Role of neutrophil derived oxidants and elastase in lipopolysaccharide-mediated renal injury

Gram-negative bacterial sepsis is frequently associated with acute renal failure but the specific effects of lipopolysaccharide (LPS) and other bacterial products on kidney function are not known. Since either LPS or formyl-methionyl-leucyl-phenylalanine (FMLP)--a chemotactic peptide from bacterial cell walls--activate neutrophils (PMN) to release a number of potentially toxic factors in vitro, we determined the effect of adding PMN with LPS and/or FMLP to isolated perfused rat kidneys. Isolated rat kidneys perfused with LPS alone or LPS and normal PMN had normal glomerular filtration rates (GFR) and tubular Na reabsorption (TNa). Kidneys perfused with FMLP alone or FMLP and normal PMN also had normal GFR and TNa. In contrast, addition of PMN with both FMLP and LPS caused progressive renal dysfunction. For example, after 60 minutes of perfusion, GFR was reduced from 610 +/- 31 to 147 +/- 17 microliters/min/g and TNa from 97 +/- 1 to 72 +/- 2%, both P less than 0.01. Perfusion with the O2 metabolite scavengers catalase or dimethylthiourea afforded no protection while perfusion with the neutrophil elastase inhibitor Eglin C conferred substantial, but not complete, protection: GFR 492 +/- 34 microliters/min/g; TNa 91 +/- 3%. However, perfusion with both Eglin C and catalase completely prevented the toxic effects of LPS and FMLP-treated PMN on renal function. We conclude that in isolated kidneys, 1) the toxic effects of LPS requires FMLP-treated PMN and that 2) LPS and FMLP treated PMN cause progressive renal injury which is mediated by both O2 metabolites and neutrophil elastase.     

Benefical effect of neutrophil elastase inhibitor on renal warm ischemia-reperfusion injury in the rat

Renal ischemia-reperfusion (I/R) injury is a significant problem in renal transplantation. Neutrophils play an important role in renal I/R injury. Several reports have demonstrated that neutrophil elastase derived from the activated neutrophils might play an important role in this injury. We investigated the effect of a neutrophil elastase inhibitor in renal I/R injury. Male Lewis rats (270-320 g) were used in the model. The right kidney was harvested and the left renal artery and vein were clamped at laparotomy. The kidney was reperfused after 90 minutes of ischemia. Neutrophil elastase inhibitor (ONO-5046: 30 mg/kg) was delivered intravenously before ischemia and after reperfusion to prevent neutrophil activation. In the nontreatment I/R group, no hosts survived 4 days. However, after treatment with neutrophil elastase inhibitor, 3 of 10 rats in the I/R group, survived more than 7 days. These results demonstrated that treatment with neutrophil elastase inhibitor ameliorated renal I/R injury.     

The association of renal tubular inflammatory and injury markers with uric acid excretion in chronic kidney disease patients

International Urology and Nephrology - To investigate the correlation of renal tubular inflammatory and injury markers with renal uric acid excretion in chronic kidney disease (CKD) patients....     

Urine neutrophil gelatinase-associated lipocalin in septic patients with and without acute kidney injury

Introduction: Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a rapidly emerging biomarker for early detection of acute kidney injury (AKI). We aimed to investigate the prevalence and prognostic value of the early uNGAL in patients with AKI induced by sepsis. Methods: In this prospective cohort study, we analyzed the case records of 126 septic patients with and without AKI and evaluated the uNGAL for early prediction and risk stratification of septic patients with AKI. Results: Of 126 patients analyzed, 58 (46%) developed septic AKI. Men comprised more than half (68%) of the sample population, the mean age (SD) was 57 years. The prognostic accuracy of uNGAL, as quantified by the area under the receiver-operating-characteristic curve (AU-ROC), was highest with peak uNGAL (AU-ROC: 0.86; 95% CI: 0.81–0.93), as compared with the admission uNGAL (AU-ROC: 0.81; 95% CI: 0.73–0.89). The peak uNGAL correlated with the levels of peak blood urea nitrogen (r?=?0.674) and serum creatinine (r?=?0.608), the length of hospital stay (r?=?0.602) and weakly correlated with the number of hemodialysis sessions that each patient received during hospital stay (r?=?0.405). By multivariate analysis, increased peak uNGAL remained independently associated with the development of septic AKI (odds ratio: 32.12; 95% CI: 6.21–90.37; p?Conclusions: uNGAL is independently associated with subsequent AKI among patients with sepsis.     

