Hemorrhagic fever with renal syndrome: clinical aspects

Hemorrhagic fever with renal syndrome (HFRS) is an acute viral fever which typically progresses through five stages: an acute grippe, followed by hemorrhage and shock, acute renal insufficiency from tubulo-interstitial nephritis, and recovery. Death from circulatory or renal failure occurs in 5%-15% of cases. In mild or abortive forms of the disease, associated with viral strains enzootic in Scandinavia the illness is milder. Hemorrhage and shock occur with lower frequency and the fatality rate is less than 1%. Pathologic examination of HFRS cases from Asia discloses generalized congestion, hyperemia, and hemorrhage, with scattered foci of necrosis in numerous organs. Congestion and hemorrhage are most evident in the kidney medulla. Widespread microscopic evidence of capillary and vascular dysfunction is found, with endothelial cell swelling, perivascular edema, diapadesis of erythrocytes and mononuclear cell infiltration. Hemorrhage and inflammation in the renal interstitium and tubular epithelial degeneration characterize the kidney pathology. Limited data indicate pathogenic roles for cell destruction from viral infection as well as immune mediated mechanisms. No specific therapy is available.     

Characterization of acute renal allograft rejection by proteomic analysis of renal tissue in rat

Rapid and reliable biomarkers of renal allograft rejection have not been available. This study aimed to investigate biomarkers in renal allograft tissue using proteomic analysis. Orthotopic kidney transplantations were performed using Fisher (F344) or Lewis rats as donors and Lewis rats as recipients. Syngenic control group (Group I) constituted F344-to-F344 orthotopic kidney allo-transplantations (n = 8); and allogenic group (Group II) consisted of F344-to-Lewis orthotopic kidney allo-transplantations (n = 8). Renal tissues were harvested 7 days after transplantation. Samples were analyzed using 2-D electrophoresis and matrix assisted laser desorption ionization-time of flight mass spectrometry. 6 differentially expressed proteins were identified between allogenic group and syngenic control group. A rat model of acute renal allograft rejection was successfully set up. Differentially expressed proteins in renal allograft tissue of rat were detected using proteomic analysis and might serve as novel diagnostic and therapeutic targets in human. Quantitative proteomics, using MALDL-TOF-MS methodology has the potential to provide a profiling and a deeper understanding of acute renal rejection.     

Circulating human monocytes in the acute coronary syndrome express a characteristic proteomic profile

We examined the proteome of circulating monocytes of patients with acute coronary syndrome at different times in comparison to that of patients with stable coronary artery disease. On admission, the expression of 18 spot proteins was altered, 10 of which were totally absent. This pattern changed progressively, and at 6 months, there were no differences with the monocyte proteome of stable patients.     

Prediction of acute cellular renal allograft rejection by urinary metabolomics using MALDI-FTMS

The present study investigated small molecule analysis of urinary samples as a noninvasive method to detect acute cellular renal allograft rejection. Matrix-assisted laser desorption/ionization Fourier transform mass spectrometry (MALDI-FTMS) was used to analyze 15 urinary samples from transplant patients with different grades of biopsy showing improved clinical acute cellular rejection (ACR) and 24 urinary samples from 8 transplant patients without evidence of rejection. Seven small molecules demonstrated highly successful diagnostic performance (m/z): 278.1 (t = 3.398, p = 0.004), 293.0 (t = 2.169, p = 0.048), 294.1 (t = 2.154, p = 0.05), 382.2 (t = 2.961, p = 0.010), 383.3 (t = 2.270, p = 0.040), 402.2 (t = 2.994, p = 0.010), 424.0 (t = 2.644, p = 0.019). Kidney transplant patients with ACR could be distinguished from those without ACR using four individual small molecules with a specificity of 100%. In conclusion, the combination of MALDI-FTMS technology with a clear definition of patient groups can detect urine small molecule associated with ACR.     

Local synthesis of complement component C3 regulates acute renal transplant rejection

Accumulating evidence suggests that innate immunity interacts with the adaptive immune system to identify potentially harmful antigens and eliminate them from the host. A central facet of innate immunity is complement, which for some time has been recognized as a contributor to inflammation in transplant rejection but without detailed analysis of its role in what is principally a T cell mediated process. Moreover, epithelial and vascular tissues at local sites of inflammation secrete complement components; however, the role of such local synthesis remains unclear. Here we show that the absence of locally synthesized complement component C3 is capable of modulating the rejection of renal allografts in vivo and regulating T-cell responses in vivo and in vitro. The results indicate that improved success in kidney transplantation could come from therapeutic manipulation of innate immunity in concert with T cell directed immunosuppression.     

