Chronic Kidney Disease–Associated Pruritus is Caused by Dysregulated Ion Channels in Sensory Neurons

Background: We investigated ion channels at the skin, including peripheral nerve endings, which serve as output machines and molecular integrators of many pruritic inputs mainly received by multiple G protein-coupled receptors (GPCRs). Methods: Based on the level of chronic kidney disease–associated pruritus (CKD-aP), subjects were divided into two groups: non-CKD-aP (no or slight pruritus; n=12) and CKD-aP (mild, moderate, or severe pruritus; n=11). Skin samples were obtained from the forearm or elbow during operations on arteriovenous fistulas. We measured ion channels expressed at the skin, including peripheral nerve endings by RT-PCR: Nav1.8, Kv1.4, Cav2.2, Cav3.2, BKCa, Anoctamin1, TRPV1, TRPA1, and ASIC. Results: Expression of Cav3.2, BKCa, and anoctamin1 was significantly elevated in patients with CKD-aP. On the other hand, expression of TRPV1 was significantly reduced in these patients. We observed no significant difference in the levels of Cav2.2 or ASIC between subjects with and without CKD-aP. TRPA1, Nav1.8，and Kv1.4 were not expressed. Conclusions: It was concluded that this greater difference in expression of ion channels at the skin tissue including specific for cutaneous peripheral nerve endings in CKD patients with CKD-aP may increase generator potential related to itching.

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Role of Dysregulated Ion Channels in Sensory Neurons in Chronic Kidney Disease-Associated Pruritus

Medicines ◽

10.3390/medicines6040110 ◽

2019 ◽

Vol 6 (4) ◽

pp. 110 ◽

Cited By ~ 3

Author(s):

Akishi Momose ◽

Micihihiro Yabe ◽

Shigetoshi Chiba ◽

Kenjirou Kumakawa ◽

Yasuo Shiraiwa ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Ion Channels ◽

Kidney Disease ◽

Peripheral Nerve ◽

Nerve Endings ◽

Generator Potential ◽

Arteriovenous Fistulas ◽

Significant Difference ◽

G Protein Coupled

Background: We investigated ion channels at the skin, including peripheral nerve endings, which serve as output machines and molecular integrators of many pruritic inputs mainly received by multiple G protein-coupled receptors (GPCRs). Methods: Based on the level of chronic kidney disease–associated pruritus (CKD-aP), subjects were divided into two groups: non-CKD-aP (no or slight pruritus; n = 12) and CKD-aP (mild, moderate, or severe pruritus; n = 11). Skin samples were obtained from the forearm or elbow during operations on arteriovenous fistulas. We measured ion channels expressed at the skin, including peripheral nerve endings by RT-PCR: Nav1.8, Kv1.4, Cav2.2, Cav3.2, BKCa, Anoctamin1, TRPV1, TRPA1, and ASIC. Results: Expression of Cav3.2, BKCa, and anoctamin1 was significantly elevated in patients with CKD-aP. On the other hand, expression of TRPV1 was significantly reduced in these patients. We observed no significant difference in the levels of Cav2.2 or ASIC between subjects with and without CKD-aP. TRPA1, Nav1.8, and Kv1.4 were not expressed. Conclusions: It was concluded that this greater difference in the expression of ion channels in the skin tissue including, specially cutaneous peripheral nerve endings in CKD patients with CKD-aP may increase generator potential related to itching.

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Ion channels and G protein-coupled receptors as targets for invertebrate pest control: from past challenges to practical insecticides

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab089 ◽

2021 ◽

Author(s):

Yoshihisa Ozoe

Keyword(s):

Ion Channels ◽

G Protein ◽

Pest Control ◽

Gaba Receptors ◽

Chloride Channels ◽

Structural Changes ◽

G Protein Coupled Receptors ◽

Octopamine Receptors ◽

Sites Of Action ◽

G Protein Coupled

Abstract In the late 1970s, we discovered that toxic bicyclic phosphates inhibit the generation of miniature inhibitory junction potentials, implying their antagonism of γ-aminobutyric acid (GABA) receptors (GABARs; GABA-gated chloride channels). This unique mode of action provided a strong incentive for our research on GABARs in later years. Furthermore, minor structural changes conferred insect GABAR selectivity to this class of compounds, convincing us of the possibility of GABARs as targets for insecticides. Forty years later, third-generation insecticides acting as allosteric modulator antagonists at a distinctive site of action in insect GABARs were developed. G protein-coupled receptors (GPCRs) are also promising targets for pest control. We characterized phenolamine receptors functionally and pharmacologically. Of the tested receptors, β-adrenergic-like octopamine receptors were revealed to be the most sensitive to the acaricide/insecticide amitraz. Given the presence of multiple sites of action, ion channels and GPCRs remain potential targets for invertebrate pest control.