A neutrophil elastase inhibitor, sivelestat, improves leukocyte deformability in patients with acute lung injury

BACKGROUND: The objective of this study was to evaluate whether the neutrophil elastase (NE) inhibitor, sivelestat, improves leukocyte deformability and pulmonary function in patients with acute lung injury (ALI). PATIENTS AND METHODS: Twenty-four patients with systemic inflammatory response syndrome (SIRS) were divided into two groups: those with ALI (ALI group, n = 14), and those without ALI (non-ALI group, n = 10). Within 72 hours after the diagnosis, we measured the total leukocyte count (TLC), C-reactive protein (CRP) level, NE concentration, APACHE II score, Goris multiple organ failure (MOF) index, respiratory index (RI), lung injury score (LIS), and oxygenation index (P/F ratio). Leukocyte deformability was examined with a microchannel array etched on a single-crystal silicon tip that simulates the microvasculature. The number of obstructed microchannels (NOM) because of stiffened neutrophils and transit time (TT), defined as the time needed for 100 microL of whole blood to pass through the microchannels, were determined.We then administered sivelestat (4.8 mg/kg/d) to nine ALI patients (sivelestat group) for 5 days and compared with seven ALI patients treated previously without sivelestat (conventional group). The factors described above were measured before and 5 days after treatment. RESULTS: There were no significant differences in age, TLC, CRP, APACHE II score, and MOF index between ALI and non-ALI group. RI and LIS were higher and the P/F ratio was significantly lower in the ALI group than in the non-ALI group. NE concentration, NOM, and TT were significantly higher in the ALI group than in the non-ALI group (p < 0.05).After 5 days of treatment with sivelestat, the APACHE II score, MOF index, RI, LIS, NE concentration, TT, and NOM were lower and the P/F ratio was significantly higher than baseline values and those in the conventional group (p < 0.05). CONCLUSION: NE concentration and neutrophil rigidity are significantly increased in SIRS patients with ALI. Sivelestat appears to reduce NE concentration and neutrophil stiffness and improve pulmonary oxygenation in patients with ALI.     

Acute effects of acetaminophen on renal function and urinary excretion of some proteins and enzymes in patients with kidney disease.

The acute effects of acetaminophen, a commonly used as analgesic drug, upon the urinary excretion of some proteins and enzymes as markers of kidney damage, was investigated. Patients with chronic glomerulonephritis (GN) and Balkan endemic nephropathy (BEN), having kidney vulnerable to toxic drugs, were enrolled in the study. Timed urine specimens were collected: before drug administration, and in 3-hour periods for 24 hours after an oral dose of 2 g of acetaminophen. Urinary excretion of albumin before acetaminophen treatment was significantly higher in patients with GN and BEN than in healthy adults, however, beta 2-microglobulin excretion was increased in BEN patients only. Urinary excretion of creatinine markedly increased immediately after acetaminophen ingestion. Urinary excretion of total protein and albumin was not changed after acetaminophen administration. However, acetaminophen treatment produced a significant increase in beta 2-microglobulin excretion in patient with BEN and GN, and in clinically healthy members of nephropathic families. Excretion of aminopeptidase N (APN) activity before acetaminophen treatment was significantly higher in patients with GN, however, NAGA excretion was higher in both GN and BEN patients than in healthy controls. After acetaminophen administration urinary excretion of APN, dipeptidylpeptidase IV (DPP IV), gamma-glutamyltranspeptidase (GGT) and N-acetyl-beta-D-glucosaminidase (NAGA) did not increase significantly in any group studied. This study has shown that urinary excretion of APN, DPP IV, NAGA and GGT, as markers of kidney brush border and lysosomal damage, did not change after 2 g of acetaminophen taken orally. beta 2-microglobulin was a marker of acute acetaminophen nephrotoxicity in kidney disease patients and in clinically healthy adults from nephropathic families.     

