assay, RT-qPCR, Western blot (WB) and immunofluorescence (IF) analyses.

Results

The in vitro scratch assay showed that differentiated (H) podocytes migrated at a slower rate compared with control (V) podocytes, both at baseline and after a 12-hour treatment with Adriamycin. Hence, we hypothesized that heparanase may alter podocyte adhesion properties. Indeed, IF staining of differentiated (H) podocytes exhibited an increase in focal contacts containing vinculin compared with control (V) cells treated with Adriamycin. Of note, we observed no differences in vinculin abundance by WB, suggesting that heparanase mediates the active form of vinculin. Moreover, among the integrins, we noticed temporal upregulation of ITGB1 transcription, as early as two hours after Adriamycin treatment, in (H) compared with control (V) podocytes (P = 0.032).

Conclusions

Collectively, our results suggest that in response to Adriamycin injury, constitutive heparanase overexpression could stabilize podocyte focal adhesions and control motility. Although further research is needed, improving the anchoring of podocytes over the basement membrane may provide an additional cellular mechanism by which heparanase conferred protection against Adriamycin toxicity.
#5666 FATTY ACID BINDING PROTEINS (FABPS) INHIBITION IMPAIRS METABOLIC HOMEOSTASIS IN RENAL TUBULAR CELLS
Authors: García-Giménez Jorge , David Gina Marcela Córdoba , Ortiz Alberto , Cortassa Adrián Mario Ramos
Published: June 2023

Background and Aims

The fatty acid binding proteins family of lipid chaperones (FABPs) mediate lipid trafficking and lipid-mediated metabolic pathways. Despite inhibition of induced FABPs may be beneficial in kidney damage, their enrolment in renal metabolic homeostasis remains elusive. Therefore, we approached this issue in cultured renal tubular cells.

Method

FABP mRNA and protein expression were evaluated in C57/BL6 mice subjected to folic-acid kidney injury. Mitochondrial redox status, proliferation, death rate, and fatty acid oxidation (FAO) were studied in renal tubular cells in conditions of overall FABP inhibition with BMS309403. In these conditions, lipid trafficking was addressed by oil red content and pulse-chase assays using the fluorescent lipid RedC12. Delivery of RedC12 within LD or mitochondria was followed with BODIPY493/503 and Mitotracker and confocal microscopy. Free and esterified RedC12 species were assessed by thin-layer chromatography (TLC). The impact of ATGL lipase activity on cellular behaviour and bioenergetics were assessed by diethylumbelliferyl phosphate (DEUP)-mediated inhibition.

Results

Kidneys from mice with AKI exhibited early lowered FABPs tubular expression. In serum-depleted murine tubular cells, pharmacological FABPs inhibition with BM309403 (BMS) led to sudden necrosis, whereas, in non-depleted cells, BMS eventually leads to apoptosis, increased the mRNA expression of proinflammatory cytokines and oxidative stress-responsive genes, and restrained proliferation. BMS also rapidly decreased ATP levels consistent with FAO inhibition and induced adaptive AMPK phosphorylation/activation and FAO gene program (but not glycolytic gene expression). BMS also mediates mitochondrial depolarization, mitochondrial oxidative stress and decrease of mitochondria number. Serum-depleted cells revealed lipid droplet (LD) voiding and RedC12 delivery to mitochondria. By contrast, in BMS-treated cells growing in serum, despite the lowered ATP content and transcriptional FAO upregulation, RedC12 neither localized with LDs nor with mitochondria, suggesting a low-energy state by impairment of both lipid transit and FAO. Accordingly, TLC assessment did not show lipid breakdown-derived products, which otherwise did appear in serum-depleted cells doing FAO. Mechanistically, ATGL inhibition protects from general ROS production, LD voiding and apoptosis.

Conclusion

In brief, FABP inhibition disrupts tubular energetic status and favours cell stress. Thus, protecting FABP activity could help to preserve tubular metabolic homeostasis during early kidney damage.
#5667 PULMONARY CONGESTION IN HEMODIALYSIS: PREVALENCE, DYNAMICS AND ASSOCIATED FACTORS
Authors: Saleh Kaysi , Pacha Bakhtar , Antoine Marie Hélène , De Prez Eric , Collart Frederic E , Nortier Joelle
Published: June 2023

Background and Aims

Lung ultrasound (LUS) helps detecting pulmonary congestion (PC) among haemodialysis (HD) patients. This study investigated the relation between PC, cardiac function parameters, volume status and ultrafiltration, as well as chronic inflammation in two consecutive HD sessions with different inter-dialytic intervals.

