bluuebunny/crossref_metadata_2025 huggingface dataset:
#207 Early single session of hyperbaric oxygen therapy mitigates renal apoptosis in lipopolysaccharides-induced endotoxemia in rats
Authors: Kim Jin , Lee Hyoung Youn , Kim Injin , Choi Hong Sang , MA Seong Kwon , Kim Soo Wan , Bae Eun Hui
Published: May 2024

Background and Aims

Sepsis-associated acute kidney injury (SA-AKI) is a prominent sepsis complication, often having adverse clinical outcomes. Hyperbaric oxygen therapy (HBOT), known for its anti-inflammatory characteristics, antioxidant effects, and ability to deliver high oxygen tension to hypo-perfused tissues, may offer potential benefits for SA-AKI. This study investigated whether HBOT improved renal injury in sepsis and elucidated its underlying mechanisms.

Method

An lipopolysaccharides (LPS)-induced endotoxemia model was established using eight-week-old C57BL/6 mice. Thirty minutes post-LPS administration, a subset of mice underwent HBOT at a 2.5 atmospheric pressure absolute with 100% oxygen for 60 minutes. After 24 hours, all mice were euthanized for measurements.

Results

Our results demonstrated that HBOT effectively mitigated renal tubular cell apoptosis, as evidenced by decreased apoptosis-associated proteins, including Bax/Bcl-2 and cleaved caspase 3/caspase 3 ratios. HBOT significantly reduced phosphorylated p53 proteins and cytochrome C levels, suggesting that HBOT may attenuate renal apoptosis through decreased p53 activation and cytochrome C release. Notably, HBOT preserved manganese-dependent levels of superoxide dismutase, an antioxidant enzyme, compared to the LPS group. Furthermore, transforming growth factor-β (TGF- β)/Smad4 and alpha-smooth muscle actin expressions were significantly reduced in the LPS+HBOT group.

Conclusion

An early single session of HBOT exhibited renoprotective effects in LPS-induced endotoxemia mice models by mitigating apoptosis by suppressing p53 activation and cytochrome C levels. The observed TGF-β decrease, downstream Smad expression reduction, and antioxidant capacity preservation following HBOT may contribute to these effects.
#2385 Inhibition of histone lysine demethylases 5 attenuates acute kidney injury but not acute kidney disease or chronic kidney disease
Authors: Lee So Young , Koh Eun Sil , Chung Sungjin
Published: May 2024

Background and Aims

The histone lysine demethylases 5 (KDM5) are members of the family of Jumonji C domain-containing histone demethylases and catalyze the removal of di- and tri-methyl moieties from the fourth lysine of histone 3 (H3K4me2/3). It has been reported that the KDM5 family mediates a range of physiological and pathological events including cell differentiation, motility, senescence and epithelial-mesenchymal transition (EMT) via activating or repressing transcription in demethylase-dependent or independent manners in both homeostasis and disease. This study investigated the potential role of KDM5 in the development and progression of renal fibrosis in acute kidney injury (AKI), chronic kidney disease (CKD) or AKI to CKD transition (acute kidney disease, AKD).

Method

We evaluated therapeutic effects of KDM5 inhibition in AKI model of unilateral nephrectomy plus contralateral ischemia-reperfusion (IR) injury, AKI to CKD transition model of unilateral IR injury plus removal of contralateral uninjured kidney after 8 days of IR injury, and CKD model of unilateral ureteral obstruction (UUO) in mice.

Results

KDM5 C70 inhibitor prevented the increase of blood urea nitrogen and positive areas of trichrome, Sirius red, F4/80 and α-smooth muscle actin in injured kidneys 7 days after IR injury. Significant reductions in renal mRNA levels of pro-inflammatory cytokine/chemokine, EMT and pro-fibrotic markers (IL-1β, IL-6, TNF-α, CCL2, CCL3, GM-CSF, MMP9, fibronectin, vimentin, TGF-β1, COL4A1) were also observed with attenuated mRNA levels of KDM5a-c. In addition, renal protein levels of antioxidants such as catalase, SOD1 and SOD2 were increased in injured kidneys of KDM5 inhibitor-treated mice. However, parameters of renal fibrosis and inflammation were similar between mice without and with KDM5 inhibitor in both AKD and CKD models.

Conclusion

These data demonstrate that inhibition of KDM5 could prevent renal inflammation and fibrosis after acute and severe IR injury. The activation of KDM5 might be an early step in the development of renal fibrosis after AKI insult.
#1256 Comparison of clinical characteristics of acute kidney injury between glufosinate and glyphosate poisoning
Authors: Cho A Young , Sun In O
Published: May 2024

Background and Aims

There are few studies comparing the clinical characteristics of acute kidney injury (AKI) between glufosinate and glyphosate poisoning. In this study, we investigated the clinical characteristics of AKI in patients with glufosinate and glyphosate poisoning, and compared the clinical features of AKI between two groups.

Method

This study performed between 2008 and 2021 included 76 patients with glufosinate poisoning and 184 patients with glyphosate poisoning. This study included 76 patients with glufosinate poisoning and 184 patients with glyphosate poisoning in the period from 2008 to 2021. Based on Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease classification, we investigated the incidence, clinical characteristics, and severity of AKI between two groups [(glufosinate-induced AKI (Glu-AKI, n=54) and glyphosate-induced AKI (Gly-AKI, n=82)].