High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients

BACKGROUND: Chronic transplant dysfunction is characterized by renal function decline and proteinuria. Kidney injury molecule (KIM)-1, a transmembrane tubular protein with unknown function, is undetectable in normal kidneys, but markedly induced after injury. Urinary KIM-1 excretion has been quantified as biomarker of renal damage. We prospectively studied whether urinary KIM-1 predicts graft loss, independent of renal function and proteinuria. METHODS: Renal transplant recipients (n=145) visiting our outpatient clinic between August 2001 and July 2003 collected 24-hour urine samples for assessment of baseline urinary KIM-1 excretion (microsphere-based Luminex technology), and were followed for graft loss. RESULTS: Recipients participated at a median (interquartile range) of 6.0 (2.5-12.0) years posttransplant in baseline measurements. Follow-up beyond baseline was 4.0 (3.2-4.5) years. Urinary KIM-1 excretion was 0.72 (0.42-1.37) ng per 24 hours. Occurrence of graft loss increased over tertiles of KIM-1 excretion: 3 (6.3%), 11 (22.4%), and 17 cases (35.4%; P=0.001), respectively. High KIM-1 excretion was associated with proteinuria, low creatinine clearance, and high donor age (all P<0.01). In multivariate Cox regression analyses, prediction of graft loss by KIM-1 appeared independent of creatinine clearance, proteinuria, and donor age. Hazard ratios (95% CI) for the second and third tertile of KIM-1 excretion were 3.6 (0.9-13.5) and 5.1 (1.5-17.8) in the final model. CONCLUSIONS: Urinary excretion of KIM-1 is an independent predictor of long-term graft loss and therefore a promising new biomarker in early prediction of graft loss.     

心脏术后尿中性粒细胞明胶酶相关脂质运载蛋白和白细胞介素18与急性肾损伤的关系

目的 探讨接受体外循环心脏手术患者尿中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和尿白细胞介素18（IL-18）与急性肾损伤（AKI）的关系。 方法 根据AKI的诊断标准，将33例体外循环心脏手术的患者分为AKI组及非AKI组，分别留取术前及术后不同时间点的血液和尿液标本，测定Scr、尿NGAL和IL-18水平。 结果 33例中有9例发生AKI，发生率为27.27%。AKI组Scr升高峰值出现在12～48 h内。与术前相比， AKI组术后2 h、4 h尿NGAL及IL-18水平升高，差异有统计学意义（P < 0.01）。与非AKI组比较，AKI组术后各时间点的尿NGAL水平、术后2 h及4 h的尿IL-18水平都较高，差异有统计学意义（P < 0.01）。经尿肌酐（Ucr）校正后，相应时间点的NGAL/Ucr和IL-18/Ucr差异仍有统计学意义（P < 0.01）。术后2 h尿NGAL和尿NGAL/Ucr的界定（cutoff） 值分别在250 µg/L和250 µg/mmol时；术后2 h尿IL-18和尿IL-18/Ucr的界定值分别在1800 ng/L和1800 ng/mmol时，体现出较好的敏感性和特异性。 AKI组术后12 h Scr水平与术后2 h尿NGAL水平呈正相关（r = 0.638，P < 0.05）。结论 体外循环下接受心脏手术的患者AKI发生率较高；术后2 h尿NGAL和NGAL/Ucr、术后2 h尿IL-18和尿IL-18/Ucr当达到一定界定值时，均可作为体外循环下心脏手术后AKI发生的早期诊断参考指标，其中术后2 h尿NGAL/Ucr为250 µg/mmol时更敏感。     

Acute kidney injury with renal replacement therapy in trauma patients

Background: Acute kidney injury (AKI) with renal replacement therapy (RRT) is rare in trauma patients. The primary aim of the study was to assess incidence, mortality and chronic RRT dependency in this patient group. Methods: Adult trauma patients with AKI receiving RRT at a regional trauma referral center over a 12‐year period were retrospectively reviewed. Results: Population‐based incidence of post‐traumatic AKI with RRT was 1.8 persons per million inhabitants per year (p.p.m./year) [95% confidence the interval (CI) 1.5–2.1 p.p.m./year]. In trauma patients admitted to hospital, incidence was 0.5‰ (95% CI 0.3–0.7‰) of those treated in intensive care unit (ICU), it was 8.3% (95% CI 5.9–10.8%). The median age was 46 years. Odds ratio (OR) for post‐traumatic AKI requiring RRT was higher in males than in females in general population (OR 5.6, 95% CI 2.2–14.0), and in trauma patients admitted to hospital (OR 4.4, 95% CI 1.9–10.3) and ICU (OR 4.5, 95% CI 1.9–10.7). The in‐hospital mortality rate was 24% (95% CI 11–37%), 3‐month mortality 36% (95% CI 21–51%) and 1‐year mortality 40% (95% CI 25–55%). Age was a risk factor for death after 1 year, with 57% (95% CI 7–109%) increased risk for each 10 years added. None of the survivors was dialysis‐dependent 3 months or 1 year after trauma. Conclusion: AKI in trauma patients requiring RRT was rare in this single‐center study. More males than females were affected. Mortality was modest, and renal recovery was excellent as none of the survivors became dependent on chronic RRT.     

