Acute kidney injury pathology and pathophysiology: a retrospective review
急性肾损伤病理学和病理生理学：回顾性评价

Abstract 抽象

Acute kidney injury (AKI) is the clinical term used for decline or loss of renal function. It is associated with chronic kidney disease (CKD) and high morbidity and mortality. However, not all causes of AKI lead to severe consequences and some are reversible. The underlying pathology can be a guide for treatment and assessment of prognosis. The Kidney Disease: Improving Global Outcomes guidelines recommend that the cause of AKI should be identified if possible. Renal biopsy can distinguish specific AKI entities and assist in patient management. This review aims to show the pathology of AKI, including glomerular and tubular diseases.
急性肾损伤 （AKI） 是用于肾功能下降或丧失的临床术语。它与慢性肾脏病 （CKD） 以及高发病率和死亡率有关。然而，并非所有 AKI 的原因都会导致严重的后果，有些是可逆的。潜在病理学可作为治疗和预后评估的指南。肾脏病：改善全球结局指南建议，如果可能，应确定 AKI 的病因。肾活检可以区分特定的 AKI 疾病并协助患者管理。本综述旨在显示 AKI 的病理学，包括肾小球和肾小管疾病。

AKI PERSPECTIVE AKI 视角

Acute kidney injury (AKI), previously called acute renal failure (ARF), is a condition of sudden kidney failure in patients with or without preexisting chronic kidney disease (CKD); severe kidney dysfunction within a few hours or days results in a significant decrease (oliguria) or complete elimination of urine (anuria), with electrolyte imbalance, often requiring hemodialysis.
急性肾损伤 （AKI），以前称为急性肾功能衰竭 （ARF），是患有或不患有慢性肾病 （CKD） 的患者突然肾衰竭的一种疾病;在几小时或几天内出现严重的肾功能不全会导致尿液显著减少（少尿）或完全消除（无尿），伴有电解质失衡，通常需要血液透析。

While it is unclear when AKI was first recognized, incidences are scattered in the medical literature over the centuries (http://www.renalmed.co.uk). Most experts agree that the pathology was first described during World War II when four cases of crush injury characterized by diffuse acute tubular damage with pigmented casts followed by impaired renal function were reported [1]. Homer W. Smith introduced the term ‘ARF’ in 1951 [2]. In 2004, ARF was replaced by AKI [3, 4]. Before 2004 there were at least 35 ARF definitions. This situation of having various definitions has given rise to a wide range of incidence estimates for AKI from 1 to 25% of intensive care unit (ICU) patients and has led to mortality rate estimates from 15 to 60% [5, 6].
虽然尚不清楚 AKI 何时首次被发现，但几个世纪以来 （http://www.renalmed.co.uk） 的发病率分散在医学文献中。大多数专家都认为，这种病变最早是在第二次世界大战期间报道的，当时报道了 4 例挤压伤，其特征是弥漫性急性肾小管损伤伴色素沉着管型，随后肾功能受损 [1]。Homer W. Smith 于 1951 年引入了“ARF”一词 [2]。2004 年，ARF 被 AKI 取代 [3， 4]。在 2004 年之前，至少有 35 个 ARF 定义。这种定义多种多样的情况导致 AKI 的发病率估计范围很广，占重症监护病房 （ICU） 患者的 1% 至 25%，导致死亡率估计为 15% 至 60% [5， 6]。

AKI is now defined by the RIFLE criteria (risk, injury, failure, loss, end-stage kidney disease) and is not just ARF. It incorporates the entire spectrum of the syndrome, from minor changes in renal function to the requirement for renal replacement therapy [7]. In practice, most nephrologists follow the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, which recommend determining the cause of AKI whenever possible [5, 6]. The incidence of AKI on renal biopsy is not entirely known, but is common either as an isolated finding or concurrent with other diseases. This review is an account of the spectrum of entities identified on renal biopsy from patients presenting with AKI.
AKI 现在由 RIFLE 标准（风险、损伤、失败、损失、终末期肾病）定义，而不仅仅是 ARF。它包括该综合征的整个范围，从肾功能的微小变化到需要肾脏替代治疗 [7]。在实践中，大多数肾脏科医生遵循肾脏疾病改善全球结局（Kidney Disease： Improving Global Outcomes， KDIGO）标准，该标准建议尽可能确定AKI的病因[5,6]。 肾活检中 AKI 的发病率尚不完全清楚，但通常为孤立发现或与其他疾病合并。本综述介绍了 AKI 患者肾活检中发现的一系列疾病。