Method

Prospective observational study, where 18 HD patients underwent LUS to calculate the B Lines Score (BLS) using the 8 zone method, inferior vena cava (IVC) dimensions measurement, and echocardiography before and after their regular first (S1) and second (S2) HD sessions of the week. The cut-off for BLS was fixed as 0.54 line per zone. Total body volume using Bio-electrical Impedance Analysis (BIA) was measured before both HD sessions besides serum NT-pro BNP (N-Terminal Pro-Brain Natriuretic Peptide Type B) levels. Moreover, circulating markers of inflammation (soluble urokinase Plasminogen Activator Receptor [suPAR] and soluble Suppression of Tumorigenicity 2 [sST2]) were measured before each session.

Results

Interdialytic interval did not impact BLS, which was high before and after both sessions. There was no significant difference in BLS before and after S1, whereas the difference was significant in S2 (P: 0.03, ES: 0.54). BIA was correlated to PC only before S2 (R² = 0.374, P = 0.007). BLS and the systolic cardiac function represented by the ejection fraction were correlated only after S2. Nt-ProBNP levels and BLS were correlated before both sessions (R²: 0.421, P: 0.004; R² = 0.505, P = 0.001), respectively. Cardiac diastolic function was correlated with BLS before S1 (R² = 0.476, P = 0.002) and after S2 (R² = 0.193, P = 0.034). Mean levels (± SD, ng/ml) of suPAR (7.88 ± 3.07), (7.78 ± 3.02) remained significantly above the normal range (< 4 ng/ml), while sST2 levels reached 2-fold the upper normal value in some patients (27.4 ± 17.8).

Conclusion

PC is common in HD patients even after reaching their dry weight at the end of their two consecutive sessions. It is not only correlated to volume status and cardiac function. Chronic inflammation may be involved in PC pathophysiology. A better management strategy is thus needed to better reduce PC in HD patients.
#5680 FIRST REPORT OF AN EVOLOCUMAB INDUCED NEPHROTIC SYNDROME
Authors: Saleh Kaysi , Badawaki Hanaa , Baz Mahmoud , Farah Ibrahim
Published: June 2023

Background and Aims

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9 inhibitors) reduce LDL-C and short-term risk of cardiovascular events by acting on the proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme produced in the liver. This article highlights the case of a 69 year-old man who developed nephrotic syndrome (NS) secondary to EVOLOCUMAB injection. To our knowledge, this is the first time that minimal change disease is described as associated with EVOLOCUMAB.

Method

Case Report describing a 69-year-old male with coronary artery disease who started EVOLOCUMAB injection every two weeks. Six weeks later, after the third dose of Evolocumab, he developed edema, and high blood pressure 180/90 mmHg. Laboratory tests showed a creatinine of 88 µmol/l and a GFR of 77 ml/min/m² associated with severe proteinuria of 9g/24H, normal level of anti-PLA2R, negative ANA (<1/80) and ANCA (<1/80), and negative hepatitis B and C serology.

Results

Kidney biopsy was obtained to investigate this nephrotic syndrome and showed minimal change disease. There was a mild focal mesangial prominence not exceeding three or four cells per segment by light microscopy (LM). Immunofluorescence was negative. EVOLOCUMAB was stopped and proteinuria dropped from 9g to 6g/25H, and stabilized at that level, so treatment with prednisone 1mg/kg was initiated, reducing proteinuria to 3g/24H one month later with clinical improvement.

Conclusion

The occurrence of reversible glomerular lesions reported here should be considered as a potential adverse effect when administrating a prolonged treatment of Evolocumab. We suggest performing urine test at least once a week, to detect early proteinuria in patients receiving this medication.
#5690 COMBINED USE OF SOLUBLE ST2 AND NT-PROBNP FOR PREDICTING MAJOR ADVERSE CARDIOVASCULAR EVENTS IN TYPE 2 DIABETES AND DIVERSE RENAL FUNCTION
Authors: Olloquiegui Xabier Irazusta , Gutierrez Jose Maria Mora , Castañeda-Infante Laura Juliana , Andueza Saioa Echeverria , Izco Marina Pascual , Ravassa Susanna , Diaz-Dorronsoro Agnes , Fernandez-Seara Maria A , Escalada Francisco Javier , Garcia-Fernandez Nuria
Published: June 2023

Background and Aims

Plasma levels of soluble ST2 protein (sST2), a biomarker associated with fibrosis and inflammation, have been related with an increased risk of adverse events in patients with heart failure (HF) [1,2]; however, data is limited on the prognostic value of sST2 in patients with type 2 diabetes mellitus (T2DM) [3], particularly in association with chronic kidney disease (CKD)4. We aimed to evaluate the impact on cardiovascular (CV) prognosis of sST2 in a population of T2DM with diverse renal function.

