scholarly journals Tenofovir and Severe Symptomatic Hypophosphatemia

2019 ◽  
Vol 7 ◽  
pp. 232470961984879 ◽  
Author(s):  
Asim Kichloo ◽  
Savneek Singh Chugh ◽  
Sanjeev Gupta ◽  
Jay Panday ◽  
Ghazaleh Goldar
Keyword(s):  
Renal Damage ◽  
Organic Anion ◽  
Significant Risk ◽  
Anion Transporters ◽  
Immunodeficiency Virus ◽  
Tubular Lumen ◽  
Associated Proteins ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Initial Results

Tenofovir is a broadly used drug used for the treatment of human immunodeficiency virus (HIV). Although the initial results of the clinical trials supported the renal safety of Tenofovir, clinical use of it has caused a low, albeit a significant, risk of renal damage either in the form of AKI or CKD. The pathophysiology has been linked to the effect of this medication on the proximal tubular cell. Although the exact mechanism is unknown, studies have suggested that Tenofovir accumulates in proximal tubular cells which are rich in mitochondria. It is both filtered in the glomerulus and actively secreted in the tubules for elimination and is excreted unchanged in the urine. Studies have shown an active transportation of 20-30% of this drug into the renal proximal tubule (PCT) cells via the organic anion transporters in the baso-lateral membrane (primarily hOAT1, and OAT3 to a lesser extent) and ultimate excretion of the drug into the tubular lumen via the transporters in the proximal tubular apical membrane MRP4 and MRP2 (multidrug resistance-associated proteins 2 & 4). Subsequently, the mitochondrial injury caused by Tenofovir can lead to the development of Fanconi’s syndrome which causes renal tubular acidosis, phosphaturia, aminoaciduria, glucosuria with normoglycemia, and tubular proteinuria. Here we present a case where Tenofovir treatment resulted in severe hypophosphatemia requiring hospitalization for parentral phosphate repletion.

Micropuncture study of proximal renal tubular chloride transport during hypercapnea in the rat

1965 ◽  
Vol 209 (3) ◽  
pp. 655-658 ◽  
Author(s):  
Michael Kashgarian ◽  
Yves Warren ◽  
Howard Levitin
Keyword(s):  
Chloride Transport ◽  
Electrical Potential ◽  
Stopped Flow ◽  
Electrical Potential Difference ◽  
Micropuncture Study ◽  
Tubular Lumen ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
Electrochemical Equilibrium ◽  
Anion Pump

The electrical potential difference and the concentration of chloride in tubular fluid and plasma were measured in stopped-flow microperfusion of the proximal tubule of rats breathing either air or 12% CO2 in air. Perfusion with 10% PVP completely stopped net transtubular fluid movement. Chloride was not in electrochemical equilibrium under these conditions and hypercapnea increased the concentration of chloride in tubular fluid relative to that in plasma. This suggests that the net reabsorption of chloride must overcome a force which moves chloride into the tubular lumen. An anion pump is postulated which secretes chloride into the tubular lumen and is linked to acidification of proximal tubular fluid.

Retention of fetuin-A in renal tubular lumen protects the kidney from nephrocalcinosis in rats

2013 ◽  
Vol 304 (6) ◽  
pp. F751-F760 ◽  
Author(s):  
Isao Matsui ◽  
Takayuki Hamano ◽  
Satoshi Mikami ◽  
Kazunori Inoue ◽  
Akihiro Shimomura ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Proximal Tubules ◽  
Fetuin A ◽  
Receptor Associated Protein ◽  
Tubular Lumen ◽  
Proximal Tubular ◽  
Normal Rat ◽  
Natural Inhibitor ◽  
Renal Tubular

The serum glycoprotein fetuin-A is an important inhibitor of extraosseous calcification. The importance of fetuin-A has been confirmed in fetuin-A null mice, which develop widespread extraosseous calcification including the kidney. However, the mechanism how fetuin-A protects kidneys from nephrocalcinosis remains uncertain. Here, we demonstrate that intratubular fetuin-A plays a role in the prevention of nephrocalcinosis in the proximal tubules. Although normal rat kidney did not express mRNA for fetuin-A, we found punctate immunohistochemical staining of fetuin-A mainly in the S1 segment of the proximal tubules. The staining pattern suggested that fetuin-A passed through the slit diaphragm, traveled in the proximal tubular lumen, and was introduced into proximal tubular cells by megalin-mediated endocytosis. To test this hypothesis, we inhibited the function of megalin by intravenous injection of histidine-tagged soluble receptor-associated protein (His-sRAP), a megalin inhibitor. His-sRAP injection diminished fetuin-A staining in the proximal tubules and led to urinary excretion of fetuin-A. We further analyzed the role of fetuin-A in nephrocalcinosis. Continuous injection of parathyroid hormone (PTH) 1–34 induced nephrocalcinosis mainly in the proximal tubules in rats. His-sRAP retained fetuin-A in renal tubular lumen and thereby protected the kidneys of PTH-treated rats from calcification. Our findings suggest that tubular luminal fetuin-A works as a natural inhibitor against calcification in the proximal tubules under PTH-loaded condition.

