High serum concentrations of kidney-derived protein uromodulin [Tamm-Horsfall protein (THP)] have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with postsurgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity, and our findings might help explain how circulating THP deficiency is linked with poor outcomes and increased mortality.
IntroductionImpaired wound healing has been widely reported in diabetes. Linoleic acid (LA) accelerates the skin wound healing process in non-diabetic rats. However, LA has not been tested in diabetic animals.ObjectivesWe investigated whether oral administration of pure LA improves wound healing in streptozotocin-induced diabetic rats.MethodsDorsal wounds were induced in streptozotocin-induced type-1 diabetic rats treated or not with LA (0.22 g/kg b.w.) for 10 days. Wound closure was daily assessed for two weeks. Wound tissues were collected at specific time-points and used to measure fatty acid composition, and contents of cytokines, growth factors and eicosanoids. Histological and qPCR analyses were employed to examine the dynamics of cell migration during the healing process.ResultsLA reduced the wound area 14 days after wound induction. LA also increased the concentrations of cytokine-induced neutrophil chemotaxis (CINC-2αβ), tumor necrosis factor-α (TNF-α) and leukotriene B4 (LTB4), and reduced the expression of macrophage chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1 (MIP-1). These results together with the histological analysis, which showed accumulation of leukocytes in the wound early in the healing process, indicate that LA brought forward the inflammatory phase and improved wound healing in diabetic rats. Angiogenesis was induced by LA through elevation in tissue content of key mediators of this process: vascular-endothelial growth factor (VEGF) and angiopoietin-2 (ANGPT-2).ConclusionsOral administration of LA hastened wound closure in diabetic rats by improving the inflammatory phase and angiogenesis.
Acute kidney injury (AKI) is a common complication, impacting short- and long-term patient outcomes. Although the application of the classification systems for AKI has improved diagnosis, early clinical recognition of AKI is still challenging, as increments in serum creatinine may be late and low urine output is not always present. The role of urinary biochemistry has remained unclear, especially in critically ill patients. Differentiating between a transient and persistent acute kidney injury is of great need in clinical practice, and despite studies questioning their application in clinical practice, biochemistry indices continue to be used while we wait for a novel early injury biomarker. An ideal marker would provide more detailed information about the type, intensity, and location of the injury. In this review, we will discuss factors affecting the fractional excretion of sodium (FeNa) and fractional excretion of urea (FeU). We believe that the frequent assessment of urinary biochemistry and microscopy can be useful in evaluating the likelihood of AKI reversibility. The availability of early injury biomarkers could help guide clinical interventions.
Background Acute kidney injury (AKI) is a common complication in patients undergoing liver transplant (LT) and is associated with high morbidity and mortality. We aim to evaluate the pattern of urine and plasma neutrophil gelatinase-associated lipocalin (NGAL) elevation during the perioperative period of LT and to assess it as a prognostic marker for AKI progression, need for dialysis and mortality. Methods We assessed NGAL levels before induction of anesthesia, after portal reperfusion and at 6, 18, 24, and 48 h after surgery. Patients were monitored daily during the first week after LT. Results Of 100 enrolled patients undergoing liver transplant, 59 developed severe AKI based on the KDIGO serum creatinine (sCr) criterion; 34 were dialysed, and 21 died within 60 days after LT. Applying a cut-off value of 136 ng/ml, UNGAL values 6 h after surgery was a good predictor of AKI development within 7 days after surgery, having a positive predictive value (PPV) of 80% with an AUC of 0.76 (95% CI 0.67–0.86). PNGAL at 18 h after LT was also a good predictor of AKI in the first week, having a PPV of 81% and AUC of 0.74 (95% CI 0.60–0.88). Based on PNGAL and UNGAL cut-off criteria levels, time to AKI diagnosis was 28 and 23 h earlier than by sCr, respectively. The best times to assess the need for dialysis were 18 h after LT by PNGAL and 06 h after LT by UNGAL. Conclusion In conclusion, the plasma and urine NGAL elevation pattern in the perioperative period of the liver transplant can predict AKI diagnosis earlier. UNGAL was an early independent predictor of AKI development and need for dialysis. Further studies are needed to assess whether the clinical use of biomarkers can improve patient outcomes. Trial registration Registered at Clinical Trials (clinicaltrials.gov) in March 24th, 2014 by title “Acute Kidney Injury Biomarkers: Diagnosis and Application in Pre-operative Period of Liver Transplantation (AKIB)” and identifier NCT02095431, retrospectively registered.
