Progressive Loss Of Renal Function Research Articles

High Protein Diets and Glomerular Hyperfiltration in Athletes and Bodybuilders: Is Chronic Kidney Disease the Real Finish Line?

Several observational and experimental studies in humans have suggested that high protein intake (PI) causes intraglomerular hypertension leading to hyperfiltration. This phenomenon results in progressive loss of renal function with long-term exposure to high-protein diets (HPDs), even in healthy people. The recommended daily allowance for PI is 0.83g/kg per day, which meets the protein requirement for approximately 98% of the population. A HPD is defined as a protein consumption > 1.5g/kg per day. Athletes and bodybuilders are encouraged to follow HPDs to optimize muscle protein balance, increase lean body mass, and enhance performance. A series of studies in resistance-trained athletes looking at HPD has been published concluding that there are no harmful effects of HPD on renal health. However, the aim of these studies was to evaluate body composition changes and they were not designed to assess safety or kidney outcomes. Here we review the effects of HPD on kidney health in athletes and healthy individuals with normal kidney function.

Therapeutic approaches and novel antifibrotic agents in renal fibrosis: A comprehensive review.

Renal fibrosis (RF) is one of the underlying pathological conditions leading to progressive loss of renal function and end-stage renal disease (ESRD). Over the years, various therapeutic approaches have been explored to combat RF and prevent ESRD. Despite significant advances in understanding the underlying molecular mechanism(s), effective therapeutic interventions for RF are limited. Current therapeutic strategies primarily target these underlying mechanisms to halt or reverse fibrotic progression. Inhibition of transforming growth factor-β (TGF-β) signaling, a pivotal mediator of RF has emerged as a central strategy to manage RF. Small molecules, peptides, and monoclonal antibodies that target TGF-β receptors or downstream effectors have demonstrated potential in preclinical models. Modulating the renin-angiotensin system and targeting the endothelin system also provide established approaches for controlling fibrosis-related hemodynamic changes. Complementary to pharmacological strategies, lifestyle modifications, and dietary interventions contribute to holistic management. This comprehensive review aims to summarize the underlying mechanisms of RF and provide an overview of the therapeutic strategies and novel antifibrotic agents that hold promise in its treatment.

Megaureter in adults: a review of the current literature.

Megaureter (MU) is an uncommon condition in adults. The aim is to present a review of the current literature. A literature search was conducted to explore the current literature including case reports on MU in adults in the period 2003-2023. Each case was characterised in terms of the eight categories: sex, age, etiology, location, symptoms, diagnostic tool used, type of treatment and follow-up. There was no meta-analysis but two reviews. Total, 39 case reports were included based on 35 articles. The most common observations for the first four categories were male (sex), age below 40 (age), obstructed MU (etiology) and left-sided MU (location). Almost every patient appeared with symptoms, most frequently flank pain, abdominal pain and recurrent urinary tract infections. CT scan and transabdominal ultrasonography are the most commonly used diagnostic tools. Most cases underwent either laparoscopic or open surgical treatment with ureteral reimplantation as the most performed surgical procedure. A majority of the patients had an uneventful follow-up. MU in adults is a rare condition presenting with heterogeneous symptoms. CT scan and transabdominal ultrasonography should be used as diagnostic tools. Nearly all patients underwent surgical treatment with an uneventful follow-up. Complications such as stone formation and altered function of the affected kidney are common. Surgical treatment is recommended and is determined by consideration of age, symptoms, ureteral extension and progressive loss of renal function.

Identification of Pathogenic Pathways for Recurrence of Focal Segmental Glomerulosclerosis after Kidney Transplantation.

