scholarly journals Increased colonic K+ excretion through inhibition of the H,K-ATPase type 2 helps reduce plasma K+ level in a murine model of nephronic reduction

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Christine Walter ◽  
Chloé Rafael ◽  
Anthony Genna ◽  
Stéphanie Baron ◽  
Gilles Crambert
Keyword(s):  
Enzyme Inhibitor ◽  
Specific Method ◽  
Proof Of Concept ◽  
Cation Exchange Resins ◽  
Severe Hyperkalemia ◽  
Dependent Absorption ◽  
Targeted Inhibition ◽  
Exchange Resins ◽  
End Stage

AbstractHyperkalemia is frequently observed in patients at the end-stage of chronic kidney disease (CKD), and has possible harmful consequences on cardiac function. Many strategies are currently used to manage hyperkalemia, one consisting of increasing fecal K+ excretion through the administration of cation-exchange resins. In this study, we explored another more specific method of increasing intestinal K+ secretion by inhibiting the H,K-ATPase type 2 (HKA2), which is the main colonic K+ reabsorptive pathway. We hypothetised that the absence of this pump could impede the increase of plasma K+ levels following nephronic reduction (N5/6) by favoring fecal K+ secretion. In N5/6 WT and HKA2KO mice under normal K+ intake, the plasma K+ level remained within the normal range, however, a load of K+ induced strong hyperkalemia in N5/6 WT mice (9.1 ± 0.5 mM), which was significantly less pronounced in N5/6 HKA2KO mice (7.9 ± 0.4 mM, p < 0.01). This was correlated to a higher capacity of HKA2KO mice to excrete K+ in their feces. The absence of HKA2 also increased fecal Na+ excretion by inhibiting its colonic ENaC-dependent absorption. We also showed that angiotensin-converting-enzyme inhibitor like enalapril, used to treat hypertension during CKD, induced a less severe hyperkalemia in N5/6 HKA2KO than in N5/6 WT mice. This study therefore provides the proof of concept that the targeted inhibition of HKA2 could be a specific therapeutic maneuver to reduce plasma K+ levels in CKD patients.

scholarly journals Patiromer in a Patient with Severe Hyperkalemia on Incremental Hemodialysis with 1 Session per Week: A Case Report and Literature Review

2021 ◽  
pp. 158-166
Author(s):  
José C. De La Flor ◽  
Javier Deira ◽  
Alexander Marschall ◽  
Francisco Valga ◽  
Tania Linares ◽  
...  
Keyword(s):  
Volume Overload ◽  
Sodium Polystyrene Sulfonate ◽  
Dialysis Dose ◽  
Cation Exchange Resins ◽  
Incremental Hemodialysis ◽  
Severe Hyperkalemia ◽  
Exchange Resins ◽  
Potassium Binders ◽  
Sodium Zirconium Cyclosilicate

Hyperkalemia is common in patients with ESRD, undergoing hemodialysis (HD), and is associated with an increase in hospitalization and mortality. Residual kidney function in long-term dialysis patients is associated with lower morbidity and mortality in HD patients. Although the 2015 National Kidney Foundation-Kidney Disease Outcomes Quality Initiate (NKD-KDOQI) guidelines allow the reduction in the weekly HD dose for patients with a residual kidney urea clearance (Kur) &#x3e;3 mL/min/1.73 m<sup>2</sup>, very few centers adjust the dialysis dose based on these criteria. In our center, the pattern of incremental hemodialysis (iHD) with once-a-week schedule (1 HD/W) has been an option for a group of patients showing very good results. This pattern is maintained as long as residual diuresis is &#x3e;1,000 mL/24 h, Kur is &#x3e;4 mL/min, and there is no presence of edema or volume overload, as well as no analytical parameters persistently outside the advisable range (serum phosphorus &#x3e;6 mg/dL or potassium [K<sup>+</sup>] &#x3e;6.5 mmol/L). Management of hyperkalemia in HD patients includes reduction of dietary intake, dosing of medications that contribute to hyperkalemia, and use of cation-exchange resins such as calcium or sodium polystyrene sulfonate. Two newer potassium binders, patiromer sorbitex calcium and sodium zirconium cyclosilicate, have been safely used for potassium imbalance treatment in patients with ESRD in HD with a conventional regimen of thrice weekly, but has not yet been studied in 1 HD/W schedules. We present the case of a 76-year-old woman in iHD (1 HD/W) treated with patiromer for severe HK and describe her clinical characteristics and outcomes. In addition, we review the corresponding literature. Based on these data, it can be anticipated that the use of patiromer may overcome the risk of hyperkalemia in patients with incident ESRD treated with less-frequent HD regimens.