Objectives: This study aims to verify the new-onset diabetes after kidney transplant (NODAT) incidence in recipients within 1 year after kidney transplantation from a single center in Southern Brazil and to assess the associated conditions. Subjects and methods: A retrospective study of 258 postrenal transplant patients was performed. Demographic (gender, age, ethnic background) and clinical (origin of graft, associated infections, body mass index (BMI) at transplant time and 6 and 12 months after, causes of renal failure, and comorbidities) data were analyzed. All patients were on tacrolimus, mycophenolate mofetil, and prednisone treatment. Patients with and without NODAT were compared. Results: A NODAT incidence of 31.2% was noted 1 year post transplantation. In the univariate analysis, patients with NODAT were older (p = 0.001), mostly had African-American ethnic background (p = 0.02), and had renal failure secondary to high blood pressure (HBP) (p = 0.001). The group of patients with NODAT also had more incidence of post-transplant HBP (p = 0.01), heart failure (p = 0.02), and dyslipidemia (p = 0.001). Logistic regression showed that African-American ethnic background, posttransplant HBP, and dyslipidemia were independently associated with NODAT. Conclusion: This study shows a NODAT incidence that is greater in patients with African-American ethnic background and that is associated with HBP and dyslipidemia.
Acute kidney injury (AKI) is a frequent event in hospitalized patients, with an incidence that continues to rise, reaching as high as 70–80% in intensive care settings. The need for dialysis and progression to end-stage kidney disease (ESKD) after an episode of AKI is relatively low, from 5 to 20%. However, it is now recognized that patients with AKI may have very different kidney outcomes, varying from complete recovery, incipient chronic kidney disease (CKD), to progression to ESKD. Recent studies have shown that even mild AKI episodes can be associated with a 90% increased risk of developing CKD during long-term follow-up. There is a significant need to focus our efforts on factors that could mitigate the progression of kidney dysfunction and ultimately improve outcomes from AKI. The first step toward this goal encompasses a better understanding of tubular and glomerular alterations during and following an AKI episode. Our current approach, based solely on glomerular filtration rate (GFR), is flawed, since the loss of kidney function does not correspond to the degree of decline in estimated GFR (eGFR), and eGFR does not reflect tubular function. Changes in tubular concentration, reabsorptive and secretory capacity are recognized in AKI; however, they have not been incorporated in clinical assessments of overall kidney function. Here we review a few candidates to assess glomerular filtration/permeability, tubular dysfunction, and injury and how we expect these markers to alter during the development and recovery phase of AKI.
Acute kidney injury (AKI) is a common complication in several settings inside and outside hospitals. It affects millions of people around the world, and despite high levels of research funding, there is no specific treatment that changes the disease course. The basis for unfavorable outcomes related to this disease is the failure to provide early diagnosis. Currently, the diagnosis of AKI is based on serum creatinine and urine output, and both measures have several limitations, making early diagnosis difficult. In recent decades, several biomarkers of kidney injury have been proposed, with neutrophil gelatinase-associated lipocalin (NGAL) being one of most studied and promising for use in early diagnosis. Despite there being several studies on NGAL, it has not yet been applied in clinical practice; thus, furthering the understanding of the development, interpretation, and limitations of NGAL in the diagnosis of AKI is the objective of this chapter.
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