"Point of no return" in unilateral renal ischemia reperfusion injury in mice.

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-ß1 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.

Remote Ischemic Preconditioning and Contrast-Induced Nephropathy: A Systematic Review.

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.

Presence of arteriolar hyalinosis in post-reperfusion biopsies represents an additional risk to ischaemic injury in renal transplant.

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.

Role of Oxidative Stress in Drug-Induced Kidney Injury.

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.

Magnetic resonance imaging with hyperpolarized [1,4-(13)C2]fumarate allows detection of early renal acute tubular necrosis.

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.

Acute oxalate nephropathy associated with Clostridium difficile colitis.

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.

Glomerular haemodynamics, the renal sympathetic nervous system and sepsis-induced acute kidney injury.

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.

Survey of acute kidney injury and related risk factors of mortality in hospitalized patients in a third-level urban hospital of Shanghai.

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.

Kielin/chordin-like protein attenuates both acute and chronic renal injury.

The secreted kielin/chordin-like (KCP) protein, one of a family of cysteine-rich proteins, suppresses TGF-ß 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-ß 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-ß/BMP signaling axis by KCP, and by extension possibly other cysteine-rich domain proteins, can attenuate both acute and chronic renal injury.

Age sensitizes the kidney to heme protein-induced acute kidney 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.

Generation of urinary albumin fragments does not require proximal tubular uptake.

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.

Inhibition of glycogen synthase kinase-3ß prevents NSAID-induced acute kidney injury.

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)3ß 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 GSK3ß targets beyond COX-2 functioned in renal protection. Indeed, TDZD-8 diminished the mitochondrial permeability transition in DCLF-injured kidneys. In vitro, GSK3ß 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 GSK3ß, and promoted a mitochondrial permeability transition by interacting with cyclophilin D, a key component of the mitochondrial permeability transition pore. TDZD-8 blocked GSK3ß activity and prevented GSK3ß-mediated cyclophilin D phosphorylation and the ensuing mitochondrial permeability transition, concomitant with normalization of intracellular ATP. Conversely, ectopic expression of a constitutively active GSK3ß abolished the effects of TDZD-8. Hence, inhibition of GSK3ß ameliorates NSAID-induced acute kidney injury by induction of renal cortical COX-2 and direct inhibition of the mitochondrial permeability transition.

Diagnosis and treatment of hyper-delayed graft function after renal transplantation.

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.

Tubular epithelial injury and inflammation after ischemia and reperfusion in human kidney transplantation.

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-ß--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.

An integrative view of the pathophysiological events leading to cisplatin nephrotoxicity.

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.

Ga-67 scintigraphy in the differential diagnosis between acute interstitial nephritis and acute tubular necrosis: an experimental study.

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.

Chemokine receptor CCR1 regulates inflammatory cell infiltration after renal ischemia-reperfusion injury.

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.

Soluble thrombomodulin protects ischemic kidneys.

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.

Outcomes following diagnosis of acute renal failure in U.S. veterans: focus on acute tubular necrosis.

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.