AKI clinical and pathologic classifications
AKI 临床和病理分类

It should be remembered that AKI is a clinical term. Pathologists use descriptive pathologic findings that cumulate to the term ‘acute tubular injury’ (ATI). Prerenal, intrarenal, postrenal and even unilateral insults can cause ATI. A dissociation between structural and functional changes was first recognized at autopsy of World War II soldiers with acute kidney failure and death who were found to have mild kidney findings (so-called shock kidneys) [1]. Examples of dissociation between clinical symptoms and histopathological findings include prerenal AKI caused by volume depletion as in cardiogenic, allergic or hemorrhagic shock. In such cases, ATI may be mild and/or even absent. Postrenal AKI is caused by urinary flow obstruction and can be unilateral or bilateral, e.g. unilateral hydronephrosis, lithiasis and/or pyelonephritis. The recent AKI classification that includes categories designated as declining renal function (glomerular filtration rate) instead of renal failure are in range and extent the histopathological ATI spectrum [6]. In practice, a semiquantitative histopathological scoring of ATI as mild, moderate or severe (or focal versus diffuse) is preferable instead of the term acute tubular necrosis (ATN), which was previously used despite the absence of necrosis in many cases.
应该记住，AKI 是一个临床术语。病理学家使用描述性病理结果，这些发现累积为术语“急性肾小管损伤”（ATI）。肾前、肾内、肾后甚至单侧损伤都可导致 ATI。对二战时期急性肾衰竭和死亡的士兵进行尸检时，首次发现结构和功能变化之间的分离，这些士兵被发现有轻度肾脏表现（所谓的休克肾）[1]。临床症状与组织病理学发现分离的例子包括由血容量不足引起的肾前性 AKI，如心源性休克、过敏性休克或出血性休克。在这种情况下，ATI 可能是轻微的和/或甚至不存在。肾后性 AKI 由尿流阻塞引起，可以是单侧或双侧的，例如 单侧肾积水、结石和/或肾盂肾炎。最近的 AKI 分类包括肾功能下降（肾小球滤过率）而不是肾功能衰竭的类别，其范围和范围属于组织病理学 ATI 谱 [6]。在实践中，将 ATI 的半定量组织病理学评分为轻度、中度或重度（或局灶性与弥漫性）优于急性肾小管坏死 （ATN） 一词，尽管在许多情况下没有坏死，但以前使用过该术语。

Histopathological definitions of AKI
AKI 的组织病理学定义

ATI is characterized by focal or diffuse tubular luminal dilatation, simplification of the lining epithelium, loss of the brush border in proximal tubules, loss of nuclei and/or the presence of nucleoli (Figure 1A). Epithelial cell mitoses and cytoplasmic basophilia can also be seen and are thought to represent epithelial cell regeneration. Both proximal and distal tubules can be affected by ATI. ATN is characterized by focal or diffuse tubular epithelial cell coagulative-type necrosis and detachment from the basement membrane (Figure 1B and C). Epithelial cell necrosis consists of cytoplasmic swelling (oncosis), degeneration of cytoplasmic organelles and a ghost-like tubular appearance staining dark pink on hematoxylin and eosin (H&E) stain. ATN is much less common compared with ATI and requires prolonged and sustained tubular injury that is usually absent in acute AKI. The exception is cortical necrosis caused by an acute ischemic process, leading to degeneration of large number of tubules (coagulation necrosis). ATI and ATN may coexist (Figure 1C).
ATI 的特征是局灶性或弥漫性肾小管管腔扩张、衬里上皮简化、近端肾小管刷状缘缺失、细胞核缺失和/或核仁的存在（图 1A）。上皮细胞有丝分裂和细胞质嗜碱性粒细胞增多也可见，并被认为代表上皮细胞再生。近端和远端小管都可能受到 ATI 的影响。ATN 的特征是局灶性或弥漫性肾小管上皮细胞凝固型坏死和从基底膜脱离（图 1B 和 C）。上皮细胞坏死包括细胞质肿胀（肿瘤）、细胞器变性以及在苏木精和伊红 （H&E） 染色上呈深粉红色的鬼状肾小管外观。与 ATI 相比，ATN 要少得多，需要长期和持续的肾小管损伤，这在急性 AKI 中通常不存在。急性缺血过程引起的皮质坏死是例外，导致大量肾小管变性（凝血坏死）。ATI 和 ATN 可能共存（图 1C）。