Impact of kidney function and urinary protein excretion on pulmonary function in Japanese patients with chronic kidney disease

Background

Although the cardiorenal relationship in chronic kidney disease has been investigated, information about the lung?kidney relationship is limited. Here, we investigated the impact of kidney function and urinary protein excretion on pulmonary dysfunction.

Methods

The data from pulmonary function tests and kidney function (estimated glomerular filtration rate [eGFR] and urinary protein) between 1 April 2005 and 30 June 2010 were selected from our laboratory database. Data were classified into 4 categories according to eGFR and proteinuria. Category 1, eGFR ≥60 ml/min/1.73 m² and urinary protein <0.3 g/gCr; category 2, eGFR <60 ml/min/1.73 m² and urinary protein <0.3 g/gCr; category 3, eGFR ≥60 ml/min/1.73 m² and urinary protein ≥0.3 g/gCr; and category 4, eGFR <60 ml/min/1.73 m² and urinary protein ≥0.3 g/gCr. Pulmonary function data were evaluated according to these 4 categories.

Results

A total of 133 participants without major respiratory disease, abnormal computed tomography and smoking history were enrolled. Hemoglobin (Hb)-adjusted percentage carbon monoxide diffusing capacity (%DL_CO) in category 4 (46.2 ± 7.5) and category 2 (63.6 ± 17.8) were significantly lower than in category 1 (75.8 ± 18.9) (P < 0.05). In addition, Hb-adjusted %DL_CO was weakly correlated with eGFR in participants with urinary protein <0.3 g/gCr (R = 0.30, P = 0.001). Hb-adjusted %DL_CO was strongly correlated with eGFR in participants with urinary protein ≥0.3 g/gCr (R = 0.81, P < 0.001). Other pulmonary function test markers (percentage (%) vital capacity, % forced expiratory volume in one second (FEV1), FEV1/forced vital capacity, % total lung capacity, and % residual volume) were not significantly different between categories.

Conclusion

This study suggests that decreased eGFR is associated with decreased %DL_CO in proteinuric patients.     

Disposition and urinary excretion of vecuronium bromide in anesthetized patients with normal renal function or renal failure

The effect and plasma concentrations of vecuronium bromide were measured in normal patients after an intravenous dose of 50, 100, or 150 micrograms/kg and in patients with renal failure after 50 or 100 micrograms/kg. Urinary excretion of vecuronium was studied in normal patients after the 150 micrograms/kg dose. Pharmacokinetic parameters of patients with or without renal failure were similar. No metabolites of vecuronium were found in the plasma. Twenty percent of vecuronium was excreted unchanged in the urine; 5% as the 3-hydroxy derivative. No other metabolites of vecuronium were found in the urine. Increasing doses of vecuronium shortened the onset, but prolonged the duration of action and the recovery rate, to a similar extent in patients with or without renal failure. It was concluded that the disposition of vecuronium was best described by a three compartment model. Both the disposition and the effect of vecuronium are only marginally disturbed by renal failure.     

Effect of valsartan on urinary protein excretion and renal function in patients with chronic renal allograft nephropathy

Chronic allograft nephropathy (CAN) remains a significant cause of late renal allograft loss. Although many factors may be involved in pathogenesis, the hemodynamic and fibrogenic consequences of long-term therapy with cyclosporine (CsA) have been implicated as important potentially reversible causes. CsA's effect on CAN is mediated in part through increased renal expression of TGF-beta, which can be modified by administration of angiotensin receptor blockers (ARBs). A pilot study was undertaken to evaluate the safety and efficacy of the ARB valsartan on renal function and proteinuira in patients with CAN. Ten patients on CsA-based therapy with evidence of CAN received valsartan in an initial dose of 80 mg/d, force titrated to 160 mg/d after 4 weeks, for a total of 52 weeks. Renal function was evaluated by serum creatinine, 24-hour creatinine clearance (CrCl), and isotope, GFR and urinary protein by 24-hour protein excretion. The 10 patients were aged 20 to 71 years and had been transplanted for 88.2 +/- 64.8 months at the time of study. After 52 weeks of valsartan therapy mean blood pressure (BP) fell from 152/88 mm Hg to 138/77 mm Hg (P =.06); serum creatinine rose from 206 +/- 55 micromol/L to 238 +/- 81 micromol/L (P =.22.); GFR fell from 39.8 +/- 17.6 to 31.9 +/- 19 mL/min (P =.23); and urine protein fell from 2.16 +/- 2.7 to 1.12 +/-.095 g/24 hours (P =.13). Side effects of valsartan therapy were few and included transient hyperkalemia in 2/10 patients. The small rise in serum creatinine and fall in GFR observed were not statistically significant. Urine protein fell by more than 50%, though the small patient numbers in this pilot study prevent this from achieving statistical significance. It is concluded that valasartan reduces BP and proteinuria in CAN patients without inducing a serious worsening in renal function. Valsartan may have a role to play in the management of patients with CAN.     