烧伤合并急性肾功能衰竭的早期指标检测

目的:探讨烧伤合并急性肾功能衰竭(ARF)的早期指标检测以及各种危险因素.方法:选择本院2008年1月～2009年6月收治的75例中重度热烧伤患者.Ⅱ度或ⅡⅢ度烧伤面积累计20%-70%TBSA.所有患者在入院时、入院后3d、7d、14d和21d检测血清肌酐(Scr)、血尿素氮(BUN)、尿微量白蛋白(mALB)和滤过钠排泄分数(FeNa).结果:75例烧伤患者中有14例(18.7%)并发ARF,其中10例进行了血液净化治疗.烧伤合并ARF组烧伤面积和脓毒症发生率均明显高于烧伤未合并ARF组(P均＜0.05).烧伤合并ARF组Scr和BUN水平分别在住院7d和14d后明显高于烧伤未合并ARF组(P均＜0.05).烧伤合并ARF组入院时mALB水平已达到正常值34倍,21d时达到最大值,在观察期间一直高于烧伤未合并ARF组(P均＜0.05).烧伤合并ARF组滤过钠排泄分数均大于2%.烧伤面积与脓毒症是烧伤后ARF发生的主要危险因素(复相关系数R分别为0.52和0.23,P均＜0.05).结论:烧伤合并ARF与烧伤面积与脓毒症相关,mALB是早期监测ARF的有用指标.     

Discovery, clinical and etiological characteristic of hemorrhagic fever with renal syndrome in the subtropical zone of Krasnodar region

Twenty-six patients with hemorrhagic fever with renal syndrome (HFRS) were revealed as a result of serological examination of 582 patients with fever living around Sochi town. Etiologic role of Dobrava virus subtype as the cause of HFRS was assessed by immunofluorescent and ELISA assays, and neutralization test. The principal host of this virus and source of infection for humans is Caucasian forest mouse Apodemus ponticus. HFRS morbidity was sporadic and not dependent from patients' occupation and season. Comparative analysis of clinical and laboratory data from HFRS cases caused by DOB/Sochi and DOB/Lipetsk subspecies, as well as Puumala virus showed higher proportion of severe forms of disease in patients with HFRS from Sochi.     

Severe acute respiratory syndrome: clinical and laboratory manifestations

Severe acute respiratory syndrome (SARS) is a recently emerged infectious disease with significant morbidity and mortality. An epidemic in 2003 affected 8,098 patients in 29 countries with 774 deaths. The aetiological agent is a new coronavirus spread by droplet transmission. Clinical and general laboratory manifestations included fever, chills, rigor, myalgia, malaise, diarrhoea, cough, dyspnoea, pneumonia, lymphopenia, neutrophilia, thrombocytopenia, and elevated serum lactate dehydrogenase (LD), alanine aminotransferase (ALT) and creatine kinase (CK) activities. Treatment has been empirical; initial potent antibiotic cover, followed by simultaneous ribavirin and corticosteroids, with or without pulse high-dose methylprednisolone, have been used. The postulated disease progression comprises (1) active viral infection, (2) hyperactive immune response, and (3) recovery or pulmonary destruction and death. We investigated serum LD isoenzymes and blood lymphocyte subsets of SARS patients, and found LD1 activity as the best biochemical prognostic indicator for death, while CD3+, CD4+, CD8+ and natural killer cell counts were promising predictors for intensive care unit (ICU) admission. Plasma cytokine and chemokine profiles showed markedly elevated Th1 cytokine interferon (IFN)-gamma, inflammatory cytokines interleukin (IL)-1beta, IL-6 and IL-12, neutrophil chemokine IL-8, monocyte chemoattractant protein-1 (MCP-1), and Th1 chemokine IFN-gamma-inducible protein-10 (IP-10) for at least two weeks after disease onset, but there was no significant elevation of inflammatory cytokine tumor necrosis factor (TNF)-alpha and anti-inflammatory cytokine IL-10. Corticosteroid reduced IL-8, MCP-1 and IP-10 concentrations from 5-8 days after treatment. Measurement of biochemical markers of bone metabolism demonstrated significant but transient increase in bone resorption from Day 28-44 after onset of fever, when pulse steroid was most frequently given. With tapering down of steroid therapy, there was a decrease in bone resorption marker together with an increase in bone formation markers round Day 50, suggesting that some of the bone loss might be reversed. Our research studies on the chemical pathology and clinical immunology of SARS should have implications for the pathophysiology and therapy of this potentially lethal infection.     