Results

The incidence of AKI in patients with glufosinate poisoning is higher than that of glyphosate poisoning (57.5% vs 44.5%, P<0.05). However, there is no difference of AKI severity between two groups (Glu-AKI; Risk 56.2%, Injury 36.9%, Failure 6.9% vs Gly-AKI; Risk 56.2%, Injury 14.6%, Failure 29.2%, P=NS). Comparing two groups, there is also no difference in age (62.6 ± 14.2 years vs. 63.3 ± 16.2 years, P=NS) and renal function on admission (63.9 ± 25.2 mL/min/1.73 m2 vs. 62.2 ± 22.9 mL/min/1.73 m2, P=NS). The length of hospitalization was longer (17.2 ± 17.2 days vs. 10.7 ± 12.1 days, P<0.05) in Glu-AKI group than that of Gly-AKI group. The mortality rate was higher in the Gly-AKI group than Glu-AKI (11.1% vs. 18.3%, P=NS). Multivariate logistic regression analysis showed that serum bicarbonate concentration on admission was a significant predictors of AKI in patients with AKI after glyphosate and glufosinate intoxication.

Conclusion

Although there is a higher incidence of AKI in glufosinate poisoning, there is no difference in clinical characteristics between the two types of intoxication.
#1304 Clinical characteristics of acute kidney injury caused by Phytolaccaceae ingestion
Authors: Sun In O , Cho A Young
Published: May 2024

Background and Aims

Phytolaccaceae is a poisonous plant that is associated with cardiac and gastrointestinal toxicity. However, there are limited data about acute kidney injury (AKI) in patients with Phytolaccaceae ingestion. We conducted this study to investigate the clinical characteristics of AKI by Phytolaccaceae overdose.

Method

From 2010 to 2022, 15 patients with Phytolaccaceae ingestion were enrolled in this study. The incidence, clinical characteristics, and severity of AKI were compared between AKI (N=8) and non-AKI (N=7) groups according to the RIFLE classification.

Results

Of the 15 patients, 8 patients experienced AKI during hospitalization period. There is no difference in age (54.3 ± 7.2 years vs. 67.1 ± 13.5 years, P=0.057) and comorbidities such as hypertension and diabetes (37.5% vs 28.5%, P=0.563) between two groups. In addition, there is also no difference in total leukocyte count (10.8 × 103/mL vs. 11.4 × 103/mL, P=0.84) and serum albumin level (4.5 ± 2.6 vs 4.3 ± 0.5, P=0.498). Compared to patients without AKI, the estimated glomerular filtration rate was lower in the AKI group (57 ± 12 ml/min/1.73 m2 vs. 77 ± 24 ml/min/1.73 m2, p<0.05) on admission. The AKI group had a significantly longer hospital stay (9.7 ± 6.2 vs 6.1 ± 3.1 days, p<0.001). The overall AKI incidence was 61.5%, of which 46.1% and 15.4% cases were classified as risk and injury, respectively. All patients recovered baseline renal function without renal replacement therapy following antibiotics therapy and supportive care.

Conclusion

The incidence of AKI in patient with Phytolaccaceae ingestion is 61.5%. Most patients with AKI had a mild type of AKI during admission period. In cases of AKI patients with Phytolaccaceae ingestion, aggressive supportive care including hydration is very important.
#916 Outcomes of renal replacement therapy in ICU adult patients with acute kidney injury: a retrospective cohort study
Authors: Mattus Miguel Manuel , Anson Jose Maria
Published: May 2024

Background and Aims

Continuous renal replacement therapy (CRRT) and sustained low-efficiency dialysis (SLED) are usually used for critically ill patients with acute kidney injury when indicated. Most studies done throughout the years showed no statistically significant difference in outcomes between the two modalities. Thus, this study aims to determine the outcomes and associated factors of both CRRT and SLED in patients with AKI. Hence, this will allow us to determine our competency as an institution in using CRRT and SLED to formulate recommendations and protocols in the future.

Method

We conducted a retrospective cohort study of patients who developed acute kidney injury and underwent either SLED or CRRT in the ICU of a tertiary hospital in Makati City, Metro Manila. Patients who are on maintenance hemodialysis, who underwent both sustained low-efficiency dialysis and continuous replacement therapy, and who did not complete or tolerate 1 session of SLED or 24 hours of CRRT were excluded in the study. Key outcomes investigated were all-cause mortality at 30 days and dialysis dependence at 30 days after initiation of treatment.

Results

Eighty-four patients who were initiated with either SLED (N=48) or CRRT (N=36). There was a significant difference in terms of all-cause mortality between modalities 20 (42%) for SLED and 33 (92%) for CRRT, p-value=0.000). Among variables used in the study, higher vasopressor requirement (aOR 2.78, 95% CI: 1.47-5.25, p=0.002) and age (aOR 2.21, 95% CI: 1.13-4.33, p=0.021) at initiation were associated with higher likelihood of mortality across modalities. Thirteen patients (28%) who underwent SLED were dependent on dialysis at 30 days. Baseline serum creatinine (aOR 3.21 95% CI: 1.17-8.79, p=0.023) and serum creatinine at initiation (aOR 4.11, 95% CI: 1.43-22.56, p=0.014) were identified to be associated with dialysis dependence. Sub-analysis of the CRRT group showed continuous veno-venous hemodialysis (CVVHD) (aOR 16.57, 95% CI: 3.54-77.49, p<0.001) was associated with higher likelihood of mortality among CRRT modalities.

Conclusion

Increased mortality was seen in patients who underwent CRRT especially CVVHD and was associated with age and number of vasopressors present during initiation of renal replacement therapy.
#330 Pattern of short-term outcomes of renal function in postpartum acute kidney injury patients: a single-center study in Bangladesh
Authors: Islam Hasanul
Published: May 2024

Background and Aims

Postpartum acute kidney injury (PPAKI) is a formidable health problem in pregnant woman especially in developing country. Monitoring outcomes like serum creatinine levels and glomerular filtration rates is vital. Understanding these short-term results is crucial for timely interventions and better patient care, improving prognosis in this critical condition. The aim of the study was to assess the short-term outcomes of renal function in postpartum acute kidney injury patients.