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The Copenhagen chronic kidney disease echo study (COInCYDE)

European Heart Journal ◽

10.1093/ehjci/ehaa946.3326 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

N Landler ◽

S Bro ◽

B Feldt-Rasmussen ◽

D Hansen ◽

A.L Kamper ◽

...

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Cohort Study ◽

Kidney Disease ◽

Cardiac Function ◽

Left Ventricular ◽

Funding Source ◽

Ckd Stage ◽

Significant Difference ◽

Stage 1

Abstract Background The cardiovascular mortality of patients with chronic kidney disease (CKD) is 2–10 times higher than in the average population. Purpose To estimate the prevalence of abnormal cardiac function or structure across the stages CKD 1 to 5nonD. Method Prospective cohort study. Patients with CKD stage 1 to 5 not on dialysis, aged 30 to 75 (n=875) and age-/sex-matched controls (n=173) were enrolled consecutively. All participants underwent a health questionnaire, ECG, morphometric and blood pressure measurements. Blood and urine were analyzed. Echocardiography was performed. Left ventricle (LV) hypertrophy, dilatation, diastolic and systolic dysfunction were defined according to current ESC guidelines. Results 63% of participants were men. Mean age was 58 years (SD 12.6 years). Mean eGFR was 46.7 mL/min/1,73 m (SD 25.8) for patients and 82.3 mL/min/1,73 m (SD 13.4) for controls. The prevalence of elevated blood pressure at physical exam was 89% in patients vs. 53% in controls. Patients were more often smokers and obese. Left ventricular mass index (LVMI) was slightly, albeit insignificantly elevated at CKD stages 1 & 2 vs. in kontrols: 3.1 g/m2, CI: −0.4 to 6.75, p-value 0.08. There was no significant difference in LV-dilatation between patients and controls. Decreasing diastolic and systolic function was observed at CKD stage 3a and later: LVEF decreased 0.95% (CI: −1.5 to −0.2), GLS increased 0.5 (CI: 0.3 to 0.8), and OR for diastolic dysfunction increased 3.2 (CI 1.4 to 7.3) pr. increment CKD stage group. Conclusion In accordance to previous studies, we observe in the CPHCKD cohort study signs of early increase of LVMI in patients with CKD stage 1 & 2. Significant decline in systolic and diastolic cardiac function is apparent already at stage 3 CKD. Figure 1. Estimated GFR vs. GLS & histogram of GLS Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): The Capital Region of Denmark

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Mini-review: antibody therapeutics targeting G protein-coupled receptors and ion channels

Antibody Therapeutics ◽

10.1093/abt/tbaa023 ◽

2020 ◽

Vol 3 (4) ◽

pp. 257-264

Author(s):

Catherine J Hutchings

Keyword(s):

Ion Channels ◽

Research And Development ◽

Small Molecules ◽

G Protein ◽

Clinical Studies ◽

G Protein Coupled Receptors ◽

Protein Targets ◽

Antibody Therapeutics ◽

Wide Range ◽

G Protein Coupled

Abstract Antibodies are now well established as therapeutics with many additional advantages over small molecules and peptides relative to their selectivity, bioavailability, half-life and effector function. Major classes of membrane-associated protein targets include G protein-coupled receptors (GPCRs) and ion channels that are linked to a wide range of disease indications across all therapeutic areas. This mini-review summarizes the antibody target landscape for both GPCRs and ion channels as well as current progress in the respective research and development pipelines with some example case studies highlighted from clinical studies, including those being evaluated for the treatment of symptoms in COVID-19 infection.