Method

A prospective observational study was conducted in patients with T2DM. Demographic, clinical and analytical data were collected. The main objective was to analyze a composite of combined CV events (major adverse cardiovascular events; MACE) including: CV death, acute myocardial infarction, stroke, coronary revascularization, hospitalization for heart failure, atrial fibrillation, significant valvular heart disease, and hospitalization for any other CV cause). The levels of sST2 and NT-proBNP were analyzed in association with the primary endpoint, as well as with each event separately by survival analysis (log-rank test).

Results

Ninety-three patients were included with a mean follow-up of 3.5 (3.4-4.2) years. Median sST2 concentrations were 29.8 ng/mL. Table 1 shows the baseline characteristics of patients according to sST2 levels. Univariate analysis showed that higher sST2 levels independently predicted the occurrence of MACE (HR = 2.92; 95% CI: 1.35-6.33) (Figure 1). These results persisted after adjusting for age, sex, and glomerular filtration rate. In addition, a significant interaction was found between sST2 and NT-proBNP, showing a significant relationship between the combination of both biomarkers and the main event (Figure 1).

Conclusion

Elevated sST2 levels are associated with the occurrence of long-term major cardiovascular events in patients with T2DM, independently of renal function. These findings could allow stratification of patients with T2DM according to their cardiovascular risk in order to develop therapeutic strategies based on precision medicine.
#5729 HIGHER DAILY PROTEIN INTAKE CAN IMPROVE THE GRAFT FUNCTION OF KIDNEY TRANSPLANT RECIPIENTS IN THE EARLY POSTTRANSPLANT PERIOD
Authors: Yang Binqi , Liu Yuan , Tao Ye , Shi Yunying
Published: June 2023

Background and Aims

Protein-energy wasting (PEW) is commonly seen among uremic patients, which may still exist after they received kidney transplantation,[1,2] and it is a determining factor in the progression of chronic kidney disease (CKD).[3] The use of immunosuppressants and glucocorticoids after transplantation will also affect the patients' metabolism and aggravate their malnutrition.[4,5] Adequate daily protein intake (DPI) in the early posttransplant period facilitates the rapid recovery of surgical wounds.[6] However, few studies focused on the impact of DPI on the early recovery of graft function. This study aimed to explore the relationship between DPI and graft function at month 3 posttransplant, which may provide a basis for clinical nutritional regimen of kidney transplant recipients.

Method

This is a retrospective observational study. 176 kidney transplant recipients (KTRs) who underwent kidney transplant in West China Hospital from December 2021 to June 2022 were included and followed up regularly. 24-hour urine urea data were collected at month 3 posttransplant to calculate their DPI. These KTRs were further divided into two groups according to the recommended DPI for KTRs by the 2021 Practice Guidelines for the Nutritional Management of Chronic Kidney Disease,[7] namely high intake group (Group 1, with DPI ≥ 1.4g/kg·d, n = 66) and low intake group (Group 2, with DPI < 1.4g/kg·d, n = 110). Laboratory data and posttransplant adverse events within 3 months were recorded. Multiple logistic regression was used to analyze the relationship between DPI and early posttransplant graft function.

Results

Mean DPI levels at month 3 posttransplant were 1.75±0.56 g/kg·d in Group 1 and 0.98±0.24 g/kg·d in Group 2, respectively. There was no significant difference in age, gender, pretransplant body mass index (BMI), dialysis type and time, donor type, or the ratio of delayed graft function (DGF) between the two groups. The levels of estimated glomerular filtration rate (eGFR), body mass index(BMI), hemoglobin (Hb), high-density lipid-cholesterol (HDL), and urinary protein at month 3 posttransplant in Group 1 were significantly higher than those in Group 2 (P < 0.005, Fig. 1). No statistical difference was found in the incidence of adverse events between the two groups at month 3 posttransplant. The results of multiple logistic regression analysis showed that higher DPI in the early posttransplant period was a protective factor for graft function after kidney transplantation.

Conclusion

In the early posttransplant period, higher dietary protein intake (DPI ≥ 1.4 g/kg·d) may improve graft kidney function, lipid metabolism, and renal anemia.