Intrarenal AKI is associated with numerous diseases, including glomerular, tubulointerstitial and vascular. Intrinsic toxic insults to tubular epithelial cells include heavy proteinuria, hematuria, interstitial nephritis and ischemia secondary to microvascular (endothelial) injury, e.g. renal vasculitis and thrombotic microangiopathies (TMAs). Glomerular diseases, acute or chronic, can be complicated by ATI. Examples include diabetic nephropathy, immunoglobulin A (IgA) nephropathy, hypertensive kidney disease, myeloma cast nephropathy, transplant rejection and TMAs.
肾内 AKI 与许多疾病有关，包括肾小球、肾小管间质和血管疾病。对肾小管上皮细胞的内在毒性损伤包括大量蛋白尿、血尿、间质性肾炎和继发于微血管（内皮）损伤的缺血，例如肾血管炎和血栓性微血管病 （TMA）。急性或慢性肾小球疾病可并发 ATI。例如糖尿病肾病、免疫球蛋白 A （IgA） 肾病、高血压肾病、骨髓瘤管型肾病、移植排斥反应和 TMA。

A list of specific entities leading to intrarenal ATI is shown in Table 1. The pathology of the most common entities is described below.
导致肾内 ATI 的特定实体列表见 表 1。最常见实体的病理学描述如下。

ATI with distinct pathology
具有不同病理的 ATI

Rhabdomyolysis 横纹肌溶解症

Rhabdomyolysis causes ARF in 7–15% of all AKI cases in the USA and affects 13–50% of hospitalized patients, with worse prognosis and greater mortality in critically ill patients [8]. In our recent study of renal biopsies accrued from 2011 through June 2014 among 27 850 renal biopsies in our search, 249 biopsies (∼1%) were positive for myoglobin casts [9]. On H&E stain, myoglobin casts are focal, light pink, almost translucent, but may vary from pink to dark red, granular or chain-like clumps (Figure 2A). Myoglobin casts are difficult to diagnose accurately because they have overlapping morphology with hemoglobin casts, myeloma casts and Tamm–Horsfall protein casts. Myoglobin immunohistochemistry is very helpful in arriving at a definitive diagnosis, highlighting greater numbers of injured tubules (not obvious on H&E) by staining luminal deposits (casts) and/or proximal and occasionally collecting duct epithelium (Figure 2B). Notably, ATI marked by the kidney injury molecule-1 (KIM-1) antibody is more widespread, highlighting the majority of tubules, compared with focal myoglobin staining (Figure 2C). KIM-1 is not currently routinely used to assess ATI in renal biopsies even though it is US Food and Drug Administration approved as a biomarker believed to participate in the process of both AKI and healing [10].
横纹肌溶解症导致美国 7-15% 的 AKI 病例发生 ARF，并影响 13-50% 的住院患者，危重患者的预后更差，死亡率更高 [8]。在我们最近对 2011 年至 2014 年 6 月期间 27 850 例肾活检的研究中，249 例活检 （∼1%） 肌红蛋白管型呈阳性 [9]。在 H&E 染色上，肌红蛋白管型是局灶性的、浅粉红色的、几乎半透明的，但可能从粉红色到深红色、颗粒状或链状团块不等（图 2A）。肌红蛋白管型很难准确诊断，因为它们的形态与血红蛋白管型、骨髓瘤管型和 Tamm-Horsfall 蛋白管型重叠。肌红蛋白免疫组化对于做出明确诊断非常有帮助，通过对管腔沉积物（管型）和/或近端和偶尔聚集的导管上皮进行染色来突出更多受伤的小管（在 H&E 上不明显）（图 2B）。值得注意的是，与局灶性肌红蛋白染色相比，由肾损伤分子 1 （KIM-1） 抗体标记的 ATI 更为普遍，突出了大多数肾小管（图 2C）。KIM-1 目前不常规用于评估肾活检中的 ATI，尽管它已被美国食品药品监督管理局批准为生物标志物，被认为参与了 AKI 和愈合过程 [10]。

