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Background: In the past years evidence has been growing about the interconnection of chronic kidney disease and acute kidney injury. The underlying pathophysiological mechanisms remain unclear. We hypothesized, that a threshold ischemia time in unilateral ischemia/reperfusion injury sets an extent of ischemic tubule necrosis, which as "point of no return" leads to progressive injury. This progress is temporarily associated by increased markers of inflammation and results in fibrosis and atrophy of the ischemic kidney., Methods: Acute tubule necrosis was induced by unilateral ischemia/reperfusion injury in male C57BL/6 N mice with different ischemia times (15, 25, 35, and 45 min). At multiple time points between 15 min and 5 weeks we assessed gene expression of markers for injury, inflammation, and fibrosis, histologically the injury of tubules, cell death (TUNEL), macrophages, neutrophil influx and kidney atrophy., Results: Unilateral ischemia for 15 and 25 min induced upregulation of markers for injury after reperfusion for 24 h but no upregulation after 5 weeks. None of the markers for inflammation or fibrosis were upregulated after ischemia for 15 and 25 min at 24 h or 5 weeks on a gene expression level, except for Il-6. Ischemia for 35 and 45 min consistently induced upregulation of markers for inflammation, injury, and partially of fibrosis (Tgf-β1 and Col1a1) at 24 h and 5 weeks. The threshold ischemia time for persistent injury of 35 min induced a temporal association of markers for inflammation and injury with peaks between 6 h and 7 d along the course of 10 d. This ischemia time also induced persistent cell death (TUNEL) throughout observation for 5 weeks with a peak at 6 h and progressing kidney atrophy beginning 7 d after ischemia., Conclusions: This study confirms the evidence of a threshold extent of ischemic injury in which markers of injury, inflammation and fibrosis do not decline to baseline but remain upregulated assessed in long term outcome (5 weeks). Excess of this threshold as "point of no return" leads to persistent cell death and progressing atrophy and is characterized by a temporal association of markers for inflammation and injury.

Purpose: Kidney transplantation from elderly donors with acute kidney injury (AKI) has increased recently due to donor shortage, but the safety and prognosis are not well known. We examined the effect of donor age on the outcomes of kidney transplantation (KT) from donors with histologic AKI., Materials and Methods: We retrospectively analyzed the medical records of 59 deceased-donor KTs with acute tubular necrosis (ATN) on preimplantation donor kidney biopsy between March 2012 and October 2017. Histologic evaluations of ATN, inflammation, glomerulosclerosis (GS), interstitial fibrosis, tubular atrophy, and arterial sclerosis were performed., Results: Twenty and 39 recipients received kidneys from elderly (> 60, 68.9 ± 5.0 years) and young (≤ 60, 45.9 ± 9.6 years) donors with ATN, respectively. Among the elderly donors, significantly increased donor creatinine was observed in only 44% donors, and there were more diabetic patients and women and a higher proportion of GS than among the young donors. Six months after KT, estimated glomerular filtration rate was significantly lower in recipients who received kidneys from elderly donors compared to young donors. Donor creatinine level and AKI severity did not significantly affect the recipient outcomes in either group. However, the presence of ATN and GS were significant factors that exacerbated renal outcomes after KT from elderly donors only. On multivariate analysis, severe ATN was the strongest independent predictor of elderly recipient renal function., Conclusions: Histologic injury may predict renal outcomes in KT from elderly donors. A donor allocation protocol including preimplantation renal histology should be established for KT from elderly donors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Maternal undernutrition is known to reduce glomerular number but it may also affect tubulointerstitium, capillary density, and response to oxidative stress. To investigate whether the latter elements are affected, we examined the response to unilateral ureteral obstruction (UUO), an established model of renal tubulointerstitial fibrosis, in the kidney of offspring from control and nutrient restricted rats. Six-week old male offspring from rats given food ad libitum (CON) and those subjected to 50% food restriction throughout pregnancy (NR) were subjected to UUO for 7 days. Body weight was significantly lower in NR. Systolic blood pressure and blood urea nitrogen increased similarly in CON and NR after UUO. Tubular necrosis in the obstructed kidney, on the other hand, was more extensive in NR. Also, the collagen area, a marker of fibrosis, of the obstructed kidney was significantly increased compared with the contralateral kidney only in NR. Capillary density was decreased similarly in the obstructed kidney of CON and NR compared with the contralateral kidney. Urine nitrate/nitrite, a marker of nitric oxide production, from the obstructed kidney was significantly increased in NR compared with CON. Nitrotyrosine, a marker of nitric oxide-mediated free radical injury, was increased in the obstructed kidney compared with the contralateral kidney in both CON and NR, but the extent was significantly greater in NR. In conclusion, more severe tubular necrosis and fibrosis after UUO was observed in NR, which was thought to be due to increased nitrosative stress., Competing Interests: The authors have declared that no competing interests exist.

Several lines of evidence have demonstrated the anti-inflammatory and cytoprotective effects of alpha-1-antitrypsin (AAT), the major serum serine protease inhibitor. The aim of the present study was to investigate the effects of human AAT (hAAT) monotherapy during the early and recovery phase of ischemia-induced acute kidney injury. Mild renal ischemia-reperfusion (I/R) injury was induced in male C57Bl/6 mice by bilateral clamping of the renal artery and vein for 20 min. hAAT (80 mg/kg, Prolastin®) was administered daily intraperitoneally (i.p.) from day -1 until day 7 after surgery. Control animals received the same amount of human serum albumin (hAlb). Plasma, urine and kidneys were collected at 2h, 1, 2, 3, 8 and 15 days after reperfusion for histological and biochemical analysis. hAAT partially preserved renal function and tubular integrity after induction of bilateral kidney I/R injury, which was accompanied with reduced renal influx of macrophages and a significant decrease of neutrophil gelatinase-associated lipocalin (NGAL) protein levels in urine and plasma. During the recovery phase, hAAT significantly decreased kidney injury molecule-1 (KIM-1) protein levels in urine but showed no significant effect on renal fibrosis. Although the observed effect size of hAAT administration was limited and therefore the clinical relevance of our findings should be evaluated carefully, these data support the potential of this natural protein to ameliorate ischemic and inflammatory conditions.