Identification of a urine metabolite constellation characteristic for kidney allograft rejection

Introduction

Allograft rejection is still an important complication after kidney transplantation. Currently, monitoring of these patients mostly relies on the measurement of serum creatinine and clinical evaluation. The gold standard for diagnosing allograft rejection, i.e. performing a renal biopsy is invasive and expensive. So far no adequate biomarkers are available for routine use.

Objectives

We aimed to develop a urine metabolite constellation that is characteristic for acute renal allograft rejection.

Methods

NMR-Spectroscopy was applied to a training cohort of transplant recipients with and without acute rejection.

Results

We obtained a metabolite constellation of four metabolites that shows promising performance to detect renal allograft rejection in the cohorts used (AUC of 0.72 and 0.74, respectively).

Conclusion

A metabolite constellation was defined with the potential for further development of an in-vitro diagnostic test that can support physicians in their clinical assessment of a kidney transplant patient.

     

Evaluation of biomarker discovery approaches to detect protein biomarkers of acute renal allograft rejection

Management of host responses to allografts by immunosuppressive therapy is the cornerstone of transplantation medicine, but it is still deficient in one important element: biomarkers that are readily accessible and predict the fate of the transplant early, specifically, and reliably. Using a Brown Norway (BN)-to-Lewis rat renal allograft model of kidney transplantation, this study aims at evaluating two proteomic approaches to discover biomarkers for acute rejection: SELDI-MS technology and 2D gel electrophoresis combined with mass spectrometry. Several novel potential serum biomarkers have been identified for follow up. Overall, the conclusion is that apparently at the serum protein level, dramatic changes only occur at a stage where kidney function is already severely affected. Multivariate analysis of serum profiles suggests that there is an ensemble of subtle changes, comprising a proteomic signature of acute rejection at an early stage, a more detailed evaluation of which might provide novel opportunities for the diagnosis of acute rejection. Profiling of the excreted proteins indicates that urine might even present the earliest signs of the rejection process.     

Influence of GSTO2 (N142D) genetic polymorphism on acute renal rejection

Acute renal allograft rejection remains an important problem following kidney transplantation. Several immunological and non-immunological factors intervene in renal graft rejection. Glutathione S-transferase super family is one of the important enzymes for biotransformation of both exogenous and endogenous xenobiotic compounds such as immunosuppressive drugs. The new class of this family is omega that includes two subunits GSTO1 and GSTO2. In this study 282 samples were collected from renal recipients of Namazi hospital in Shiraz-Iran during 2007–2010 years. Also 300 healthy samples as control group were collected from Shiraz population, included in our study. The primary outcome of this study was defined as biopsy-proven acute rejection during 1 year of renal transplantation. We applied polymerase chain reaction–restriction fragment length polymorphism method for determination of GSTO2 N142D polymorphism. Our result showed no significant association between GSTO2 polymorphism and acute rejection. Also this genetic variant has no significant effect with the risk of end stage renal disease. Cadaveric donor type for acute rejection significantly differed between acute rejection and non acute rejection patients (P = 0.004). The combination effect of donor type and GSTO2 polymorphism indicates DD genotype with cadaver donor type increase risk of acute rejection (OR = 3.82, 95 % CI 1.80–12.37, P = 0.02).     

Met-RANTES reduces vascular and tubular damage during acute renal transplant rejection: blocking monocyte arrest and recruitment.

Chemokines are thought to contribute to the cellular infiltrate characteristic of renal transplant rejection. We show that Met-RANTES, a chemokine receptor antagonist, suppresses recruitment of inflammatory cells into renal allografts. In a renal transplant model (Fisher RT1(lvl) rat kidney into Lewis RT1(l) rat) where no additional immune suppressant was used, Met-RANTES-treated animals showed a significant reduction in vascular injury score (16.10 +/- 5.20 vs. 62.67 +/- 18.64) and tubular damage score (15.70 +/- 5.22 vs. 33.00 +/- 6.44) relative to untreated animals. In a more severe rejection model (Brown-Norway RT1(n) rat kidney into Lewis RT1(1) rat), Met-RANTES significantly augmented low-dose cyclosporin A treatment to reduce all aspects of renal injury including interstitial inflammation (score 71.00 +/- 6.10 vs. 157.30 +/- 21.30). The majority of infiltrating cells in these models (60-70%) consisted of monocytes. Potential mechanisms of action of Met-RANTES were tested using monocyte attachment assays on microvascular endothelium under physiological flow conditions. Preexposure of microvascular endothelium to RANTES resulted in RANTES immobilization and RANTES-induced firm adhesion of monocytes only after prestimulation of the endothelium with IL-1beta. Met-RANTES completely inhibited this RANTES-mediated arrest. Thus, Met-RANTES may counter acute rejection by blocking leukocyte firm adhesion to inflamed endothelium.