bluuebunny/crossref_metadata_2025 huggingface dataset:
#657 Obinutuzumab is effective for the treatment of frequently-relapsing/steroid-dependent minimal change disease in adults
Authors: Jin L I , Lu Wanhong , LI Xueying
Published: May 2024

Background and Aims

Higher relapse rates and steroid dependency are challenges in the treatment of minimal change disease (MCD). The aim of this study was to evaluate the efficacy and safety of obinutuzumab, a humanised type II anti-CD20 monoclonal antibody, in adults with frequently relapsing (FR) or steroid-dependent (SD) minimal change disease (MCD).

Method

Patients with FR/SD MCD receiving obinutuzumab at our center between September 2022 and February 2023 were enrolled. Complete remission was defined as the reduction of proteinuria to 0.3g/d. The time to remission, the relapse rate, and adverse events were evaluated.

Results

Six patients with FR/SD MCD were included in the present study. The median age of the patients was 30.44 years (range 18.80-72.09 years) and 3 of them were male. Prior to treatment with obinutuzumab, five patients remained in nephrotic syndrome and one patient was in partial remission after previous treatment. One or two doses of 1g obinutuzumab were given. All six patients achieved a complete remission. Five patients with nephrotic syndrome achieved complete recovery within a range of 14 to 57 days. The patient, who initially achieved partial remission, reached complete remission within 27 days after receiving the first obinutuzumab dose. The average follow-up duration was 12.53 ± 1.97 months, during which there was no observed relapse. Furthermore, None of the patients experienced infusion-related adverse effects, serious infectious complications or neutropenia following treatment with obinutuzumab.

Conclusion

Obinutuzumab is an effective and safe treatment option for adult patients with FR/SD minimal change disease. Further randomized trials are needed to confirm these findings.
#1170 Efficacy and safety of telitacicept in IgA nephropathy: a real-world study
Authors: Dong Lingqiu , Qin Wei
Published: May 2024

Background and Aims

IgA nephropathy (IgAN) is the most common primary glomerular disease in the world, and the specific therapeutic methods are limited in IgAN. Telitacicept is a humanized fusion protein composed of a transmembrane activator and calcium-modulating cyclophilin ligand interactor receptor and human IgG. This study was designed to evaluate the efficacy and safety of telitacicept in adult patients with IgAN in a real-world study.

Method

Biopsy-proven IgAN patients with 24-hour proteinuria greater than 0.5 g/day who received telitacicept 240 mg once a week were recruited in this study and 1:1 matched with patients who received supportive treatment only or immunosuppressive treatment by propensity score matching. The primary outcome was the change from baseline in 24-hour proteinuria over the 3-month follow-up.

Results

Twenty-one patients in each group were enrolled. The mean eGFR was 80.1 ml/min/1.73 m2, and the median 24-hour urine protein level was 1.48 g/day. At the end of the 3-month follow-up period, telitacicept reduced median proteinuria by 0.72 g/d (54.6%) from baseline, compared with a reduction of 0.18 g/d (20%) in the supportive treatment group (P < 0.001), and 1.12 g/d (72.1%) in the immunosuppressive treatment group (P = 0.814). Preserved eGFR levels were observed in the telitacicept group (1.9 ml/min/1.73 m2 [4.3%]), while the eGFR level declined in the supportive treatment group (- 2.9 ml/min/1.73 m2 [- 5.8%]) and immunosuppression group (- 6.1 ml/min/1.73 m2 [- 8.4%]). No serious adverse events were observed in the telitacicept treatment group. Injection site reactions were more prevalent in the telitacicept group (8/21 [38.1%]), meanwhile immunosuppression group had more respiratory tract infections (7/21, [33.3%]).

Conclusion

Telitacicept can reduce proteinuria in patients with IgAN and showed a favourable safety profile in patients with IgAN.
#2840 Early tolerance of SGLT2i therapy in patients with ATTR V30M amyloidosis: staging the disease to establish standard of care
Authors: de Bessa e Silva João Pedro Peixoto , Campos Andreia , Pereira Sandra , Santos Josefina , Lobato Luísa
Published: May 2024

Background and Aims

Studies of sodium-glucose co-transporter 2 inhibitors (SGLT2i) therapy on ATTR cardiomyopathy are scarce and focus wild-type and V122I. In ATTRv, namely V30M, SGLT2i introduction to preserve kidney function or improve cardiorenal syndrome is not an outlined practice. Our aim was to assess the clinical evolution and difficulties with SGLT2i therapy in ATTR V30M amyloidosis, a population with neurogenic bladder, dysautonomia and prone to dehydration.

Methods

Patients with ATTR V30M amyloidosis and criteria for SGLT2i started standard dosages. Gillmore score (GS) for ATTR cardiomyopathy, kidney failure risk equation (KFRE) and the renal system score (RSS) of the FASTEX model (Fabry disease) were calculated. Estimation of heart amyloid load was based on Tc-99-DPD scintigraphy.

Results

Eight patients were followed on median of 7 months [IQR 5.6-9.4]; 7 treated with dapagliflozin, 1 with empagliflozin. 6 had type-2 diabetes. 4 were treated with tafamidis, 1 inotersen and 1 patisiran. 3/7 had positive DPD scintigraphy. Heart failure decompensation, new arrhythmias and renal adverse events were absent. Neurogenic bladder was present in 4 patients, 2 had urinary tract infections. 1 had symptomatic hypotension, leading to discontinuation of therapy. EGFR and RSS improved in 5 and 3 patients, respectively; NT-proBNP/albuminuria/proteinuria and KFRE at 2 and 5 years decreased. In terms of cardiomyopathy, 1 patient improved to GSI; 2 using CKD-EPI creatinine and none using CKD-EPI cystatin C. 1 progressed to GSII in all equations.