Oat1/3 restoration protects against renal damage after ischemic AKI

2015 ◽  
Vol 308 (3) ◽  
pp. F198-F208 ◽  
Author(s):  
R. Schneider ◽  
M. Meusel ◽  
B. Betz ◽  
C. Held ◽  
K. Möller-Ehrlich ◽  
...  
Keyword(s):  
Renal Function ◽  
Beneficial Effect ◽  
Renal Damage ◽  
Low Dose ◽  
Organic Anion ◽  
Kidney Injury ◽  
Renal Perfusion ◽  
Monocyte Chemoattractant Protein 1 ◽  
Beneficial Effects ◽  
Proximal Tubular

Expression of proximal tubular organic anion transporters Oat1 and Oat3 is reduced by PGE2 after renal ischemia and reperfusion (I/R) injury. We hypothesized that impaired expression of Oat1/3 is decisively involved in the deterioration of renal function after I/R injury. Therefore, we administered probenecid, which blocks proximal tubular indomethacin uptake, to abolish the indomethacin-mediated restoration of Oat1/3 regulation and its effect on renal functional and morphological outcome. Ischemic acute kidney injury (iAKI) was induced in rats by bilateral clamping of renal arteries for 45 min with 24-h follow-up. Low-dose indomethacin (1 mg/kg) was given intraperitoneally (ip) at the end of ischemia. Probenecid (50 mg/kg) was administered ip 20 min later. Indomethacin restored the expression of Oat1/3, PAH net secretion, and PGE2 clearance. Additionally, indomethacin improved kidney function as measured by glomerular filtration rate (GFR), renal perfusion as determined by corrected PAH clearance, and morphology, whereas it reduced renal cortical apoptosis and nitric oxide production. Notably, indomethacin did not affect inflammation parameters in the kidneys (e.g., monocyte chemoattractant protein-1, ED1+ cells). On the other hand, probenecid blocked the indomethacin-induced restoration of Oat1/3 and moreover abrogated all beneficial effects. Our study indicates that the beneficial effect of low-dose indomethacin in iAKI is not due to its anti-inflammatory potency, but in contrast to its restoration of Oat1/3 expression and/or general renal function. Inhibition of proximal tubular indomethacin uptake abrogates the beneficial effect of indomethacin by resetting the PGE2-mediated Oat1/3 impairment, thus reestablishing renal damage. This provides evidence for a mechanistic effect of Oat1/3 in a new model of the induction of renal damage after iAKI.

Nocodazole inhibition of organic anion secretion in teleost renal proximal tubules

1994 ◽  
Vol 267 (3) ◽  
pp. R695-R704 ◽  
Author(s):  
D. S. Miller ◽  
J. B. Pritchard
Keyword(s):  
Organic Anion ◽  
Basolateral Membrane ◽  
Organic Anions ◽  
Tubular Secretion ◽  
Anion Secretion ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
The Impact ◽  
Organic Anion Secretion

The impact of the microtubule-disrupting drug nocodazole on renal tubular secretion of organic anions was examined in vitro using proximal tubular masses from teleost fish. Nocodazole reversibly inhibited 20-30% of the tubular accumulation of two model organic anions, p-aminohippurate and fluorescein (FL), by winter flounder tubular masses. However, the drug had no effect on the initial rate of organic anion uptake. Thus it did not reduce transport into the cells at the basolateral membrane, either directly by affecting basolateral organic anion transport proteins or indirectly by altering metabolism or ion gradients. Instead, epifluorescence video microscopy and digital image analysis of killifish tubules showed that nocodazole greatly reduced luminal accumulation of FL and had a smaller effect on cellular dye accumulation. Luminal FL accumulation returned to control levels when tubules were incubated in drug-free medium. Confocal fluorescence microscopy confirmed the marked reduction in luminal FL concentration and demonstrated that intracellular punctate FL accumulation was also markedly reduced. Finally, immunohistochemistry with an anti-tubulin antibody showed that the concentrations of nocodazole used in the above experiments reversibly disrupted microtubules within renal epithelial cells. These data indicate that a component of organic anion secretion in teleost proximal tubule is dependent on an intact microtubular network.