The kidney plays a primary role in maintaining homeostasis and detoxification of numerous hydrophilic xenobiotics as well as endogenous compounds. Because the kidney is exposed to a larger proportion and higher concentration of drugs and toxins than other organs through the secretion of ionic drugs by tubular organic ion transporters across the luminal membranes of renal tubular epithelial cells, and through the reabsorption of filtered toxins into the lumen of the tubule, these cells are at greater risk for injury. In fact, drug-induced kidney injury is a serious problem in clinical practice and accounts for roughly 20% of cases of acute kidney injury (AKI) among hospitalized patients. Therefore, its early detection is becoming more important. Usually, drug-induced AKI consists of two patterns of renal injury: acute tubular necrosis (ATN) and acute interstitial nephritis (AIN). Whereas AIN develops from medications that incite an allergic reaction, ATN develops from direct toxicity on tubular epithelial cells. Among several cellular mechanisms underlying ATN, oxidative stress plays an important role in progression to ATN by activation of inflammatory response via proinflammatory cytokine release and inflammatory cell accumulation in tissues. This review provides an overview of drugs associated with AKI, the role of oxidative stress in drug-induced AKI, and a biomarker for drug-induced AKI focusing on oxidative stress., Competing Interests: The author declares no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Aim: The role of post-reperfusion biopsy findings as a predictor of early and long-term graft function and survival is still a target of research., Methods: We analyzed data from 136 post-reperfusion biopsies performed in deceased donor renal transplanted patients from November 2008 to May 2012. We analyzed the presence of acute tubular necrosis (ATN), arteriolar hyalinosis (AH), intimal thickness (IT), interstitial fibrosis (IF) and glomerulosclerosis (GS). We also analyzed the impact of donor features on the following outcomes: delayed graft function (DGF) and chronic allograft dysfunction defined as eGFR < 60 mL/min at 1 year., Results: The mean donor age was 41 years, 26% of whom were extended criteria donors (ECD), 33% had hypertension and 50% had cerebral vascular accident (CVA) as the cause of death. ATN was present in 87% of these biopsies, AH in 31%, IF in 21%, IT in 27% and GS in 32%. DGF occurred in 80% and chronic allograft dysfunction was present in 53%. AH was the only histological finding associated with DGF and chronic allograft dysfunction at 1 year. Patients with AH had a lower eGFR at 1 year than patients without it (49.8 mL/min × 64.5 mL/min, P = 0.02). In the multivariate analysis, risk variables for development of chronic graft dysfunction were male sex (odds ratio [OR] = 3.159 [CI: 1.22-8.16]; P = 0.018), acute rejection (OR = 8.91 [CI: 2.21-35.92]; P = 0.002), donor hypertension (OR = 2.94 [CI: 1.10-7.84]; P = 0.031), AH (OR = 3.96 [CI: 1.46-10.70]; P = 0.007) and eGFR at discharge (OR = 0.96 [CI: 0.93-0.98]; P = 0.005). In multivariate analysis, risk factors for AH were donor age ≥ 50 years (OR = 2.46 [CI: 1.10-5.44]; P = 0.027) and CVA as the cause of donor death (OR = 2.33 [CI: 1.05-5.15]; P = 0.007)., Conclusion: The presence of AH in post-reperfusion biopsies is a marker of ageing and vascular disease and was associated with DGF and a one year poorer renal function. AH in donor biopsies superimposed to long ischaemic time is a predictor of renal function. The management of immunosuppression based on the presence of AH in post-reperfusion biopsy could be useful to improve long term graft function., (© 2015 Asian Pacific Society of Nephrology.)

Background: The use of imaging is increasing in clinical practice either for diagnosis or intervention. In these aims, contrast medium (CM) is widely used. However, CM administration can induce contrast-induced nephropathy (CIN). The incidence of CIN varies from 2% to 50% depending on patient risk factors, and CIN is the third cause of renal insufficiency. To date, methods such as hyperhydration to prevent CIN have a low level of evidence. Remote ischemic preconditioning (RIPC), which has already proved its efficiency in the cardiology field, seems to be a promising technique for CIN prevention. The aim of this work was to carry out a systematic review of the literature of the randomized clinical studies on RIPC in the prevention of CIN in man., Methods: We conducted a systematic review of randomized clinical studies on the RIPC in the prevention of CIN in man. Documentary sources were PubMed articles published until June 2015. Randomized clinical trials of RIPC in preventing CIN in human were reviewed., Results: Five articles were selected for the analysis. One article studied the impact of RIPC in a population at high risk of CIN, whereas the other 4 analyzed populations at low, moderate or unknown risk of CIN. In 4 studies, except the later one, the risk of CIN was based on the Mehran score that was previously published. In the high-risk population, a decrease in the incidence of CIN was found in the RIPC group compared with the control group (12% against 40%; P = 0.002). Among the 3 other studies using the Mehran's score, one also demonstrated the interest of such a procedure in a subgroup of high-risk patients. A second one found a low incidence of CIN in the RIPC group ([5 of 47; 10%] as compared with a control group [17 of 47; 36%] P = 0.003) in patients at the low risk of CIN. In another low-risk population, a significant lower level of a biological marker (liver-type fatty acid-binding protein) that assesses a renal impairment was found in the RIPC compared with the control group., Conclusions: Only 5 studies were found in this search, which may constitute a limitation. However, RIPC appears as a promising method to prevent CIN since it is a noninvasive, low cost, easy, and safe method. More randomized controlled trials are needed to confirm these preliminary results., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background/aims: The potential physiologic roles of Klotho in acute kidney injury (AKI) have recently been demonstrated in animal models. However, to date, there have been no human studies investigating the expression of renal Klotho in AKI., Methods: We retrospectively collected biopsy specimens and clinical data of AKI patients between January 2001 and December 2012. Klotho expression was determined by immunohistochemical staining, and the clinical-pathological correlation was examined., Results: Among the 34 patients diagnosed with acute tubular necrosis or acute tubulointerstitial nephritis, 21 patients without chronic histological lesions were included. The mean age was 37.3 ± 18.5 years and the mean peak creatinine level was 8.2 ± 5.5 mg/dL. In total, 10 patients (47.6%) received temporary renal replacement therapy (RRT); however, 17 patients (81%) showed functional recovery with creatinine levels of < 1.3 mg/dL after 1 month. The intensity of Klotho expression was scored as a percentage of Klotho-positive area. The renal Klotho score showed a significant negative correlation with the initial or peak creatinine level. When the patients were divided into three groups according to the Klotho score (low, middle, high), the low group had a significantly higher peak creatinine level and a more frequent requirement for RRT. However, the Klotho score was not a significant predictor of renal recovery., Conclusions: The results demonstrated that renal Klotho expression in humans decreased significantly according to the severity of AKI, regardless of the etiology, and that low expression was associated with a poor short-term outcome.

Background: To describe recent insights into glomerular haemodynamics in septic acute kidney injury (AKI)., Methods: We reviewed the literature with particular emphasis on recent findings in animal experiments and human studies in relation to renal macro- and micro-renal haemodynamics during septic AKI., Results: The dominant paradigm is that septic AKI is due to decreased renal perfusion with ischaemic loss of glomerular filtration rate (GFR), ischaemic tubular cell injury and acute tubular necrosis (ATN). However, recent experimental and human studies challenge this view of the pathogenesis of septic AKI. In addition, rapid post-mortem and experimental histological studies do not support ATN as the histological substrate of septic AKI. Finally, more recent experimental evidence suggests that changes in the glomerular and peri-glomerular haemodynamics provide a more likely explanation for the loss of GFR seen in the early phases of septic AKI., Conclusions: Despite a long-standing paradigm that septic AKI is due to renal hypo-perfusion and associated ATN, experimental and human studies increasingly suggest that changes in the state of the glomerular and peri-glomerular micro-vasculature are a more likely additional explanation for this condition., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Introduction: Doppler ultrasound (US) has become the primary imaging technique for the evaluation of renal transplants. It provides information about the intrarenal resistance index (RI). A high RI is seen in every form of graft dysfunction. In this article, we review the utility of sonography, particularly the intrarenal RI measured early after renal transplant, as a predictor of acute and chronic clinical outcome in patients., Results: RI is a valuable marker to determine graft function and related vascular complications. It reveals a strong correlation with serum creatinine levels measured days after transplant. Its elevation is typical for acute tubular necrosis and can be used to predict its duration. An RI >1 (absent end-diastolic flow) seen in the first weeks after transplant is associated with impaired renal graft recovery. In addition, it is an early predictor of chronic allograft nephropathy (even correlated with biopsy results), which will allow a change in therapy., Conclusions: RI measured serially in the early period after kidney transplantation is a valuable marker for determining renal graft function. It is also useful for demonstrating various types of graft dysfunction; however, it cannot differentiate between them. In recent studies, extrarenal factors in kidney transplantation (eg, recipient's age) may significantly influence RI in the recipient, demonstrating that RI depends on the vascular characteristics of the recipient and not on the graft itself.