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Alteration of circadian machinery in monocytes underlies chronic kidney disease-associated cardiac inflammation and fibrosis

Nature Communications ◽

10.1038/s41467-021-23050-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yuya Yoshida ◽

Naoya Matsunaga ◽

Takaharu Nakao ◽

Kengo Hamamura ◽

Hideaki Kondo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Clock Genes ◽

Serum Levels ◽

Serum Retinol ◽

Cardiac Inflammation ◽

Physiological Processes ◽

G Protein Coupled ◽

Clock Protein

AbstractDysfunction of the circadian clock has been implicated in the pathogenesis of cardiovascular disease. The CLOCK protein is a core molecular component of the circadian oscillator, so that mice with a mutated Clock gene (Clk/Clk) exhibit abnormal rhythms in numerous physiological processes. However, here we report that chronic kidney disease (CKD)-induced cardiac inflammation and fibrosis are attenuated in Clk/Clk mice even though they have high blood pressure and increased serum angiotensin II levels. A search for the underlying cause of the attenuation of heart disorder in Clk/Clk mice with 5/6 nephrectomy (5/6Nx) led to identification of the monocytic expression of G protein-coupled receptor 68 (GPR68) as a risk factor of CKD-induced inflammation and fibrosis of heart. 5/6Nx induces the expression of GPR68 in circulating monocytes via altered CLOCK activation by increasing serum levels of retinol and its binding protein (RBP4). The high-GPR68-expressing monocytes have increased potential for producing inflammatory cytokines, and their cardiac infiltration under CKD conditions exacerbates inflammation and fibrosis of heart. Serum retinol and RBP4 levels in CKD patients are also sufficient to induce the expression of GPR68 in human monocytes. Our present study reveals an uncovered role of monocytic clock genes in CKD-induced heart failure.

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MicroRNA-451 as an Early Predictor of Chronic Kidney Disease in Diabetic Nephropathy

International Journal of Nephrology ◽

10.1155/2020/8075376 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Mostafa Abdelsalam ◽

A. M. Wahab ◽

Maysaa El Sayed Zaki ◽

Mohamad Motawea

Keyword(s):

Chronic Kidney Disease ◽

Diabetic Nephropathy ◽

Kidney Disease ◽

Early Diagnosis ◽

Serum Creatinine ◽

High Sensitivity ◽

Urinary Albumin ◽

Significant Difference ◽

Plasma Microrna ◽

Stage Renal Disease

Background. Diabetes mellitus is the leading cause of end-stage renal disease worldwide. Microalbuminuria is the cornerstone for the diagnosis of diabetic nephropathy. However, it is an inadequate marker for early diagnosis. MicroRNAs are not only new and promising markers for early diagnosis but also, but they may also play a role in the prevention of disease progression. Methods. This study included ninety patients with type 2 DM in addition to 30 control subjects. MicroRNA-451 expression in blood and plasma using real-time PCR was evaluated in addition to the classic diabetic nephropathy markers (serum creatinine, urinary albumin, and eGFR). Results. There was a significant difference between the studied groups versus control regarding serum creatinine, eGFR, urinary, and plasma microRNA-451 with p=0.0001. Patients with eGFR 60 ml/min/1.73 m2 showed a significantly higher plasma microRNA-451 (29.6 ± 1.6) and significantly lower urinary microRNA-451 (21 ± 0.9) in comparison to patients with eGFR >60 ml/min/1.73 m2 and p=0.0001. eGFR showed a positive correlation with urinary microRNA-451 and negative correlation with both plasma microRNA-451 and urinary albumin. Both plasma and urinary microRNA-451 are highly sensitive and specific markers for chronicity in diabetic nephropathy patients with sensitivity of 90.9% and 95.5% and specificity of 67.6% and 95.6%, respectively. Conclusion. MicroRNA-451 is a promising early biomarker for chronic kidney disease in diabetic nephropathy with high sensitivity and specificity.

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Safety and efficacy of iron isomaltoside 1000/ferric derisomaltose versus iron sucrose in patients with chronic kidney disease: the FERWON-NEPHRO randomized, open-label, comparative trial

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa011 ◽

2020 ◽

Vol 36 (1) ◽

pp. 111-120 ◽

Cited By ~ 14

Author(s):

Sunil Bhandari ◽

Philip A Kalra ◽

Mario Berkowitz ◽

Diogo Belo ◽

Lars L Thomsen ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Single Dose ◽

Kidney Disease ◽

Iron Deficiency ◽

Iron Sucrose ◽

Hypersensitivity Reactions ◽

Open Label ◽

Pronounced Increase ◽

Safety And Efficacy ◽

Significant Difference

Abstract Background The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia. Methods In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs). Results A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: –0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met. Conclusions Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs.