The pathogenesis of rhabdomyolysis is attributed to the release of myoglobin into the circulation, subsequently filtered by the glomeruli and cleared in the tubules where it accumulates either as tubular myoglobin casts or intraepithelial deposits with either a ropey or finely granular appearance [9]. Diagnosing rhabdomyolysis clinically is complicated by frequently absent classic clinical symptoms (triad of muscle pain, weakness and dark urine) and/or nondiagnostic values of laboratory tests such as creatine phosphokinase (CPK). CPK increases within 12 h of the onset of muscle injury, has a serum half-life of ∼36 h and declines 3–5 days after cessation of muscle injury [11]. At the time of biopsy, CPK may already have dissipated. The exact mechanism of ATI due to myoglobin pigment deposits is still debated but it is thought that myoglobin itself rarely leads to kidney injury in the absence of other risk factors such as ischemia, volume depletion and hypotension. Acid urine enhances the renal toxicity of myoglobin by converting heme in myoglobin to ferrihemate (hematin), shown to produce free hydroxy radicals that are directly toxic to renal tubular epithelial cells or via renal vasoconstriction due to inhibition of nitric oxide synthesis. In addition, the heme fraction of myoglobin induces the release of free radicals, further contributing to ischemic tubular damage [9].
横纹肌溶解症的发病机制归因于肌红蛋白释放到循环中，随后被肾小球过滤并在肾小管中清除，在那里它以管状肌红蛋白管型或上皮内沉积物的形式积累，呈绳状或细颗粒状 [9]。临床诊断横纹肌溶解症因经常不存在典型临床症状（肌肉疼痛、无力和尿色深）和/或实验室检查（如肌酸磷酸激酶 （CPK））的非诊断价值而复杂化。CPK 在肌肉损伤开始后 12 小时内增加，血清半衰期为 ∼36 h，在肌肉损伤停止后 3-5 天下降 [11]。在活检时，CPK 可能已经消散。肌红蛋白色素沉积导致 ATI 的确切机制仍存在争议，但人们认为，在没有其他危险因素（如缺血、血容量不足和低血压）的情况下，肌红蛋白本身很少导致肾损伤。酸性尿通过将肌红蛋白中的血红素转化为铁血红素（血红素）来增强肌红蛋白的肾毒性，铁红蛋白（血红素）被证明产生自由羟基自由基，这些自由基对肾小管上皮细胞直接有毒，或者由于抑制一氧化氮合成而通过肾血管收缩。此外，肌红蛋白的血红素组分会诱导自由基的释放，进一步导致缺血性肾小管损伤 [9]。

Underlying etiologies of myoglobin casts include drugs of abuse (heroin, cocaine, opioids), infections [including human immunodeficiency virus (HIV)], bacterial sepsis, chemotherapy and immunosuppression (transplantation medicines, e.g. rapamycin), dehydration (intense exercise), malignant hypertension, trauma (surgery, traffic accidents) and myopathies [12] . The importance of making the correct diagnosis of rhabdomyolysis has prognostic implications. Full renal function recovery occurs in about half of the patients; the rest remain dialysis dependent or progress to CKD [9].
肌红蛋白管型的潜在病因包括滥用药物（海洛因、可卡因、阿片类药物）、感染 [包括人类免疫缺陷病毒 （HIV）]、细菌败血症、化疗和免疫抑制（移植药物，例如 雷帕霉素）、脱水（剧烈运动）、恶性高血压、创伤（手术、交通事故）和肌病 [12] .正确诊断横纹肌溶解症的重要性具有预后意义。大约一半的患者肾功能完全恢复;其余的仍然依赖透析或进展为 CKD [9]。

Hemoglobinuria and red blood cell casts, including Coumadin nephropathy and hemosiderosis
血红蛋白尿和红细胞管型，包括 Coumadin 肾病和含铁血黄素沉着症