To evaluate the role of power Doppler in the identification and differentiation between acute renal transplant rejection and acute tubular necrosis (ATN), we studied 67 live donor renal transplant recipients. All patients were examined by spectral and power Doppler sonography. Assessment of cortical perfusion (CP) by power Doppler was subjective, using our grading score system: P0 (normal CP); homogenous cortical blush extending to the capsule, P1 (reduced CP); cortical vascular cut-off at interlobular level, P2 (markedly reduced CP); scattered cortical color flow at the interlobar level. Renal biopsies were performed during acute graft dysfunction. Pathological diagnoses were based on Banff classification 1997. The Mann- Whitney test was used to test the difference between CP grades with respect to serum creatinine (SCr), and resistive index (RI). For 38 episodes of acute graft rejection grade I, power Doppler showed that CP was P1 and RI ranging from 0.78 to 0.89. For 21 episodes of acute graft rejection grade II, power Doppler showed that CP was P1, with RI ranging from 0.88 to >1. Only one case of grade III rejection had a CP of P2. Twelve biopsies of ATN had CP of P0 and RI ranging from 0.80 to 0.89 There was a statistically significant correlation between CP grading and SCr (P <0.01) as well as between CP grading and RI (P <0.05). CP grading had a higher sensitivity in the detection of early acute rejection compared with RI and cross-sectional area measurements. We conclude that power Doppler is a non-invasive sensitive technique that may help in the detection and differentiation between acute renal transplant rejection and ATN, particularly in the early post-transplantation period.

Background: Venom-induced acute kidney injury (AKI) is a frequent complication of Bothrops snakebite with relevant morbidity and mortality. The aim of this study was to assess the effects of Schizolobium parahyba (SP) extract, a natural medicine with presumed anti-Bothrops venom effects, in an experimental model of Bothrops jararaca venom (BV)-induced AKI., Methodology: Groups of 8 to 10 rats received infusions of 0.9% saline (control, C), SP 2 mg/kg, BV 0.25 mg/kg and BV immediately followed by SP (treatment, T) in the doses already described. After the respective infusions, animals were assessed for their glomerular filtration rate (GFR, inulin clearance), renal blood flow (RBF, Doppler), blood pressure (BP, intra-arterial transducer), renal vascular resistance (RVR), urinary osmolality (UO, freezing point), urinary neutrophil gelatinase-associated lipocalin (NGAL, enzyme-linked immunosorbent assay [ELISA]), lactate dehydrogenase (LDH, kinetic method), hematocrit (Hct, microhematocrit), fibrinogen (Fi, Klauss modified) and blinded renal histology (acute tubular necrosis score)., Principal Findings: BV caused significant decreases in GFR, RBF, UO, HcT and Fi; significant increases in RVR, NGAL and LDH; and acute tubular necrosis. SP did not prevent these changes; instead, it caused a significant decrease in GFR when used alone., Conclusion: SP administered simultaneously with BV, in an approximate 10∶1 concentration, did not prevent BV-induced AKI, hemolysis and fibrinogen consumption. SP used alone caused a decrease in GFR.

Objective: The main aim of this study is to investigate the incidence and prognosis of acute kidney injury (AKI) and to clarify the risk factors associated with the prognosis of AKI in hospitalized patients., Method: All patients hospitalized from January 1st to December 31st 2012 in Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University were screened by the Lab Administration Network. All the patients with an intact medical history of AKI according to the Acute Kidney Injury Network (AKIN) were enrolled in the study cohort. AKI's incidence and etiology, as well as the patient's characteristics and prognosis, were retrospectively analyzed. Logistic regression analysis was used to investigate the risk factors on the patient prognosis and renal outcome., Results: 934 AKI patients were enrolled. The incidence of AKI in hospitalized patients was 2.41%. The ratio of males to females of patients was 1.88:1 and the mean age was 60.82 ± 16.94. The incidence of AKI increased with increase in age. Among hospitalized patients, 63.4% were from the surgical department, 35.4% from the internal medicine department, and 1.2% from the obstetric and gynecologic department. Regarding the cause of AKI, pre-renal AKI, acute tubular necrosis (ATN), acute glomerulonephritis and vasculitis (AGV), acute interstitial nephritis (AIN), and post-renal AKI contributed with 51.7, 37.7, 3.8, 3.5, and 3.3%, respectively. The survival rate on the day 28 after AKI was 71.8%. In addition, 65.7% patients got complete renal recovery, while 16.9% got partial renal recovery and 17.4% got renal loss. The mortality of AKI in hospitalized patients at Stage I, Stage II and Stage III was 24.8, 31.2 and 43.7%, respectively. Multivariate Logistic regression analysis showed that use of nephrotoxic drugs, [Odds Ratio (OR) = 2.313], hypotension in the previous week (OR = 4.482), oliguria (OR = 5.267), the number of extra-renal organ failures (OR = 1.376), and need for renal replacement therapy (RRT) (OR = 4.221) were independent risk factors for mortality. The number of extra-renal organ failures (OR = 1.529) and RRT (OR = 2.117) were independent risk factors for renal loss., Conclusion: AKI is one of the most common complications in hospitalized patients. The mortality is high and renal prognosis is poor after AKI. The prognosis is closely associated with the severity of AKI. Nephrotoxic drugs, hypotension within the last week, oliguria, the number of extra-renal organ failures, and RRT are independent risk factors for mortality, while the number of extra-renal organ failures and RRT are independent risk factors for renal loss., (© 2014 S. Karger AG, Basel.)

We report the case of a 69-year-old man who presented with acute kidney injury in the setting of community-acquired Clostridium difficile-associated diarrhea and biopsy-proven acute oxalate nephropathy. We discuss potential mechanisms, including increased colonic permeability to oxalate. We conclude that C difficile-associated diarrhea is a potential cause of acute oxalate nephropathy., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Renal ischemia/reperfusion (I/R) injury is manifested by acute renal failure (ARF) and acute tubular necrosis (ATN). The aim of this study was to evaluate the effectiveness of preconditioning with 3, 3, 5 triiodothyronine (T3) to prevent I/R renal injury., Methodology/principal Findings: The rats were divided into four groups: sham-operated, placebo-treated (SO-P), sham-operated T3- treated (SO- T3), I/R-injured placebo-treated (IR-P), and I/R-injured T3-treated (IR- T3) groups. At 24 h before ischemia, the animals received a single dose of T3 (100 μg/kg). Renal function and plasma, urinary, and tissue variables were studied at 4, 24, and 48 h of reperfusion, including biochemical, oxidative stress, and inflammation variables, PARP-1 immunohistochemical expression, and ATN morphology. In comparison to the SO groups, the IR-P groups had higher plasma urea and creatinine levels and greater proteinuria (at all reperfusion times) and also showed: increased oxidative stress-related plasma, urinary, and tissue variables; higher plasma levels of IL6 (proinflammatory cytokine); increased glomerular and tubular nuclear PARP-1 expression; and a greater degree of ATN. The IR-T3 group showed a marked reduction in all of these variables, especially at 48 h of reperfusion. No significant differences were observed between SO-P and SO-T3 groups., Conclusions: This study demonstrates that preconditioning rats with a single dose of T3 improves the clinical signs and ATN of renal I/R injury. These beneficial effects are accompanied by reductions in oxidative stress, inflammation, and renal PARP-1 expression, indicating that this sequence of factors plays an important role in the ATN induced by I/R injury.