scholarly journals Antifibrotic Effect of a Novel Selective 11β-HSD2 Inhibitor (WZ51) in a rat Model of Myocardial Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Fei Zhuang ◽  
Qin Ge ◽  
Jiangchang Qian ◽  
Zhe Wang ◽  
Yaoyao Dong ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Myocardial Fibrosis ◽  
Myocardial Injury ◽  
Therapeutic Agent ◽  
Enzyme Inhibitor ◽  
Hydroxysteroid Dehydrogenase ◽  
Underlying Mechanism ◽  
Mineralocorticoid Receptors ◽  
End Stage

Myocardial fibrosis (MF) is one of the leading causes of end-stage heart disease. Many studies have confirmed that inflammation caused by aldosterone may play an important role in the process of MF. A selective 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) enzyme inhibitor can reduce the inactivation of cortisol, allowing cortisol to compete for mineralocorticoid receptors. This study investigated the protective effect of a novel selective 11βHSD2 inhibitor (WZ51) on MF and described its underlying mechanism. The administration of WZ51 in rats with MF significantly alleviated myocardial injury, accompanied by a decrease in lactate dehydrogenase and the creatine kinase myocardial band. Furthermore, WZ51 significantly inhibited the development of MF and increased the protein level of 11β-HSD2. The results of this study demonstrate that 11β-HSD2 plays an important pathological role in MF. Thus, WZ51 may be a potential therapeutic agent for the treatment of this condition.

scholarly journals The Severity of Diabetic Retinopathy Is an Independent Factor for the Progression of Diabetic Nephropathy

2020 ◽  
Vol 10 (1) ◽  
pp. 3
Author(s):  
Shi-Chue Hsing ◽  
Chia-Cheng Lee ◽  
Chin Lin ◽  
Jiann-Torng Chen ◽  
Yi-Hao Chen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Diabetic Retinopathy ◽  
Kidney Disease ◽  
Renal Disease ◽  
Disease Progression ◽  
Renal Disease Progression ◽  
Hazard Ratios ◽  
Stage Renal Disease ◽  
End Stage

(1) Background: It has rarely been studied whether the severity of diabetic retinopathy (DR) could influence renal disease progression in end-stage renal disease (ESRD) and chronic kidney disease (CKD) in patients with type 2 diabetes. The aim of this study was to evaluate renal disease progression in ESRD and CKD according to DR severity in patients with type 2 diabetes. (2) Methods: We included 1329 patients and divided the cohort into two end-points. The first was to trace the incidence of ESRD in all enrolled participants and the other was to follow their progression to CKD. (3) Results: Significantly higher crude hazard ratios (HRs) of ESRD incidence in all enrolled participants were noted, and this ratio increased in a stepwise fashion. However, after adjustment, DR severity was not associated with ESRD events. Therefore, a subgroup of 841 patients without CKD was enrolled to track their progression to CKD. Compared with no diabetic retinopathy, the progression of CKD increased in a stepwise fashion, from mild nonproliferative diabetic retinopathy (NPDR) to moderate NPDR, to severe NPDR and to proliferative diabetic retinopathy (PDR), both in the crude and adjusted models. (4) Conclusions: The severity of retinopathy appeared to be associated with renal lesions and the development of CKD. Our findings suggest that the severity of DR is a risk factor for progression to CKD. Therefore, diabetic retinopathy is useful for prognosticating the clinical course of diabetic kidney disease.

scholarly journals IGFBP-1 expression is reduced in human type 2 diabetic glomeruli and modulates β1-integrin/FAK signalling in human podocytes

Diabetologia ◽  
2021 ◽  
Author(s):  
Abigail C. Lay ◽  
Lorna J. Hale ◽  
Holly Stowell-Connolly ◽  
Robert J. P. Pope ◽  
Viji Nair ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Igf Binding Proteins ◽  
Impedance Sensing ◽  
Human Type ◽  
Early Stages ◽  
Igf Binding ◽  
Phosphoinositide 3 Kinase ◽  
End Stage