Method

This prospective observational study was conducted at Mymensingh Medical College Hospital in Bangladesh between March 2020 and April 2021. The study enrolled 153 postpartum acute kidney injury (AKI) patients from the Departments of Nephrology and Departments of Obstetrics & Gynaecology using purposive sampling. Data on patient demographics, etiology, and presentation were collected. Statistical analysis was performed using SPSS version 23.0 and a p- value of <0.05 was considered statistically significant.

Results

After three months, among 153 postpartum acute kidney injury (PPAKI) patients, 77.8% of the patients fully recovered, 5.2% of the patients developed chronic kidney disease. Dialysis was required in 24.2% of the patients, among them 2.2% remained on dialysis. Sadly, 15.7% didn't survive, that highlight the severity of postpartum acute kidney injury. Mortality rates didn't significantly differ between vaginal delivery (14.9%) and cesarean section (16.0%) groups (p=0.488). Both groups show positive outcomes, with 75.5% of vaginal delivery and 79.2% of cesarean section patients achieving full recovery. Blood urea also significantly decreased from 128.51 ± 39.59 to 101.65 ± 55.57 mg/dl during this period

Conclusion

Most postpartum acute kidney injury patients show promising recovery, but some still grapple with persistent renal impairment. Tragically, mortality rates underscore the severity of this condition. Importantly, survival rates don't significantly differ between vaginal delivery and cesarean section patients, emphasizing timely interventions.
#1090 POCUS for diagnosis of congestive kidney due to severe acidemia
Authors: Shibagaki Yugo , Shirai Kana
Published: May 2024

Background and Aims

Point-of-Care Ultrasonography (POCUS) is a novel approach where the treating physician directly performs ultrasonography at the bedside, enabling rapid understanding of the patient's condition, diagnosis, and immediate connection to treatment. Venous Excess Ultrasound (VExUS), one method in POCUS, can swiftly identify structural or functional abnormalities in internal organs, allowing for more accurate assessment of congestion in organs. Here, we report a typical case which illustrates the usefulness of VExUS in correct diagnosis and appropriate management of congestive kidney failure.

Method

A case report.

Results

A 51-year-old woman with mitochondrial myopathy with chronic heart failure was admitted due to loss of appetite and failure to thrive. She presented with acute kidney injury (AKI) and severe acidemia. Given her medical history and physical examination, prerenal causes (hypovolemia/hypotension) of AKI were considered most likely. However, with a significantly elevated NT-proBNP level of 14700, congestive kidney was also considered. Bedside echocardiography showed no evidence of low output syndrome, whereas VExUS (Venous Excess Ultrasound) Score indicated assessed as Grade 2 (moderate congestion). In addition to administering fluids for the suspected prerenal causes (hypovolemia/hypotension), sodium bicarbonate was administered suspecting a negative impact of severe acidemia on cardiac function. With the improvement of acidemia and only a small volume of fluid therapy, there was a rapid improvement in AKI with normalization of VExUS score. This suggested that the main cause of AKI was congestive kidney.

Conclusion

This case demonstrated the significant contribution of VExUS in accurate diagnosis and treatment.
#2026 Hypokalemia associated to neuroendocrine carcinoma of the cervix
Authors: González David Menéndez , Rosado Consolación , Cornejo Gilda Carreño , Felipe Maria Carmen , Manzanedo Rosario , Jiménez Miguel Ángel Navas , Garcia Jesus Martin
Published: May 2024

Background and Aims

Hypokalemia is one of the most common electrolyte disorders seen in clinical practice. Hypokalemia can be caused by decreased intake of potassium, redistribution of potassium (K+) in cells or by excessive gastrointestinal losses or renal losses. In this setting, hypokalemia may also be caused by the paraneoplastic production of ectopic adrenocorticotropic hormone (ACTH) by some tumors.

Cancer of the uterine cervix is the fourth common cancer affecting women worldwide and the fourth most common gynecologic cancer in Spain. Neuroendocrine carcinoma of the cervix represents about 2% of all cervical neoplasms.

Method

We report the case of a 44-year-old Peruvian woman with hypokalemia who was diagnosed with Cushing syndrome secondary to paraneoplastic production of ACTH by neuroendocrine carcinoma of cervix.

Results

Patient was overweight and affected by uterine myoma and anemia without further investigations. She was admitted to our hospital due to lower back pain, leg swelling and constipation. Blood pressure was normal, chest radiography did not show abnormal findings and ECG showed the U wave. Laboratory tests at admission revealed hypokalemia (2.3 mmol/L), metabolic alkalosis, anemia (hemoglobin 9.5 g/dL), hyperkaliuria (K+ urine/Creatinine urine 70 mmol/g) with an elevated transtubular potassium gradient (TTKG=12) and normal renal function. Laboratory data are presented in Table 1.

She developed hypertension in the first day of hospitalization. Renin, aldosterone and cortisol tests was performed. Hypercortisolism was observed and confirmed with 24-hour urinary cortisol excretion. Because of an elevated ACTH (263 pg/mL), pituitary magnetic resonance imaging was performed without lesions.

Whole-body computed tomography revealed a cervical mass. PET scan showed pelvic, adrenal, hepatic and local lymphadenopathy activity (see Fig. 1).

After the histopathological study, diagnostic of small cell neuroendocrine carcinoma of the cervix was made. Chemotherapy therapy was initiated with cisplatin/etoposide regimen. The patient decide to return to Peru because of the poor prognosis of her illness. At discharge, potassium level was 3 mmol/L despite the treatment with spironolactone, ramipril, losartan and oral potassium chloride (160 mmol).