Heme proteins can cause AKI via at least three mechanisms: direct cytotoxicity of released hemoglobin products, decreased renal perfusion and interaction of the intratubular hemoglobin with Tamm–Horsfall protein (hemoglobin casts). Free hemoglobin is bound to serum haptoglobin; when haptoglobin is saturated, free plasma hemoglobin dissociates to dimeric molecules that filter more easily through the glomeruli. Hemoglobin is taken up by the megalin–cubilin receptors on the apical surface of tubular epithelium and deposits into proximal tubules [9]. Intracellular hemoglobin dissociates into heme and globin and heme is degraded by heme oxygenase (HO). The inducible HO-1 isoform increases rapidly, accompanied by increased intracellular ferritin. These intracellular reactions lead to binding of iron to ferritin. Even though the response is aimed to diminish damage to cytoplasmic organelles, mitochondrial injury occurs by impairment of mitochondrial oxygenation. Tubular epithelial cell apoptosis, oxidative stress and release of pro-inflammatory cytokines follow. Other organs, such as the liver and lungs, are more likely to be affected because the hemoglobin–haptoglobin complex is too large to be filtered by the glomerulus. Therefore hemoglobin deposits rarely cause AKI.
血红素蛋白至少可通过三种机制引起 AKI：释放的血红蛋白产物的直接细胞毒性、肾灌注减少以及肾小管内血红蛋白与 Tamm-Horsfall 蛋白的相互作用（血红蛋白管型）。游离血红蛋白与血清结合珠蛋白结合;当结合珠蛋白饱和时，游离血浆血红蛋白解离成二聚体分子，这些分子更容易通过肾小球过滤。血红蛋白被肾小管上皮顶端表面的巨蛋白-肘蛋白受体吸收并沉积到近端肾小管中 [9]。细胞内血红蛋白解离成血红素和珠蛋白，血红素被血红素加氧酶 （HO） 降解。诱导型 HO-1 亚型迅速增加，伴随着细胞内铁蛋白的增加。这些细胞内反应导致铁与铁蛋白结合。尽管该反应旨在减少对细胞质细胞器的损伤，但线粒体损伤是由线粒体氧合受损引起的。随后是肾小管上皮细胞凋亡、氧化应激和促炎细胞因子的释放。其他器官，如肝脏和肺，更容易受到影响，因为血红蛋白-结合珠蛋白复合物太大，无法被肾小球过滤。因此，血红蛋白沉积很少引起 AKI。

On light microscopy, hemoglobin casts appear pale or granular and closely resemble myoglobin casts. Occasionally hemoglobin appears light brown. Immunohistochemistry with antibodies to hemoglobin is the only way to reliably distinguish from myoglobin casts (Figure 2D and E). Of note, renal biopsies with myoglobin-positive casts may also have evidence of hemolysis in the background. Intact red blood cells (RBCs) also stain with hemoglobin stain (internal control). Strenuous exercise, hemolysis secondary to infection (case shown in Figure 2D and E), incompatible blood transfusion and hematologic disorders are common causes of hemoglobinuria [13, 14]. Another reported cause of hemoglobinuria is transurethral prostate resection when distilled water is used as an irrigant [15].
在光学显微镜下，血红蛋白管型呈苍白或颗粒状，与肌红蛋白管型非常相似。血红蛋白偶尔呈浅棕色。使用血红蛋白抗体进行免疫组织化学是可靠地区分肌红蛋白管型的唯一方法（图 2D 和 E）。值得注意的是，肌红蛋白阳性管型的肾活检也可能有溶血的证据。完整的红细胞 （RBC） 也用血红蛋白染色（内部对照）染色。剧烈运动、继发于感染的溶血（病例如图 2D 和 E 所示）、血型不合和血液系统疾病是血红蛋白尿的常见原因 [13， 14]。血红蛋白尿的另一个报道原因是经尿道前列腺切除术，当时使用蒸馏水作为冲洗剂[15]。