Primary focal segmental glomerulosclerosis (FSGS) is a disease of the podocytes and glomerulus, leading to nephrotic syndrome and progressive loss of renal function. One of the most serious aspects is its recurrence of disease in over 30% of patients following allogeneic kidney transplantation, leading to early graft loss. This research investigates the individual genetic predispositions and differences in the immune responses leading to recurrence of FSGS after transplantation. We performed exome sequencing on six patients with recurrent FSGS to identify variants in fifty-one genes and found significant variations in the alpha-2-macroglobulin (A2M). Immunoblotting was used to investigate effects of specific gene variants at the protein level. Further expression analysis identified A2M, exophilin 5 (EXPH5) and plectin (PLEC) as specific proteins linked to podocytes, endothelial cells, and the glomerulus. Subsequent protein array screening revealed the presence of non-HLA-specific antibodies, including TRIM21, after transplantation. Using Metascape for pathway and process enrichment analysis, we focused on the IL-17 signaling and chemotaxis pathways. ELISA measurements showed significantly elevated IL-17 levels in patients with recurrent FSGS (32.30 ± 9.12 pg/mL) compared to individuals with other glomerular diseases (23.16 ± 2.49 pg/mL; p < 0.01) and healthy subjects (22.28 ± 0.94 pg/mL; p < 0.01), with no significant difference in plasma CCL2/MCP-1 levels between groups. This study explores the molecular dynamics underlying recurrence of FSGS after transplantation, offering insights into potential biomarkers and therapeutic targets for the future development of individualized treatments for transplant patients.

Clinical and pathogenetic features of the development of endothelial dysfunction in patients with chronic kidney disease and its contribution to the development of cognitive impairments

THE AIM: to study the clinical and pathogenetic features of the development of endothelial dysfunction (ED) in patients with chronic kidney disease stages 3A-5D and its contribution to the development of cognitive impairment.PATIENTS AND METHODS: The study included 80 patients with CKD stages 3A-5D aged from 26 to 79 years (average age 58.9 ± 1.4 years): 43 women (average age 60.1 ± 1.9 years) and 37 men (average age 57.4±2.3 years). The patients were divided into 2 groups: group 1 included 40 patients with CKD 3A-5 (average age 59.9 ± 2.1 years), group 2 included 40 patients with CKD 5D (average age 58.1 ± 2 years). All patients underwent common and biochemical blood tests, the levels of endothelial nitric oxide synthase 3 (eNOS-3) and endothelin-1 (END-1) were determined, an endothelium-dependent vasodilation test (EDVD) was performed, testing for the presence and severity of cognitive disorders using the Montreal Cognitive Assessment Scale (MoCA) and the Mini Mental State Examination (MMSE).RESULTS: The prevalence of ED in the overall cohort of patients based on the results of a positive test with EDVD was 55 % of cases. ED was statistically significantly more often detected in the group of patients receiving hemodialysis treatment compared to patients in group 1: 70 % versus 40 %, respectively (p=0.007). The level of eNOS-3 in group 1 was higher compared to group 2 and amounted to 1.01±0.5 ng/ml versus 0.76±0.3 ng/ml (p=0.008). While the level of END-1 was statistically significantly lower in patients of group 1 compared to group 2 and amounted to 45.4±9.1 pg/ml versus 54.9±4.7 pg/ml (p&lt;0.001). Cognitive impairments were identified in the general cohort: according to MMSE – in 67.5 % of cases, according to MoCA – in 71.3 %, and were more common in group 2. There were no statistically significant relationships between the results of the EDVD test and testing on the MoCA and MMSE scales. The level of eNOS-3 was lower in the subgroup of patients with cognitive impairment according to MoCA compared to the subgroup without it: 0.73±0.1 ng/ ml versus 0.94±0.2 ng/ml (p=0.127). The content of END-1 was statistically significantly higher in the subgroup of patients with cognitive impairment according to MoCA – 52.98±1.2 pg/ml compared to the subgroup without it – 47.67±1.5 pg/ml (p=0.043). When assessing the relationship between the levels of eNOS-3 and END-1 and the results of the EDVD test, it was found that in patients with a positive test in group 1, the level of eNOS-3 was statistically significantly higher compared to group 2 (p=0.01). An inverse relationship was observed for END-1; its level was lower in patients of group 1 compared to group 2 (p&lt;0.01).CONCLUSION. Thus, the study revealed a high prevalence of endothelial dysfunction in patients with CKD stages 3A-5D. Progressive loss of renal function leads to dysregulation of the molecular mechanisms controlling vascular tone and the development of ED. eNOS-3 and END-1 have demonstrated high sensitivity for ED verification, and their detection improves the quality of the EDVD test. The development and progression of ED in patients with CKD is a multifactorial process that leads to hemodynamic disturbances in various organs and tissues, their damage and has a negative impact on the patient’s quality of life, his cognitive status and life expectancy.