Conclusion

In this pilot study, we evidenced that ATTR V30M patients meet the criteria for SGLT2i therapy. Dysautonomia and neurogenic bladder were not an impediment for therapy. In addition to disease modifying drugs, SGLT2i may improve kidney and cardiovascular outcomes in ATTR V30M amyloidosis.
#1150 Neutrophil rich infiltrate in immunotherapy induced acute interstitial nephritis
Authors: Glezerman Ilya , Gutgarts Victoria , Salvatore Steven
Published: May 2024

Background and Aims

Acute interstitial nephritis (AIN) is a well-recognized cause of acute kidney injury (AKI) in patients treated with Immune checkpoint inhibitors (ICI). Kidney biopsy typically shows tubular interstitial infiltration with well-differentiated mononuclear cells with occasional granulomas and eosinophils. Neutrophil rich tubular interstitial infiltration is typically associated with pyelonephritis. We report a case series of neutrophil rich ICI induced AIN.

Method

After obtaining approval from the institutional review board, medical records of the nephrology service at a large cancer center were reviewed. Patients were included in the study if they underwent a kidney biopsy for the diagnosis of ICI associated AKI, the biopsy was consistent with atypical AIN with neutrophil rich infiltrate, there was no glomerular involvement, they exhibited no symptoms of pyelonephritis including but not limited to fever, nausea, vomiting, flank pain and dysuria and had a negative urine culture.

Results

Forty eight patients who had a biopsy proven ICI associated AIN were identified from the medical records. Four (8.3%) patients met the study criteria (Table 1). There were three males and one female. The mean age was 75.5 years. One patient had a history of pre-existing CKD stage 3. Mean number of ICI therapy cycles prior to the development of AIN was seven with two patients treated with pembrolizumab (2 and 14 cycles), one patient treated with nivolumab (1 cycle) and one patient treated with the combination of nivolumab and ipilimumab (2 cycles). All patients presented with asymptomatic rise in serum creatinine (sCr). Kidney biopsy showed neutrophil rich infiltrate and neutrophilic tubulitis in all patients. Neutrophilic casts were present in three biopsies. One patient had evidence of granulomatous inflammation. All patients had mild to moderate interstitial fibrosis. Three patients were initially treated with flat dose prednisone 60 mg daily and one was treated with weight adjusted dose of prednisone 1 mg/kg at 75 mg/day. Three patients had complete renal recovery (sCr < 0.5 mg/dl above baseline) after steroid taper. One patient developed a relapse but achieved partial recovery (sCr < 2x baseline) after the second taper. Two patients remain alive three and 12 months after the kidney biopsy. Two patients died due to the progression of cancer two and 10 months after the biopsy.

Conclusion

AIN with neutrophil rich infiltrate likely represents a subset of ICI induced AIN. In the absence of clinical signs of pyelonephritis and with evidence of negative urine cultures the treatment should be geared towards addressing inflammation with systemic corticosteroids which have been shown to be effective in management of ICU induced AIN. Avoidance of antibiotics in this setting would lead to better antibiotic stewardship.
#2487 Deleterious renal outcome in patients with thrombotic microangiopathy after lung transplantation: the lung TMA trial
Authors: Rosseels Wouter , Claes Kathleen , Godinas Laurent , Kuypers Dirk
Published: May 2024

Background and Aims

Thrombotic microangiopathy (TMA) is a rare but severe complication following lung transplantation. The pathogenesis is poorly understood, involving endothelial damage and various risk factors, including calcineurin inhibitor (CNI) toxicity. We aimed to evaluate diagnostic accuracy, identify risk factors for and assess the renal and overall survival of TMA in this patient group.

Method

We performed a retrospective study of patients with TMA after lung transplant between 01/01/2000-01/01/2021. Matching controls were selected based on underlying lung disease, age, gender, CMV risk, and immunosuppressive regimen. Overall survival and baseline data (age, gender) were collected for the whole lung transplant group.

Results

A total of 29 TMA cases (2.9%) were identified out of 1025 lung transplantations. 48% of patients had a complete hematological assessment with Coombs testing as the most frequent (52%) missing test. The median time from transplantation to TMA was 5.9 months. 76% of the episodes occurred before 12 months. 77% of patients had organ damage with acute kidney injury in 72%. At the time of TMA 38% of patients had a cytomegalovirus (CMV) infection. Arterial hypertension was found in 31% and acute rejection in 11%. The immunosuppressive scheme consisted of tacrolimus/mycophenolate mofetil and corticosteroids in the majority of cases (56%). Tacrolimus (n = 22) and cyclosporine (n = 7) trough levels were respectively 11.8 and 207 µg/l at the time of TMA. Treatment consisted of change in immunosuppressive regimen (72%), 31% received plasmapheresis. When comparing the TMA patients with the control group a higher rate of donor specific antibodies were found (11% vs 1%), a lower median time till chronic lung allograft dysfunction (37 m vs 91 m) and a higher prevalence of end-stage renal disease (24% vs 6%) and overall death (97% vs 44%) with mortality being significantly higher (p < 0.01). Fig. 1 illustrates the overall outcome.

