Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit

Westhuyzen, Justin; Endre, Zoltán H.; Reece, Graham; Reith, David; Saltissi, David; Morgan, Thomas J.

doi:10.1093/ndt/18.3.543

Cited by 312 publications

(242 citation statements)

References 22 publications

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“…23,39,40 It is expressed on the surface of polymorphonuclear leukocytes and in several organs, including the kidney, in which it is localized, with a high density, on the brush border of proximal tubular CLINICAL RESEARCH www.jasn.org cells and on the cell surface of glomerular podocytes. 41,42 Debiec et al 42,43 showed that NEP may represent the target antigen in a rare subset of patients with alloimmune antenatal membranous nephropathy.…”

Section: Discussionmentioning

confidence: 99%

The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

Dell'Oglio

Zaza

Rossini

et al. 2010

Journal of the American Society of Nephrology

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Mycophenolic acid (MPA) appears to have anti-fibrotic effects, but the molecular mechanisms underlying this are unknown. We prospectively studied 35 stable kidney transplant recipients maintained on cyclosporine and azathioprine. We converted 20 patients from azathioprine to enteric-coated mycophenolate sodium (EC-MPS) and continued the remaining 15 patients on azathioprine. Exploratory mRNA expression profiling, performed on five randomly selected EC-MPS patients, revealed significant upregulation of neutral endopeptidase (NEP), which is an enzyme that degrades angiotensin II. We confirmed these microarray data by measuring levels of NEP expression in all subjects; in addition, we found that NEP gene expression correlated inversely with proteinuria. In an additional 33 patients, glomerular and tubular NEP protein levels from renal graft biopsies were significantly higher among the 13 patients receiving cyclosporine ϩ EC-MPS than among the 12 patients receiving cyclosporine ϩ azathioprine or 8 patients receiving cyclosporine alone. Glomerular NEP expression inversely correlated with glomerulosclerosis and proteinuria, and tubular NEP expression inversely correlated with interstitial fibrosis. Incubation of human proximal tubular cells with MPA increased NEP gene expression in a doseand time-dependent manner. Moreover, MPA reduced angiotensin II-induced expression of the profibrotic factor plasminogen activator inhibitor-1, and a specific NEP inhibitor completely reversed this effect. Taken together, our data suggest that MPA directly induces expression of neutral endopeptidase, which may reduce proteinuria and slow the progression of renal damage in kidney transplant recipients. 21: 215721: -216821: , 201021: . doi: 10.1681 Over the last decade, the continuous progress in the development of immunosuppressive agents has enhanced both the efficacy and safety of antirejection regimens after renal transplantation, leading to a dramatic reduction in the incidence of acute rejection. 1 This significant improvement in short-term graft outcome was not followed by a similar advance in preventing graft loss caused by chronic graft injury. 2,3 The addition of mycophenolic acid (MPA) into contemporary immunosuppressive regimens represented an important step forward in the development of new therapeutic protocols in kidney transplantation. J Am Soc NephrolMPA exerts its immunosuppressive effect by inhibiting the inosine 5Ј monophosphate dehydro-

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Section: Discussionmentioning

confidence: 99%

The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

Dell'Oglio

Zaza

Rossini

et al. 2010

Journal of the American Society of Nephrology

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“…Serum creatinine was estimated by Jaffe"s method using commercial reagent kit and α -GST was estimated in all the urine samples by colorimetric kinetic assay using NBD-Cl [18].…”

Section: B Evaluation Of the Temporal Pattern Of Serum Creatinine Anmentioning

confidence: 99%

“…Hence we designed this study to evaluate the efficiency of renal tubular cell specific enzyme α-Glutathione-s-transferase(α-GST) as a predictor of kidney injury in cancer patients treated with cisplatin, by studying the urinary excretion of alpha-GST at different time intervals and by comparing that with the changes in serum creatinine in cisplatin treated patients Cell specific biomarkers can predict toxic insults earlier and can provide information on sites of injury. Hence the urinary levels of α-GST, studied in a timely manner may help in identifying patients who may benefit from early interventions thus reducing the rate of morbidity and mortality associated with kidney injury [17], [18].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Urinary α-Glutathione-S-Transferase (α-GST) as a Marker of Early Cisplatin Induced Kidney Injury

Saleena¹,

Athiyamaan²,

Vadhiraja³

et al. 2012

IJBBB

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Abstract-Cisplatin is a very effective chemotherapeutic, but the risk of nephrotoxicity frequently hinders the use of its higher dose. This study was designed as a prospective observational cohort study to evaluate the efficacy of urinary renal tubular enzyme α-Glutathione-s-transferase(α-GST) for predicting kidney injury in cisplatin treated cancer patients. Venous blood samples were collected from all the patients, before the administration of cisplatin (baseline), and at 12h, 24h, 48h and 20days after cisplatin infusion and a random urine sample was collected before and at 2h , 6h, 12h, 24h and 48h after cisplatin administration. Serum creatinine was estimated by Jaffe's method using commercial reagent kit and α -GST was estimated in all the urine samples by colorimetric kinetic assay using NBD-Cl. There was a 20.5% incidence of acute kidney injury after cisplatin administration based on AKIN criteria. The mean urinary α-Glutathione S Transferase levels at different time intervals show a clear temporal rise, especially from 2hrs after cisplatin administration, till 12hrs and at a slower rate thereafter. The AUC of >0.8 for α-GST in all the timed urine samples after cisplatin administration indicated its good performance in predicting kidney injury. Urinary levels of proximal tubular enzyme, α-GST is found to be useful in predicting early kidney injury induced by cisplatin.