scholarly journals Pharmacokinetics and Toxicokinetics Roles of Membrane Transporters at Kidney Level

2020 ◽  
Vol 23 ◽  
pp. 333-356
Author(s):  
Jéssica Veiga-Matos ◽  
Fernando Remião ◽  
Ana Motales
Keyword(s):  
Renal Damage ◽  
Organic Cation ◽  
Organic Anion ◽  
Efflux Transporters ◽  
Cancer Resistance ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Proximal Tubular ◽  
Resistance Protein ◽  
Uptake Transporters

Transporters are large membrane proteins, which control the passage of various compounds through biological membranes. These proteins are divided into uptake and efflux transporters and play an important role in the toxicokinetics of many endobiotics and xenobiotics. The uptake transporters facilitate the absorption of these compounds from the blood into the proximal tubular cells, while the efflux transporters eliminate these compounds into tubular fluid (urine). Overall, the uptake is performed by the superfamily solute carrier (SLC) transporters, which are, mostly, located in the basolateral membrane. The organic anion transporters (OATs; SLC22), the organic cation transporters (OCTs; SLC22), the organic cation/carnitine transporters (OCTNs), and the organic anion transporting polypeptides (OATP; SLC21/SLCO) are some examples of uptake transporters of the SLC superfamily. On the other hand, the superfamily ATP-binding cassette (ABC) transporters carry out the elimination of the substances through the apical membrane of the proximal tubular cells. The multidrug resistance proteins 1 (MDR; ABCB), the multi resistance protein (MRP2; ABCC) and the breast cancer resistance protein (BCRP, ABCG) along with the multidrug and toxin extrusion (MATE), which is an SLC transporter, carry out the substance efflux of the cell, However, uptake transporters seem to be more efficient than efflux transporters, leading to an accumulation of compounds in proximal tubular cells and, consequently, to renal damage. The accumulation of compounds can also occur due to variations in the number of transporters that exist due to differences in sex, age, genetic polymorphisms and epigenetics. Furthermore, some substances can inhibit, induce or, eventually, activate these transporters, with consequent drug-drug interactions (DDIs) as a result of alterations on the toxicokinetics of xenobiotics, leading to an increase of their accumulation and, consequently, to renal damage. These compounds may be exogenous, such as antibiotics, antivirals, cisplatin, metals, herbicides, mycotoxins and drugs; or endogenous, like uric acid, bile acids, bilirubin conjugates and conjugated steroids. Thus, in this review, we will focus on the accumulation of exogenous compounds due to variations on renal transporters and the consequent biological effects caused by them.

scholarly journals VERNONIA CINEREA (NEICHITTI KEERAI) REGENERATES PROXIMAL TUBULES IN CISPLATININDUCED RENAL DAMAGE IN MICE

2019 ◽  
Vol 12 (1) ◽  
pp. 332
Author(s):  
Arul Amuthan ◽  
Vasudha Devi ◽  
Chandrashekara Shastry Shreedhara ◽  
Venkata Rao ◽  
Kunal Puri ◽  
...  
Keyword(s):  
Renal Damage ◽  
Tubular Damage ◽  
Aqueous Fraction ◽  
Renal Tubular Cells ◽  
Damage Grade ◽  
Proximal Tubular ◽  
Proximal Tubular Damage ◽  
Grade 3 ◽  
Renal Tubular ◽  
Vernonia Cinerea

Objective: The aim of the study was to evaluate whether Vernonia cinerea (VC) regenerates the proximal renal tubular cells in cisplatin-induced necrosis in male Swiss albino mice.Methods: The crude aqueous extract (CAE) of VC was fractionated from non-polar to polar using different solvents. Mice were injected a single dose of cisplatin (15 mg/kg) on day 1, which took 5 days to cause maximal renal damage. From day 6, CAE and all fractions were orally administered (200, 300, and 400 mg/kg) for 5 continuous days. On day 11, blood was collected to estimate urea and creatinine. Kidney was collected for histology and grading was done.Results: Cisplatin induced proximal renal tubular damage (grade 5) in corticomedullary junction, characterized by necrosis, proximal tubular dilatation, inflammation and vasodilation. Aqueous fraction (AF) did not show any regeneration; whereas, 400 mg/kg dose of CAE and butanol fraction (BF) showed a significant reduction (p<0.001) in proximal tubular damage (Grade 3) and 50–75% regeneration of proximal tubular epithelial cells.Conclusion: This is the first study to demonstrate the regenerative potential of Neichitti kashayam (CAE of VC) and its BF in cisplatin-induced proximal tubular damage in kidney. Further study is warranted to find out the dose regimen for complete regeneration, lead compounds, and molecular mechanism.

