Abstract：
:Many xenobiotics including the pharmacoenhancer cobicistat increase serum creatinine by inhibiting its renal active tubular secretion without affecting the glomerular filtration rate. This study aimed to define the transporters involved in creatinine secretion, applying that knowledge to establish the mechanism for xenobiotic-induced effects. The basolateral uptake transporters organic anion transporter OAT2 and organic cation transporters OCT2 and OCT3 were found to transport creatinine. At physiologic creatinine concentrations, the specific activity of OAT2 transport was over twofold higher than OCT2 or OCT3, establishing OAT2 as a likely relevant creatinine transporter and further challenging the traditional view that creatinine is solely transported by a cationic pathway. The apical multidrug and toxin extrusion transporters MATE1 and MATE2-K demonstrated low-affinity and high-capacity transport. All drugs known to affect creatinine inhibited OCT2 and MATE1. Similar to cimetidine and ritonavir, cobicistat had the greatest effect on MATE1 with a 50% inhibition constant of 0.99 μM for creatinine transport. Trimethoprim potently inhibited MATE2-K, whereas dolutegravir preferentially inhibited OCT2. Cimetidine was unique, inhibiting all transporters that interact with creatinine. Thus, the clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition.
journal_name
Kidney Intjournal_title
Kidney internationalauthors
Lepist EI,Zhang X,Hao J,Huang J,Kosaka A,Birkus G,Murray BP,Bannister R,Cihlar T,Huang Y,Ray ASdoi
10.1038/ki.2014.66subject
Has Abstractpub_date
2014-08-01 00:00:00pages
350-7issue
2eissn
0085-2538issn
1523-1755pii
S0085-2538(15)30293-3journal_volume
86pub_type
杂志文章abstract：BACKGROUND:The growth hormone (GH)/insulin-like growth factor (IGF) system is thought to participate in the glomerulosclerosis process. Because IGF-binding proteins (IGFBPs) modulate IGF actions and hence GH secretion, this study assessed whether mice transgenic for human IGFBP-1 have altered susceptibility to glomerul...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1046/j.1523-1755.2000.00090.x
更新日期：2000-06-01 00:00:00
abstract：:Utilizing [5-15N] and [2-15N]-labeled glutamine and gas chromatography mass spectrometry methodology, we examined the pathways of ammoniagenesis under basal and acute acidotic conditions of pH 7.0 and pH 6.8, respectively. LLC-PK1 cultures were incubated for one hour with gentle rocking in a bicarbonate buffer of pH 7...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1994.137
更新日期：1994-04-01 00:00:00
abstract：BACKGROUND:The induction of stress response (heat shock) proteins (HSPs) is a highly conserved response that protects many cell types from diverse physiological and environmental stressors. We tested the hypothesis that the induction of HSPs is protective in experimental renal ischemia/reperfusion injury. METHODS:The ...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1046/j.1523-1755.2001.0590051798.x
更新日期：2001-05-01 00:00:00
abstract：BACKGROUND:The peritoneum is progressively denuded of its mesothelial cell monolayer in patients on continuous ambulatory peritoneal dialysis (CAPD). These alterations of the mesothelium cause membrane dysfunction and progressive peritoneal fibrosis. Integrins regulate cell motility and play an important role in wound ...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1046/j.1523-1755.2003.00772.x
更新日期：2003-02-01 00:00:00
abstract：BACKGROUND:Inbred miniature swine treated for 12 days with high-dose cyclosporine A develop tolerance to histocompatibility complex (MHC) class I-mismatched renal allografts. When this protocol was modified by adding thymectomy before transplant, all animals developed acute rejection. Thereafter, by day 100, one half d...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1046/j.1523-1755.2000.00440.x
更新日期：2000-12-01 00:00:00
abstract：:The monoclonal antibody (mAb) 3G5 was found, by indirect immunofluorescence, to bind to renal cortical structures in frozen sections of human, rat and calf kidneys. Double indirect immunofluorescence studies on frozen sections of rat kidneys showed that 3G5 stained only the glomerulus and the distribution of the 3G5 a...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1992.236
更新日期：1992-06-01 00:00:00
abstract：:Using a combination of intra-operative digital photography and micro-biopsy we measured renal cortical and papillary changes in five patients with primary hyperparathyroidism and abundant calcium phosphate kidney stones. Major tissue changes were variable papillary flattening and retraction, dilation of the ducts of B...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.2008.161
更新日期：2008-07-01 00:00:00
