急性肾损伤后慢性肾脏病发病机制及其诊治进展

急性肾损伤后常出现肾小管间质纤维化等慢性肾脏病表现,甚至进展至终末期肾病,发病机制包括小管上皮细胞适应不良性修复、免疫炎症过度反应、毛细血管稀疏、氧化应激等。随着人们对急性肾损伤后慢性化转归机制的深入认识,近年来相关的干预新靶点和新策略相继问世,展示了人类攻克急性肾损伤预后不良的良好前景。     

Chronic epithelial kidney injury molecule-1 expression causes murine kidney fibrosis

Acute kidney injury predisposes patients to the development of both chronic kidney disease and end-stage renal failure, but the molecular details underlying this important clinical association remain obscure. We report that kidney injury molecule-1 (KIM-1), an epithelial phosphatidylserine receptor expressed transiently after acute injury and chronically in fibrotic renal disease, promotes kidney fibrosis. Conditional expression of KIM-1 in renal epithelial cells (Kim1^RECtg) in the absence of an injury stimulus resulted in focal epithelial vacuolization at birth, but otherwise normal tubule histology and kidney function. By 4 weeks of age, Kim1^RECtg mice developed spontaneous and progressive interstitial kidney inflammation with fibrosis, leading to renal failure with anemia, proteinuria, hyperphosphatemia, hypertension, cardiac hypertrophy, and death, analogous to progressive kidney disease in humans. Kim1^RECtg kidneys had elevated expression of proinflammatory monocyte chemotactic protein-1 (MCP-1) at early time points. Heterologous expression of KIM-1 in an immortalized proximal tubule cell line triggered MCP-1 secretion and increased MCP-1–dependent macrophage chemotaxis. In mice expressing a mutant, truncated KIM-1 polypeptide, experimental kidney fibrosis was ameliorated with reduced levels of MCP-1, consistent with a profibrotic role for native KIM-1. Thus, sustained KIM-1 expression promotes kidney fibrosis and provides a link between acute and recurrent injury with progressive chronic kidney disease.     

Therapeutic translation in acute kidney injury: the epithelial/endothelial axis

Acute kidney injury (AKI) remains a major clinical event with rising incidence, severity, and cost; it now has a morbidity and mortality exceeding acute myocardial infarction. There is also a documented conversion to and acceleration of chronic kidney disease to end-stage renal disease. The multifactorial nature of AKI etiologies and pathophysiology and the lack of diagnostic techniques have hindered translation of preclinical success. An evolving understanding of epithelial, endothelial, and inflammatory cell interactions and individualization of care will result in the eventual development of effective therapeutic strategies. This review focuses on epithelial and endothelial injury mediators, interactions, and targets for therapy.     

Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells

Following injury, the clearance of apoptotic and necrotic cells is necessary for mitigation and resolution of inflammation and tissue repair. In addition to macrophages, which are traditionally assigned to this task, neighboring epithelial cells in the affected tissue are postulated to contribute to this process. Kidney injury molecule-1 (KIM-1 or TIM-1) is an immunoglobulin superfamily cell-surface protein not expressed by cells of the myeloid lineage but highly upregulated on the surface of injured kidney epithelial cells. Here we demonstrate that injured kidney epithelial cells assumed attributes of endogenous phagocytes. Confocal images confirm internalization of apoptotic bodies within KIM-1-expressing epithelial cells after injury in rat kidney tubules in vivo. KIM-1 was directly responsible for phagocytosis in cultured primary rat tubule epithelial cells and also porcine and canine epithelial cell lines. KIM-1 was able to specifically recognize apoptotic cell surface-specific epitopes phosphatidylserine, and oxidized lipoproteins, expressed by apoptotic tubular epithelial cells. Thus, KIM-1 is the first nonmyeloid phosphatidylserine receptor identified to our knowledge that transforms epithelial cells into semiprofessional phagocytes.     

A FUNCTIONAL AND PATHOLOGICAL STUDY OF THE CHRONIC NEPHROPATHY INDUCED IN THE DOG BY URANIUM NITRATE

1. Uranium nitrate is relatively more toxic for old animals than for young animals. 2. This relative toxicity is not only expressed in the old animals by a greater functional disturbance of the kidney, but is also shown by an inability on the part of these animals to repair the kidney injury and reestablish its functional capacity. 3. The intoxication in younger animals has been followed by a repair of the renal injury and a partial restoration of kidney function. 4. In these animals the processes of repair lead to the development of a chronic diffuse type of nephropathy in which the acid-base equilibrium of the blood may be maintained at the point of normality. In these animals renal functional tests indicate the presence of severe kidney injury.     

Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney

Ischemic injury to the kidney produces acute tubular necrosis and apoptosis followed by tubular regeneration and recovery of renal function. Although mitotic cells are present in the tubules of postischemic kidneys, the origins of the proliferating cells are not known. Bone marrow cells (BMCs) can differentiate across lineages to repair injured organs, including the kidney. However, the relative contribution of intrarenal cells and extrarenal cells to kidney regeneration is not clear. We produced transgenic mice that expressed enhanced GFP (EGFP) specifically and permanently in mature renal tubular epithelial cells. Following ischemia/reperfusion injury (IRI), EGFP-positive cells showed incorporation of BrdU and expression of vimentin, which provides direct evidence that the cells composing regenerating tubules are derived from renal tubular epithelial cells. In BMC-transplanted mice, 89% of proliferating epithelial cells originated from host cells, and 11% originated from donor BMCs. Twenty-eight days after IRI, the kidneys contained 8% donor-derived cells, of which 8.4% were epithelial cells, 10.6% were glomerular cells, and 81% were interstitial cells. No renal functional improvement was observed in mice that were transplanted with exogenous BMCs. These results show that intrarenal cells are the main source of renal repair, and a single injection of BMCs does not make a significant contribution to renal functional or structural recovery.     

Disease biomarkers for CKD

As novel urinary biomarkers for kidney injury, neutrophil gelatinase-associated lipocalin (Ngal), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein(L-FABP) et al. have emerged. Recent studies elucidated their usefulness in chronic kidney disease and acute kidney injury. Meanwhile, the understanding of clinical significance of albuminuria, a classical biomarker, has changed as well. In this review, the progress and current status of urinary biomarker research in the field of chronic kidney disease will be described and future problems to be solved will be discussed.     

Integrin α6β4 defines a novel lung epithelial progenitor cell: a step forward for cell-based therapies for pulmonary disease

The many challenges associated with lung transplantation provide a strong rationale for the development of cell- and tissue-based therapies for patients with respiratory failure caused by the loss of lung tissue that is associated with chronic pulmonary disease, injury, or resection. In this issue of the JCI, Chapman et al. take an important step forward in the development of regenerative medicine for the treatment of lung disease by identifying a novel integrin α6β4-expressing alveolar epithelial cell that serves as a multipotent progenitor during repair of the severely injured lung.     

THE RENAL LESION OF EXPERIMENTAL CANTHARIDIN POISONING

Although the study of experimental nephritis by physiological methods shows that the most striking effect of cantharidin is injury of the blood vessels, the great abundance of mitotic figures in the tubular epithelium in the stage of repair points to an equally widespread and severe epithelial injury. Caution must therefore be observed in ascribing the physiological disturbances of kidney function caused by cantharidin as due exclusively to a vascular injury, and in regarding cantharidin nephritis as a pure type of vascular nephritis.     

慢性肾脏病发生急性肾损伤临床分析

目的探讨慢性肾脏病合并急性肾损伤的病因、临床特点及治疗与转归情况,提高急性肾损伤的防治水平。方法对慢性肾脏病发生急性肾损伤68例住院患者的临床特点进行回顾性分析。结果慢性肾脏病合并急性肾损伤的临床特征表现为短时间内肾功能急剧恶化。所有患者均给予激素和细胞毒药物,同时给予控制感染、利尿、抗凝等综合治疗,其中32例进行血液透析治疗,27例肾功能恢复。结论慢性肾病并发急性肾损伤临床并不少见,一旦确定诊断并给予及时治疗,多数患者预后较好,肾功能可恢复正常。     

腹膜透析治疗慢性肾脏病基础上的急性肾损伤

目的观察腹膜透析(peritoneal dialysis,PD)对慢性肾脏病基础上的急性肾损伤的疗效,并与间歇性血液透析(inermittent hemodialysis,IHD)进行比较。方法回顾性分析上海交通大学附属第一人民医院2005年至2009年收治的共183例慢性肾脏病基础上的急性肾损伤患者,其中78例采用PD或IHD治疗:PD组(35例):使用持续不卧床腹膜透析(continuous ambulatory peritoneal dialysis,CAPD)、间歇性腹膜透析(intermittent peritoneal dialysis,IPD)或自动腹膜透析(automated peritoneal dialysis,APD)治疗;IHD组(45例):采用IHD 1周3～4次治疗。观察一般资料(年龄、性别、原发病),透析前和透析后连续血尿素氮、肌酐、钾的变化,预后(肾功能恢复和存活),透析相关并发症。使用SPSS 10.0软件进行统计学分析,进行两组比较。结果两组患者治疗前年龄、性别、原发病构成及疾病严重程度差异无统计学意义(P0.05)。PD组透析后连续血尿素氮、肌酐水平明显高于IHD组(P0.05),而两组患者血钾、二氧化碳结合力等临床指标差异无统计学意义(P0.05)。随访显示,PD组肾功能恢复及存活与IHD组差异无统计学意义(P0.05)。PD组患者透析相关并发症发生率为11.4%,与IHD组(14.0%)相比差异无统计学意义(P0.05)。结论 PD治疗慢性肾脏病基础上的急性肾损伤效果与IHD基本相同,有利于患者肾脏功能的恢复,并且透析相关并发症发生率较低。     