scholarly journals VERNONIA CINEREA (NEICHITTI KEERAI) REGENERATES PROXIMAL TUBULES IN CISPLATININDUCED RENAL DAMAGE IN MICE

2019 ◽  
Vol 12 (1) ◽  
pp. 332 ◽  
Author(s):  
Arul Amuthan ◽  
Vasudha Devi ◽  
Chandrashekara Shastry Shreedhara ◽  
Venkata Rao ◽  
Kunal Puri ◽  
...  
Keyword(s):  
Renal Damage ◽  
Tubular Damage ◽  
Aqueous Fraction ◽  
Renal Tubular Cells ◽  
Damage Grade ◽  
Proximal Tubular ◽  
Proximal Tubular Damage ◽  
Grade 3 ◽  
Renal Tubular ◽  
Vernonia Cinerea

Objective: The aim of the study was to evaluate whether Vernonia cinerea (VC) regenerates the proximal renal tubular cells in cisplatin-induced necrosis in male Swiss albino mice.Methods: The crude aqueous extract (CAE) of VC was fractionated from non-polar to polar using different solvents. Mice were injected a single dose of cisplatin (15 mg/kg) on day 1, which took 5 days to cause maximal renal damage. From day 6, CAE and all fractions were orally administered (200, 300, and 400 mg/kg) for 5 continuous days. On day 11, blood was collected to estimate urea and creatinine. Kidney was collected for histology and grading was done.Results: Cisplatin induced proximal renal tubular damage (grade 5) in corticomedullary junction, characterized by necrosis, proximal tubular dilatation, inflammation and vasodilation. Aqueous fraction (AF) did not show any regeneration; whereas, 400 mg/kg dose of CAE and butanol fraction (BF) showed a significant reduction (p<0.001) in proximal tubular damage (Grade 3) and 50–75% regeneration of proximal tubular epithelial cells.Conclusion: This is the first study to demonstrate the regenerative potential of Neichitti kashayam (CAE of VC) and its BF in cisplatin-induced proximal tubular damage in kidney. Further study is warranted to find out the dose regimen for complete regeneration, lead compounds, and molecular mechanism.

scholarly journals Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 348 ◽  
Author(s):  
Yiting Yang ◽  
Xiaodong Liu
Keyword(s):  
Drug Transport ◽  
Drug Disposition ◽  
Organic Anion ◽  
Efflux Transporters ◽  
Cancer Resistance ◽  
Cytochrome P450 Enzymes ◽  
Organic Anion Transporting Polypeptides ◽  
Glycoprotein P ◽  
Anion Transporters ◽  
Associated Proteins

The pharmacokinetics of a drug is dependent upon the coordinate work of influx transporters, enzymes and efflux transporters (i.e., transporter-enzyme interplay). The transporter–enzyme interplay may occur in liver, kidney and intestine. The influx transporters involving drug transport are organic anion transporting polypeptides (OATPs), peptide transporters (PepTs), organic anion transporters (OATs), monocarboxylate transporters (MCTs) and organic cation transporters (OCTs). The efflux transporters are P-glycoprotein (P-gp), multidrug/toxin extrusions (MATEs), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP). The enzymes related to drug metabolism are mainly cytochrome P450 enzymes (CYP450s) and UDP-glucuronosyltransferases (UGTs). Accumulating evidence has demonstrated that diabetes alters the expression and functions of CYP450s and transporters in a different manner, disordering the transporter–enzyme interplay, in turn affecting the pharmacokinetics of some drugs. We aimed to focus on (1) the imbalance of transporter-CYP450 interplay in the liver, intestine and kidney due to altered expressions of influx transporters (OATPs, OCTs, OATs, PepTs and MCT6), efflux transporters (P-gp, BCRP and MRP2) and CYP450s (CYP3As, CYP1A2, CYP2E1 and CYP2Cs) under diabetic status; (2) the net contributions of these alterations in the expression and functions of transporters and CYP450s to drug disposition, therapeutic efficacy and drug toxicity; (3) application of a physiologically-based pharmacokinetic model in transporter–enzyme interplay.

Sign in / Sign up

Export Citation Format

Share Document