Conclusion

This study illustrates the clinical characteristics and outcomes of TMA after lung transplantation. Even though the prevalence is low the effects are deleterious with acute kidney injury in the majority of cases and higher risk of end-stage renal disease and mortality. Our study emphasizes the need for higher further research into risk factors, and therapeutic strategies to prevent and improve patient outcomes. Furthermore, the findings underscore the importance of vigilant monitoring and tailored interventions for TMA in lung transplant patients.
#1289 The effect of desmopressin in reducing post-kidney biopsy bleeding complication in patients with reduced renal function: a randomised control trial
Authors: Chaturvedy Manish , Jhorawat Rajesh , Chakrabarti Uttayan , Bajpai Nitin Kumar , Nalwa Aasma , Khera Pushpinder
Published: May 2024

Background and Aims

Percutaneous kidney biopsy remains the gold standard for diagnosis of kidney disease. The incidence of bleeding complications following kidney biopsy ranges from 13 to 34%. This study aimed to evaluate the effect of prebiopsy administration of intranasal desmopressin on the incidence of post-biopsy bleeding complications in patients undergoing ultrasound-guided percutaneous native kidney biopsy with an estimated GFR of 60 ml/min/1.73 m2.

Method

It was a single-centre, double-blind, randomized controlled trial. Patients undergoing percutaneous ultrasound-guided biopsy of the native kidney in the department with age >18 years, BP before biopsy ≤140/90 mm Hg, and eGFR < 60 mL/min/1.73 m2. The patients were divided into experimental (intranasal desmopressin) and control group (intranasal normal saline), and block randomization was done by a computer-generated random number list prepared by an investigator with no clinical involvement in the study into an experimental and control group. The experimental group was treated using intranasal desmopressin acetate (dosage of 3 mcg/kg, each puff delivering 10 mcg) 1 hour before the kidney biopsy. The control group was treated with a placebo (equivalent dose of intranasal saline)(CTRI/2023/01/048812)

Results

A total of 152 patients were included (78 male and 74 female), the experimental group had 74 patients, and the control group had 78 patients. The mean age was 39.08 ± 15.03 yrs and 38.83 ± 15.67 yrs., respectively (p = 0.921). The experimental group had significantly less hematoma formation at 24 hrs. post kidney biopsy compared to the control group (p = 0.019). The hematoma volume at six hrs. (p = 0.342) and 24 hrs. (p = 0.698); post-kidney biopsy was not different between the two groups.

Conclusion

Intranasal desmopressin administration effectively reduces post-biopsy native kidney peri-renal hematoma formation at 24 hrs post-procedure. However, other bleeding complications were not different in the two groups of our studies.
#684 Safety and Tolerability of adipose-derived mesenchymal stem cell “ADR-001” in the treatment of immunoglobulin A nephropathy
Authors: Maruyama Shoichi , Tanaka Akihito , Furuhashi Kazuhiro , Fujieda Kumiko , Maeda Kayaho , Mimura Tetsushi , Saka Yosuke , Naruse Tomohiko , Ishimoto Takuji , Kosugi Tomoki
Published: May 2024

Background and Aims

Immunoglobulin A (IgA) nephropathy is one of the most frequent glomerular diseases and is sometimes refractory, requiring kidney replacement therapy. Although corticosteroids are mainly used for treatment, infection is a serious adverse event, and evidence for therapeutic efficacy is insufficient; therefore, new therapeutic options are highly desired. Mesenchymal stem cells (MSCs) contribute to the amelioration of inflammation and recovery of organ function. Due to these properties of MSCs, they have been clinically applied to various inflammatory diseases. Therefore, we decided to conduct the world's first investigator-initiated clinical trial to administer MSCs for refractory IgA nephropathy.

Method

This trial was a phase 1, open-label, multiple-center, dose-escalation study of adult patients with refractory IgA nephropathy resistant to or difficult to treat with existing therapies. This trial was registered and assigned the number, jRCT2043200002 and NCT04342325. ADR-001 was administered intravenously from three to six patients at a dose of 1 × 108 cells once in the first cohort and to six patients twice at two-week intervals in the second cohort (Fig. 1A). When MSCs were administered, heparin was also administered. The observational period continued until 52 weeks. The primary endpoint was the safety up to 6 weeks after ADR-001 administration. Secondary endpoints will be the respective percentages of patients with adverse events and efficacy, such as clinical remission, partial remission, remission of urine protein, remission of hematuria, time to remission, changes in urine protein, hematuria, and estimated glomerular filtration rate.

Results

First, regarding the primary endpoint, three patients in the first cohort received single dose of ADR-001, and the data safety monitoring board determined that the safety of the ADR-001 was well controlled because no adverse clinical events occurred. Therefore, the trial shifted the second cohort, and six patients received two doses of ADR-001. In the second cohort, the data safety monitoring board determined that safety was well controlled and that ADR-001 was safe and well tolerated for clinical use. Next, regarding the secondary endpoint, especially regarding to efficacy, kidney damage marker (Fig. 1B) and urinary protein were drastically reduced immediately after administration of ADR-001.

Conclusion

The safety and tolerability of ADR-001, an adipose-derived MSC, were confirmed. Furthermore, the efficacy of ADR-001 is strongly expected.
#1950 Burosumab activity on osteomalacia—a TIO case report
Authors: Foligno Nadia Edvige , Kato Hajime , Hoshino Yoshitomo , Kimura Soichiro , Sunouchi Takashi , Hidaka Naoko , Watanabe So , Vezzoli Giuseppe , Ito Nobuaki
Published: May 2024

Background and Aims

Tumor-Induced Osteomalacia (TIO) is a rare paraneoplastic disorder caused by a tumor (PMT), usually of small size and benign, secreting FGF23.

FGF23 suppresses the reabsorption of phosphate and the synthesis of 1,25(OH)2 vitamin D in the proximal tubular cells of the kidney; consequently, affected patients develop hypophosphatemia and osteomalacia, resulting in bone pain and pathological fractures.