A dynamic online nomogram for predicting renal outcomes of idiopathic membranous nephropathy

BackgroundBecause spontaneous remission is common in IMN, and there are adverse effects of immunosuppressive therapy, it is important to assess the risk of progressive loss of renal function before deciding whether and when to initiate immunosuppressive therapy. Therefore, this study aimed to establish a risk prediction model to predict patient prognosis and treatment response to help clinicians evaluate patient prognosis and decide on the best treatment regimen.MethodsFrom September 2019 to December 2020, a total of 232 newly diagnosed IMN patients from three hospitals in Liaoning Province were enrolled. Logistic regression analysis selected the risk factors affecting the prognosis, and a dynamic online nomogram prognostic model was constructed based on extreme gradient boost, random forest, logistic regression machine learning algorithms. Receiver operating characteristic and calibration curves and decision curve analysis were utilized to assess the performance and clinical utility of the developed model.ResultsA total of 130 patients were in the training cohort and 102 patients in the validation cohort. Logistic regression analysis identified four risk factors: course ≥ 6 months, UTP, D-dimer and sPLA2R-Ab. The random forest algorithm showed the best performance with the highest AUROC (0.869). The nomogram had excellent discrimination ability, calibration ability and clinical practicability in both the training cohort and the validation cohort.ConclusionsThe dynamic online nomogram model can effectively assess the prognosis and treatment response of IMN patients. This will help clinicians assess the patient’s prognosis more accurately, communicate with the patient in advance, and jointly select the most appropriate treatment plan.

Propionate and butyrate counteract renal damage and progression to chronic kidney disease.

Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. SCFA levels were measured in chronic kidney disease (CKD) patients (n=54) at different stages of the disease and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by TNF-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.

Customization of hormone therapy in women with autosomal dominant polycystic kidney disease (ADPKD): actionable strategies and future perspectives

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetically inherited kidney disease and the fourth leading cause of renal replacement therapy worldwide. It is characterized by the development of multiple cysts in the kidneys and in other organs, the increase in renal volume and the progressive loss of renal function. ADPKD outcome seems to be sensitive to hormonal fluctuations, particularly those of sex hormones. Despite the limited literature available, this review presents the first comprehensive overview of contraception and hormonal replacement therapy in women with ADPKD, delving into the risks and benefits associated with different contraceptive methods, including hormonal, intrauterine devices, and non-hormonal approaches. It also explores personalized strategies for contraception based on the severity of renal disease and the presence of comorbidities. Although the protective role of female sex hormones in slowing the progression of renal failure is acknowledged, hormonal therapy in women with ADPKD remains intricate and challenging due to its potential impact on liver disease progression. Women with ADPKD typically experience a slower progression of renal disease compared to men, largely influenced by hormonal dynamics. This literature review underscores the importance of a multidisciplinary assessment and a thorough patient discussion to identify the most suitable contraceptive method for each woman affected by polycystic kidney disease.

Zinc oxide nanoparticles prevent the onset of diabetic nephropathy by inhibiting multiple pathways associated with oxidative stress