The secreted kielin/chordin-like (KCP) protein, one of a family of cysteine-rich proteins, suppresses TGF-β signaling by sequestering the ligand from its receptor, but it enhances bone morphogenetic protein (BMP) signaling by promoting ligand-receptor interactions. Given the critical roles for TGF-β and BMP proteins in enhancing or suppressing renal interstitial fibrosis, respectively, we examined whether secreted KCP could attenuate renal fibrosis in mouse models of chronic and acute disease. Transgenic mice that express KCP in adult kidneys showed significantly less expression of collagen IV, α-smooth muscle actin, and other markers of disease progression in the unilateral ureteral obstruction model of renal interstitial fibrosis. In the folic acid nephrotoxicity model of acute tubular necrosis, mice expressing KCP survived high doses of folic acid that were lethal for wild-type mice. With a lower dose of folic acid, mice expressing KCP exhibited improved renal recovery compared with wild-type mice. Thus, these data suggest that extracellular regulation of the TGF-β/BMP signaling axis by KCP, and by extension possibly other cysteine-rich domain proteins, can attenuate both acute and chronic renal injury.

Age increases the risk for ischemic acute kidney injury (AKI). We questioned whether a similar age-dependent injury occurs following exposure to hemoglobin, a known nephrotoxin. Old mice (~16 mo old), but not young mice (~6 mo old), when administered hemoglobin, exhibited marked elevation in blood urea nitrogen (BUN) and serum creatinine, and acute tubular necrosis with prominent tubular cast formation. The aged kidney exhibited induction of heme oxygenase-1 (HO-1) and other genes/proteins that may protect against heme-mediated renal injury, including ferritin, ferroportin, haptoglobin, and hemopexin. Old mice did not evince induction of HO-2 mRNA by hemoglobin, whereas a modest induction of HO-2 mRNA was observed in young mice. To determine the functional significance of HO-2 in heme protein-induced AKI, we administered hemoglobin to relatively young HO-2(+/+) and HO-2(-/-) mice: HO-2(-/-) mice, compared with HO-2(+/+) mice, exhibited greater renal dysfunction and histologic injury when administered hemoglobin. In addition to failing to elicit a protective system such as HO-2 in response to hemoglobin, old mice exhibited an exaggerated maladaptive response typified by markedly greater induction of the nephrotoxic cytokine IL-6 (130-fold increase vs. 10-fold increase in mRNA in young mice). We conclude that aged mice, unlike relatively younger mice, are exquisitely sensitive to the nephrotoxicity of hemoglobin, an effect attended by a failure to induce HO-2 mRNA and a fulminant upregulation of IL-6. Age thus markedly augments the sensitivity of the kidney to heme proteins, and HO-2 confers resistance to such insults.

Acute kidney injury (AKI) is a common and important medical problem, affecting 10% of hospitalized patients, and it is associated with significant morbidity and mortality. The most frequent cause of AKI is acute tubular necrosis (ATN). Current imaging techniques and biomarkers do not allow ATN to be reliably differentiated from important differential diagnoses, such as acute glomerulonephritis (GN). We investigated whether (13)C magnetic resonance spectroscopic imaging (MRSI) might allow the noninvasive diagnosis of ATN. (13)C MRSI of hyperpolarized [1,4-(13)C(2)]fumarate and pyruvate was used in murine models of ATN and acute GN (NZM2410 mice with lupus nephritis). A significant increase in [1,4-(13)C(2)]malate signal was identified in the kidneys of mice with ATN early in the disease course before the onset of severe histological changes. No such increase in renal [1,4-(13)C(2)]malate was observed in mice with acute GN. The kidney [1-(13)C]pyruvate/[1-(13)C]lactate ratio showed substantial variability and was not significantly decreased in animals with ATN or increased in animals with GN. In conclusion, MRSI of hyperpolarized [1,4-(13)C(2)]fumarate allows the detection of early tubular necrosis and its distinction from glomerular inflammation in murine models. This technique may have the potential to identify a window of therapeutic opportunity in which emerging therapies might be applied to patients with ATN, reducing the need for acute dialysis with its attendant morbidity and cost.

In addition to antiasthmatic effect, the cysteinyl leukotriene receptor 1 (CysLT₁) antagonist montelukast shows renoprotective effect during ischemia/reperfusion and cyclosporine-induced renal damage. Here, we proposed that montelukast protects against rhabdomyolysis-induced acute renal failure. Compared with saline-treated rats, at 48 h following the induction of rhabdomyolysis using intramuscular glycerol (10 ml 50% glycerol/kg), significant elevations in serum levels of urea, creatinine, phosphate and acute renal tubular necrosis were observed. This was associated with elevations in serum Fas, interleukin-10, tumor necrotic factor-alpha, and transforming growth factor-beta1 and renal malondialdehyde and nitrite and detrimental reductions in renal catalase and superoxide dismutase activities. The effects of rhabdomyolysis on renal functional, biochemical and structural integrity and the associated changes in cytokines and Fas levels were abolished upon concurrent administration of montelukast (10 mg/kg i.p.) for 3 days (1 day before and 2 days after induction of rhabdomyolysis). Alternatively, administration of the anti-oxidant, α-tocopherol (400 mg/kg i.m.) for 3 days, succeeded in alleviating renal oxidative stress, but had no significant effect on the circulating levels of most cytokines and partially restored kidney functional and structural damage. Serum level of interleukin-6 was not altered by rhabdomyolysis but showed significant elevations in rats treated with montelukast or α-tocopherol. Collectively, motelukast abrogated functional and structural renal damage induced by rhabdomyolysis via ameliorating renal oxidative stress and modulation of systemic cytokines and apoptotic factors production. The results of this work are expected to open new avenues for early prevention of rhabdomyolysis-induced acute renal failure using selective CysLT₁ antagonists such as montelukast., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Clinical use of nonsteroidal anti-inflammatory drugs (NSAIDs) like diclofenac (DCLF) is limited by multiple adverse effects, including renal toxicity leading to acute kidney injury. In mice with DCLF-induced nephrotoxicity, TDZD-8, a selective glycogen synthase kinase (GSK)3β inhibitor, improved acute kidney dysfunction and ameliorated tubular necrosis and apoptosis associated with induced cortical expression of cyclooxygenase-2 (COX-2) and prostaglandin E2. This renoprotective effect was blunted but still largely preserved in COX-2-null mice, suggesting that other GSK3β targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3β inhibition reinstated viability and suppressed necrosis and apoptosis in DCLF-stimulated tubular epithelial cells. DCLF elicited oxidative stress, enhanced the activity of the redox-sensitive GSK3β, and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3β activity and prevented GSK3β-mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3β abolished the effects of TDZD-8. Hence, inhibition of GSK3β ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition.

Urinary albumin excretion is an important diagnostic and prognostic marker of renal function. Both animal and human urine contain large amounts of albumin fragments, but whether these fragments originate from renal tubular degradation of filtered albumin is unknown. Here, we used mice with kidneys lacking megalin and cubilin, the coreceptors that mediate proximal tubular endocytosis of albumin, to determine whether proximal tubular degradation of albumin forms the detectable urinary albumin fragments. After intravenous administration of (125)I-labeled mouse albumin to knockout and control mice, we examined kidney uptake of albumin and urinary excretion of both intact albumin and its fragments using size exclusion chromatography. In control mice, all labeled albumin eluted as albumin fragments in the urine. In megalin/cubilin-deficient mice, we observed decreased uptake and degradation of albumin and increased urinary excretion of intact albumin; we did not, however, detect a decrease in the excretion of albumin fragments. These results show that the generation of urinary albumin fragments occurs independently of renal tubular uptake and degradation of albumin, suggesting that the pathophysiological implications of changes in urinary albumin fragments require reevaluation.

Acute renal failure, now referred to as acute kidney injury, is a common and clinically important problem. Acute kidney injury frequently occurs as a result of acute tubular necrosis (ATN), which is often caused by a reduction in systemic blood pressure or renal blood flow (e.g., as observed in severe sepsis or during renal transplantation). The disease course in ATN is variable, including prolonged dialysis-dependence and chronic renal dysfunction, but there is currently no specific therapy for ATN. There is increasing evidence that the inflammatory response in ATN significantly contributes to disease severity and outcome. In this review, we summarize recent developments in the understanding of how the immune system responds to dying cells, and the relevance of these discoveries to ATN. In particular, NLRP3 inflammasome activation and IL-1β-mediated neutrophil recruitment are likely to play a key role and may provide novel therapeutic targets for immunotherapy in ATN.