abstract：BACKGROUND:Rats that recover from acute puromycin nephrosis later develop widespread glomerular and tubulointerstitial injury. The current study sought to identify structural changes present in the recovery phase that could precipitate progressive renal disease. METHODS:Stereologic studies were performed 10 weeks afte...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1046/j.1523-1755.2002.00481.x
更新日期：2002-08-01 00:00:00
abstract：:The inner medullary collecting duct (IMCD) is a major target site of atrial natriuretic peptide (ANP) for diuresis and natriuresis, and it is in a hypertonic condition made by the renal countercurrent multiplication system. We investigated the effects of hyperosmolality on ANP-stimulated cGMP generation in IMCD and gl...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1994.178
更新日期：1994-05-01 00:00:00
abstract：BACKGROUND:The superiority of renin-angiotensin system (RAS) blockade in providing renoprotection has been attributed to class-specific blood pressure "(BP)-independent" mechanisms. However, the conventional BP measurement methodology on which such conclusions are based is inherently limited for an accurate assessment ...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1046/j.1523-1755.2000.00009.x
更新日期：2000-04-01 00:00:00
abstract：:Compared to normal tissue, hyperplastic parathyroid glands of patients with chronic kidney disease on dialysis express lower levels of FGFR1 and Klotho proteins. Similar findings are reported in uremic rats with advanced chronic kidney disease. Moreover, in these animals, FGF23 administration fails to reduce PTH serum...
journal_title：Kidney international
pub_type： 评论,杂志文章
doi：10.1038/ki.2009.512
更新日期：2010-03-01 00:00:00
abstract：:There are two fundamentally different growth responses for cells comprising the nephron: hyperplasia or hypertrophy. Cells that progress through the normal cell cycle double their DNA content and eventually divide during mitosis. Those cells that hypertrophy stop the growth process in the G1-phase of the cell cycle; w...
journal_title：Kidney international
pub_type： 杂志文章,评审
doi：10.1046/j.1523-1755.1999.00695.x
更新日期：1999-10-01 00:00:00
abstract：:The primary goal of this study was to determine if the ability to undergo catch-up growth following a transient injury is preserved in an experimental model of moderate chronic renal failure (CRF) and the effect of growth hormone (GH) administration on such phenomenon. Young rats were subtotally nephrectomized (days 0...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/sj.ki.5001949
更新日期：2006-12-01 00:00:00
abstract：BACKGROUND:Tubulointerstitial fibrosis is a morphologic hallmark of chronic kidney disease and is a key factor in the prediction of progression to end-stage renal failure. Disruption of tubular basement membrane and interstitial extracellular matrix (ECM) via cytokine-induced alterations in matrix metalloproteinases (M...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1111/j.1523-1755.2004.00900.x
更新日期：2004-10-01 00:00:00
abstract：:The introduction of two-photon microscopy, along with the development of new fluorescent probes and innovative computer software, has advanced the study of intracellular and intercellular processes in the tissues of living organisms. Researchers can now determine the distribution, behavior, and interactions of labeled...
journal_title：Kidney international
pub_type： 杂志文章,评审
doi：10.1038/sj.ki.5002315
更新日期：2007-08-01 00:00:00
abstract：BACKGROUND:In X-linked Alport syndrome, mutations in the COL4A5 gene encoding the alpha 5 chain of type IV collagen result in progressive renal failure. This nephropathy appears to relate to the arrest of a switch from an alpha 1/alpha 2 to an alpha 3/alpha 4/alpha 5 network of type IV collagen in the developing glomer...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1046/j.1523-1755.1998.00188.x
更新日期：1998-12-01 00:00:00
abstract：:The mean renal tubular diameters, number of tubules per unit of cross-sectional area, and fraction of the total volume occupied by each medullary structure were determined at various levels of the renal medulla of the rat and rabbit. Statistical estimates of anatomic variables were made using spatial sampling techniqu...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1977.118
更新日期：1977-11-01 00:00:00
abstract：:In normal subjects, beta-adrenergic stimulation lowers the serum potassium, whereas alpha-stimulation raises it. Epinephrine, a mixed alpha and beta agonist, acutely lowers the blood potassium in normal subjects, but not in patients with end-stage renal disease. This study was designed to determine whether the resista...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1991.321
更新日期：1991-12-01 00:00:00
abstract：BACKGROUND:Elevated glucose levels and glomerular hypertension (Pgc) are considered to contribute to the elaboration of matrix protein by mesangial cells (MCs) in diabetic glomeruli. MCs grown in 30 mM of glucose produce excessive matrix protein, as do MCs exposed to cyclic strain, and the combination of the two exacer...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1046/j.1523-1755.1999.00743.x