Conclusion

Hypokalemia is a common clinical disorder. In some patients it may be caused by an increased mineralocorticoid activity due to ectopic ACTH-secreting tumors. Applying diagnostic algorithms to electrolyte disorders, beyond their simple treatment, can unmask secondary causes and serious diseases.
#2462 Impact of tacrolimus peak concentration on kidney graft outcomes
Authors: Monchal Quentin , Mariat Christophe , Maillard Nicolas , Claisse Guillaume
Published: May 2024

Background and Aims

Low tacrolimus (Tac) trough concentration-to-dose ratio (C0/D ratio) identifies kidney transplant patients with high level of Tac metabolization and has been shown to be associated with lower graft function and survival. Why fast metabolizers experience poorer outcomes is however unclear. We hypothesized that fast metabolization is associated with higher maximal Tac blood concentration (Cmax) and that Tac Cmax has a detrimental effect by itself.

Method

We retrospectively selected consecutive kidney transplant patients who (I) were treated by Tac (irrespective of the pharmaceutical formulation), (ii) had systematic abbreviated pharmacokinetic tac evaluation at 3- and 12-months’ post-transplant, and (iii) had a minimal follow-up of 5 years. Fast metabolizers were defined by a C0/D ratio <1.05. Cmax was defined by the higher value of Tac concentration observed at 30, 90 or 180 minutes after Tac morning ingestion and was indexed to C0 in order to exclusively focus on patients with no obvious Tac overexposure. Association between Tac Cmax/C0 with traditional transplant outcomes was analysed by univariate and multivariate cox model and logrank test when appropriate.

Results

436 patients transplanted from 2008 to 2016 (64% of male, mean age of 55 ± 13 y) with a median follow-up of 8 years (Q1: 6; Q3: 11) were analysed. Fast metabolizers had lower C0 while receiving higher dose of Tac and displayed significantly higher median Cmax (20 vs 17 μg/l, p < 0.001). Median Cmax/C0 was 3 and 2 in fast and non-fast metabolizers, respectively (p < 0.001). At 15 years’ post-transplant, death-censored graft survival was 13% lower for patients with the highest Cmax/C0 values (p = 0.04). In multivariate cox analysis, higher Cmax/C0 was independently associated with death-censored graft survival (HR = 1.30 (1.03;1.64), p = 0.026).

Conclusion

Our data support the hypotheses 1—that fast metabolizers exhibit higher Tac Cmax even in situations where Tac C0 are not elevated and 2—that exposure to high Cmax is a potential mechanism underlying their poorer outcome. Tac formulations prone to mitigate pharmacokinetic peak could thus be particularly beneficial to fast metabolizers and should be thoroughly evaluated in this indication.
#370 Macroscopic hematuria-associated severe acute kidney injury from thin basement membrane disease
Authors: Kaneko Shuzo , Murata Ririko , Hoshimoto Ainori , Hisada Rina , Harano Makiko , Anno Emi , Hagiwara So , Imai Eri , Nagata Michio , Tsukamoto Yusuke
Published: May 2024

Background

Macroscopic hematuria-associated acute kidney injury (MH-AKI) is a rare condition reported in IgA nephropathy and others, and the mechanism of renal tubular damage caused by red blood cells in the tubules appears to be similar to that of anticoagulant nephropathy.

Case presentation

A 66-year-old Japanese woman with no previous medical history was referred to our hospital with anuric severe kidney injury. Seven days earlier, she had transient acute lumbar back pain, which was followed by gradual worsening of malaise and loss of appetite. On admission, her serum BUN was 147.8 mg/dL, serum Cr 18.57 mg/dL, hemoglobin 11.2 g/dL, urinary red blood cells> 100/HPF, urinary protein 28.8 g/gCr, no hydronephrosis in either kidney, but a small stone in the right kidney. After admission, while starting hemodialysis, she was treated with methylprednisone 1000 mg for 3 days followed by prednisone 40 mg/day because of suspected rapidly progressive glomerulonephritis, but both MPO-/PR3-ANCA and anti-GBM antibodies were negative. Renal biopsy from left kidney showed acute tubular injury with large amounts of red blood cells and red blood cell casts filling the distal tubules (Figure), and prednisone was discontinued. Subsequently, urine flowed out with gross hematuria, and her hematuria and renal function improved with increased urine output, and she was weaned from hemodialysis. Electron microscopy showed glomerular thin basement membrane (TBMD) (Figure). Her renal function and hematuria slowly improved and the right kidney stone disappeared. Microscopic hematuria eventually disappeared, and her serum Cr level was 1.1 mg/dL one year after onset.

Conclusions

This is the first report of MH-AKI in TBMD without a background of anticoagulation, severe thrombocytopaenia, or iron overload. In one report, compared to IgA nephropathy, TBMD is associated with increased urinary Ca and uric acid excretion, which is associated with gross hematuria and back pain [1]. In this case of MH-AKI from TBMD, both red blood cells and crystal formation in the tubular lumens may have transiently and synergistically caused renal tubular obstruction and heme iron-induced tubular damage.
#569 Proenkephalin A 119-159 (penKid) for the early identification and risk stratification of delayed graft function following kidney transplantation
Authors: Benning Louise , Reineke Marvin , Kälble Florian , Speer Claudius , Göth Daniel , Hartmann Oliver , Mieth Markus , Zeier Martin , Mehrabi Arianeb , Weigand Markus A , Morath Christian , Nusshag Christian
Published: May 2024

Background and Aims

Delayed graft function (DGF) frequently occurs following kidney transplantation, and prolonged duration of DGF adversely affects 1-year graft function and long-term graft survival. Recently, Proenkephalin A 119-159 (penKid) was shown to reflect kidney function and predict acute kidney injury (AKI) in critically ill patients. Given the similarities between DGF in transplanted and AKI in native kidneys, we hypothesized that penKid may aid in identifying and risk-stratifying DGF post-transplantation.