Background: Renal transplant recipients may experience delayed graft function (DGF), but recovery can take many months, a condition we define as hyper-delayed graft function (HDGF)., Methods: A retrospective review of 50 renal transplant recipients who had HDGF and comparison with patients who had immediate graft function (IGF) and DGF., Results: Acute renal tube necrosis (ATN) during or soon after surgery was the most common cause of HDGF. Following standard treatment, 48 HDGF patients transitioned from oliguria to polyuria in 45 days (± 3) and renal function of the kidney fully recovered in 73 days (± 1). These HDGF patients had similar overall survival and kidney survival rates as IGF and DGF patients who were matched for age, sex, primary underlying disease, tissue matching, warm and cold ischemia time, and surgery time., Conclusions: Appropriate care and monitoring of HDGF patients allows them to regain normal renal function and to achieve patient and renal survival rates similar to those of IGF and DGF patients., (Copyright © 2012 S. Karger AG, Basel.)

Cisplatin is among the most effective chemotherapeutic agents against solid tumors. Nephrotoxicity is the most common side effect of cisplatin chemotherapy, which limits the clinical use of cisplatin and seriously worsens the quality of life of cancer patients resulting in dosage reduction and discontinuation of treatment. Cisplatin involves a complex multifactorial process, as it has direct toxic effect on cells of the renal tubules, vasculature and glomeruli, and causes alterations in renal blood flow and glomerular filtration rate. Indirectly, cisplatin also induces inflammation of the renal interstitium, which contributes to the acute damage and may lead to chronic interstitial fibrosis, indicative of irreversible renal damage. This review presents an integrative view of the pathophysiological effects of cisplatin on tubular, vascular, glomerular, and interstitial function and the interplay among these actions. Moreover, it reviewed human clinical trials of the last ten years in order to evaluate the incidence and severity of the renal injury induced by cisplatin at the doses and therapeutic guidelines used in the clinical practice.

Among the different etiologies of acute renal failure (ARF), acute tubular necrosis (ATN) is one of the most common causes. There is no consensus on the duration of follow-up needed among these patients and also on choosing a reliable screening test to recognize early signs of chronic kidney injury that may ensue. The aim of this study was to evaluate the clinical and biochemical findings in children with a history of clinically recovered ischemic ATN, to detect the patients who may be at risk of ensuing chronic kidney disease. A cross-sectional study was carried out on 20 children between six months and 10 years of age, admitted at St. Al Zahra Hospital and Amin Children's Hospital, Isfahan, Iran, with a past history of ischemic ATN. Eighteen patients were evaluated between 12 and 24 months, and two patients were evaluated at 30 months. The second sample of urine while still fasting was used for assessing urinary sodium, creatinine and magnesium. The mean ages for study and control groups were 3.4 ± 1.3 years and 4.5 ± 1.1 years, respectively. Glomerular filtration rate, urinary magnesium, fractional excretion of magnesium (FEMg), urinary sodium and fractional excretion of sodium (FENa) were significantly higher in the study group compared to those in the control group. No significant differences were demonstrated in systolic and diastolic blood pressures between the two groups. Since FEMg can reflect tubular function for both the ability of tubules for reabsorption of the filtered magnesium and for retaining the intracellular magnesium, FEMg can be used as a marker to detect early stages of chronic renal injury. However, further studies with larger number of cases are needed to evaluate the sensitivity of this test.

Objective: To provide an integrated insight into the kinetics of tubular injury, inflammation, and oxidative stress after human kidney transplantation., Background: Tissue injury due to ischemia and reperfusion is an inevitable consequence of kidney transplantation. Tubular epithelial injury, inflammation, and oxidative stress play major roles in the pathophysiology of acute kidney injury in small animals, but it remains to be established whether this paradigm holds true for human kidney transplantation., Methods: Markers of tubular injury, inflammation, and oxidative stress were compared between recipients of kidneys from donors after cardiac death (DCD; N = 8) with prolonged ischemia and recipients of living donor kidneys with minimal ischemia (N = 8)., Results: In the early postoperative period, creatinine clearance and tubular sodium reabsorption were profoundly reduced in DCD kidneys, coinciding with significantly increased urinary concentrations of tubular injury markers (neutrophil gelatinase-associated lipocalin, N-acetyl-β--glucosaminidase, and cystatin C) and an 18-fold increase in renal production of cytokeratin-18, indicating extensive necrotic cell death. Tubular injury in DCD kidneys was followed by greater systemic inflammatory activity and oxidative stress in the postoperative period (measured with 17-plex cytokine arrays and as plasma F2-isoprostanes, respectively). In contrast, no evidence of oxidative damage to either of the 2 kidney types was found in the early reperfusion period., Conclusions: These findings establish the relevance of observations in animal models for human kidney transplantation and form the basis for development of novel therapies to improve early graft function and expand the use of donor kidneys with prolonged ischemia.

For decades severe tubular necrosis has been the hallmark of experimental models of acute renal failure (ARF), such as prolonged ischemia and reflow. This fits well with the still widely used traditional clinical term 'acute tubular necrosis'. Nevertheless, the rareness of tubular necrosis in human kidney biopsies in the background of hypoxic, toxic and septic AKI led to the adoption of a new term, 'acute kidney injury' (AKI), which refers to such clinical scenarios irrespective of the renal morphology. Indeed, experimental AKI models, which have more limited acute renal parenchymal compromise, underscore the focal and regional tissue injury patterns that range from adaptive stress response, through cellular dysfunction, apoptotic cell death and frank acute tubular necrosis. Such stress and injury patterns, short of necrosis, may go unnoticed morphologically and even functionally, and may even confer resistance to subsequent insults. Herein we describe the spectrum of what we call 'sublethal injury', referring to a condition, which by itself is insufficient to produce cellular death, but may or may not produce organ failure. Such sublethal injury can be detected by overt morphological changes, by the upregulation of cell survival factors, and by recently developed biomarkers and imaging techniques of organ physiology and dysfunction. The use of combined sublethal insults in animal models is an attempt to replicate the clinical situation of comorbidities, a circumstance which underlies most situations of AKI. This review will discuss the definition of such sublethal injury and the modes of its detection., (Copyright © 2011 S. Karger AG, Basel.)