The treatment of choice is the surgical resection of the tumor, but when the latter is not detected or cannot be removed, phosphate salts and active vitamin D can be employed to improve TIO symptoms.

Burosumab, a monoclonal antibody directed against FGF23 introduced for the treatment of X-linked hypophosphatemic rickets, has recently been tested for the treatment of TIO non-surgical patients with encouraging results, even if few data are currently available.

Method

Starting from January 2021, a 56M patient affected by TIO without identified PMT has been treated with burosumab at the dosage of 1 mg/kg s.c. every 4 weeks.

Results

Before the introduction of burosumab, his blood exams showed hypophosphatemia (1.9 mg/dL), low 1,25(OH)2 vitamin D levels (15 pg/mL) and hyperparathyroidism (81 pg/mL) secondary to previous administrations of phosphate salts.

He also reported widespread bone pain, suspect of multiple fractures and pseudofractures, confirmed by whole skeleton bone scintigraphy (BS) as numerous areas of pathological accumulation in the ribs, sacrum, bilateral femur, right proximal tibia, sternoclavicular joint and vertebral bodies.

After the initiation of burosumab, serum phosphate, PTH and 1,25(OH)2 vitamin D levels gradually normalized. The patient also reported an improvement in bone pain, and later BS described a notable and continuous reduction in pathological accumulations, which almost completely disappeared after 24 months, confirming the absence of new fractures and the improvement of existing ones.

Conclusion

Therefore, burosumab is suggested as an alternative treatment for non-surgical TIO patients, especially since, unlike conventional therapy with phosphate salts and active vitamin D, its therapeutic action seems to contribute to the further improvement of osteomalacia.
#2776 Monoclonal gammopathies and amyloidosis unit (UGAM-A): importance of the nephrologist in the multidisciplinary approach
Authors: Moreno Fernando Bertomeu , Almenara-Tejederas Marina , Garcia Fabiola Alonso , Millán Rafael Duro , Lazo Mercedes Salguiera
Published: May 2024

Background and Aims

The Monoclonal Gammopathies and Amyloidosis Unit (UGAM-A) is a multidisciplinary hospital subcommittee that discusses complex cases in relation to the diagnosis and treatment of patients with blood dyscrasia and amyloidosis.

Method

Retrospective observational study of the cohort of patients presented at UGAM-A

The data were extracted from the minutes of the UGAM-A for the period Jan/18-Dec/22.

Results

81 patients were assessed with a median age of 69 years, 52 men (64.2%). HT 58 (71.6%), DM 22 (27.2%), cardiovascular disease 14 (17.3%), Neoplasm 12 (14.8%).

56 patients (69.1%) had renal damage at the time of assessment, 54 with CKD criteria, with a mean creatinine of 1.7 ± 1.0 mg/dl and proteinuria of 1.3 ± 1.7 g/mg. Cardiac involvement was found in 19 patients.

There were 37 (45.7%) diagnostic changes after assessment by the UGAM.

A total of 22 (27.2%) therapeutic modifications, initiation or change were made. 17 (77.3%) occurred in patients with renal involvement.

There were 10 (12.3%) treatment changes, with 22.7% of them improving renal function vs. 7% in the group with no change in treatment (p = 0.04).

8 (9.9%) patients required SDB, with a median time to onset of 452d.

A total of 25 (30.9%) patients died, with a median time of 370d, with 12 being the most common cardiac cause, followed by infectious 8.

Conclusion

Nephrologists should be involved in the complex clinical cases that accompany hematologic diagnoses. In our study, almost 80% of patients had renal involvement concomitant with haematological pathology.

The role of the nephrologist is fundamental in clarifying mechanisms of kidney damage and enhancing the initiation of treatment even when they do not meet criteria from the haematological point of view, so that more than 77% of the therapeutic actions took place in patients with renal involvement.
#2440 https://era.m-anage.com/era24/en-GB/Submit/submission/abstracts/197764/guidelines
Authors: Jiang Wei , Tang Tao-Tao , LV Linli , Liu Bicheng
Published: May 2024

Background and Aims

Acute kidney injury (AKI) is a critical condition that is strongly related to elevated risks for the progression of chronic kidney disease (CKD). While tubulointerstitial inflammation (TII) is widely accepted as a significant factor in driving this process, the underlying mechanisms responsible for the development of TII are still largely unknown. T cells are increasingly recognized to be involved in tissue injury and exacerbation of the inflammatory response. However, the dynamic landscape of T cell infiltration and their contribution to the chronic transition of AKI remain largely unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to obtain a high-resolution profile of T cells in a model of unilateral ischemia-reperfusion injury (uIRI) induced AKI to CKD (AtoC) transition and intended to explain their roles during this progress.

Method

Unilateral ischemia-reperfusion injury (uIRI) at multiple time points was used to simulate the transformation of AtoC. Next, the kidneys were isolated into single-cell suspensions and single-cell RNA sequencing (sRNA-seg) was performed to observe the dynamic evolution of T cells during AtoC transition. Further subpopulations of T cells were analyzed and T cell maps were constructed by UMAP. These subpopulations were defined by characteristic genes and their functions were analyzed. The dynamic changes of T cell subsets during AtoC transformation were observed. RNA velocity and pseudotime analysis were used to observe the evolution of T cell subpopulations. Receptor and ligand interaction analysis of the mechanism by T cell subsets role during AtoC. Finally, the sequencing results were further verified by detailed in vitro and in vivo experiments.