Method

In a prospective study of 159 consecutive kidney transplant recipients at Heidelberg University Hospital from November 2021 to July 2023, penKid was quantified using an immunoluminometric assay until patient discharge. DGF was primarily defined as the necessity for dialysis within 7 days post-transplant. Additionally, penKid was examined in the context of DGF severity, discriminating the different durations of post-transplant dialysis treatment. Similarly, penKid was assessed to differentiate uptake of graft function, defined as slow or immediate by a serum creatinine reduction ratio of pre-transplant and 7 days post-transplant levels of <0.7 and ≥0.7, respectively.

Results

DGF, defined as the need for dialysis within the first week post-transplant, occurred in 53/159 (33.3%) patients. penKid enabled the differentiation of patients with and without DGF from the first day post-transplant onward (P < 0.001, Fig. 1), and consistently outperformed SCr in discriminating DGF from no DGF at all time points studied (P < 0.001). Additionally, penKid allowed identification of DGF severity from the first day post-transplant (P < 0.001) and early differentiation between slow and delayed graft function (AUC 0.79 [95% CI 0.68-0.90]). In a multivariate model, delta penKid from pre-transplant to the first day post-transplant emerged as the strongest predictor for DGF (C index = 0.88). On the first day post-transplant, penKid, with a cut-off at 300 pmol/L, discriminated DGF from no DGF with a sensitivity of 95.1% (95% CI 83.9–98.7) and a specificity of 56.5% (95% CI 46.3–66.2).

Conclusion

penKid is a promising biomarker shown to accurately differentiate DGF from no DGF as early as the first day post-transplant and to predict DGF severity, allowing for earlier intervention in these at-risk patients. Due to its high discriminatory power to identify and predict DGF post-transplantation, penKid shows great potential to accompany future studies examining the occurrence of DGF in transplant programs, where DCD is introduced into practice, machine perfusion techniques are assessed, or in trials that assess potential therapeutic interventions in patients with DGF.
#2205 Varying practice patterns in prevention, screening and treatment of diabetes early after kidney transplantation: a European survey
Authors: Laghrib Yassine , Hilbrands Luuk , Oniscu Gabriel , Crespo Marta , Gandolfini Ilaria , Mariat Christophe , Mjøen Geir , Watschinger Bruno , Velioglu Arzu , Dedinská Ivana , Pippias Maria , Hellemans Rachel
Published: May 2024

Background and Aims

Although post-transplant diabetes mellitus (PTDM) is a common complication after kidney transplantation, there is no consensus on preventive measures, nor on the optimal screening and treatment strategy.

Method

The European Renal Association—DESCARTES working group—distributed a web-based survey to transplant centers across Europe to gather information on the risk assessment, screening procedures and management practices for the prevention and treatment of PTDM in kidney-transplant recipients.

Results

Answers were obtained from 121 transplant centers across 15 European countries. Screening practices for pre-existing diabetes during the transplant work-up varied considerably, with only 13% of centers using the recommended oral glucose tolerance test (OGTT), while 14% did not screen at all. At transplantation, 19% (n = 23) of centers tailored the immunosuppressive regimen based on perceived PTDM risk, employing strategies like cyclosporin use (12/23), or early steroid withdrawal (2/23). Fifty-two percent adopted strict glycemic control with long-acting insulin in the first days post-transplant. Sixty-eight percent had defined screening protocols for early PTDM (45 days—six months), mostly based on fasting glycemia and/or HbA1c, while only 8/82 incorporated an OGTT. Changes in immunosuppression were considered by 41% in cases of early hyperglycemia (<45 days) and by 58% in established PTDM (>45 days). Besides insulin therapy, dipeptidyl peptidase-4 (DPP4) inhibitors and metformin were most frequently used to manage early hyperglycemia (<45 days) and PTDM (>45 days).

Conclusion

This European survey underscores significant variation in PTDM prevention, screening, and treatment practices, emphasizing the imperative for clearer guidance in approaching this complication.
#1463 Assessment of salt-sensitive hypertension in a novel Lanosterol Synthase knock-in mouse model
Authors: Lanzani Chiara Livia , Faienza Sipontina , Boustani Maguie E l , Migliaro Vincenzina , Citterio Lorena , Messaggio Elisabetta , Zagato Laura , Canciani Barbara , Simonini Marco , Manunta Paolo
Published: May 2024

Background and Aims

The diversity in blood pressure (BP) response to various salt intakes, known as Salt Sensitivity (SS), exhibits significant differences among individuals within the hypertensive subjects relative to the general population. Hypertension (HT) and SS are correlated to elevated levels of plasma Endogenous Ouabain (EO).

We aimed at delineating the role of the missense variation rs2254524 (Val642Leu; C>A) within the Lanosterol Synthase gene (LSS), encoding for an enzyme involved in steroid biosynthesis. Individuals with the AA LSS variant, adherent to a low-salt diet, had a more significant BP reduction compared to those with CC genotype.

Method

Utilising CRISPR-Cas9, we established a knock-in mouse model carrying the analogous LssV643L/V643L. Male mice were subjected to a normal-salt diet (0.5% NaCl), high-salt diet (4% NaCl), or low-salt diet (<0.03% Na) and BP was monitored every two days using a tail-cuff system for 10 days. Blood and urine were collected separately in metabolic cages.