Gross or microscopic hematuria manifested by large amounts of RBCs in the urine may cause ATI by tubular obstruction. Hematuric syndromes, e.g. IgA nephropathy (Figure 2F), or minimal change disease presenting with hematuria, vasculitis and anticoagulation are the most frequent causes of obstructive ATI caused by RBC casts.
尿液中大量红细胞表现为肉眼或镜下血尿，可通过肾小管梗阻引起 ATI。血染综合征，例如 IgA 肾病（图 2F），或表现为血尿、血管炎和抗凝治疗的微小病变疾病是红细胞管型引起的阻塞性 ATI 的最常见原因。

Anticoagulation nephropathy has potentially fatal consequences, particularly in patients with CKD. Clinical presentation with AKI is sometimes without overt creatinine changes, thus so-called warfarin nephropathy can be clinically overlooked. The incidence and severity were only recently recognized [16, 17]. Renal biopsy typically shows large numbers of intratubular RBC casts associated with tubular epithelial thinning, luminal dilation and loss of brush border (Figure 2G).
抗凝肾病具有潜在的致命后果，尤其是在 CKD 患者中。AKI 的临床表现有时没有明显的肌酐变化，因此临床上可以忽略所谓的华法林肾病。发病率和严重程度直到最近才被发现 [16， 17]。肾活检通常显示大量肾小管内红细胞管型，与肾小管上皮变薄、管腔扩张和刷状缘丧失有关（图 2G）。

Hemosiderosis is a known complication of chronic hemolytic anemias, including paroxysmal nocturnal hemoglobinuria, and mechanical cardiac valves with residual valvular regurgitation or perivalvular leak. ATI is due to hemosiderin, an iron storage complex. The breakdown of heme gives rise to biliverdin and iron. Released iron is trapped and stored as hemosiderin in tissues. Hemosiderin is also generated from the abnormal metabolic pathway of ferritin. With H&E, hemosiderin stains as brown and granular deposits within tubular epithelial cells. Prussian blue iron specifically stains hemosiderin deposits (Figure 2H). Additional causes of hemosiderosis include sepsis, iron overload as in hereditary hemochromatosis and multiple transfusions for sickle cell disease. Some cases of infectious hemosiderosis may be reversible. For example, while Clostridium difficile–induced hemolysis may be complicated by hemoglobinuria-induced ATI, rarely is hemosiderosis reported; these deposits may resolve with resolution of the infection [18]. Supratherapeutic doses of Coumadin and other blood thinners (e.g., dabigatran) should also be excluded in patients with artificial valves or heart disease since anticoagulation is routinely prescribed.
含铁血黄素沉着症是慢性溶血性贫血的一种已知并发症，包括阵发性睡眠性血红蛋白尿症和机械心脏瓣膜伴残余瓣膜反流或瓣周渗漏。ATI 是由含铁铁黄素（一种铁储存复合物）引起的。血红素的分解产生胆绿素和铁。释放的铁被捕获并作为含铁血黄素储存在组织中。含铁血黄素也是由铁蛋白的异常代谢途径产生的。使用 H&E，含铁血黄素在肾小管上皮细胞内染成棕色和颗粒状沉积物。普鲁士蓝铁专门染色含铁血黄素沉积物（图 2H）。含铁血黄素沉着症的其他原因包括败血症、遗传性血色素沉着症中的铁过载和镰状细胞病的多次输血。一些感染性含铁血黄素沉着症病例可能是可逆的。例如，虽然艰难梭菌诱导的溶血可能并发血红蛋白尿诱导的 ATI，但很少报道含铁血黄素沉着症;这些沉积物可能随着感染的消退而消退[18]。对于人工瓣膜或心脏病患者，也应排除超治疗剂量的香豆素和其他血液稀释剂（例如达比加群），因为常规开具抗凝治疗。

BILE CAST NEPHROPATHY (CHOLEMIC NEPHROSIS)
胆汁管型肾病（胆汁性肾病）

Bile cast nephropathy is an infrequent cause of ATI, typically observed in patients with liver disease and jaundice. There is a spectrum of histopathological findings in renal biopsies ranging from mild ATI to epithelial cell swelling and bile cast formation [19, 20]. The casts may vary in color from yellow to brown to green and stain dark green with Hall stain (Figure 2I). At autopsy of severely jaundiced patients, kidneys have a green discoloration. This is due to conversion of bilirubin to biliverdin after formalin fixation. Green streaks of bile casts may be seen grossly.
胆管型肾病是 ATI 的不常见原因，通常见于肝病和黄疸患者。肾活检的组织病理学发现范围从轻度 ATI 到上皮细胞肿胀和胆管型形成 [19， 20]。铸型的颜色可能从黄色到棕色再到绿色不等，并用霍尔染色染成深绿色（图 2I）。在对严重黄疸患者进行尸检时，肾脏呈绿色变色。这是由于福尔马林固定后胆红素转化为胆绿素。可能会粗略地看到胆管管型的绿色条纹。

