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Biomedicines Mar 2024Nephrotic edema stands out as one of the most common complications of nephrotic syndrome. The effective management of hypervolemia is paramount in addressing this... (Review)
Review
Nephrotic edema stands out as one of the most common complications of nephrotic syndrome. The effective management of hypervolemia is paramount in addressing this condition. Initially, "the underfill hypothesis" suggested that proteinuria and hypoalbuminemia led to fluid extravasation into the interstitial space, causing the intravascular hypovolemia and activation of neurohormonal compensatory mechanisms, which increased the retention of salt and water. Consequently, the recommended management involved diuretics and human-albumin infusion. However, recent findings from human and animal studies have unveiled a kidney-limited sodium-reabsorption mechanism, attributed to the presence of various serine proteases in the tubular lumen-activating ENaC channels, thereby causing sodium reabsorption. There is currently no standardized guideline for diuretic therapy. In clinical practice, loop diuretics continue to be the preferred initial choice. It is noteworthy that patients often exhibit diuretic resistance due to various factors such as high-sodium diets, poor drug compliance, changes in pharmacokinetics or pharmacodynamics, kidney dysfunction, decreased renal flow, nephron remodeling and proteasuria. Considering these challenges, combining diuretics may be a rational approach to overcoming diuretic resistance. Despite the limited data available on diuretic treatment in nephrotic syndrome complicated by hypervolemia, ENaC blockers emerge as a potential add-on treatment for nephrotic edema.
PubMed: 38540182
DOI: 10.3390/biomedicines12030569 -
Biomedicines Feb 2024Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) has a detrimental effect on long-term kidney graft survival. However, the pathogenesis of TAC...
Tacrolimus (TAC)-induced chronic nephrotoxicity (TAC nephrotoxicity) has a detrimental effect on long-term kidney graft survival. However, the pathogenesis of TAC nephrotoxicity remains largely unknown. We explored it by focusing on metabolic changes in renal tissues. In this study, mice were separated into TAC and control groups (n = 5/group). TAC was administered to the TAC group (1 mg/kg/d for 28 days) subcutaneously. The control group was similarly treated with normal saline. Renal tissue metabolomes were evaluated. Renal fibrosis was observed only in the TAC group. Metabolomic analysis showed that carnitine and related metabolites were substantially lower in the TAC group than in the control group, presumably due to impaired biosynthesis and reabsorption. Low carnitine levels impair antioxidation in renal tissues and β-oxidation in mitochondria, which may lead to renal tissue damage. This metabolomic analysis revealed that carnitine deficiency in renal tissue appears to explain TAC nephrotoxicity.
PubMed: 38540134
DOI: 10.3390/biomedicines12030521 -
Journal of Nephrology Mar 2024Cystinuria is an autosomal recessive disorder associated with defective proximal tubular reabsorption of divalent amino acids. It leads to increased cystine, ornithine,...
Cystinuria is an autosomal recessive disorder associated with defective proximal tubular reabsorption of divalent amino acids. It leads to increased cystine, ornithine, lysine, and arginine excretion in the urine. Cystine is insoluble in physiological pH, and cystinuria leads to crystalluria and nephrolithiasis. We present a case of acquired cystinuria in a renal transplant recipient, that is, to the best of our knowledge, the first case of acquired cystinuria ever documented in the literature.
PubMed: 38512367
DOI: 10.1007/s40620-023-01877-5 -
Royal Society Open Science Mar 2024The kidneys are crucial for maintaining Mg homeostasis. Along the proximal tubule and thick ascending limb, Mg is reabsorbed paracellularly, while along the distal...
The kidneys are crucial for maintaining Mg homeostasis. Along the proximal tubule and thick ascending limb, Mg is reabsorbed paracellularly, while along the distal convoluted tubule (DCT), Mg is reabsorbed transcellularly via transient receptor potential melastatin 6 (TRPM6). TRPM6 and other renal transporter expressions are regulated by sex hormones. To investigate renal Mg handling, we have developed sex-specific computational models of electrolyte transport along rat superficial nephron. Model simulations indicated that along the proximal tubule and thick ascending limb, Mg and Na transport occur parallelly, but they are dissociated along the DCT. In addition, our models predicted higher paracellular Mg permeability in females to attain similar cortical thick ascending limb fractional Mg reabsorption in both sexes. Furthermore, DCT fractional Mg reabsorption is higher in females than in males, allowing females to better fine-tune Mg excretion. We validated our models by simulating the administration of three classes of diuretics. The model predicted significantly increased, marginally increased and significantly decreased Mg excretions for loop, thiazide and K-sparing diuretics, respectively, aligning with experimental findings. The models can be used to conduct studies on kidney adaptations to Mg homeostasis alterations during conditions such as pregnancy, diabetes and chronic kidney disease.