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“…Although advances in medicine have improved outcomes in these fields, the concept of the golden hour remains loosely applied and increasingly investigated in the setting of AKI. With recent advances in critical care nephrology, including consensus definitions, improved risk stratification, and biomarkers, intensivists and nephrologists are ideally positioned to investigate how best to improve patient outcomes and decrease the severity of renal damage in the golden hours of early AKI (4-6).In the past, AKI research has focused on the earlier identification of AKI before the rise in serum creatinine or drop in urine output (7,8). Recently, investigators have shifted their focus beyond simply replacing serum creatinine with a new gold standard and have sought to augment the information provided by serum creatinine and urine output, combining them with biochemical biomarkers, functional assessment of urine-making capacity, or both (9-11).…”

mentioning

confidence: 99%

“…In the past, AKI research has focused on the earlier identification of AKI before the rise in serum creatinine or drop in urine output (7,8). Recently, investigators have shifted their focus beyond simply replacing serum creatinine with a new gold standard and have sought to augment the information provided by serum creatinine and urine output, combining them with biochemical biomarkers, functional assessment of urine-making capacity, or both (9-11).…”

mentioning

confidence: 99%

The Golden Hours of AKI

Koyner¹

2015

Clinical Journal of the American Society of Nephrology

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Throughout various fields of scientific investigation, including neonatology and trauma medicine, the idea of the golden hour of treatment has long been debated (1-3). Defined as an interval most critical for successful emergency treatment and improved patient outcomes, the golden hour(s) is contingent on the delivery of early and frequently, protocol-driven care. Although advances in medicine have improved outcomes in these fields, the concept of the golden hour remains loosely applied and increasingly investigated in the setting of AKI. With recent advances in critical care nephrology, including consensus definitions, improved risk stratification, and biomarkers, intensivists and nephrologists are ideally positioned to investigate how best to improve patient outcomes and decrease the severity of renal damage in the golden hours of early AKI (4-6).In the past, AKI research has focused on the earlier identification of AKI before the rise in serum creatinine or drop in urine output (7,8). Recently, investigators have shifted their focus beyond simply replacing serum creatinine with a new gold standard and have sought to augment the information provided by serum creatinine and urine output, combining them with biochemical biomarkers, functional assessment of urine-making capacity, or both (9-11). Although these studies and others have shown that functional and damage biomarkers with physiologic links to the kidney are useful tools in predicting the risk of progression of early AKI, they were part of observational studies and require additional investigation.Additionally, an increasing number of controlled trials has shown efficacy when attempting to prevent severe AKI. Judicious intravenous fluid selection of nonhyperchloremic solutions (12) and remote ischemic preconditioning (13) showed renoprotective effects, which decreased the incidence of severe AKI (regardless of the need for RRT). Similarly, a meta-analysis investigating perioperative hemodynamic optimization, Brienza et al. (14) showed that trials targeting both supranormal and normal hemodynamic targets decreased the risk of postoperative AKI. However, not every controlled trial targeting hemodynamics parameters has shown a clinical benefit in preventing AKI. Two recent large-scale multicenter investigations of resuscitation protocols in the setting of severe sepsis and septic shock showed relatively low severe AKI event rates (2.8%-13.5%) and no difference in the duration of treatment in those requiring RRT (15,16). Although the ideal resuscitation strategy, intravenous fluid selection, and hemodynamic parameters to prevent the development of AKI continue to take shape, much less is known about how best to treat and optimize the patient just entering the golden hours that follow a new diagnosis of AKI.For those with newly diagnosed AKI, there is a dearth of proven interventions to prevent AKI progression. Data surrounding the use of automated, electronic medical record alerts for those with new-onset AKI seemed promising at first (17,18), but when pati...

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Measurement of tubular enzymuria facilitates early detection of acute renal impairment in the intensive care unit

Abstract: Tubular enzymuria on admission to the ICU is useful in predicting ARF. The cheapness and wide availability of automated assays for gamma GT and AP suggests that estimation of these enzymes in random urine samples may be particularly useful for identifying patients at high risk of ARF.

Cited by 312 publications

References 22 publications

The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

The Anti-Fibrotic Effect of Mycophenolic Acid–Induced Neutral Endopeptidase

Evaluation of Urinary α-Glutathione-S-Transferase (α-GST) as a Marker of Early Cisplatin Induced Kidney Injury

The Golden Hours of AKI

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