Numerous hepatic disorders in children and adults including biliary cirrhosis (alcoholic cirrhosis in particular), bile duct atresia, nonalcoholic hepatitis, sclerosing cholangitis, shock liver, hepatotoxic drugs (including anabolic steroids), fulminant autoimmune hepatitis and intrahepatic malignancy can lead to bile cast nephropathy. Hepatic disease may cause prerenal, intrarenal and rarely postrenal ATI. The umbrella term ‘cholemic nephrosis’ is used to cover the spectrum of etiologies. Prerenal AKI is due to nonvolume responsive hepatorenal syndrome causing rapid renal failure in patients with acute or chronic renal failure. Most authors agree that bile casts require sustained liver disease and high levels of serum bilirubin. The term bile cast nephropathy is used when bile or bilirubin casts obstruct the nephrons, usually the distal tubules. Whether bilirubin itself causes direct injury to tubular epithelia or additional factors (vasoconstriction and volume depletion) contribute to precipitation of bile in the tubules is debated [21].
儿童和成人的许多肝脏疾病，包括胆汁性肝硬化（尤其是酒精性肝硬化）、胆管闭锁、非酒精性肝炎、硬化性胆管炎、休克肝、肝毒性药物（包括合成代谢类固醇）、暴发性自身免疫性肝炎和肝内恶性肿瘤，可导致胆管型肾病。肝脏疾病可导致肾前、肾内和罕见的肾后 ATI。“胆汁性肾病”这一总称用于涵盖一系列病因。肾前性 AKI 是由于非容量反应性肝肾综合征引起的急性或慢性肾功能衰竭患者的快速肾功能衰竭。大多数作者同意胆管管型需要持续的肝病和高水平的血清胆红素。当胆汁管型或胆红素管型阻塞肾单位（通常是远端肾小管）时，使用胆管型肾病一词。胆红素本身是直接损伤肾小管上皮细胞，还是其他因素（血管收缩和血容量不足）导致胆汁在肾小管中沉淀，目前尚存在争议[21]。

MYELOMA CAST NEPHROPATHY AND RELATED DISORDERS
骨髓瘤 CAST 肾病及相关疾病

About 50% of patients with multiple myeloma develop renal disease. AKI is increasingly recognized as the first presentation of multiple myeloma [22, 23]. The most common pathologic findings on renal biopsy are myeloma cast nephropathy, light chain proximal tubulopathy and light chain deposition disease (LCDD). Light microscopy can be unimpressive, but immunofluorescence is usually diagnostic. AKI complicating multiple myeloma is associated with worse 1-year survival and reduces the therapeutic options available to patients [22].
约 50% 的多发性骨髓瘤患者会发展为肾脏疾病。AKI 越来越被认为是多发性骨髓瘤的首发表现 [22， 23]。肾活检最常见的病理发现是骨髓瘤管型肾病、轻链近端肾小管病和轻链沉积病 （LCDD）。光学显微镜检查可能没有起到显著的作用，但免疫荧光通常具有诊断意义。AKI并发多发性骨髓瘤与较差的1年生存率相关，并减少了患者可用的治疗选择[22]。