PubMed: 38511086
DOI: 10.1098/rsos.231484 -
Diabetes, Obesity & Metabolism Jun 2024Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose...
Dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter 2 inhibitor additively ameliorate hepatic steatosis through different mechanisms of action in high-fat diet-fed mice.
AIM
Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin-independent manner by inhibiting renal reabsorption of glucose. DPP-4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high-fat diet-fed mice.
METHOD
C57BL/6J male mice were fed a 60% high-fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP-4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4-week intervention were evaluated.
RESULTS
There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation- and chemokine-related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups.
CONCLUSION
The combination therapy with the DPP-4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti-inflammatory effects during the early phase of diet-induced liver steatosis.
Topics: Animals; Male; Mice; Blood Glucose; Diet, High-Fat; Dipeptidyl-Peptidase IV Inhibitors; Drug Synergism; Drug Therapy, Combination; Fatty Liver; Glucosides; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Pyrimidines; Sodium-Glucose Transporter 2 Inhibitors; Sorbitol
PubMed: 38504118
DOI: 10.1111/dom.15548 -
Heliyon Mar 2024The proximal convoluted tubule (PCT) of the kidney is a crucial functional segment responsible for reabsorption, secretion, and the maintenance of electrolyte and water...
The proximal convoluted tubule (PCT) of the kidney is a crucial functional segment responsible for reabsorption, secretion, and the maintenance of electrolyte and water balance within the renal tubule. However, there is a lack of a well-defined endogenous transgenic line for studying PCT morphogenesis. By analyzing single-cell transcriptome data from the adult zebrafish kidney, we have identified the expression of odd-skipped-related 2 (, which encodes an odd-skipped zinc-finger transcription factor) in the PCT. To gain insight into the role of in PCT morphogenesis, we have generated a transgenic zebrafish line , expressing enhanced green fluorescent protein (EGFP). The EGFP expression pattern closely mirrors that of endogenous Osr2, faithfully recapitulating its native expression profile. During kidney development, we can use EGFP to track PCT development, which is also preserved in adult zebrafish. Additionally, -labeled zebrafish PCT fragments displayed short lengths with infrequent overlap, rendering them conducive for nephrons counting. The generation of transgenic line is accompanied by simultaneous disruption of activity. Importantly, our findings demonstrate that inactivation had no discernible impact on the development and regeneration of zebrafish nephrons. Overall, the establishment of this transgenic zebrafish line offers a valuable tool for both genetic and chemical analysis of PCT.
PubMed: 38496848
DOI: 10.1016/j.heliyon.2024.e27582 -
Hematology, Transfusion and Cell Therapy Feb 2024This study aims to evaluate the markers of tubular phosphate handling in adults with sickle cell anemia (SCA) and the influence of hydroxyurea (HU), the degree of anemia...
OBJECTIVE
This study aims to evaluate the markers of tubular phosphate handling in adults with sickle cell anemia (SCA) and the influence of hydroxyurea (HU), the degree of anemia and Hb F concentration on these markers.
METHODS
Eighty-eight steady state SCA patients in outpatient follow-up in Fortaleza, Ceara, Brazil and 31 healthy individuals were included in this study. Vitamin D (25OHD) was measured by enzyme-bound fluorescence assay, intact parathyroid hormone (iPTH) by electrochemiluminescence, and serum and urinary phosphate and creatinine by colorimetric methods. Details of Hb F and HU use were obtained from clinical records. Tubular reabsorption of phosphate (TRP) and maximum tubular reabsorption of phosphate (MTRP) were calculated. SCA patients were stratified according to the use of HU, degree of anemia and percentage of Hb F. The significance level was set for p-values <0.05.
RESULTS
Compared to controls the 25OHD level (25 ± 11 vs. 30 ± 9 pg/mL) was lower in SCA, while serum phosphate and MTRP were higher (3.86 ± 0.94 vs. 3.46 ± 0.72 and 3.6 ± 1.21 vs. 3.21 ± 0.53, respectively). There was no significant difference in iPTH, TRP and phosphaturia. Serum phosphate showed correlation with TRP (r = 0.32; p-value = 0.008) and MTRP (r = 0.9; p-value <0.001) in SCA. Patients taking HU, especially those with Hb F >10 % presented reduced serum phosphate levels, and TRP and MTRP rates. Those with mild anemia presented reduced serum phosphate levels and MTRP rates.