Results

PAS and Masson showed that the model of unilateral ischemia-reperfusion injury (uIRI) induced AKI to CKD transition was successfully established. In the chronic phase after AKI, the aggregation of T cells gradually increased. During the transition from AKI to CKD, T cells can be divided into 9 cell subsets, mainly including CD8, TH1 and Treg cells. The proportion of CD8 subsets increased significantly during this process and may originate from proliferating T cell subtypes that emerged rapidly after AKI. Interestingly, CD8 T cells can specifically induce apoptosis of vascular endothelial cells through Fas ligand (FasI)-Fas signaling, which leads to the thinning of peritubular capillaries (PTCs), ultimately leading to the progression of renal fibrosis.

Conclusion

Our results suggest that CD8 T cells can cause the rarefaction of peritubular capillaries and ultimately lead to renal fibrosis, and targeted clearance of CD8 T cells is expected to become a new therapeutic target in the AtoC process.
#245 Deficiency of GADD45α expression mediated tubulointerstitial injury in diabetic nephropathy
Authors: LI Xue Qi , Zhang Jia Xiu , LI Liang , Wu Qin Yi , MA Kun Ling
Published: May 2024

Background and Aims

The tubulointerstitial injury plays crucial roles in the development of diabetic nephropathy (DN). Recently, some studies have reported that disorder of mitochondrial fatty acid β-oxidation in proximal tubules is involved in tubulointerstitial injury of DN. The growth arrest and DNA damage-inducible gene 45 (GADD45) family proteins, especially, GADD45α, plays a crucial role in various cellular processes, such as mitochondrial biogenesis and lipid metabolism. Recent studies have demonstrated that GADD45α facilitates gene activation by inducing DNA demethylation. Therefore, this study aimed to investigate the role of GADD45α in tubulointerstitial injury of DN and its underlying mechanisms.

Methods

Bioinformatics and machine learning techniques were employed to identify differentially expressed genes between healthy individuals and DN patients. Experiments were conducted by using high glucose-treated HK-2 cells and streptozotocin (STZ)-induced mice. Lentivirus carrying the GADD45α gene was used to induce GADD45α overexpression in HK-2 cells. Adeno-Associated Virus vectors carrying LoxP-flanked GADD45α were intravenously injected into γGT-Cre transgenic mice expressing Cre recombinase in renal proximal tubular cells, specifically leading to GADD45α overexpression in proximal tubules.

Results

Through bioinformatics and machine learning techniques, GADD45α was identified and found to exhibit a strong association with tubulointerstitial injury in DN. Further analysis revealed that the expression of GADD45α was decreased in the kidneys of DN patients, diabetic mice, and high glucose-treated HK-2 cells. Notably, GADD45α overexpression ameliorated kidney damage and mitochondrial injury, leading to improved fatty acid β-oxidation, restored ATP production, and reduced ROS production. Transcriptomics analyses further demonstrated that GADD45α overexpression enhanced the expression of genes related to mitochondrial biogenesis, dynamics, and electron transport chain, with six transmembrane epithelial antigen of prostate 4 (STEAP4) being a key protein in this process. Knocking down STEAP4 using siRNA in HK-2 cells exacerbated the damage induced by high glucose. In addition, our further results indicated that high glucose increased methylation of the STEAP4 promoter, while GADD45α overexpression decreased methylation and increased STEAP4 expression.

Conclusions

Deficiency of GADD45α expression mediated tubulointerstitial injury in DN, which was mainly through the decreased STEAP4 expression by demethylating CpG motifs in the STEAP4 promoter region, thereby resulting in reduced fatty acid oxidation, energy synthesis, and increased ROS production, and finally accelerated tubular injuries. These findings suggested that targeting the GADD45α-STEAP4 pathway could be a potential therapeutic strategy for DN.
#489 UCP1 regulates cardiolipin metabolism and mediates mitochondrial homeostasis maintenance of ANXA1 in diabetic nephropathy
Authors: LI Zihan
Published: May 2024

Background and Aims

Diabetic nephropathy (DN) is accounted for a large proportion of chronic kidney disease (CKD) and is the leading cause of end-stage renal disease (ESRD) nowadays. The complex pathogenesis of DN has hindered the development of a single effective medicine, so it is of great significance to seek new therapeutic targets. Uncoupling of mitochondrial respiration by chemical uncouplers has proven effective in ameliorating obesity, insulin resistance, and hyperglycemia, which were risk factors for DN. Recently, we found that ANXA1 could improve mitochondrial function to mitigate DN progression. However, the underlying mechanism is not fully clear yet.

Method

We used kidney samples from patients in our hospital. ANXA1-KO mice with local renal overexpression of UCP1 were constructed, UCP1-KO mice were constructed for STZ/HFD modeling, and db/db mice were treated with CL316243. UCP1-KO mice with renal overexpression of CRLS1 were constructed. Mice with PTECs-specific deletion of ANXA1 were constructed. Cell lines with UCP1/ANXA1/GATA3 knockdown and UCP1/ANXA1/GATA3 overexpression were constructed, and cell reversal tests were performed using Ac2-26, CL316243 and siRNA targeting the above genes.

Results

Here, we identified uncoupling protein 1 (UCP1), an inner membrane protein of mitochondria, as a key to mitochondrial homeostasis improved by ANXA1. Specifically, ANXA1 attenuated mitochondrial dysfunction via appropriately upregulating UCP1 by stabilizing its transcription factor GATA binding protein 3 (GATA3) through combining with thioredoxin. Moreover, specific overexpression of UCP1 in renal cortex rescued renal injuries in diabetic Anxa1-KO mice. UCP1 deletion aggravated renal injuries in HFD/STZ-induced diabetic mice. Mechanistically, UCP1 reduced mitochondrial fission through the aristaless-related homeobox (ARX)/cardiolipin synthase 1 (CRLS1) pathway. Therapeutically, CL316243, a UCP1 agonist, could attenuate established DN in db/db mice.