Podocyte injury and glomerular sclerosis

Recently, our understanding of podocytes has been greatly advanced by genetic analysis of human kidney diseases and corresponding animal models, establishment of podocyte cell lines, and discovery of podocyte specific promoters that facilitate transgenic research. Accumulating data indicate that podocyte injury initiates the process of the disease progression to glomerular sclerosis, a hallmark of chronic renal failure. In the progression to glomerular sclerosis, damages that initially affect only podocytes propagate to mesangial cells, glomerular endothelial cells and parietal epithelial cells. However, the mechanism underlying the propagation of injury from podocytes to other glomerular cells is largely unknown. Several recent topics regarding the mechanism of podocyte injury are also discussed.     

Annexin A1–containing extracellular vesicles and polymeric nanoparticles promote epithelial wound repair

Epithelial restitution is an essential process that is required to repair barrier function at mucosal surfaces following injury. Prolonged breaches in epithelial barrier function result in inflammation and further damage; therefore, a better understanding of the epithelial restitution process has potential for improving the development of therapeutics. In this work, we demonstrate that endogenous annexin A1 (ANXA1) is released as a component of extracellular vesicles (EVs) derived from intestinal epithelial cells, and these ANXA1-containing EVs activate wound repair circuits. Compared with healthy controls, patients with active inflammatory bowel disease had elevated levels of secreted ANXA1-containing EVs in sera, indicating that ANXA1-containing EVs are systemically distributed in response to the inflammatory process and could potentially serve as a biomarker of intestinal mucosal inflammation. Local intestinal delivery of an exogenous ANXA1 mimetic peptide (Ac2-26) encapsulated within targeted polymeric nanoparticles (Ac2-26 Col IV NPs) accelerated healing of murine colonic wounds after biopsy-induced injury. Moreover, one-time systemic administration of Ac2-26 Col IV NPs accelerated recovery following experimentally induced colitis. Together, our results suggest that local delivery of proresolving peptides encapsulated within nanoparticles may represent a potential therapeutic strategy for clinical situations characterized by chronic mucosal injury, such as is seen in patients with IBD.     

干细胞移植治疗慢性肾脏疾病的可行性

背景：慢性肾脏疾病的发病率呈逐年递增趋势,传统血液透析和同种异体肾移植仍是目前仅有的治疗选择。随着以干细胞为基础的再生医学研究的进展,有可能从干细胞的角度找到慢性肾病治疗的理想治疗措施。目的：就不同来源干细胞治疗慢性肾脏的作用机制及临床应用的可能性等进行综述。方法：应用计算机检索CNKI和PubMed数据库中2006-01/2009-12关于干细胞治疗慢性肾病的文章,在标题和摘要中以＂胚胎干细胞;骨髓干细胞;诱导性多少能干细胞;慢性肾脏疾病＂或＂Embryonic stem cells;Bone marrow stem cells;induced pluripotent stem cells;chronic kidney disease＂为检索词进行检索。选择文章内容与干细胞治疗慢性肾病相关,同一领域文献则选择近期发表或发表在权威杂志文章。初检得到128篇文献,根据纳入标准选择30篇文章进行综述。结果与结论：多种来源的干细胞具有向肾组织细胞分化的潜能,大量实验研究表明干细胞移植对急性肾损伤修复有积极作用,同时对于肾脏纤维化疾病、终末期肾病的治疗等也有相关研究报道。通过对干细胞相关特性的描述及干细胞治疗肾病的相关机制的研究,希望能通过新的方法治疗慢性肾病。     

Management of chronic kidney disease--preventing the progression of renal disease

Intraglomerular hypertension, and glomerular hypertrophy, leading to glomerular scarring are suggested to have an effect on the progression in chronic kidney disease, unrelated to the initial cause of kidney injury. Tubulointerstitial disease is another factor, which may affect the prognosis. Strategies to prevent or minimize the progression of kidney disease consist of treating these disease-worsening mechanisms, including smoking cessation, treatment of hyperlipidemia, sodium and protein restriction, antihypertensive therapy, inhibition of renin-angiotensin-aldosterone system, and treatment of anemia. Studies in experimental animals and humans suggest that these therapies are effective to prevent the progression in chronic kidney disease and there are some evidences that these therapies have benefits in the patients with chronic kidney disease.     

Wnt诱导信号通路蛋白1在肾脏疾病中应用的研究进展

Wnt诱导信号通路蛋白1是一种与炎症,损伤修复,肿瘤发生、发展等病理过程密切相关的蛋白,广泛参与了慢性肾脏病、赭曲霉毒素A相关性肾病、肾脏肿瘤等肾脏疾病的发病过程,有望成为诊断肾脏疾病的新型分子生物标志物及肾脏疾病治疗的靶点之一.本文就Wnt诱导信号通路蛋白1在肾脏疾病中应用的研究进展作一综述.     