Results

Homozygous mice for Lss mutation demonstrated normal viability and healthy phenotype, undistinguishable from the WT. At baseline, the Lss AA mice were affected by a significant augmentation in kidney weight at 3 and 12 months of age, relative to WT. The Lss V643L does not influence EO levels or systolic BP (SBP), specifically at 3 and 12 months, but affects the SBP response to dietary salt. AA mice showed a high SBP in a high-salt diet against control diet at the same time intervals. Moreover, the Lss variant impacted the pressure-natriuresis relationship, with the mutated AA strain showing a less steep curve both in control diet versus the high-salt diet and in control diet versus the low-salt diet, displaying the SS phenotype of the AA mice. The 12-month-old mice in high-salt diet displayed cardiac hypertrophy with the AA genotype exhibiting an elevated prevalence of cardiac fibrosis. The level of Lss mRNA decreased in the adrenal glands in response to a high-salt diet. RNASeq analysis identified distinct patterns in several Slc genes, Cbr2 and Arhgap26 within the kidneys of these mice, in control or high-salt dietary conditions.

Conclusion

The established LssV643L/V643L mouse model effectively mirrors the SS-HT phenotype. Our findings highlight the significance of the Lss in modulating BP in response to salt stimuli suggesting a potential organ damage pathway requiring further exploration in older mice.
#1548 The involvement of soluble fms-like tyrosine kinase-1 in the transition from acute kidney injury to chronic kidney disease
Authors: Hikari Tasaki , Tsushima Hideo , Eriguchi Masahiro , Uemura Takayuki , Tamaki Hiroyuki , Nishimoto Masatoshi , Kosugi Takaaki , Samejima Ken-Ichi , Tsuruya Kazuhiko
Published: May 2024

Background and Aims

Fms-like tyrosine kinase-1 (Flt-1) is a receptor for vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) and, playing a crucial role in angiogenesis and inflammation pathways. Soluble Flt-1 (sFlt-1) acts as a decoy for both VEGF and PlGF, regulating Flt-1-mediated angiogenesis and inflammation. We investigated the involvement of sFlt-1 in the transition from acute kidney injury to chronic kidney disease (CKD).

Method

Wild-type (WT) and sFlt-1 knock-out (KO) mice underwent ischemia-reperfusion injury (IRI) treatment. A unilateral 23-minute IRI and contralateral nephrectomy were performed to examine kidney function (AKI to CKD) for 2 weeks. To explore the downstream signaling pathway for sFlt-1 in the kidney, a unilateral 28-minute IRI was performed, and angiogenesis and cytokine expression arrays (Proteome Profiler Array Kits) were used to compare the relative expressions between 28-minute IRI and the contralateral untreated kidney cortices in both WT and sFlt-1 KO mice.

Results

A plasma sFlt-1 concentration was elevated just after IRI and reached its peak after 12 hours. Blood urea nitrogen (BUN) and plasma creatinine (pCre) levels peaked at 24 hours after IRI. The peak levels of BUN and pCre were significantly lower in sFlt-1 KO compared to those in WT mice (BUN 43.23 ± 5.9 mg/dL and 82.7 ± 13.0 mg/dL, p = 0.008, pCre 0.18 ± 0.03 mg/dL and 0.31 ± 0.04 mg/dL, p = 0.008 in KO and WT mice, respectively). Urinary KIM-1 (uKIM-1) levels 12 hours after IRI in WT mice were higher than those in sFlt-1 KO mice (WT vs sFlt-1 KO; uKIM-1 4.82 ± 0.83 pg/day vs 2.39 ± 0.98 pg/day, p = 0.09). Histopathological evaluation of the kidneys showed reduced monocyte infiltration in sFlt-1 KO mice compared to WT mice 14 days after IRI. In cytokine expression assay of kidney cortices 3 days after IRI, IRI-induced increased expressions of tissue repairs and immune response proteins such as TIMP-1, C5/C5a, and TREM-1 were alleviated in sFlt-1 KO mice compared to those in WT mice. In the Angiogenesis expression array of kidney cortices 1 day after IRI, there were no significant differences in the levels of IRI-induced increased expression of anti-/pro-angiogenesis factors, including TIMP-1, Cyr61, SerpinE1, angiogenin, platelet factor 4, collagen factor 3, MMP-9, and SDF-1, between WT and sFlt-1 KO mice.

Conclusion

The acute and chronic kidney damages after IRI was reduced in sFlt-1 KO mice compared to WT mice. The protective effect on the kidneys by eliminating sFlt-1 would be associated with immune response signaling such as TIMP-1, C5/C5a, and TREM-1 but not with anti-/pro-angiogenesis factors.
#1457 Human renal proximal tubule-on-a-chip model to study prevention of ischemia and reperfusion injury
Authors: Tool Laura , Vormann Marianne , Ohbuchi Masato , Gijzen Linda , Van Vught Remko , Hankemeier Thomas , Kiyonaga Fumiko , Kawabe Tetsuhiro , Goto Takayuki , Fujimori Akira , Lanz Henriëtte , Tetsuka Kazuhiro
Published: May 2024

Background and Aims

Renal ischemia/reperfusion injury (rIRI) is characterized by restriction of blood supply followed by restoration of blood flow and re-oxygenation and is a leading cause of acute kidney injury (AKI). While animal models are useful for studying systemic manifestations of AKI, their translational relevance is limited. Human in vitro models provide valuable mechanistic insights into rIRI, but often fail to incorporate crucial aspects such as reperfusion injury. To address these limitations, this study aims to develop an advanced in vitro model to study rIRI comprising a perfused three-dimensional (3D) human renal proximal tubule-on-a-chip.