Conclusion

Thus, our data unraveled specific mechanism by which UCP1 mediated mitochondrial homeostasis maintenance via the ANXA1-GATA3-UCP1-ARX-CRLS1 signaling pathway. This work established a novel principle to harness the power of uncouplers for the treatment of DN.
#1581 Anoctamin 3 inhibits gluconeogenesis and contributes to renal interstitial fibrosis through EZH2
Authors: Wu Ming , Lin Pinglan , Ye Chaoyang
Published: May 2024

Background and Aims

Renal fibrosis is the common pathological pathway of various chronic kidney diseases progressing to the end stage of renal failure. Anoctamin 3 (ANO3) has been identified as a K-channel regulator and been extensively studied in the field of neurobiology. The role of ANO3 in kidney diseases is currently unknown.

Method

Mouse models of renal fibrosis were established by unilateral ureteral obstruction (UUO) operation or aristolochic acid I (AAI) injection. Human proximal tubular cell line (HK2) was used as an in vitro model. ANO3 was deleted in vitro by siRNA. Western blotting analysis was performed. Glucogenic metabolites were measured.

Results

We found that ANO3 is upregulated in mouse kidneys with unilateral ureteral obstruction (UUO) or aristolochic acid nephropathy (AAN), and tightly correlated with the progression of renal fibrosis and negatively correlated with expression of several rate-limiting enzymes of renal gluconeogenesis. Knockdown of ANO3 with siRNA increased the concentration of glucose and reduced the concentration of lactate in the supernatant of TGF-β stimulated renal proximal tubular (HK2) cells. In parallel, transfection of ANO3 siRNA significantly reduced the expression of epithelial-to-mesenchymal transition (EMT) and fibrotic markers in TGF-β stimulated HK2 cells. We further showed that ANO3 expression is positively correlated with the expression of a methyltransferase enhancer of zeste homologue 2 (EZH2) in UUO and AAN mouse kidneys by time. Transfection of ANO3 siRNA significantly reduced the expression of EZH2 in TGF-β stimulated HK2 cells. Overexpression of EZH2 by adenovirus reversed the pro-gluconeogenic and anti-fibrotic effect of ANO3 siRNA in TGF-β stimulated HK2 cells by measuring the concentration of glucose and lactate in supernatant and analyzing the expression of EMT or fibrotic markers.

Conclusion

In conclusion, ANO3 inhibits renal gluconeogenesis through EZH2 and contributes to renal fibrosis. ANO3 could be promising therapeutic target to inhibit renal fibrosis in chronic kidney disease patients.
#273 Identification of epipin expression in progression of chronic kidney disease—a multi-omic approach
Authors: Kademani Sangeetha , Nelaturi Prabhudas , Sagar K Sathya , Sambandam Ravikumar
Published: May 2024

Background and Aims

Chronic kidney disease (CKD) is characterized by irreversible reduction in kidney function eventually leading to end-stage renal disease (ESRD). ESRD is a stage when kidney function is no longer adequate for long-term survival without dialysis or kidney transplant. Over the past the prevalence is increased more than 3 fold. Impaired activity of endogenous renal matrix-degrading proteases enhance interstitial matrix accumulation but specific pathways are involved remain unclear. Hence, an urgent need for sensitive biomarkers can detect disease earlier than traditional one and predict disease progression. Present study intended to identify epipin during chronic kidney disease and also we highlight promising kidney biomarkers that have robust underpinnings in the pathophysiology of kidney damage.

Method

A cross sectional study was conducted on patients with CKD compared with patients with diabetes mellitus (DM) and healthy controls. The collected samples were analyzed for the biochemical investigations included renal profile tests such as urea, serum creatinine, uric acid and urine spot test was analyzed for the screen of kidney problems. Firstly we identified the novel epipin protein through LC-MS then we estimated its gene expression levels using RT-PCR and levels of protein expression measured by ELISA.

Results

Epipin was shown higher expression in CKD compared to controls and moderately expressed in patients with diabetes mellitus compared to controls. The expression level of epipin gene was 4 fold in DM compared with controls, 19 fold in CKD compared with controls and 5 fold change between CKD and DM. Epipin showed AUC of 0.99 and 1.00 in DM and CKD respectively. The present study found that epipin was highly expressed in CKD patients and moderately expressed in patients with diabetes mellitus when compared to controls. In a present study, we identified one of the epipin with increased expression in renal disease progression.

Conclusion

The expression of epipin in virtually all samples suggests that this intracellular protein may have diverse and an extensive biological roles and may be an important therapeutic target for development of renal disease and its progression.
#2104 Neutrophil extracellular traps have a pivotal role in tubulointerstitial fibrosis
Authors: Cao Jingyuan , Hu Xinhui , Liu Haifei , Ni Weijie , Liu Hong
Published: May 2024

Background and Aims

Tubulointerstitial fibrosis (TIF) is a typical pathological change in chronic kidney disease (CKD). However, the mechanisms underlying tubulointerstitial fibrosis are still to be fully elucidated. Neutrophil extracellular traps (NETs) participate in the pathophysiological processes of various kidney diseases, but their role in CKD-TIF has not been reported. Here, we investigated the role of NETs in tubulointerstitial fibrosis.