更新日期：1999-11-01 00:00:00
abstract：:The present study was undertaken to evaluate some pathophysiological mechanisms of edema formation in diabetic nephropathy. Sixty-three subjects were investigated: 9 normal subjects (I), 9 normoalbuminuric Type 1 (insulin-dependent) diabetic patients (II), 15 microalbuminuric Type 1 diabetic patients (III), 16 Type 1 ...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1990.332
更新日期：1990-12-01 00:00:00
abstract：BACKGROUND:Patients initiating dialysis after a failed kidney transplant are a subgroup of chronic kidney disease (CKD) patients who have not been characterized. Exposure to immunosuppressive medications differentiates these patients from the general incident end-stage renal disease (ESRD) population. METHODS:Data fro...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1046/j.1523-1755.2002.00373.x
更新日期：2002-06-01 00:00:00
abstract：:Adenosine is known to decrease renal blood flow and glomerular filtration rate. We have tested the hypothesis that adenosine exerts contractile effects on mesangial cells. Furthermore, we have studied, using selective agonists and antagonists for adenosine, which kind of adenosine receptor, A1 or A2, is mainly implica...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1989.126
更新日期：1989-06-01 00:00:00
abstract：:Major features of a long-standing inflammation in the kidney are vascular proliferation, glomerulosclerosis, interstitial fibrosis and tubular atrophy, leading to a gradual deterioration of the renal function. In this study we have investigated the expression of B-type receptors for platelet-derived growth factor (PDG...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1989.306
更新日期：1989-12-01 00:00:00
abstract：:Micropuncture studies were carried out in surface nephrons of rats with nephrotoxic-serum (NTS)-induced nephrotic syndrome during a period of active sodium and water retention. It was found that hydrostatic pressure and tubular diameter were increased in the proximal tubules (13.4 +/- 0.2 vs. 10.4 +/- 0.2 mm Hg; 31.3 ...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1979.166
更新日期：1979-11-01 00:00:00
abstract：:The beta-amino acid transport capabilities of rat renal epithelium were assessed using brushborder membrane vesicles (BBMV). Taurine, a metabolically inert sulfur-containing amino acid, was studied with emphasis on the renal adaptation to dietary sulfur amino acid alteration. Three isoproteinic diets were given to Spr...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1983.198
更新日期：1983-11-01 00:00:00
abstract：:Current practice recommends metabolic evaluation of patients who have formed multiple renal stones, but not those with one stone or temporally remote stones. This presumes that recentness and recurrence imply greater risk of new future stones. We hypothesize that number of stones reflects how long patients are permitt...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1994.224
更新日期：1994-06-01 00:00:00
abstract：:Autologous and allogeneic bone marrow grafting both require cytoreductive therapy but only the allogeneic procedure requires immunosuppressive agents. Allogeneic bone marrow transplantation has been reported to be associated with a high incidence of both renal failure and veno-occlusive disease (VOD) of the liver, the...
journal_title：Kidney international
pub_type： 临床试验,杂志文章
doi：10.1038/ki.1996.405
更新日期：1996-09-01 00:00:00
abstract：:Excess fatty acids accompanied by triglyceride accumulation in parenchymal cells of multiple tissues including skeletal and cardiac myocytes, hepatocytes, and pancreatic beta cells results in chronic cellular dysfunction and injury. The process, now termed lipotoxicity, can account for many manifestations of the 'meta...
journal_title：Kidney international
pub_type： 杂志文章,评审
doi：10.1038/sj.ki.5001834
更新日期：2006-11-01 00:00:00
abstract：:Cytomegalovirus (CMV) seropositivity is associated with increased risk for atherosclerotic disease in patients with end-stage renal disease. This association is due to a unique peripheral blood CD4(+) T cell population which lack CD28 (CD4(+)CD28(-) T cells). Here we found that this patient population has a significan...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.2008.301
更新日期：2008-09-01 00:00:00
abstract：:To assess in vitro erythropoietic cultures as a tool to discriminate between patients whose anemia improves with and those whose anemia fails to improve with androgens, bone marrows of 24 anemic patients receiving maintenance hemodialysis in hormone-depleted plasma clots were cultured. While erythroid colony prolifera...
journal_title：Kidney international
pub_type： 杂志文章
doi：10.1038/ki.1982.186
更新日期：1982-10-01 00:00:00