Introduction: Cholemia and bacterial translocation with portal endotoxemia are integral in the pathogenesis of obstructive jaundice (OJ). There is sufficient experimental data about hemodynamic and histopathological consequences of OJ. In contrast, pathological information of renal changes in patients with OJ is still lacking. Therefore; the primary objective of this prospective study is to show the specific histopathological changes in kidneys of patients with short-term biliary tract obstruction receiving a standard perioperative medical treatment protocol., Materials and Methods: Twenty consecutive patients with biliary obstruction were included in the study. Fluid replacement, prevention of biliary sepsis, and portal endotoxemia were mainstays of the perioperative treatment protocol. Fluid and electrolyte balance was maintained by twice daily body weight calculations, central venous pressure, and mean arterial pressure monitoring. Renal function was assessed by glomerular filtration rate estimation by modification of diet in renal disease-7 formula. Kidney biopsy evaluation was focused on tubular changes, thrombotic microangiopathy, endothelial damage, and peritubular capillary (PTC) dilatation with or without C4d staining. Fresh frozen sections were evaluated with immunofluorescence microscopy for glomerular IgG, IgA, IgM, C3, and C1q staining., Results: The mean duration of OJ was 15.5 ± 1.4 days. Body weight increased before surgery through volume expansion (P = 0.001). All patients have shown mean arterial pressure ≥ 70 and ≤ 120 mmHg and renal function was very well preserved in all but one subject during the perioperative period. Despite those favorable figures, dilatation of peritubular venules and acute tubular necrosis were shown synchronously in all cases. C4d staining in PTC and arterioles and thrombotic microangiopathy were entirely absent in the study group. Immune complex deposits in PTCs and in glomeruli were not detected. Three patients had isolated glomerular C4d deposition without accompanying thrombotic microangiopathy and IgG, IgA, IgM, C3, and C1q staining of glomerular capillaries in I immunofluorescence microscopy., Discussion: This study is the first in the literature to address the histopathological changes that occur in humans with short-term biliary obstruction. Acute tubular necrosis and venous dilatation was observed in all biopsies, without exception, despite the maintenance of strict volume control in all patients. The adequacy of volume control may not be implicated in those results; rather a possible mechanism related to untrapped endotoxin in the gut lumen or systemic circulation might lead to prolonged PTC dilatation and hypoperfusion with synchronous acute tubular necrosis. Absolute recovery of renal function in all patients and the demonstration of solitary acute tubular necrosis with no microvascular-glomerular-interstitial inflammation or injury, suggests that the perioperative treatment regime in this study is fairly efficacious in short-term OJ.

Background: The differentiation between acute interstitial nephritis (AIN) and acute tubular necrosis (ATN) is crucial in patients with acute kidney injury. Gallium-67 citrate (Ga-67) has been used clinically in the differential diagnosis between these entities, but its efficacy is disputed. The aim of this study was to evaluate Ga-67 scintigraphy efficacy in the differentiation between experimental models of drug-induced AIN and ATN., Methods: Animals were divided into three groups: AIN (n = 8), ATN (n = 8) and control (NL, n = 10). The AIN group received intraperitoneal puromycin aminonucleoside (single dose, 150 mg/kg). The ATN group received a single intraperitoneal injection of cisplatin (6 mg/kg). The NL group did not receive active drugs. All of the animals were submitted to Ga-67 scintigraphy, serum creatinine (Cr) and urinary osmolality assessment, and blinded renal histology evaluation., Results: Renal Ga-67 uptake was strikingly more intense in the AIN group when compared to the ATN (P < 0.0001) and NL (P < 0.001) groups. The ATN group had increased Cr when compared to the NL group (P < 0.001) and lower urinary osmolality vs the NL (P < 0.001) and AIN (P < 0.01) groups. Renal histology showed severe acute tubular injury in the ATN group and intense interstitial inflammation in the AIN group, and was normal in control animals., Conclusion: Ga-67 scintigraphy was extremely effective in the differentiation between experimental drug-induced ATN and AIN.

To determine the incidence and determinants of delayed graft function due to post-transplant acute tubular necrosis in live related donor renal transplantation. This is a retrospective study of 337 recipients of live related donor renal graft performed between 1986 and 2006. Of these recipients, 24 (7.1%) subjects developed delayed graft function with no evidence of acute rejection, cyclosporin toxicity, vascular catastrophe or obstructive cause and had evidence of acute tubular necrosis (ATN Group). These subjects were compared with recipients (n= 313, 92.9%) who had no clinical or biochemical evidence of ATN. Mean age, and gender distribution of recipients was similar in the two groups (ATN group 35.7 +/- 8.3, non-ATN group 34.3 +/- 7.5, P= 0.43). Gender distribution of the recipients (men 279, 89.1% vs. 21, 87.5%, P= 0.80) as well as donors (women 221, 70.6% vs. 18, 75.0%, P= 0.75) was also similar. In ATN group as compared with non-ATN group the donor age was significantly greater (56.6 +/- 8.3 vs. 46.6 +/- 11.2 years, P< 0.0001). There was marginal difference in pre-operative systolic BP (154.5 +/- 18.3 vs. 147.4 +/- 20.2 mm Hg, P= 0.077) and significant difference in diastolic BP (87.8 +/- 9.5 vs. 83.4 +/- 11.4 mmHg, P= 0.041). Incidence of multiple renal arteries was similar (16.7% vs. 7.3%, P= 0.22). The warm ischemia time was significantly greater in ATN group (33.3 +/- 6.2 min) as compared to non-ATN group (30.4 +/- 5.7 min, P= 0.042). Duration of hospital stay was more in ATN group (19.9 +/- 6.7 vs. 16.8 +/- 8.4 days, P= 0.04) but there was no difference in 1 year survival (284 subjects, 90.7% vs. 21 subjects, 87.5%, P= 0.873). This study shows that greater donor age, higher baseline diastolic BP and greater warm ischemia time are major determinants of delayed graft function due to acute tubular necrosis after related donor renal transplantation.

Background and Purpose: We have established an in vitro model of acute tubular necrosis in rat kidney tubular cells, using combined oxygen-glucose deprivation (COGD) and screened a library of 1280 pharmacologically active compounds for cytoprotective effects., Experimental Approach: We used in vitro cell-based, high throughput, screening, with cells subjected to COGD using hypoxia chambers, followed by re-oxygenation. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and the Alamar Blue assay measured mitochondrial respiration and the lactate dehydrogenase assay was used to indicate cell death. ATP levels were measured using a luminometric assay., Key Results: Adenosine markedly reduced cellular injury, with maximal cytoprotective effect at 100 microM and an EC(50) value of 14 microM. Inosine was also found to be cytoprotective. The selective A(3) adenosine receptor antagonist MRS 1523 attenuated the protective effects of adenosine and inosine, while an A(3) adenosine receptor agonist provided a partial protective effect. Adenosine deaminase inhibition attenuated the cytoprotective effect of adenosine but not of inosine during COGD. Inhibition of adenosine kinase reduced the protective effects of both adenosine and inosine during COGD. Pretreatment of the cells with adenosine or inosine markedly protected against the fall in cellular ATP content in the cells subjected to COGD., Conclusions and Implications: The cytoprotection elicited by adenosine and inosine in a model of renal ischaemia involved both interactions with cell surface adenosine receptors on renal tubular epithelial cells and intracellular metabolism and conversion of adenosine to ATP.

When patients develop acute kidney injury, a small fraction of them will develop end-stage renal disease later. The severity of renal impairment in the remaining patients is uncertain because studies have not carefully examined renal function over time or the precise timing of entry into a late stage of chronic kidney disease. To determine these factors, we used a United States Department of Veterans Affairs database to ascertain long-term renal function in 113,272 patients. Of these, 44,377 had established chronic kidney disease and were analyzed separately. A cohort of 63,491 patients was hospitalized for acute myocardial infarction or pneumonia and designated as controls. The remaining 5,404 patients had diagnostic codes indicating acute renal failure or acute tubular necrosis. Serum creatinine, estimated glomerular filtration rates, and dates of death over a 75-month period were followed. Renal function deteriorated over time in all groups, but with significantly greater severity in those who had acute renal failure and acute tubular necrosis compared to controls. Patients with acute kidney injury, especially those with acute tubular necrosis, were more likely than controls to enter stage 4 chronic kidney disease, but this entry time was similar to that of patients who initially had chronic kidney disease. The risk of death was elevated in those with acute kidney injury and chronic kidney disease compared to controls after accounting for covariates. We found that patients who had an episode of acute tubular necrosis were at high risk for the development of stage 4 disease and had a reduced survival time when compared to control patients.