CONCLUSION
Serum phosphate levels and renal phosphate reabsorption rate were increased in SCA. HU use, high Hb F concentration and total Hb were associated with better control of tubular phosphate handling markers.
PubMed: 38485550
DOI: 10.1016/j.htct.2023.11.015 -
Clinical and Translational Science Mar 2024Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of...
Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium.
Topics: Humans; Colistin; Anti-Bacterial Agents; Acute Kidney Injury; Risk Factors; Genetic Predisposition to Disease; Retrospective Studies; Solute Carrier Family 22 Member 5
PubMed: 38476095
DOI: 10.1111/cts.13764 -
Nutrients Feb 2024Bone represents a metabolically active tissue subject to continuous remodeling orchestrated by the dynamic interplay between osteoblasts and osteoclasts. These cellular... (Review)
Review
Bone represents a metabolically active tissue subject to continuous remodeling orchestrated by the dynamic interplay between osteoblasts and osteoclasts. These cellular processes are modulated by a complex interplay of biochemical and mechanical factors, which are instrumental in assessing bone remodeling. This comprehensive evaluation aids in detecting disorders arising from imbalances between bone formation and reabsorption. Osteoporosis, characterized by a reduction in bone mass and strength leading to heightened bone fragility and susceptibility to fractures, is one of the more prevalent chronic diseases. Some epidemiological studies, especially in patients with chronic kidney disease (CKD), have identified an association between osteoporosis and vascular calcification. Notably, low bone mineral density has been linked to an increased incidence of aortic calcification, with shared molecules, mechanisms, and pathways between the two processes. Certain molecules emerging from these shared pathways can serve as biomarkers for bone and mineral metabolism. Detecting and evaluating these alterations early is crucial, requiring the identification of biomarkers that are reliable for early intervention. While traditional biomarkers for bone remodeling and vascular calcification exist, they suffer from limitations such as low specificity, low sensitivity, and conflicting results across studies. In response, efforts are underway to explore new, more specific biomarkers that can detect alterations at earlier stages. The aim of this review is to comprehensively examine some of the emerging biomarkers in mineral metabolism and their correlation with bone mineral density, fracture risk, and vascular calcification as well as their potential use in clinical practice.
Topics: Humans; Chronic Kidney Disease-Mineral and Bone Disorder; Osteoporosis; Bone Density; Renal Insufficiency, Chronic; Fractures, Bone; Vascular Calcification; Biomarkers; Minerals
PubMed: 38474734
DOI: 10.3390/nu16050605 -
Cells Mar 2024The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does... (Review)
Review
A Possible Therapeutic Application of the Selective Inhibitor of Urate Transporter 1, Dotinurad, for Metabolic Syndrome, Chronic Kidney Disease, and Cardiovascular Disease.
The reabsorption of uric acid (UA) is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) in the kidneys. Dotinurad inhibits URAT1 but does not inhibit other UA transporters, such as GLUT9, ATP-binding cassette transporter G2 (ABCG2), and organic anion transporter 1/3 (OAT1/3). We found that dotinurad ameliorated the metabolic parameters and renal function in hyperuricemic patients. We consider the significance of the highly selective inhibition of URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). The selective inhibition of URAT1 by dotinurad increases urinary UA in the proximal tubules, and this un-reabsorbed UA may compete with urinary glucose for GLUT9, reducing glucose reabsorption. The inhibition by dotinurad of UA entry via URAT1 into the liver and adipose tissues increased energy expenditure and decreased lipid synthesis and inflammation in rats. Such effects may improve metabolic parameters. CKD patients accumulate uremic toxins, including indoxyl sulfate (IS), in the body. ABCG2 regulates the renal and intestinal excretion of IS, which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into the kidneys, thereby increasing plasma IS, which produces oxidative stress and induces vascular endothelial dysfunction in CKD patients. The highly selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD, and CVD.
Topics: Humans; Rats; Animals; Cardiovascular Diseases; Metabolic Syndrome; Uricosuric Agents; Uric Acid; Renal Insufficiency, Chronic; Glucose; Organic Anion Transporters; Benzothiazoles
PubMed: 38474414
DOI: 10.3390/cells13050450