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P0949EFFECT OF DIETARY PHOSPHORUS RESTRICTION ON FIBROBLAST GROWTH FACTOR,KLOTHO AND BODY COMPOSITION IN CHRONIC KIDNEY DISEASE PATIENTS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0949 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Trisha Sachan ◽

Anita Saxena ◽

Amit Gupta

Keyword(s):

Chronic Kidney Disease ◽

Body Composition ◽

Renal Function ◽

Kidney Disease ◽

Urinary Protein ◽

Dietary Phosphorus ◽

Ckd Stage ◽

Significant Difference ◽

The Mean ◽

Fgf 23

Abstract Background and Aims Changes in dietary phosphorus regulate serum FGF-23, parathyroid hormone, 1,25(OH)(2)D and Klotho concentrations . Cardiovascular disease (CVD) is the principal killer of patients with chronic kidney disease and hyperphosphetemia is a potent risk factor it. Of many causative factors for CVD in CKD, dietary interventions involving restriction of dietary phosphorous intake can help reduce onset of CVD at early stages of CKD with other corrective measures. Muscle wasting is a consequence of uremic syndrome which alters body composition. The aim of the study was to study effect of dietary phosphorous restriction on FGF-23, iPTH, Klotho, 1,25(OH)(2)D and body composition in chronic kidney disease patients. Method This is a longitudinal study with 12 months intervention, approved by Ethics Committee of the institute. A total 132 subjects were recruited (66 healthy controls, 66 CKD patient. of 66 patients 33 were in CKD stage 1 and 33 in stage 2. GFR was calculated with the help of MDRD formula. Biochemical parameters of subjects were evaluated at baseline, 6 and 12 months along with the anthropometric measurements (body weight, height, mid upper arm circumference (MUAC), and skin folds). Three days dietary recall was taken to evaluate energy, protein and phosphorous intake. CKD patients whose dietary phosphorous intake was more than 1000 mg/day, were given intense dietary counseling and prescribed dietary modifications by restricting dietary phosphorous between 800-1000 mg/day. Results The mean age of controls and patients was 37.01±9.62 and 38.27±12.06 and eGFR of 136.94±11.77 and 83.69±17.37 respectively. One way ANOVA showed significant difference among controls and the study groups in hemoglobin (p<0.001), s albumin (p<0.001), FGF-23 (p<0.001), klotho (p<0.001), urinary protein (p<0.001) and Nephron Index (p<0.001).The mean energy intake (p = 0.001) and dietary phosphorous intake (p<0.001) of the CKD patients decreased significantly with the decline in the renal function along with the anthropometric measures i.e. BMI (p = 0.041),WHR (p = 0.015) and all four skin folds (p<0.001). On applying Pearson’s correlation, eGFR correlated negatively with urinary protein (-0.739, 0.000), FGF-23 (-0.679, 0.000) and serum phosphorous (-0.697, 0.000) and positively with klotho (0.872, 0.000). FGF-23 correlated negatively with klotho (-0.742, 0.000). Dietary phosphorous was found to be positively correlated with urinary protein (0.496, 0.000), serum phosphorous (0.680, 0.000) and FGF-23 (0.573, 0.000) and negatively with Klotho (-0.602, 0.000). Nephron index revealed a positive correlation with eGFR (0.529, 0.000). Urinary protein correlated negatively with klotho (-0.810, 0.000). A multiple linear regression was run to predict eGFR from anthropometric variables such as BMI, WHR, MUAC, skin folds thickness and handgrip strength. All anthropometric variables predicted decline in eGFR (p<0.05, R2 =0.223). At 6 and 12 months; repeated ANOVAs analysis showed a statistically significant difference in serum creatinine (p=0.000), serum phosphorous (p=0.000), FGF-23(p=0.000) and klotho (p=0.000). Conclusion Elevated levels of FGF-23 and decreased Klotho levels, with the moderate decline in renal function improved with the restricted phosphorous diet at 6 and 12 months emphasizing the importance of phosphorus restriction at an early stage.