BackgroundZinc deficiency is strongly correlated with prolonged diabetes mellitus and diabetic nephropathy (DN). Previously, glucose-lowering, insulinomimetic, and β-cell proliferative activities of zinc oxide nanoparticles (ZON) have been reported. Considering these pleiotropic effects, we hypothesized that ZON modulates multiple cellular pathways associated with necroptosis, inflammation, and renal fibrosis, which are involved in progressive loss of renal function. AimThis study evaluated the effect of ZON on renal function, leading to the alleviation of DN in streptozotocin (STZ)-induced type 1 diabetic Wistar rats and proposed a probable mechanism for its activity. MethodsWistar rats (n = 6/group) were used as healthy controls, diabetic controls, diabetic rats treated with ZON (1, 3, and 10 mg/kg), and insulin controls. Urine and serum biochemical parameters, glomerular filtration rate (GFR), and renal histology were also evaluated. Cultured E11 podocytes were evaluated in vitro for markers of oxidative stress, proteins associated with the loss of renal function, and genes associated with renal damage. Key findingsSTZ-treated rats receiving oral doses of ZON showed enhanced renal function, with no histological alterations in the kidney tissue. ZON inhibited the TGF-β/Samd3 pathway in renal fibrosis; blocked Ripk1/Ripk3/Mlkl mediated necroptosis and protected against hyperglycemia-induced pyroptosis. In E11 podocytes, ZON reduced oxidative stress under high glucose conditions and retained podocyte-specific proteins. SignificanceA probable mechanism by which ZON prevents DN has been proposed, suggesting its use as a complementary therapeutic agent for the treatment of diabetic complications. To the best of our knowledge, this is the first study to demonstrate the in vitro effects of ZON in cultured podocytes.

Changes in the Progression of Chronic Kidney Disease in Patients Undergoing Fecal Microbiota Transplantation.

Chronic kidney disease (CKD) is a progressive loss of renal function in which gut dysbiosis is involved. Fecal microbiota transplantation (FMT) may be a promising alternative for restoring gut microbiota and treating CKD. This study evaluated the changes in CKD progression in patients treated with FMT. Patients with diabetes and/or hypertension with CKD clinical stages 2, 3, and 4 in this single-center, double-blind, randomized, placebo-controlled clinical trial (NCT04361097) were randomly assigned to receive either FMT or placebo capsules for 6 months. Laboratory and stool metagenomic analyses were performed. A total of 28 patients were included (15 FMT and 13 placebo). Regardless of CKD stages, patients responded similarly to FMT treatment. More patients (53.8%) from the placebo group progressed to CKD than the FMT group (13.3%). The FMT group maintained stable renal function parameters (serum creatinine and urea nitrogen) compared to the placebo group. Adverse events after FMT treatment were mild or moderate gastrointestinal symptoms. The abundance of Firmicutes and Actinobacteria decreased whereas Bacteroidetes, Proteobacteria and Roseburia spp. increased in the FMT group. CKD patients showed less disease progression after FMT administration. The administration of oral FMT in patients with CKD is a safe strategy, does not represent a risk, and has potential benefits.

Deep venous thrombosis in autosomal dominant polycystic kidney

ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent genetic cystic condition that results in progressive loss of renal function. The disease is associated with various complications, including compression of adjacent structures like the inferior vena cava (IVC), which can lead to deep vein thrombosis (DVT) and ultimately, pulmonary embolism. This report details a case of a 41-year-old patient with ADPKD who presented with left leg DVT. Imaging revealed IVC compression due to enlarged kidneys, and blood tests indicated low levels of coagulation proteins C and S. The patient is hypertensive and has advanced renal failure (glomerular filtration rate [GFR] 12.6 mL/min) but has not yet initiated dialysis. The patient was initiated on treatment with the novel oral anticoagulant, apixaban, and exhibited favorable outcomes. His DVT is believed to be the result of multiple factors acting in concert. IVC compression, a significant precipitant doctor of DVT, is frequently observed in ADPKD patients, with rates as high as 15% in severe cases and 15% in mild cases, according to a study by Yin et al. The incidence of venous thromboembolism (VTE) in patients with chronic kidney disease increases as GFR decreases, with rates 2.5–5.5-fold higher in moderate-to-severe end-stage renal disease than in the general population. VTE is a multifactorial disease with both acquired and inherited thrombophilia factors. This particular case presents a unique event within our medical practice, as it is relatively uncommon to witness such a correlation between DVT and polycystic kidney disease. It serves as an exemplification of a case that necessitates diligent monitoring due to the heightened risk of recurrent DVT.

Effect of SDF-1 and CXCR4 gene variants on the development of diabetic kidney disease.

Diabetic kidney disease (DKD) is the gradual loss of renal function occurring in patients with diabetes. Stromal cell-derived factor-1 (SDF-1, encoded by SDF-1 gene) is a chemokine that binds to its receptor, CXCR4, to mediate many aspects of renal biology. To test the potential impact of SDF-1/CXCR4 gene variations on the risk for DKD, single-nucleotide polymorphisms (SNPs) of SDF-1/CXCR4 genes were genotyped in 388 DKD patients and 335 DKD-free diabetic controls. Among 6 SNPs examined, we demonstrated that rs1801157 of SDF-1 gene was associated with an increased risk for DKD (GA vs GG, AOR=2.252, p=0.035; GA+AA vs GG, AOR=2.156, p=0.036). Further stratification revealed that the correlation of rs1801157 with DKD was particularly detected in diabetic patients with early CKD but not in those with severe renal impairment. Instead, another SNP of SDF-1 gene, rs266085, was found in association with the advanced form of DKD (TC vs TT, AOR=2.106, p=0.027; TC+CC vs TT, AOR=2.130, p=0.019), indicating differential impacts of SDF-1 gene polymorphisms on the progressive loss of renal function in diabetic patients. Moreover, preliminary survey of public gene expression datasets showed that rs1801157 and rs266085 modulated SDF-1 expression in many human tissues, and SDF-1/CXCR4 levels were elevated in renal tissues of DKD patients. These data suggest that allele-specific expression of SDF-1 gene may influence DKD progression.

Calculation of Kidney Volumes with Magnetic Resonance in Patients with Autosomal Dominant Polycystic Kidney Disease: Comparison between Methods

Autosomal dominant polycystic renal disease (ADPKD) is the most frequent kidney inheritable disease, characterized by the presence of numerous bilateral renal cysts, causing a progressive increase in total kidney volume (TKV) and a progressive loss of renal function. Several methods can be used to measure TKV by using MRI, and they differ in complexity, accuracy and time consumption. This study was performed to assess the performance of the ellipsoid method and the semi-automatic segmentation method, both for TKV and SKV (single kidney volume) computation. In total, 40 patients were enrolled, and 78 polycystic kidneys analyzed. Two independent operators with different levels of experience evaluated renal volumetry using both methods. Mean error for ellipsoid method for SKV computation was −2.74 ± 11.79% and 3.25 ± 10.02% for the expert and the beginner operator, respectively (p = 0.0008). A Wilcoxon test showed a statistically significant difference between the two operators for both methods (SKV p = 0.0371 and 0.0034; TKV p = 0.0416 and 0.0171 for the expert and the beginner operator, respectively). No inter-operator significant difference was found for the semi-automatic method, in contrast to the ellipsoid method. Both with a Wilcoxon test and Bland–Altman plot, statistically significant differences were found when comparing SKV and TKV measurements obtained with the two methods for both operators, even if the differences are stronger for the beginner operator than for the expert one. The semi-automatic segmentation method showed more inter-observer reproducibility. The ellipsoid method, in contrast, appears to be affected by greater inter-observer variability, especially when performed by operators with limited experience.

The crucial role of the nephrologist in the management of pregnancy in women with adult autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic kidney disease characterized by gradual kidney enlargement and progressive renal function loss. Pregnancy is a significant risk factor for adverse maternal and fetal outcomes in chronic kidney disease (CKD), regardless of the nephropathy. Women with ADPKD often face concerns about worsening their renal condition and passing the disease on to their offspring. Recent studies show better outcomes due to improved pregnancy surveillance and prior counseling. Risk factors for poor fetal and maternal outcomes include advanced maternal age, pre-existing hypertension, urinary infections, proteinuria, and renal failure. Collaboration between nephrologists and gynecologists is essential for addressing clinically significant concerns in pregnant women with ADPKD. Nephrologists should play an active role in assisting and supporting pregnant ADPKD patients as part of a multidisciplinary team.

Noscapine alleviates unilateral ureteral obstruction-induced inflammation and fibrosis by regulating the TGFβ1/Smads signaling pathways

Renal fibrosis is a common pathway leading to progressive renal function loss in various forms of chronic kidney disease. Many fibrogenic factors regulate renal fibrosis; two key players are post-injury inflammation and transforming growth factor-β1 (TGF-β1)-induced myofibroblast differentiation. Myofibroblast differentiation is tightly regulated by the microtubule polymerization. Noscapine, an antitussive plant alkaloid, is a potent microtubule-interfering agent previously identified as a potential anticancer compound. Here, we examined how noscapine affects renal fibrogenesis in an in vitro renal fibroblast model and an in vivo unilateral ureteral obstruction (UUO) model. UUO mice were intraperitoneally treated with noscapine at 1 day before UUO surgery and daily thereafter. At 7 days post-surgery, kidneys were collected for further analysis. To analyze whether noscapine inhibits downstream TGF-β1-related signaling, we pre-incubated NRK-49F fibroblasts with noscapine and then performed TGF-β1 stimulation. In UUO mice, noscapine attenuated extracellular matrix protein deposition and the expression levels of type I collagen, type IV collagen, α-smooth muscle actin, and fibronectin. In addition, noscapine decreased tubulointerstitial inflammation in UUO kidneys by reducing TLR2 expression, modulating NLRP3 inflammasome activation, reducing macrophage infiltration, and antagonizing the M2 macrophage phenotype. Furthermore, noscapine pre-incubation suppressed the TGF-β1-induced fibroblast-myofibroblast transformation by downregulating the TGF-β/Smads signaling pathways in NRK-49F cells. These results suggest that noscapine reduces tubulointerstitial inflammation and fibrosis in the kidneys of UUO mice and inhibits the fibroblast-myofibroblast transformation induced by TGF-β1. Noscapine is an over-the-counter antitussive that has been used safely for several decades. Therefore, noscapine is an attractive therapeutic agent for inhibiting renal tubulointerstitial fibrosis.

Renal biopsy pattern in diabetes mellitus patients and their correlation with clinical parameters

Background. Diabetic nephropathy is a condition marked by persistent proteinuria, hypertension, and a progressive loss of renal function. End-stage kidney disease needing continuous renal replacement treatment is now primarily caused by diabetes. According to Kimmelstiel and Wilson, the hallmark lesion of diabetic nephropathy is nodular glomerulosclerosis. Diabetic nephropathy or Nondiabetic renal disease, or the coexistence of both can be seen in renal histopathology and in differentiating between these diagnostic groups can have an impact on patient care and prognosis.Patients and Methods. Total of 21 cases of Diabetic nephropathy were included in the study. Clinical details and laboratory parameters like diastolic blood pressure, creatinine level, 24 hrs urinary protein level and HbA1C% were recorded in pretested performa in all cases. The biopsy specimens were stained with hematoxylin &amp; eosin and special stains.Results. Among the total DM cases only 21 patients have done renal biopsy, 11 cases (52.3 %) showed KW lesion (Class III) while 06 cases (28.5 %) showed diffuse diabetic glomerulosclerosis (Class IV). The remaining 04 cases (19 %) showed a mild increase in mesangial matrix and slight thickening of glomerular basement membrane (Class II). When compared with clinical parameters, they were more raised in Nodular diabetic glomerulosclerosis type (Class III) lesion as compared to diffuse diabetic glomerulosclerosis.Conclusion. Nodular diabetic glomerulosclerosis was the most common lesion in renal biopsy of type II diabetes mellitus patients. This KW lesion is responsible for more severe clinical and biochemical renal abnormality in most patients with type II diabetes mellitus.

Alpha-cyano-4-hydroxycinnamic acid alleviates renal fibrosis and inflammation in chronic kidney disease

Renal fibrosis is a crucial pathological phenomenon of chronic kidney disease (CKD) that contributes to the progressive loss of renal function. Monocarboxylate transporter 1 (MCT1) plays an important role in clear cell renal cell carcinoma; however, the role of the MCT1 inhibitor alpha-cyano-4-hydroxycinnamic acid (α-CHCA) in renal fibrosis remains unclear. In this study, we evaluated the role of α-CHCA, an MCT1 inhibitor, in treating renal fibrosis associated with CKD. We used α-CHCA in a CKD mouse model of unilateral ureteral obstruction (UUO), and mouse proximal tubular epithelial cells (mPTCs) stimulated by transforming growth factor-β1 (TGF-β1). In vivo, administration of α-CHCA improved tubulointerstitial fibrosis, which was consistent with the reduced expression of collagen I/III, fibronectin (FN1), and α-smooth muscle actin (α-SMA) in the kidneys of UUO mice. Similarly, the overexpression of inflammatory factors in UUO kidneys decreased in response to α-CHCA treatment. In vitro, α-CHCA pretreatment inhibited the induction of collagen I/III, FN1, and α-SMA production in mPTCs treated with TGF-β1. Collectively, these findings indicate that α-CHCA may play a therapeutic role in renal fibrosis associated with CKD by inhibiting collagen deposition and subsequent fibrosis and inflammation. Highlights Chronic kidney disease (CKD) mice have increased MCT1 expression. α-CHCA, a MCT1 inhibitor, alleviates renal fibrosis in CKD mice. α-CHCA improves the inflammation in CKD mice. α-CHCA inhibits TGF-β1-induced extracellular matrix secretion of proximal tubular epithelial cells.

#6428 PERCUTANEOUS RENAL BIOPSY (PRB) IN METASTATIC RENAL CELL CARCINOMA (MRCC) PATIENTS WITH ACUTE KIDNEY INJURY (AKI) ON SYSTEMIC ANTICANCER THERAPY

Abstract Background and Aims PRB is relatively contraindicated in patients with solitary kidney (SK) due to the perception that PRB is a risky procedure in this patient population. There are however situations in which a renal biopsy is essential to assess renal toxicity of systemic therapy and/or to identify the underlying kidney disease in the remaining kidney. Data on pathological findings of the kidney disease in mRCC patients receiving systemic anticancer therapy is scarce and it may influence the cancer treatment plan. The main aim of this study was to characterize the pathological findings of PRB in patients with SK undergoing systemic therapy. Method We retrospectively analyzed the pathological findings of mRCC patients with AKI who underwent PRB during systemic treatment with antiangiogenic tyrosine kinase inhibitors (TKIs) and/or immune check point inhibitors (ICIs) at the Institute of Oncology Ljubljana between 2018 and 2022. All biopsies were performed under ultrasound guidance by the treating nephrologist in patients with clinical evidence of AKI and no other formal contraindications for PRB. Results A total of 11 PRBs were performed in 10 patients, eight of whom had SK (Table 1). Six patients were treated with TKIs and ICIs, three with ICIs and one with a TKI alone. None of the patients had major bleeding or required any additional intervention as a consequence of the PRB. Histology revealed thrombotic microangiopathy (TMA) in three, diabetic nephropathy in three, acute interstitial nephritis in two and focal segmental glomerulosclerosis in three patients. Based on pathological findings, the therapy was discontinued after seven PRBs. One patient with TMA showed progressive loss of renal function (RF) after discontinuation of antiangiogenic therapy while the other two had either stable or improved RF. Conclusion Our results indicate that PRB is a safe procedure in patients with SK undergoing systemic treatment for mRCC. The pathological findings in our patients guided the decision either to continue or to discontinue the treatment, which resulted in improvement or stabilization of RF in the vast majority of patients. This study suggests that in patients with SK, PRB can provide important information, which may have a significant impact on the oncological and the nephrological therapeutic approaches.