Method

Immunofluorescence was employed to assess the levels and localization of NETs in the renal tissues of CKD patients. The GSE66494 human CKD microarray dataset was explored to analyze the changes of PAD4 levels. Three CKD mice models, including 14d unilateral ureteral obstruction (UUO), 28d ischemia/reperfusion (I/R) injury, and adenine-induced models were constructed to detect the expression levels of NETs in the kidneys. Then, we established a NETs-deficient (PAD4−/−) CKD mice model and assessed changes in renal function, NETs levels, and renal fibrosis. In vitro, phorbol-12-myristate-13-acetate (the classic inducer of NETs) was used to induce the generation of NETs. Intervention was performed on rat fibroblast NRK49F cells to investigate the mechanism of TIF induced by NETs.

Results

We first identified NETs levels were significantly elevated in the renal tissues of CKD patients. Additionally, chip data results also indicated elevated PAD4 levels in the renal tissues of CKD patients. NETs levels were elevated in the kidneys of UUO, I/R, and adenine-induced CKD mice, with deposition in the renal interstitium. PAD4-deficient mice did not form neutrophil extracellular traps. Knocking out PAD4 alleviated tubulointerstitial fibrosis in UUO, adenine, and I/R mice after blocking NETs formation. In vitro, NETs intervention in fibroblasts can promote their activation and transformation into myofibroblasts.

Conclusion

The deletion of NETs by PAD4−/− could significantly improve CKD-TIF. The inhibition of NETs might provide a new molecular target for the prevention and treatment of CKD.
#2592 Tubular cell polyploidy is involved in kidney compensatory hypertrophy
Authors: De Chiara Letizia , Lazzeri Elena , Romagnani Paola
Published: May 2024

Background and Aims

Chronic kidney disease (CKD) affects more than 10% of the population and it is associated with high risk of death for cardiovascular causes or progression towards end stage kidney disease (ESKD) requiring dialysis or kidney transplantation. CKD is characterized by progressive loss of nephrons, with consequent structural degeneration and fibrosis. Nephron number is established during prenatal kidney development and cannot increase. Consequently, following a reduction in kidney mass or in condition of altered metabolic demands, the remaining nephrons undergo compensatory hypertrophy. Compensatory hypertrophy results in increased functional output and has been observed in the absence of direct tissue injury after nephrectomy. Recently, we have identified a previously unknown mechanism of cellular adaptation: polyploidization of tubular epithelial cells (TC), and demonstrated that this is the essential mediator of kidney hypertrophy after acute kidney injury (AKI). Here, we hypothesize that TC polyploidy is involved in compensatory hypertrophy following nephrectomy.

Method

Polyploid TC are characterized by an increased DNA content in the absence of cell division. To discriminate polyploid cells from actively proliferating cells, we employed a series of in vitro and in vivo transgenic models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI2aR) technology. Nephrectomy was performed by removing the left kidney and mice were sacrificed at different days after uni- Nephrectomy (Nfx). Cytofluorimetric techniques were employed to characterize a subpopulation of polyploid TC and histology investigation was employed analyze fibrosis development. These results were further corroborated by single cell RNA-sequencing (scRNA-seq) analyses in vitro and in vivo.

Results

Employing mice that express the FUCCI2aR reported under the Pax8 promoter (which marks all TC), we found that TC polyploidy increases immediately after uni-Nfx. This was accompanied by an increased kidney to body mass ratio with a maximum peaks 3 days afterwards. Importantly, after uni-Nfx, YAP1 expression and nuclei localization (i.e., implying pathway activation) was exponentially increased, suggesting that the same mechanism that drives TC polyploidy after AKI controls TC polyploidization response after uni-Nfx. However, unlike in AKI, polyploidy after nephrectomy was not accompanied by structural alterations as shown by PAS and Masson's trichrome staining. Conversely, after uni-Nfx YAP1 knock-out mice, that are unable to undergo rapid polyploidization, displayed an impaired kidney function in the long term, characterized by extensive tubular dilations.

Conclusion

Polyploidization of TC mediates compensatory hypertrophy following nephrectomy via YAP1 activation
#2641 MiR-200b induces ZEB1 mediated upregulation of Matriptase and affects expression of podocin
Authors: Tati Ramesh , Müller-Deile Janina , Walentinsson Anna , Sopel Nina , Lassen Emelie , Ebefors Kerstin , Söderberg Magnus , Daniel Christoph , Hansen Pernille B L , Schiffer Mario , Nystrom Jenny , Buvall Lisa
Published: May 2024

Background and Aims

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and a predominant reason for renal failure. Evidence from previous research indicates that abnormal expression of microRNAs (miRs) links closely to the occurrence and progression of DKD.

Methods

Expression of miRs in urine samples from DKD patients and in cultured renal cells stressed with transforming growth factor beta 1 (TGF-β1) was evaluated by TaqMan assay. The emerging miR of interest and its downstream targets were analyzed in human renal sections, in cultured human podocytes and in zebrafish.

Results

Cell free urine screening showed increased abundance of miR-200b in samples from patients with DKD when compared to healthy controls. In situ hybridization confirmed expression of miR-200b in kidney specimens from DKD patients, but was not detected in healthy renal parenchyma. Transcriptome profiling of cultured human podocytes overexpressing miR-200b identified this miR as a regulator of the ZEB1 mediated matriptase (ST14)/ podocin pathway and found TGF- β1 stress to be upstream activators of miR-200b expression in these cells. Immunofluorescence analysis of kidney sections from DKD patients showed increased expression of ST14 and decreased expression of podocin when compared to healthy controls. Furthermore, injection of a miR-200b mimic in zebrafish larvae caused an upregulation of ST14 and was accompanied by phenotypic changes such as edema, proteinuria and podocyte effacement.