Method

Our proximal tubule-on-a-chip model comprises a renal proximal tubule alongside a endothelial vessel, separated by extracellular matrix. A microfluidic platform, the OrganoPlate 3-Lane 40, was used to establish the model. The resulting coculture was characterized in terms of its three-dimensional structure, protein expression, and response to nephrotoxins. Subsequently, we simulated rIRI by manipulating oxygen levels, nutrient availability, and perfusion flow settings. The potential protective effect of adenosine was evaluated in the coculture model during ischemia and reperfusion. The extent of injury was assessed through morphological evaluation, caspase 3/7 activation, and cell viability measurements.

Results

The combination of low oxygen, reduced glucose, and interrupted flow exerted a potent disruptive effect on the proximal tubules, which was strongly amplified upon reperfusion. Endothelial vessels were less sensitive to the ischemia–reperfusion parameters. Adenosine treatment showed a protective effect on the disruption of the epithelium and on the caspase-3/7 activation.

Conclusion

We successfully developed a human in vitro model to study rIRI utilizing a coculture of a proximal tubule and a blood vessel on-a-chip. This model allowed us to characterize the renoprotective effect of adenosine. The robustness of the model and assays, coupled with the platform's high throughput capabilities, position it as a promising tool for advancing pathophysiological research and facilitating the development of innovative therapeutic modalities aimed at treating rIRI and improving AKI outcomes.
#2529 The role of the circadian clock system in the transition from acute kidney injury to chronic kidney disease
Authors: Park Sang Hoon , Jo Sang Kyung , Kim Myung Gyu
Published: May 2024

Background and Aims

Recent studies suggest that circadian rhythms are an important factor in maintaining healthy kidney functions; however, its role in acute kidney injury (AKI) remains unclear.

Method

To investigate the role of tubule-specific clock gene disturbance in hypoxic tubular injury, we created human proximal tubule-specific BMAL1 KO cells using CRISPR-Cas9 gene editing. In mice, we also determined whether time-restricted feeding (TRF), a dietary strategy to enhance circadian rhythm, can have beneficial effect on recovery of ischemia reperfusion injury (IRI) or its progression to chronic kidney disease (CKD).

Results

BMAL1 loss in tubule cells resulted in the upregulation of cell cycle regulatory gene (p21) and inflammatory genes (TNF-α and CCL4) mRNA expression, suggesting that BMAL1 is a critical regulator of these genes. Exposure to hypoxia for 48 h resulted in more increased expressions of p21 in BMAL 1 KO cells than in WT HK-2 cells, leading to higher expression of TGF-b. In addition, loss of BMAl-1 led to significantly increased vimentin and decreased E-cadherin expression upon TGF-b stimulation, suggesting an aggravated epithelial-mesenchymal transition upon BMAL1 deletion. To clarify the role of clock system in AKI, we also tested whether TRF can have a beneficial effect during recovery phase after IRI. Despite limited access to food, TRF for 4 weeks after IRI had no effect on the total intake or weight of mice. However, we observed that TRF significantly improved renal function on day 21 and reduced renal fibrosis on day 28, which suggests that enhancing clock gene oscillations through restoring fasting/feeding cycle has a protective effect in the AKI to CKD transition.

Conclusion

We identified an important role of clock system in hypoxic tubular injury and the effects of treatment targeting circadian rhythm in AKI. Our results can provide a new perspective for developing novel therapeutic strategies for AKI.
#435 Endothelial activation and inflammation in chronic kidney disease (CKD): role of neutrophil extracellular traps (NETs)
Authors: Junho Carolina Victoria Cruz , Vondenhoff Sonja , Martin Philipp , Noels Heidi
Published: May 2024

Background and Aims

Advanced chronic kidney disease (CKD), especially in stages 4-5, amplifies cardiovascular disease (CVD) risk by around 50%. This heightened susceptibility is linked to a 1.5 to 3-fold increase in venous thromboembolism incidence, driven by coagulation dysregulation and heightened inflammation. During inflammation, neutrophils can release extracellular traps (NETs), that was described contribute to endothelial damage, through adhesion molecule elevation, and tissue factor (TF) secretion, exacerbating thrombosis. Additionally, NETs interact with von Willebrand Factor (vWF) and factor XII, further amplifying thrombus formation and the activation of the intrinsic coagulation pathway. The aim of this study was to observe whether NETs may contribute to increased CVD risk in CKD patients by inducing endothelial activation and thromboinflammatory responses to a larger extent compared to NETs from healthy donors.

Method

For that, neutrophils were isolated from healthy donors’ and CKD patients’ (stages 3-5 HD) peripheral blood, and NETs were collected by stimulating neutrophils with PMA for 3.5 hours. Human aortic endothelial cells (HAoECs) were subsequently exposed to NETs for 3 to 24 hours, followed by gene expression analysis with a focus on inflammation, endothelial activation, and prothrombotic markers. Additionally, protein analysis of the supernatant was conducted using ELISA. All experiments were performed under ethical protocol EK 225-21 from the University Hospital of Aachen.

Results

Exposure to both healthy NETs as well as the ones isolated from CKD patients resulted in a notable upregulation of endothelial activation (VCAM-1), prothrombotic (TF), and inflammatory (IL-6) gene expression within 3 hours, without difference between healthy and CKD conditions. On the other hand, when examining the cellular supernatant, a significantly higher increase in vWF secretion was observed upon treatment with CKD-NETs compared to healthy NETs. Furthermore, while secretion of the inflammatory cytokine IL-6 presented a comparable increase upon treatment with NETs derived from healthy and CKD neutrophils, IL-1β secretion was markedly enhanced after CKD-NET treatment in comparison to healthy NETs.