Plasma concentration and urinary excretion of N-terminal proatrial natriuretic peptides in patients with kidney diseases

BACKGROUND: Biologically active N-terminal fragments such as proANP(1-30), proANP(31-67), and proANP(1-98) derive from the prohormone of alpha-human atrial natriuretic peptide [proANP(99-126) or alpha-ANP]. No systematic data are available for patients with different kidney diseases. METHODS: Specific immunoassays were developed to determine plasma and urine concentrations of these fragments in 121 patients with different degrees of kidney function and urinary protein excretion, respectively. RESULTS: In patients with kidney disease and normal renal function without proteinuria, circulating proANP(1-30) and proANP(31-67) increased 2.8-fold and 6.5-fold, respectively. Urinary excretion of proANP(31-67) increased by a factor of 7.7 in these patients, whereas proANP(1-30) was not affected. Patients with impaired renal function had a dramatic increase of urinary proANP(31-67) excretion even before serum creatinine levels started to rise. The progression of renal failure caused a significant rise of circulating proANP(1-30) (4.3-fold) and proANP(31-67) (3.0-fold) compared with patients with normal renal function. Urinary excretion of proANP peptides significantly increased, particularly when the serum creatinine level was> 5.0 mg/dL [proANP(1-30) 26-fold, proANP(31-67) 8.4-fold]. Urinary excretion of proANP(1-30) increased up to 4.4-fold and urinary excretion of proANP(31-67) increased up to 2.4-fold in patients with proteinuria in excess of 3 g/24 h. CONCLUSIONS: Plasma concentrations and urinary excretion of proANP(1-30) and proANP(31-67) are affected by kidney disease and function, but not by proteinuria per se. It is proposed that the diseased kidney increases early urinary excretion of proANP fragments to participate in the regulation of renal function as well as sodium and water excretion.     

尿沉渣联合尿KIM-1、NGAL在诊断原发性肾脏病合并急性肾小管间质病变中的意义

目的 观察原发性慢性肾脏病(CKD)合并急性肾小管间质病变(ATIL)时尿沉渣积分情况和尿肾损伤因子1(KIM-1)、中性粒细胞明胶酶相关脂质运载蛋白(NGAL)水平的变化,以期早期、准确发现ATIL.方法 经临床和病理确诊为CKD并发ATIL病例52例,对照组为无急性肾损伤(AKI)的原发性CKD患者33例,15例健康人为正常对照组.比较三组尿KIM-1、NGAL水平与尿沉渣积分的不同.结果 ①三组的尿KIM-1、NGAL水平和尿沉渣积分相比较,原发性CKD并发ATIL患者均高于其他两组(P＜0.05),无AKI的CKD患者高于健康对照组(P＜0.05);②尿KIM-1、NGAL水平与尿沉渣评分呈正相关(r=0.711,0.683,P＜0.05),三者又均与CKD患者的ATIL严重程度呈正相关(r=0.892,0.735,0.745,P＜0.05);③N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、视黄醇结合蛋白(RBP)和α1-微球蛋白(α1-MG)尚在正常范围的患者尿KIM-1、NGAL水平已有升高,肾脏组织病理证实存在不同程度的ATIL;④尿KIM-1、NGAL、光抑素C(CysC)、NAG诊断ATIL的ROC曲线下面积大于尿RBP、α1-MG.尿沉渣诊断ATIL的受试者工作(ROC)曲线下面积为84％.尿KIM-1、NGAL联合尿沉渣积分诊断ATIL的准确性达100％.结论 尿沉渣联合尿KIM-1、NGAL可作为诊断原发性CKD并发ATIL的早期、无创、敏感的指标.     

糖尿病合并肾脏损害患者肾活检的临床意义

糖尿病肾脏疾病(DKD)是导致慢性肾衰竭的主要原因,其中2型糖尿病所致的肾脏病变占绝大多数。肾活检病理检查是诊断的"金标准",对患者治疗方案的选择及预后判断具有重要价值,对新药的开发具有重要意义,也是DKD流行病学调查、确定临床病理联系和开发无创诊断方法的重要依据。因此,对糖尿病尤其是2型糖尿病合并肾脏损害的患者积极开展肾活检病理检查具有重要的临床意义。