AbstractAims/hypothesisPodocyte loss or injury is one of the earliest features observed in the pathogenesis of diabetic kidney disease (DKD), which is the leading cause of end-stage renal failure worldwide. Dysfunction in the IGF axis, including in IGF binding proteins (IGFBPs), is associated with DKD, particularly in the early stages of disease progression. The aim of this study was to investigate the potential roles of IGFBPs in the development of type 2 DKD, focusing on podocytes.MethodsIGFBPexpression was analysed in the Pima DKD cohort, alongside data from the Nephroseq database, and in ex vivo human glomeruli. Conditionally immortalised human podocytes and glomerular endothelial cells were studied in vitro, where IGFBP-1 expression was analysed using quantitative PCR and ELISAs. Cell responses to IGFBPs were investigated using migration, cell survival and adhesion assays; electrical cell-substrate impedance sensing; western blotting; and high-content automated imaging.ResultsData from the Pima DKD cohort and from the Nephroseq database demonstrated a significant reduction in glomerularIGFBP-1in the early stages of human type 2 DKD. In the glomerulus, IGFBP-1 was predominantly expressed in podocytes and controlled by phosphoinositide 3-kinase (PI3K)–forkhead box O1 (FoxO1) activity. In vitro,IGFBP-1 signalled to podocytes via β1-integrins, resulting in increased phosphorylation of focal-adhesion kinase (FAK), increasing podocyte motility, adhesion, electrical resistance across the adhesive cell layer and cell viability.Conclusions/interpretationThis work identifies a novel role for IGFBP-1 in the regulation of podocyte function and that the glomerular expression ofIGFBP-1is reduced in the early stages of type 2 DKD, via reduced FoxO1 activity. Thus, we hypothesise that strategies to maintain glomerular IGFBP-1 levels may be beneficial in maintaining podocyte function early in DKD.Graphical abstract

Study on the Alkoxylation of Dihydromyrcene over Cation Exchange Resins

2019 ◽  
Vol 58 (27) ◽  
pp. 11871-11877 ◽  
Author(s):  
Si Chen ◽  
Su Wang ◽  
Zheng Zhou ◽  
Gaodong Yang ◽  
Zhibing Zhang
Keyword(s):  
Cation Exchange ◽  
Cation Exchange Resins ◽  
Exchange Resins

Lung transplantation for silicosis and recovery: an Australian case study

2021 ◽  
Vol 30 (3) ◽  
pp. 178-183
Author(s):  
Kate McEwen ◽  
Lyndell Brodie
Keyword(s):  
Lung Transplantation ◽  
Medication Management ◽  
Social Situation ◽  
Bilateral Lung Transplantation ◽  
Transplantation Surgery ◽  
Australian Case ◽  
Bilateral Lung ◽  
End Stage

Lung transplantation is a well-established treatment for a variety of end-stage pulmonary diseases. However, the journey of a lung transplant recipient is complex and multifaceted. Silicosis is a rare indication for lung transplantation, but no other treatment is yet available for this disease in its end stages. This Australian case study presents a 52-year-old man with silicosis who received bilateral lung transplantation. The patient was frequently noncompliant with noninvasive ventilation therapy and experienced the complication of type 2 respiratory failure. Patient education and support provided, particularly around medication management following transplantation surgery, are discussed here. The patient's social situation and its implications for both him and his family are also considered.

scholarly journals A novel variant in the COL4A3 gene: etiology of Alport syndrome type 2 in a 38-year-old male with suspected hereditary kidney disease

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Paula Sienes Bailo ◽  
José Luis Bancalero Flores ◽  
Raquel Lahoz Alonso ◽  
María Santamaría González ◽  
Alex Gutiérrez Dalmau ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Alport Syndrome ◽  
Clinical Symptoms ◽  
Molecular Testing ◽  
Syndrome Type ◽  
Variant Of Uncertain Significance ◽  
Type Iv ◽  
Novel Variant ◽  
End Stage

ABSTRACT Objectives Patients with Alport syndrome develop progressive kidney function deterioration, sensorineural hearing loss, and ocular abnormalities. This condition is caused by mutations in COL4A5 (X-linked inheritance), COL4A3 and COL4A4 (autosomal dominant or recessive inheritance), and encoding type IV collagen α3, α4, and α5, respectively. If left untreated, clinical symptoms progress from microscopic hematuria to proteinuria, progressive kidney failure, and end-stage kidney disease. At present, kidney transplantation is the only effective approach. Next-generation sequencing is the method of choice for the diagnosis of this condition. Case presentation We report the case of a young man with chronic kidney disease who eventually underwent transplantation. Molecular testing made it possible to determine the etiology of his clinical symptoms and autosomal recessive Alport syndrome type 2. The patient was found to be a compound heterozygote for two missense variants (trans configuration) in the COL4A3 gene: A likely pathogenic variant c.4981C>T (p.Arg1661Cys) in exon 52 inherited from the mother (described elsewhere), and another variant of uncertain significance, c.943G>A (p.Gly315Ser), in exon 17 inherited from the father that has not been previously reported in the literature or found in relevant databases. Conclusions Following genetic confirmation, genetic counseling was provided to the patient and his direct relatives.

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