Conclusion

In summary, our findings suggest that NETs exert a significant influence on endothelial cells, contributing to increased thromboinflammatory activation. Notably, CKD-NETs evoked a more rapid impact on the endothelium, accompanied by increased secretion of IL-1β and vWF, and underlying mechanisms will be further investigated.
#1326 Impairment of ACSS2 aggravates renal fibrosis and cell senescence during aging
Authors: Fu Ping , Xiang Ting , LI Lingzhi , LI Jinxi , MA Liang
Published: May 2024

Background and Aims

Age-related changes in kidney function, structure, and their relationships have been extensively recognized recently. Here, we report that acyl-CoA synthetase short chain family member 2 (Acss2) as a regulator of lipid metabolism, play an important role in age-associated renal fibrosis.

Method

21-month-old Acss2 knockout (Acss2−/−) mice were used as the renal aging models, and H2O2 also was used to induced renal tubular epithelial cells (TCMK-1) senescence. Serum creatinine (Cr) and urinary protein creatinine ratio (UACR) were measured to evaluate kidney function, and renal tissue lesions were observed by HE staining and Masson staining. The expression of gene/protein in relation to inflammation, fibrosis and cell senescence were measured by qPCR, western blot. SA-β-gal staining also used to assess cell senescence.

Results

The results indicate that Acss2 was decreased in aging mice, Acss2 knockout impaired renal function as detected by increased UACR. Additionally, HE and Masson staining showed that Acss2 deficiency was associated with more glomerular sclerosis and fibrosis (Fig. 1). RT-qPCR and Western blotting also revealed that Acss2 enhanced kidney fibrosis and cell senescence, accompanied by an increase in SA-β-gal-positive senescent cells (Fig. 2). These phenomena were most apparent in the TCMK cells treated with Acss2 siRNA and H2O2 (Fig. 3). What's more, KEGG analysis showed that fatty acid metabolism changes significantly during aging in kidney, and Acss2 knockout could impact the expression of lipid metabolism genes (Fig. 4)

Conclusion

Acss2 is associated with renal aging, and it may played a role in renal fibrosis and cell senescence by regulating fatty acid metabolism.
#2000 Analysis between site-specific N-glycosylation of monoclonal immunoglobulin and complement system activation
Authors: Lu Wanhong , LI Huixian , Xie Xinfang
Published: May 2024

Background and Aims

Monoclonal immunoglobulin produced by clonal plasma cells is the main cause in multiple myeloma (MM) and monoclonal gammopathy of renal significance (MGRS). Hypocomplementemia and deposition of complement components in the kidney is observed in some patients with MM or MGRS. Previous studies have suggested that glycosylation of the immunoglobulin was associated with complement-mediated-effector activities. Whereas, site-specific N-glycosylation characterization for monoclonal immunoglobulin in MM or MGRS and its effects on complement system activation still remains unclear.

Method

We separated plasma monoclonal IgG1 and IgA immunoglobulin from patients with MM and human plasma immunoglobulin from healthy controls (HC). Purified IgG and IgA molecules were digested by trypsin. Tryptic peptides without enrichment of intact N-glycopeptides were analyzed using a combination of electron-transfer/higher-energy collisional dissociation (EThcD) and stepped collision energy/higher-energy collisional dissociation (sceHCD) mass spectrometry (EThcD-sceHCD-MS/MS). N-glycosylation characterization was compared between monoclonal immunoglobulin from MM patients and healthy controls and its association with complement level was evaluated.

Results

A total of 46 IgG1 digestion samples (HC, n = 16; MM, n = 30) and 38 IgA1 digestion samples (HC, n = 16; MM, n = 22) were analyzed using the EThcDsceHCD-MS/MS. On average, 34 and 37 unique N-glycopeptides of IgG1, 19 unique N-glycans per IgG were identified from HC and MM. The relative abundance of fucosylated N-glycans of IgG1 in MM was significantly higher than HC (94.7% vs 88.8%, p = 0.002). Other types of N-glycans including sialylated, hybrid and complex were similar between the two groups. The types of N-glycans including fucosylated, sialylated, hybrid and complex were similar between patients with hypocomplementemia and normal complement levels. Regarding IgA1, on average, 63 and 52 unique N-glycopeptides of IgA1, 40 and 35 unique N-glycans per IgA were identified from HC and MM. The relative abundance of fucosylated (41.0% vs 26.4%, p < 0.001), sialylated (61.0% vs 45.6%, p = 0.003), mannose (2.44% vs 0.28%, p < 0.001) N-glycans of IgA1 in MM was significantly higher than HC. In MM, the relative abundance of mannose N-glycans of IgA1 in patients with hypocomplementemia was significantly lower than patients with normal complement levels (1.69% vs 7.52%, p < 0.001). The relative abundance of fucosylated and sialylated N-glycans were similar between patients with hypocomplementemia and normal complement levels.

Conclusion

Site-specific N-glycosylation characterization of monoclonal IgG1 and IgA1 in MM patients were differentially expressed from healthy controls. Certain specific N-glycan types were associated with complement levels. These findings laid a foundation for future investigations of their biological effects.
#2037 Mitochondrial fumarate promotes ischemia/reperfusion-induced tubular injury
Authors: Liu Bicheng , LI Zuolin
Published: May 2024

Background and Aims

Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood.

Method

ESI-QTRAP-MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry.

Results

We demonstrated that tubule injury occurs at the phase of reperfusion in murine models of I/RI. Meanwhile, the enhanced glycolysis and mitochondrial dysfunction are found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promotes tubular injury. Mechanistically, fumarate induces tubular injury through causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition-mediated tubule injury recovery. Reactive oxygen species/NF-κB signaling activation plays a vital role in fumarate-mediated tubule injury.

Conclusion

Our studies demonstrated that the mitochondrial-derived fumarate promotes tubular epithelial cells injury in renal I/RI. This finding represents a previously unrecognized mechanism for hypoxia-induced TECs injury. Blockade of fumarate-mediated ROS/NF-κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury.