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10 pages, 1920 KiB

Open AccessArticle

Urea Transporter Inhibitor 25a Reduces Ascites in Cirrhotic Rats

by Yi Ying, Nannan Li, Shuyuan Wang, Hang Zhang, Yinglin Zuo, Yiwen Tang, Panshuang Qiao, Yazhu Quan, Min Li and Baoxue Yang

Biomedicines 2023, 11(2), 607; https://doi.org/10.3390/biomedicines11020607 - 17 Feb 2023

Cited by 1 | Viewed by 1323

Abstract

Ascites is a typical symptom of liver cirrhosis that is caused by a variety of liver diseases. Ascites severely affects the life quality of patients and needs long-term treatment. 25a is a specific urea transporter inhibitor with a diuretic effect that does not [...] Read more.

Ascites is a typical symptom of liver cirrhosis that is caused by a variety of liver diseases. Ascites severely affects the life quality of patients and needs long-term treatment. 25a is a specific urea transporter inhibitor with a diuretic effect that does not disturb the electrolyte balance. In this study, we aimed to determine the therapeutic effect of 25a on ascites with a dimethylnitrosamine (DMN)-induced cirrhotic rat model. It was found that 100 mg/kg of 25a significantly increased the daily urine output by 60% to 97% and reduced the daily abdominal circumference change by 220% to 260% in cirrhotic rats with a water intake limitation. The 25a treatment kept the serum electrolyte levels within normal ranges in cirrhotic rats. The H&E and Masson staining of liver tissue showed that 25a did not change the cirrhotic degree. A serum biochemical examination showed that 25a did not improve the liver function in cirrhotic rats. A Western blot analysis showed that 25a did not change the expression of fibrosis-related marker protein α-SMA, but significantly decreased the expressions of type I collagen in the liver of cirrhotic rats, indicating that 25a did not reverse cirrhosis, but could slow the cirrhotic progression. These data indicated that 25a significantly reduced ascites via diuresis without an electrolyte imbalance in cirrhotic rats. Our study provides a proof of concept that urea transporter inhibitors might be developed as novel diuretics to treat cirrhotic ascites. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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15 pages, 1287 KiB

Open AccessArticle

Who Should Not Be Surveilled for HCC Development after Successful Therapy with DAAS in Advanced Chronic Hepatitis C? Results of a Long-Term Prospective Study

by Alessia Ciancio, Davide Giuseppe Ribaldone, Matteo Spertino, Alessandra Risso, Debora Ferrarotti, Gian Paolo Caviglia, Patrizia Carucci, Silvia Gaia, Emanuela Rolle, Marco Sacco and Giorgio Maria Saracco

Biomedicines 2023, 11(1), 166; https://doi.org/10.3390/biomedicines11010166 - 09 Jan 2023

Cited by 6 | Viewed by 1594

Abstract

Background and aims: The identification of patients with Hepatitis C Virus (HCV)-positive advanced chronic liver disease (aCLD) successfully treated by Direct Acting Antiviral Agents (DAAs) who really benefit from Hepatocellular Carcinoma (HCC) surveillance programs is still a matter of debate. We performed [...] Read more.