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Abstract 145: Rates of Transfusion and Progression to End-Stage Renal Disease in Chronic Kidney Disease Patients Undergoing Transradial Versus Transfemoral Cardiac Catheterization - An Analysis from the VA CART Program

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.7.suppl_1.145 ◽

2014 ◽

Vol 7 (suppl_1) ◽

Author(s):

Amit N Vora ◽

Maggie A Stanislawski ◽

John S Rumsfeld ◽

Thomas M Maddox ◽

Mladen Vidovich ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Cardiac Catheterization ◽

High Risk Population ◽

Post Procedure ◽

Increased Risk ◽

Significant Difference ◽

Independent Association ◽

Stage Renal Disease ◽

End Stage

Background: Patients with chronic kidney disease (CKD) are at increased risk of bleeding and transfusion after cardiac catheterization. Whether rates of these complications or progression to new dialysis are increased in this high-risk population undergoing transradial (TR) access compared to transfemoral (TF) access is unknown. Methods: From the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) Program between 10/2007-09/2012 we identified 40,160 CKD patients undergoing cardiac catheterization with baseline glomerular filtration rate (GFR) ≤ 60 ml/min. We used multivariable Cox modeling to determine the independent association between TR access and post-procedure transfusion as well as progression to new dialysis using TF as the reference. Results: Overall, 3,828 (9.5%) of CKD patients underwent TR access and tended to be slightly younger but overall had similar rates of CKD severity compared with TF patients (GFR 45-60 ml/min: 77.0% vs. 77.0%; GFR 30-44 ml/min: 19.7% vs. 19.3%; GFR 15-29 ml/min: 3.3% vs. 3.7%, p=0.35). TR patients had longer fluoroscopy times (8.1 vs 6.9 minutes, p=<0.0001) but decreased contrast use (90.0 vs 100.0 ml, p=<0.0001). Among the 31,692 patients with a full year of follow-up, 42 (1.7%) of TR patients and 545 (1.9%) of TF patients progressed to new dialysis within 1 year (p=0.64). However, only 33 (0.9%) of TR patients compared with 570 TF patients (1.6%) needed post-procedure blood transfusion (p=0.0006). After multivariable adjustment, there was no significant difference in progression to ESRD between TR and TF patients but TR was associated with a significant decrease in transfusion (Figure). Conclusion: Among CKD patients undergoing cardiac catheterization in the VA health system, TR access is associated with a decreased risk for post-procedure transfusion compared with TF access. There was no significant difference between the two approaches with respect to progression to ESRD. These data suggest that TR is a reasonable option for patients with any level of CKD undergoing cardiac catheterization.

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The Relationship Between Blood Pressure Variability And Renal Progression In Hypertensive Patients With Chronic Kidney Disease

Gevher Nesibe Journal, IESDR ◽

10.46648/gnj.270 ◽

2021 ◽

Vol 6 (14) ◽

pp. 80-88

Author(s):

Huseyin Duru ◽

Ekrem KARA

Keyword(s):

Blood Pressure ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Blood Pressure Measurement ◽

Rapid Progression ◽

Night Time ◽

Hypertensive Patients ◽

Significant Difference ◽

Renal Progression

Objective: To evaluate the effect of 24 hour systolic blood pressure (SBP) and diastolic blood pressure (DBP) variability (BPV) on renal progression in hypertensive patients with chronic kidney disease (CKD) Methods: A total 59 hypertensive patients (mean age: 54.2±14.6 years, 50.8% male) with CKD who underwent 24 hours ambulatory blood pressure measurement (ABPM) were included. Data on SBP, DBP, BPV coefficients (VC) for SBP (SBP-CV) and DBP (DBP-CV) were recorded. A decrease in e-GFR of <5 ml/min/year was considered as normal renal progression and a decrease in ≥5 ml/min/year was considered as rapid renal progression. Results: Overall, 40.6% of the patients had uncontrolled HT, while 45.8% had non-dipper pattern. Mean±SD daytime and night-time SBP and SBP-VC values were 135.3±17.9 mmHg, 128.6±23.0 mmHg, 11.7±2.8 and 9.5±3.6, respectively. Mean±SD daytime and nigh-time DBP and DBP-VC values were 84.5±13.4 mmHg, 77.2±16.1 mmHg, 13.8±3.8 and 12.0±3.7, respectively. Rapid renal progression was detected in 25.4% of patients with no significant difference in daytime, night-time and total SBP, SBP-VC, DBP and DBP-VC values between patients with rapid vs. natural renal progression. The regression analysis adjusted for age, gender, presence of DM, baseline e-GFR and dipping status revealed no significant impact of SBP-VC and DBP-VC in predicting rapid progression (p> 0.05). Conclusion: In conclusion, our finding revealed no significant association between BPV and renal progression in hypertensive patients with CKD. Larger scale prospective, randomized controlled trials with longer follow-up are needed to clarify this issue.

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