#5399 VONAFEXOR AS A NOVEL THERAPY FOR CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney diseases (CKD) are characterized by the progressive loss of renal function. The molecular mechanisms underlying this progression are still poorly characterized and probably multifactorial. Therefore, there is a real need to expand the very limited number of therapies able to slow down the rate of CKD progression. Recent findings indicate that NR1H4, a druggable nuclear receptor, might play an important role in CKD. The aim of this study was to investigate the benefit of Vonafexor, a novel small molecule and specific NR1H4 agonist in acquired and genetic models of CKD. Method Two complementary experimental models of CKD (the 75% excision of total renal mass (Subtotal Nephrectomy; Nx) and the Col4a3−/− mice, a model of Alport disease) were studied. NR1H4 and the expression of some of its downstream targets were evaluated by quantitative RT-PCR, western blot and immunohistochemistry. In the Nx model, mice were treated with Vonafexor by daily oral gavage from 5 to 8 weeks after the surgery. The possible beneficial effect was compared to that of Losartan and other NR1H4 agonists. In the Alport model, mice were treated by Vonafexor from 5 to 8 weeks after birth. In both models, group of mice were sacrificed at 5 weeks to evaluate the extent of renal lesions at baseline. Renal lesions were quantified using image J. Renal inflammation, myofibroblast activation and podocyte number were quantified after specific staining. Human biopsies were also studied. RNAseq was performed using Illumina NovaSeq6000. Results We observed that NR1H4 expression and OSTA and OSTB, two downstream targets of NR1H4, were significantly reduced in remnant kidneys of Nx FVB/N mice compared to sham-operated animals 8 weeks after surgery. Co-localization staining revealed that NR1H4 is mainly expressed in proximal tubules and, to a minor extent, in Henle loops. Renal lesions were already present at 5 weeks in both experimental models. Remarkably, Vonafexor stopped the progression of renal lesions, in terms of glomerulosclerosis and tubular dilatations and, more importantly, induced a regression of interstitial fibrosis 8 weeks after nephrectomy as compared to the 5-week baseline. Lymphocytes and macrophage infiltration, as well as activated myofibroblasts, were also significantly reduced. Similarly, podocyte loss was stopped by Vonafexor treatment. Of note, the beneficial effect of Vonafexor was unique compared to other classes of NR1H4 agonists and also higher than that of Losartan. The same beneficial curative effect was found in Col4a3−/− mice. RT-PCR confirmed the activation of several NR1H4 downstream targets in mice treated with Vonafexor, while RNAseq analysis revealed that Vonafexor impacted the pathological activation of pathways involved in cell cycle, cell signaling and metabolism. These results may be relevant to humans, since NR1H4 expression was significantly reduced in biopsies from patients with CKD of different etiologies as compared to control kidneys. Conclusion Altogether our results identified in Vonafexor a novel key drug to control CKD. This is consistent with recent results obtained in LIVIFY phase 2 clinical trial in which Vonafexor has already demonstrated beneficial effects on eGFR in NASH patients with mild to moderate CKD.

#4485 CLINICAL CASE OF MOSAICISM IN ADPKD PATIENT

Abstract Background and Aims Autosomal Dominant Polycystic Kidney Disease (ADPKD) it's mainly characterized by renal involvement with progressive bilateral development of renal cysts and volumetric increase of the kidneys, responsible for the progressive loss of renal function that leads to chronic kidney disease (CKD) and the need of renal replacement therapy. There are some cases (doubtful, uncertain) in which it is necessary to perform genetic testing to achieve a definitive diagnosis. It looks like in ADPKD patients, mosaicism could modulate the clinical course of the disease. Mosaicism is characterized by few cell populations with different genomes. In these special cases the diagnosis is very difficult and the genetic analysis could be an important and helpful tool. With this report, we want to highlight the importance of the use of several diagnostic methods in those ‘atypical’ cases where otherwise the analysis would have been negative from a first molecular approach. Method A 47 years old woman came to our attention with typical picture of ADPKD, arterial hypertension and chronic kidney disease CKD (3b). She had no ADPKD family history, but since she had a son, genetic testing was performed. According to our workflow, first level analysis includes Next Generation Sequencing (NGS). Second level analysis, performed to investigate other genes and large rearrangement, was based on Multiplex Ligation-dependent Probe Amplification (MLPA) analysis of PKD1 and PKD2 genes, using Salsa MLPA ProbeMix P352 PKD1PKD2 kit and ProbeMix P351 PKD1 kit ©MRC Holland. Results NGS did not detect the presence of any genomic variants. Therefore, second-level genetic analysis (several approaches), showed a large deletion in heterozygosis of the portion comprising the 3-33 exons of PKD1 gene in mosaic in percentage close to the resolution limits of the used technique (25-30%). The same analysis was confirmed in another laboratory. Conclusion We concluded that the identified large deletion, without establishing the real borders due to MLPA technical restrictions, was present as mosaicism. The variant is not reported, but due to the type of mutation and the clinical picture of the patient, it is to be considered as likely pathogenic. A stepwise genetic approach might be useful in those cases where standard methods do not allow to reach a definitive diagnosis.