Background and aims: The identification of patients with Hepatitis C Virus (HCV)-positive advanced chronic liver disease (aCLD) successfully treated by Direct Acting Antiviral Agents (DAAs) who really benefit from Hepatocellular Carcinoma (HCC) surveillance programs is still a matter of debate. We performed a long-term prospective cohort study on F3-F4 HCV-positive patients achieving Sustained Virologic Response (SVR) after DAAs treatment in order to identify patients who can safely suspend surveillance. Methods: 1000 patients with HCV-positive aCLD obtaining SVR by DAAs from January 2015 to December 2017 were divided into four groups according to baseline elastographic, ultrasonographic, clinical and biochemical features: (1) Group 1: 324 patients with Liver Stiffness Measurement (LSM) ≥ 9.5 ≤ 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (2) Group 2: 133 patients with LSM ≥ 9.5 ≤ 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5 (3) Group 3: 158 patients with LSM > 14.5 kPa, FIB-4 < 3.25 and APRI < 1.5 (4) Group 4: 385 patients with LSM > 14.5 kPa, FIB-4 ≥ 3.25 and/or APRI ≥ 1.5. FIB-4 and APRI scores were calculated at baseline and at SVR achievement. Each patient was surveiled twice-yearly by ultrasound for a median follow-up of 48 months. Results: among Group 1 patients, 1/324 (0.3%) developed HCC (0.09/100 patients/year [PY]), compared to 6/133 (4.5%) Group 2 patients (1.22/100 PY, p = 0.0009), 10/158 (6.3%) Group 3 patients (1.68/100 PY, p = 0.0001), 54/385 (14.0%) Group 4 patients (4.01/100 PY, p < 0.0001). HCC incidence was significantly lower in Group 2 compared to Group 3 (p = 0.004) and in Group 3 compared to Group 4 (p = 0.009). HCC risk fell in patients showing a decrease of FIB-4/APRI scores. Conclusions: the risk of HCC occurrence is negligible in about 90% of HCV-positive patients with baseline LSM ≥ 9.5 ≤ 14.5 kPa plus FIB-4 < 3.25 and APRI < 1.5 achieving SVR. Among this particular subset of patients, FIB-4/APRI scores may represent an accurate and inexpensive tool to distinguish patients not needing long-term HCC surveillance. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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18 pages, 5231 KiB

Open AccessArticle

The Role of NF-κB and Bax/Bcl-2/Caspase-3 Signaling Pathways in the Protective Effects of Sacubitril/Valsartan (Entresto) against HFD/STZ-Induced Diabetic Kidney Disease

by Mohamed Mohany, Mohammed M. Ahmed and Salim S. Al-Rejaie

Biomedicines 2022, 10(11), 2863; https://doi.org/10.3390/biomedicines10112863 - 09 Nov 2022

Cited by 5 | Viewed by 2376

Abstract

LCZ696 (valsartan/sacubitril) has the potential to slow the progression of diabetic kidney disease (DKD) according to previous reports. However, the renoprotective mechanism underlying LCZ696 remains unknown. This study aimed to investigate the therapeutic potential and underlying mechanism of LCZ696 in DKD in a [...] Read more.

LCZ696 (valsartan/sacubitril) has the potential to slow the progression of diabetic kidney disease (DKD) according to previous reports. However, the renoprotective mechanism underlying LCZ696 remains unknown. This study aimed to investigate the therapeutic potential and underlying mechanism of LCZ696 in DKD in a type 2 diabetic (T2D) rat model. This model was established in this experiment by feeding a high-fat diet (HFD) for six weeks with a single dose of streptozotocin (STZ, 30 mg/kg body weight). Valsartan or LCZ696 was orally administered to T2D animals for eight weeks. HFD/STZ rats showed hyperglycemia, impaired insulin secretion, significant increases in urea, creatinine, cytokines, nuclear factor kappa B (NF-κB), oxidative stress, caspase-3 activity, glomerular and tubular damage, glomerulsclerosis, Bax and caspese-3 expressions along with a significant decline in IL-10, antioxidant markers, and Bcl-2 expression. The administration of LCZ696 to diabetic rats reduced the serum concentrations of glucose, urea, and creatinine. In addition, ELISA results demonstrated that diabetic rats treated with LCZ696 exhibited a reduction in inflammatory (IL-1β, TNF-α, IL-6) and an increase in anti-inflammatory (IL-10) cytokine levels. In addition, a notable decrease in NF-κB and caspase-3 activity was observed. At the level of renal tissue homogenate, diabetic animals treated with LCZ696 demonstrated clear restorations in GSH content and other antioxidant enzyme levels, in addition to a significant decrease in TBARS levels. In addition, LCZ696 inhibited the expression of the Bax and cleaved caspase-3 proteins and enhanced the expression of the Bcl-2 protein. Improvements in histopathological changes in kidney tissues confirmed and significantly supported these biochemical findings. In summary, LCZ696 alleviated DKD with possible mechanisms including inhibition of inflammation and apoptosis. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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10 pages, 1299 KiB