Conclusion

Our results show that miR-200b is expressed in glomeruli and found at elevated levels in urine of DKD patients. Overexpression of miR-200b in cultured podocytes and in zebrafish induces upregulation of matriptase, a serine protease previously shown to cleave podocin. The observed increase in matriptase and decrease in podocin levels in glomeruli from DKD patients, together with the effect of a miR-200b mimic on proteinuria and ultrastructure of the pronephros in zebrafish positions miR-200b as a key regulator that modulates matriptase overactivation in DKD and warrants further studies.
#613 Is there a relationship between kidney stiffness identified by 2D shear wave elastography and the estimated glomerular filtration rate?
Authors: Maralescu Felix-Mihai , Raimann Jochen G , Schiller Adalbert , Petrica Ligia , Bob Flaviu
Published: May 2024

Background and Aims

Ultrasound-based elastography has been utilized as an imaging method with high utility in the liver or thyroid, but it is not yet being implemented in evaluating the chronic kidney disease (CKD) because current research indicates a high level of heterogeneity between studies. We aimed to investigate if there is a connection between kidney stiffness measured with a new, specially designed elastography software for kidneys and estimated glomerular filtration rate (eGFR).

Method

In 2022 and 2023 we performed a cross-sectional study in 150 participants (50 healthy, 50 kidney-transplanted, 50 with chronic glomerulonephritis). The mean value of five different measurements for each kidney were correlated with biological and clinical parameters. To examine the variations amongst the three groups, one-way between-groups ANOVA was employed.

Results

The mean kidney stiffness for the healthy cohort was 31.9 ± 2.9 kiloPascal (kPa), for kidney transplanted (Ktx) patients 25.9 ± 6.9 kPa and for the chronic glomerulonephritis (GN) 23.8 ± 7.45 kPa. We discovered correlations between kidney stiffness and eGFR in all three groups: healthy r = 0.61, p < 0.0001, Ktx r = 0.56, p < 0.0001, GN r = 0.70, p < 0.0001.

We also found a value of under 26 kPa for the detection of an eGFR under 60 mL/min/1.73 m2 with 94.3% sensitivity and 84% specificity (AUC = 0.905, p < 0.0001). The healthy group showed significant higher values than Ktx or GN groups, but without significant differences between the latter two.

Conclusion

Our findings demonstrate a correlation between renal function, with very good diagnostic accuracy, and these novel imaging techniques. A decrease in renal stiffness with the progression of CKD could prove to be an easy, reproducible approach to provide additional diagnostic information. However, given the limited number of participants, additional studies are required before they can be incorporated into standard clinical practice.
#785 The novel fibrosis biomarker LG1M is prognostic for long-term readmission after AKI
Authors: Sparding Nadja , Genovese Federica , Karsdal Morten Asser , Selby Nicholas
Published: May 2024

Background and Aims

People who survive Acute Kidney Injury (AKI) experience increased risk of long-term adverse outcomes, including a significantly elevated rate of readmission to hospital. This may be related to the pathophysiological consequences of AKI, including extracellular matrix (ECM) remodeling in the kidneys and other organs. Tools to monitor the long-term health risk of patients after AKI are needed to improve patient outcome. Here, we investigated the potential of the novel ECM remodeling biomarker LG1M, reflecting laminin degradation mediated by MMP-9, as a prognostic marker for readmission after AKI.

Method

We measured LG1M in plasma samples collected 1 year after the episode of AKI using the nordicLG1MTM ELISA assay in plasma samples from 791 patients from the AKI Risk in Derby (ARID) study, who were then followed prospectively until year 3. 390 of the patients had been hospitalized for an episode of AKI and 401 patients who did not sustain AKI were included as controls (non-AKI). Correlation of LG1M levels with age, serum creatinine, eGFR, PCR, ACR, and CRP was tested with Spearman rank correlation (all variables measured at year 1). Uni- and multivariate Cox regression analysis was used to analyze the association of LG1M with the risk of readmission.

Results

LG1M levels were significantly higher in the AKI group (median [IQR] = 31.9 [25.7-42.8] ng/mL) compared to the control group (median [IQR] = 30.3 [24.9-37.2] ng/mL, P < 0.01). In the AKI group, LG1M correlated with age (r = 0.16, P < 0.01), serum creatinine (r = 0.33, P < 0.0001), eGFR (r = −0.35, P < 0.0001), and ACR (r = 0.23, P < 0.0001). In the control group, LG1M only correlated with serum creatinine (r = 0.22, P < 0.0001) and eGFR (r = −0.22, P < 0.0001). By year 3, 265 out of 390 patients in the AKI group and 258 out of 401 patients in the control group were readmitted (Chi-squared test, P = 0.28). In a univariate Cox model with readmission as outcome, LG1M was significant associated with readmission in the AKI group (HR [95% CI] = 1.007 [1.001-1.013], P < 0.05) but not in the control group (HR [95% CI] = 1.005 [0.997-1.013], P = 0.23). When adjusting for age, sex, ACR, and eGFR measured at year 1 as well as baseline CKD and diabetes status, LG1M lost it significance in the AKI group (HR [95% CI] = 1.004 [0.998-1.011], P = 0.22) and was still non-significant in the control group (HR [95% CI] = 1.002 [0.994-1.011], P = 0.57).

Conclusion

In this study, we showed that the novel biomarker LG1M is prognostic for readmission in patients after AKI. Our findings may indicate that this biomarker, reflecting laminin degradation, can be used as a novel post-AKI biomarker that can help assess patients’ long-term health risks.