Functional intravital imaging of leukocytes in animal models of renal injury

An important emerging paradigm in the understanding of renal disease is the recognition of the central role of inflammation in the initiation and progression of acute and chronic kidney injury. These advances have led to an increasing awareness of the importance of leukocytes (white blood cells (WBC)) in the pathogenesis of renal disease, and the necessity for a greater understanding of the specific roles of different WBC lineages. All aspects of WBC function have been implicated in aspects of renal disease. In many cases soluble factors derived from these cells (cytokines, complement, immunoglobulins, etc.) having effects remote from the secreting cells are involved, while in other cases there is apparently more direct involvement of infiltrating cells themselves acting on their immediate surroundings. This highlights the importance of understanding the dynamic behavior of specific WBC cell types and their interactions with the intrinsic cells of the kidney during injury. New insight into this question is promised by recent developments in imaging technology that allow WBC movement and interactions with endothelial or epithelial cells or with the extracellular matrix to be visualized within tissues, even in the relatively unperturbed setting of intact organs in the live animal.     

Biomarkers of inflammation and repair in kidney disease progression

INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH.     

Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition

Hypoxia has been proposed as an important microenvironmental factor in the development of tissue fibrosis; however, the underlying mechanisms are not well defined. To examine the role of hypoxia-inducible factor-1 (HIF-1), a key mediator of cellular adaptation to hypoxia, in the development of fibrosis in mice, we inactivated Hif-1alpha in primary renal epithelial cells and in proximal tubules of kidneys subjected to unilateral ureteral obstruction (UUO) using Cre-loxP-mediated gene targeting. We found that Hif-1alpha enhanced epithelial-to-mesenchymal transition (EMT) in vitro and induced epithelial cell migration through upregulation of lysyl oxidase genes. Genetic ablation of epithelial Hif-1alpha inhibited the development of tubulointerstitial fibrosis in UUO kidneys, which was associated with decreased interstitial collagen deposition, decreased inflammatory cell infiltration, and a reduction in the number of fibroblast-specific protein-1-expressing (FSP-1-expressing) interstitial cells. Furthermore, we demonstrate that increased renal HIF-1alpha expression is associated with tubulointerstitial injury in patients with chronic kidney disease. Thus, we provide clinical and genetic evidence that activation of HIF-1 signaling in renal epithelial cells is associated with the development of chronic renal disease and may promote fibrogenesis by increasing expression of extracellular matrix-modifying factors and lysyl oxidase genes and by facilitating EMT.     

Induction of heparin-binding epidermal growth factor-like growth factor mRNA in rat kidney after acute injury.

Previous studies have suggested that EGF or other members of the EGF family of mitogenic proteins are involved in proliferation of renal tubular epithelial cells occurring during recovery from injury to the kidney. The present studies examined whether expression of mRNA for the recently identified heparin-binding EGF-like growth factor (HB-EGF) is regulated in response to renal injury induced by either ischemia/reperfusion or mercuric chloride. Increased expression of HB-EGF mRNA was demonstrated in the post-ischemic kidney within 45 min of unilateral ischemia/reperfusion in the rat. Induction of HB-EGF mRNA occurred only when ischemia was followed by reperfusion, and was not eliminated by removal of blood cells from the post-ischemic kidney by saline perfusion. In situ hybridization with 35S-labeled antisense riboprobes of HB-EGF indicated that compared with control, there was increased HB-EGF mRNA expression in the 6 h post-ischemic kidney in the inner cortex and outer medulla in a patchy distribution, with the greatest expression in the inner stripe of the outer medulla. Expression occurred primarily in tubular epithelial cells. Recombinant human HB-EGF stimulated [3H]-thymidine incorporation in both primary cultures of rabbit proximal tubule cells and NRK 52E normal rat kidney epithelial cells, with potency similar to that of EGF. Induction of HB-EGF mRNA was observed in tubules freshly isolated from rat renal cortex or outer medulla when the tubules were subjected to reoxygenation after incubation in anoxic conditions. The nephrotoxin, mercuric chloride, also caused induction of HB-EGF mRNA both in vivo and in isolated rat cortical tubules. The anoxia/reoxygenation-induced expression of HB-EGF mRNA in isolated tubules was inhibited by the free radical scavengers, di- and tetra-methylthiourea, indicating involvement of reactive oxygen species. These findings indicate that HB-EGF mRNA is inducible in the kidney in vivo by acute tubular injury and suggest that HB-EGF may act as an autocrine/paracrine growth factor involved in proliferation of tubular epithelial cells and repair of the kidney.