Altered coagulation and inflammation contribute to the pathogenesis of ischemic renal injury. Thrombomodulin is a necessary factor in the anticoagulant protein C pathway and has inherent anti-inflammatory properties. We studied the effect of soluble thrombomodulin (sTM) in a hypoperfusion model of ischemic kidney injury. To markedly reduce infrarenal aortic blood flow and femoral arterial pressures, we clamped the suprarenal aorta of rats, occluding them 90%, for 60 min. Reversible acute kidney injury (AKI) occurred at 24 h in rats subjected to hypoperfusion. Histologic analysis at 24 h revealed acute tubular necrosis (ATN), and intravital two-photon microscopy showed flow abnormalities in the microvasculature and defects of endothelial permeability. Pretreatment with rat sTM markedly reduced both I-R-induced renal dysfunction and tubular histologic injury scores. sTM also significantly improved microvascular erythrocyte flow rates, reduced microvascular endothelial leukocyte rolling and attachment, and minimized endothelial permeability to infused fluorescence dextrans, assessed by intravital quantitative multiphoton microscopy. Furthermore, sTM administered 2 h after reperfusion protected against ischemia-induced renal dysfunction at 24 h and improved survival. By using an sTM variant, we also determined that the protective effects of sTM were independent of its ability to generate activated protein C. These data suggest that sTM may have therapeutic potential for ischemic AKI.

Acute kidney injury (AKI) (previously called acute renal failure) is characterized by a reversible increase in the blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. The incidence of AKI in children appears to be increasing, and the etiology of AKI over the past decades has shifted from primary renal disease to multifactorial causes, particularly in hospitalized children. Genetic factors may predispose some children to AKI. Renal injury can be divided into pre-renal failure, intrinsic renal disease including vascular insults, and obstructive uropathies. The pathophysiology of hypoxia/ischemia-induced AKI is not well understood, but significant progress in elucidating the cellular, biochemical and molecular events has been made over the past several years. The history, physical examination, and laboratory studies, including urinalysis and radiographic studies, can establish the likely cause(s) of AKI. Many interventions such as 'renal-dose dopamine' and diuretic therapy have been shown not to alter the course of AKI. The prognosis of AKI is highly dependent on the underlying etiology of the AKI. Children who have suffered AKI from any cause are at risk for late development of kidney disease several years after the initial insult. Therapeutic interventions in AKI have been largely disappointing, likely due to the complex nature of the pathophysiology of AKI, the fact that the serum creatinine concentration is an insensitive measure of kidney function, and because of co-morbid factors in treated patients. Improved understanding of the pathophysiology of AKI, early biomarkers of AKI, and better classification of AKI are needed for the development of successful therapeutic strategies for the treatment of AKI.

Neutrophils and macrophages rapidly infiltrate the kidney after renal ischemia-reperfusion injury, however specific molecular recruitment mechanisms have not been fully delineated for these cell types. Here we provide genetic and pharmacologic evidence supporting a positive role for the chemokine receptor CCR1 in macrophage and neutrophil infiltration in a 7 day mouse model of renal ischemia-reperfusion injury. By day 7, injured kidneys from mice lacking CCR1 contained 35% fewer neutrophils and 45% fewer macrophages than injured kidneys from wild-type control mice. Pretreatment of wild-type mice with the specific CCR1 antagonist BX471 also suppressed neutrophil and macrophage infiltration in the model. Injured kidneys from mice lacking CCR1 also had reduced content of the CCR1 ligands CCL3 (MIP-1alpha) and CCL5 (RANTES) compared with injured kidneys from wild-type controls, suggesting a leukocyte source for these inflammatory chemokines and existence of a CCR1-dependent positive feedback loop for leukocyte infiltration in the model. Local leukocyte proliferation and apoptosis were detected after injury, but were not dependent on CCR1. Also, the extent of necrotic and fibrotic damage and decline in renal function in injured kidneys was similar in wild-type and CCR1-deficient mice. Thus, CCR1 appears to regulate trafficking of macrophages and neutrophils to kidney in a mouse model of renal ischemia-reperfusion injury, however this activity does not appear to affect tissue injury.

Background: In this study, we have examined rat kidneys after ischaemic injury (35 min) with regard to the dynamics of S3 tubule regeneration., Methods: One day before ischaemia, each rat received four successive i.p. injections of BrdU (5-bromo-2'-deoxyuridine: 80 mg/kg) at 2 h intervals. Groups of experimental animals (n = 4) were killed every 2 h during the first 24 h post-ischaemia as well as 2, 3, 7 and 14 days post-ischaemia. Renal sections were processed to characterize by immunohistochemistry the distribution and phenotype of BrdU-positive cells., Results: Renal regeneration after ischaemia was associated with a typical sequence of transient events: (1) absence of immunostaining during the first 8 h after reperfusion; (2) between 8 and 16 h, detection of a small population of BrdU-positive cells (CD44(+), vimentin(+), CD45(-)) restricted to the lumen of blood vessels characterized by the endothelial expression of selectin E; (3) between 16 and 24 h, progressive decrease of labelled cells in renal capillaries and a concomitant increase in the interstitial compartment; (4) after 1 day, labelled cells disappeared progressively from peritubular interstitium and were mainly observed in regenerating S3 tubules, and (5) after 3 days numerous positive cells were only present in regenerated tubules., Conclusions: Our data suggest that positive cells (BrdU(+), CD44(+), vimentin(+) and CD45(-)) observed in kidney tubules after ischaemia could originate from an extrarenal source and reach the renal parenchyma via blood vessels. We postulate that these immature cells migrate to injured tubules, proliferate and finally differentiate into mature epithelial cells leading to the replacement of a majority (>80%) of altered S3 cells.

Background: Data on long-term effects of acute kidney injury (AKI) on renal function (RF) are scarce and factors implicated in the functional outcome are not established. Our aim was to investigate these aspects., Methods: At hospital discharge and annually for 10 years, we retrospectively reviewed RF of 187 patients surviving AKI. Glomerular filtration rates estimated with MDRD equation (eGFR) and KDOQI stages were used to evaluate RF. Only 34.8% of patients had pre-existing renal dysfunction (KDOQI-3). Variables determining long-term RF were collected during AKI and at discharge and analysed with a regression model., Results: At discharge no patient necessitated dialysis, but eGFR was lower than baseline (47.5 +/- 23.3 ml/min/ 1.73 m(2) versus 75.8 +/- 25.4 ml/min/1.73 m(2)); 38.4% of survivors had recovered basal RF: 26% of those with previous normal RF and 61% of those in KDOQI-3, respectively. At 1 year, eGFR increased to 61.9 +/- 24.4 ml/min/1.73 m(2) and remained stable later. During an 8-year median follow-up (P25:2; P75:10), 31% improved RF, 50% remained stable and 19% deteriorated. In total only 46% (n = 82) definitively recovered RF. Finally, at the end of the study period 61.6% presented some degree of renal dysfunction: 40% of those with previous normal RF developed moderate-severe renal dysfunction and 37% KDOQI-3 progressed into more severe renal failure. Only two patients needed dialysis. Regression model identified age, co-morbidities, discharge eGFR and follow-up time as independent predictors of long-term RF., Conclusions: AKI carries implication for long-term RF even in patients without pre-existing renal dysfunction. Ageing, co-morbidities and RF at discharge are determinants of the long-term functional outcome.