Open AccessArticle

Intrapatient Variability (IPV) and the Blood Concentration Normalized by the Dose (C/D Ratio) of Tacrolimus—Their Correlations and Effects on Long-Term Renal Allograft Function

by Ewa Kwiatkowska, Kazimierz Ciechanowski, Leszek Domański, Violetta Dziedziejko, Jarosław Przybyciński and Andrzej Pawlik

Biomedicines 2022, 10(11), 2860; https://doi.org/10.3390/biomedicines10112860 - 08 Nov 2022

Viewed by 1276

Abstract

Tacrolimus, in combination with mycophenolate mofetil and glucocorticoids, is the basis of immunosuppressive therapy after renal transplantation. Tacrolimus intrapatient variability (IPV) and the blood concentration normalized by the dose (concentration/dose ratio, C/D ratio) both have an effect on the function of the transplanted [...] Read more.

Tacrolimus, in combination with mycophenolate mofetil and glucocorticoids, is the basis of immunosuppressive therapy after renal transplantation. Tacrolimus intrapatient variability (IPV) and the blood concentration normalized by the dose (concentration/dose ratio, C/D ratio) both have an effect on the function of the transplanted kidney. In this study, we examined whether the metabolism rate affected IPV, whether the C/D ratio value was stable in the long-term follow-up, and whether it could be used for IPV measurements. In addition, our study population was examined for the effect of the C/D ratio and IPV on long-term renal function. The C/D ratio and IPV were examined in 170 patients at appointments held at 3, 6, 12 and 24 months after RTx. The average time post renal transplantation was 70 months. Renal function defined as creatinine concentration at the last appointment was examined. Results: the mean C/D ratio in the study group was 1.63. A negative correlation between the C/D ratio and creatinine concentration at the end of the follow-up was observed. Between the C/D ratio < and ≥1.63 groups, significant differences in creatinine concentration at the last appointment were found. No relationship was identified between the mean C/D ratio and IPV. The C/D ratio values increased significantly over a longer post-transplant period (12, 24, 60 and 120 m). We did not find a correlation between the mean IPV and the creatinine concentration from the last appointment. Our study group was divided into terciles according to IPV, while no renal graft function differences were found at the same appointment. Conclusion: the C/D ratio is useful for assessing the effects of the metabolism rate of tacrolimus on the long-term renal graft function. The C/D ratio does not affect the IPV value. IPV calculated from variability of the C/D ratio does not influence transplanted kidney function. The C/D changes over time. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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14 pages, 2319 KiB

Open AccessArticle

DNAJB9 Is a Reliable Immunohistochemical Marker of Fibrillary Glomerulonephritis: Evaluation of Diagnostic Efficacy in a Large Series of Kidney Biopsies

by Alessandro Gambella, Chiara Pitino, Antonella Barreca, Alberto Nocifora, Manuela Maria Giarin, Luca Bertero, Luigi Biancone, Dario Roccatello, Mauro Papotti and Paola Cassoni

Biomedicines 2022, 10(9), 2102; https://doi.org/10.3390/biomedicines10092102 - 27 Aug 2022

Viewed by 1700

Abstract

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease characterized by a challenging diagnostic workup requiring ultrastructural identification of 20 nm-thick randomly oriented fibrillar deposits. However, the recent introduction of DNAJB9 as a putative diagnostic marker of FGN could thoroughly improve this diagnostic scenario. [...] Read more.

Fibrillary glomerulonephritis (FGN) is a rare glomerular disease characterized by a challenging diagnostic workup requiring ultrastructural identification of 20 nm-thick randomly oriented fibrillar deposits. However, the recent introduction of DNAJB9 as a putative diagnostic marker of FGN could thoroughly improve this diagnostic scenario. This study aims to assess the DNAJB9 immunohistochemical expression in a large series of FGN cases and to eventually confirm its role as a diagnostic marker of FGN. We evaluated the immunohistochemical expression of DNAJB9 (Rabbit Polyclonal, ThermoFisher) in a series of 77 FGN and 128 non-FGN cases diagnosed between January 1992 and June 2022 at the Pathology Unit of the AOU Città della Salute e della Scienza Hospital. DNAJB9 was expressed in 73 of the 74 evaluable FGN cases, mostly showing a strong glomerular positivity (68 cases). Additionally, DNAJB9 resulted positive in all challenging scenarios [early-stage (6), congophilic (4), combined (4), and uncertain (4) cases of FGN)]. DNAJB9 was negative in all non-FGN cases, eventually resulting in a specificity of 100% and sensitivity of 99%. In conclusion, we confirmed the role of DNAJB9 as a diagnostic marker of FGN. Its adoption in the clinical routine will allow a faster, more feasible, and more accurate FGN diagnosis. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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15 pages, 4442 KiB

Open AccessArticle

Combined Effects of Chronic Kidney Disease and Nonalcoholic Fatty Liver Disease on the Risk of Cardiovascular Disease in Patients with Diabetes

by Goh-Eun Chung, Kyungdo Han, Kyu-Na Lee, Eun-Ju Cho, Jung-Ho Bae, Sun-Young Yang, Su-Jong Yu, Seung-Ho Choi, Jeong-Yoon Yim and Nam-Ju Heo

Biomedicines 2022, 10(6), 1245; https://doi.org/10.3390/biomedicines10061245 - 26 May 2022

Cited by 3 | Viewed by 1972

Abstract

Background: We investigated the combined effect of chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD) on the risk of cardiovascular disease (CVD) in patients with type 2 diabetes. Methods: Data were obtained from the Korean National Health Insurance Service. Patients with [...] Read more.

Background: We investigated the combined effect of chronic kidney disease (CKD) and nonalcoholic fatty liver disease (NAFLD) on the risk of cardiovascular disease (CVD) in patients with type 2 diabetes. Methods: Data were obtained from the Korean National Health Insurance Service. Patients with diabetes who participated in health screenings from 2009 to 2011 were included. The fatty liver index (FLI) was used as a surrogate marker for NAFLD. Results: During a mean follow-up of 6.9 years, 40,863 incidents of myocardial infarction (MI), 58,427 strokes, and 116,977 deaths were reported in 1,607,232 patients with type 2 diabetes. After adjusting for conventional risk factors, patients with CKD and NAFLD showed the highest risk of MI and stroke (hazard ratio (HR) = 1.49; 95% confidence interval (CI): 1.42–1.57 and stroke, HR = 1.48; 95% CI: 1.41–1.54, respectively) compared with those without either CKD or NAFLD. Both overall and cardiovascular mortality were highest in the CKD/NAFLD group compared with other groups (HR = 2.00; 95% CI: 1.94–2.06, and HR = 2.20; 95% CI: 2.07–2.35, respectively). Advanced liver fibrosis was significantly associated with an increased risk of CVD in patients with NAFLD. Proteinuria was significantly associated with incidence of CVD events in patients with CKD. Conclusions: The combination of CKD and NAFLD was associated with an increased risk of CVD and mortality in patients with type 2 diabetes. Close monitoring and appropriate management of CKD and NAFLD may be warranted to prevent CVD in these patients. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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Review

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34 pages, 1439 KiB

Open AccessReview

Novel Approaches in Chronic Renal Failure without Renal Replacement Therapy: A Review

by Sandra Luz Martínez-Hernández, Martín Humberto Muñoz-Ortega, Manuel Enrique Ávila-Blanco, Mariana Yazmin Medina-Pizaño and Javier Ventura-Juárez

Biomedicines 2023, 11(10), 2828; https://doi.org/10.3390/biomedicines11102828 - 18 Oct 2023

Cited by 2 | Viewed by 2545

Abstract

Chronic kidney disease (CKD) is characterized by renal parenchymal damage leading to a reduction in the glomerular filtration rate. The inflammatory response plays a pivotal role in the tissue damage contributing to renal failure. Current therapeutic options encompass dietary control, mineral salt regulation, [...] Read more.

Chronic kidney disease (CKD) is characterized by renal parenchymal damage leading to a reduction in the glomerular filtration rate. The inflammatory response plays a pivotal role in the tissue damage contributing to renal failure. Current therapeutic options encompass dietary control, mineral salt regulation, and management of blood pressure, blood glucose, and fatty acid levels. However, they do not effectively halt the progression of renal damage. This review critically examines novel therapeutic avenues aimed at ameliorating inflammation, mitigating extracellular matrix accumulation, and fostering renal tissue regeneration in the context of CKD. Understanding the mechanisms sustaining a proinflammatory and profibrotic state may offer the potential for targeted pharmacological interventions. This, in turn, could pave the way for combination therapies capable of reversing renal damage in CKD. The non-replacement phase of CKD currently faces a dearth of efficacious therapeutic options. Future directions encompass exploring vaptans as diuretics to inhibit water absorption, investigating antifibrotic agents, antioxidants, and exploring regenerative treatment modalities, such as stem cell therapy and novel probiotics. Moreover, this review identifies pharmaceutical agents capable of mitigating renal parenchymal damage attributed to CKD, targeting molecular-level signaling pathways (TGF-β, Smad, and Nrf2) that predominate in the inflammatory processes of renal fibrogenic cells. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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19 pages, 1546 KiB

Open AccessReview

Challenges in Diagnosis and Therapeutic Approach of Acute on Chronic Liver Failure—A Review of Current Evidence

by Cristina Maria Marginean, Denisa Pirscoveanu, Mihaela Popescu, Corina Maria Vasile, Anca Oana Docea, Radu Mitruț, Iulia Cristina Mărginean, George Alexandru Iacob, Dan Mihai Firu and Paul Mitruț

Biomedicines 2023, 11(7), 1840; https://doi.org/10.3390/biomedicines11071840 - 26 Jun 2023

Cited by 3 | Viewed by 2265

Abstract

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by acute and severe decompensation of chronic liver disease (CLD) correlated with multiple organ failure, poor prognosis, and increased mortality. In 40–50% of ACLF cases, the trigger is not recognized; for many of these patients, [...] Read more.

Acute-on-chronic liver failure (ACLF) is a syndrome characterized by acute and severe decompensation of chronic liver disease (CLD) correlated with multiple organ failure, poor prognosis, and increased mortality. In 40–50% of ACLF cases, the trigger is not recognized; for many of these patients, bacterial translocation associated with systemic inflammation is thought to be the determining factor; in the other 50% of patients, sepsis, alcohol consumption, and reactivation of chronic viral hepatitis are the most frequently described trigger factors. Other conditions considered precipitating factors are less common, including acute alcoholic hepatitis, major surgery, TIPS insertion, or inadequate paracentesis without albumin substitution. Host response is likely the primary factor predicting ACLF severity and prognosis, the host immune response having a particular significance in this syndrome, together with the inflammatory cascade. The management of ACLF includes both the prevention of the precipitating factors that lead to acute liver decompensation and the support of vital functions, the prevention and management of complications, the estimation of prognosis, and the opportunity for liver transplantation. Full article

(This article belongs to the Special Issue Chronic Kidney and Liver Disease: From Pathophysiology to Novel Therapeutic Approaches 2.0)

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