Relationship between cirrhosis and renal dysfunction is not yet fully understood. A model of cirrhosis with acute hepatic and renal damage (RF), produced by CCl4 in rats, with hemodynamic and renal functional alterations, similar to those observed in decompensated cirrhosis (DC) in man, was used to study chemical nephrotoxicity in animals. We performed in male Wistar rats hepatic and renal functional and hemodynamic studies in control, cirrhotic and decompensated cirrhotic (DC) groups. Cirrhosis was induced with carbon tetrachloride by chronic administration. Association between liver and renal functional alterations was detected in rats with decompensated cirrhosis, showing fall in mean arterial pressure and reduction of glomerular filtration rate and filtration fraction. Renal hemodynamics did not change in cirrhotic rats, similarly to what occurs in compensated cirrhotic patients. However, DC rats exhibited increased sodium, glucose and phosphate urinary excretions and decreased ATP in renal cortex. DC animals had severe hypoglycemia. There was an extensive liver fibrosis. Glomeruli had hypercellularity and tubules showed extensive vacuolization in cirrhotic and DC rats. The present study suggests that in this model, damage typical of acute tubular necrosis ensues in cirrhotic rats. We describe functional and morphological damage in liver and kidney in a model of cirrhosis that might predispose to the development of acute renal failure when an individual with hepatic damage is exposed in acute way to chemical toxicants.

Chronic allograft dysfunction is an alteration of the renal graft's structure that causes renal function to deteriorate. It can be diagnosed histologically by the presence of interstitial fibrosis lesions and tubular atrophy beginning 3 months after transplantation. The predictive value of these lesions on graft loss is limited however. Kidney function is evaluated by measuring the glomerular filtration rate using reference methods such as urinary clearance of inulin. However, estimation of the glomerular filtration rate from plasma creatinine using the Cockroft or MDRD formulas is not a reliable marker of renal function loss in the transplantation patient; nor is it a good predictive marker of graft loss. To overcome the diagnostic and prognostic shortcomings of these traditional markers in transplantation patients, new biomarkers have been developed. Yet the advantages of these biomarkers in predicting the evolving complications of chronic allograft dysfunction as well as graft loss on the individual level now require validation.

Background: Blood oxygen level-dependent MRI (BOLD MRI) can be used to assess intra-renal oxygen bioavailability by measuring the R2(*) level, which reflects tissue deoxyhaemoglobin levels. This study was designed to identify the significance of BOLD MRI in differentiation of acute rejection (AR) and acute tubular necrosis (ATN) in patients within 6 months after kidney transplantation., Methods: Eighty-two patients with normal graft function and 28 patients with biopsy-proven AR (n = 21) or ATN (n = 7) were enrolled. Patients with normal functioning allograft underwent BOLD MRI within 2 to 3 weeks post-transplantation, while patients with AR and ATN underwent BOLD MRI within 6 days before or after kidney transplant biopsy. Cortical R2(*) (CR2(*)) and medullary R2(*) (MR2(*)) levels were measured., Results: The mean CR2(*) level was significantly higher in the ATN group (15.25 +/- 1.03/s) compared to the normal group (13.35 +/- 2.31/s, P = 0.028) and AR group (12.02 +/- 1.72/s, P = 0.001). There was a significant difference also between the AR group and normal group on CR2(*) levels (P = 0.013). The mean MR2(*) level was significantly lower in the AR group (14.02 +/- 2.68/s) compared to the normal group (16.66 +/- 2.82/s, P < 0.001) and ATN group (19.47 +/- 1.62/s, P < 0.001). There was also a significant difference between the ATN group and normal group on MR2(*) levels (P = 0.011). There were no correlations between characteristics such as patient age, post-operation time, post-biopsy time, Scr level, HB level, urine output volume, MAP level, CNI trough concentration and R2(*) levels, except between MAP level and CR2(*) level (P = 0.029)., Conclusions: BOLD MRI could be a valuable method to discriminate between AR and ATN by measuring tissue oxygen bioavailability in early kidney allograft dysfunction.

Snakebites have the highest incidence in Asia and represent an important health problem. Clinical renal manifestations include proteinuria, hematuria, pigmenturia, and renal failure. Nephropathy usually is caused by bites by snakes with hemotoxic or myotoxic venoms. These snakes are Russell's viper, saw-scaled viper, hump-nosed pit viper, green pit viper, and sea-snake. Renal pathologic changes include tubular necrosis, cortical necrosis, interstitial nephritis, glomerulonephritis, and vasculitis. Hemodynamic alterations caused by vasoactive mediators and cytokines and direct nephrotoxicity account significantly for the development of nephropathy. Hemorrhage, hypotension, disseminated intravascular coagulation, intravascular hemolysis, and rhabdomyolysis enhance renal ischemia leading to renal failure. Enzymatic activities of snake venoms account for direct nephrotoxicity. Immunologic mechanism plays a minor role.

Acute tubular necrosis (ATN) is a syndrome of intrinsic renal failure secondary to ischemic or toxic insults. The histopathologic findings of ATN are inconstant. When present, they are limited to the tubulo-interstitium and often subtle despite profound dysfunction. Experimental models of ATN in healthy animals commonly use single insults that result in extensive injury, circumstances that do not parallel the human situation. Recently, there has been a shift to more clinically relevant models using an acute insult superimposed on predisposing factors. This review discusses the complex hemodynamic interrelationships of hypoxia, tubular injury, and altered glomerular filtration, suggesting new ways to understand the pathophysiology of ATN.

Introduction: Acute tubular necrosis (ATN) is a challenging problem that still requires to be studied in animal models. Our aim was to prepare an established experimental model of inducing reversible ATN in rats by determining the optimum duration of ischemia induction to the kidney., Materials and Methods: Twenty-four hour after nephrectomy of the right kidney and clamping the pedicle of the left kidney for durations ranging from 10 to 55 minutes, the kidney function and the histologic changes were evaluated. Accordingly, the optimum duration of clamping was determined and in the next step, it was considered for induction of reversible ATN in another group of rats. This group was followed up for 14 days and the pathologic course and function of the kidney were observed., Results: Reversible ATN developed by 47-minute clamping of the renal pedicle. Blood urea nitrogen and serum creatinine levels were elevated up to threefold within 24 hours after the induction of ischemia and they decreased to their reference ranges after 12 and 6 days, respectively. In the histologic study of the kidneys, the least extend of injury was noted by the 14th day following the ATN induction. Even on the 14th day of the follow-up, some signs of ATN remained indicating that the tissue regeneration was not complete yet., Conclusions: To integrate the experimental models of ATN, a rat model with 47-minute clamping of the renal pedicle for induction of ischemia seems appropriate. The resultant ATN remains for a long duration, while kidney function is alleviated.

Renal ischemia-reperfusion (IR) injury is the major cause of acute renal failure in native and transplanted kidneys. Mononuclear leukocytes have been reported in renal tissue as part of the innate and adaptive responses triggered by IR. We investigated the participation of CD4+ T lymphocytes in the pathogenesis of renal IR injury. Male mice (C57BL/6, 8 to 12 weeks old) were submitted to 45 min of ischemia by renal pedicle clamping followed by reperfusion. We evaluated the role of CD4+ T cells using a monoclonal depleting antibody against CD4 (GK1.5, 50 micro, ip), and class II-major histocompatibility complex molecule knockout mice. Both CD4-depleted groups showed a marked improvement in renal function compared to the ischemic group, despite the fact that GK1.5 mAb treatment promoted a profound CD4 depletion (to less than 5% compared to normal controls) only within the first 24 h after IR. CD4-depleted groups presented a significant improvement in 5-day survival (84 vs 80 vs 39%; antibody treated, knockout mice and non-depleted groups, respectively) and also a significant reduction in the tubular necrosis area with an early tubular regeneration pattern. The peak of CD4-positive cell infiltration occurred on day 2, coinciding with the high expression of betaC mRNA and increased urea levels. CD4 depletion did not alter the CD11b infiltrate or the IFN-gamma and granzyme-B mRNA expression in renal tissue. These data indicate that a CD4+ subset of T lymphocytes may be implicated as key mediators of very early inflammatory responses after renal IR injury and that targeting CD4+ T lymphocytes may yield novel therapies.