Myeloma casts are typically periodic acid–Schiff (PAS) negative and appear as fractured or crackled paper-like proteinaceous deposits. Tubular casts are engulfed by giant cells or are admixed with inflammatory cells, sometimes mimicking acute pyelonephritis or interstitial nephritis (Figure 2J). Other times, paraprotein casts are devoid of an inflammatory component, are pale and translucent, mimicking rhabdomyolysis casts. Monoclonality is determined by immunofluorescence staining for kappa and lambda light chains. Tubular epithelial injury presents as epithelial simplification, epithelial cell necrosis or giant cell formation. Less frequently, paraproteins take the form of crystal deposits within tubular epithelium or in the lumen (with or without Fanconi syndrome) [24]. Light chain proximal tubulopathy (Figure 2K and L) is characterized by tubular epithelial cytoplasmic droplets staining with monoclonal light chains, either kappa or lambda [25, 26]. Light chain proximal tubulopathy may appear as generic ATI on light microscopy and, unless carefully examined and interpreted by experienced renal pathologists, can be easily overlooked. In the absence of ATI, monoclonal light chains within the tubular epithelium may alternatively represent physiologic proteinuria due to overproduction of a monoclonal light chain. A third pattern of myeloma injury is the so-called monoclonal light chain deposition disease, characterized by linear staining of the glomerular basement membranes, tubular basement membranes or both, with either kappa or lambda restriction by immunofluorescence. In rare cases, multiple myeloma pathologies involving the kidney (e.g. cast nephropathy and LCDD) are concurrently present (case shown in Figure 2 J–L) [27]. Additional pathologies such as plasma cell infiltrates and amyloidosis concurrent with cast nephropathy or other combinations are also possible. AKI is invariably in the background.
骨髓瘤管型通常为过碘酸-希夫 （PAS） 阴性，表现为断裂或裂纹纸状蛋白质沉积物。管型管型被巨细胞吞噬或与炎症细胞混合，有时类似于急性肾盂肾炎或间质性肾炎（图 2J）。其他时候，副蛋白管型没有炎症成分，苍白且半透明，类似于横纹肌溶解管型。通过 kappa 和 lambda 轻链的免疫荧光染色确定单克隆性。肾小管上皮损伤表现为上皮简化、上皮细胞坏死或巨细胞形成。较少见的是，副蛋白表现为肾小管上皮或管腔内的晶体沉积物（伴或不伴Fanconi综合征）[24]。轻链近端肾小管病（图 2K 和 L）的特征是肾小管上皮细胞质液滴染色有单克隆轻链，κ 或 λ [25， 26]。轻链近端肾小管病在光学显微镜下可能表现为一般性 ATI，除非由经验丰富的肾脏病理学家仔细检查和解释，否则很容易被忽视。在没有 ATI 的情况下，肾小管上皮内的单克隆轻链可能代表由于单克隆轻链过量产生的生理性蛋白尿。骨髓瘤损伤的第三种模式是所谓的单克隆轻链沉积病，其特征是肾小球基底膜、肾小管基底膜或两者的线性染色，免疫荧光抑制 kappa 或 lambda 限制。在极少数情况下，累及肾脏的多发性骨髓瘤病变（例如 管型肾病和 LCDD）同时存在（病例如图 2 J-L 所示）[27]。其他病理，例如浆细胞浸润和淀粉样变性，并发石型肾病或其他组合也是可能的。AKI 总是在后台。

HEMATOLOGIC MALIGNANCIES AND TUMOR LYSIS- AND LYSOZYME-INDUCED ATI
血液系统恶性肿瘤和肿瘤溶解和溶菌酶诱导的 ATI

About two-thirds of critically ill patients with hematological malignancies develop AKI at some point during the course of their disease or following treatment. AKI secondary to malignancy may manifest alongside malignant infiltrates involving the kidney parenchyma (malignant plasma cells, leukemia/lymphoma infiltrates) or be precipitated by tumor cell lysis. Hemodynamic compromise (ischemic ATI), chemotherapy-induced (toxic ATI) and tumor lysis syndrome are part of the spectrum of oncologic AKI [28].
大约 2/3 的血液系统恶性肿瘤危重患者在病程中或治疗后的某个时间点发生 AKI。继发于恶性肿瘤的 AKI 可能与累及肾实质的恶性浸润（恶性浆细胞、白血病/淋巴瘤浸润）一起出现，或由肿瘤细胞裂解诱发。血流动力学损害（缺血性 ATI）、化疗诱导的（中毒性 ATI）和肿瘤溶解综合征是肿瘤性 AKI 的一部分 [28]。

An exceptional type of ATI associated with malignancy is lysozyme nephropathy due to release of lysozyme from malignant cells [29, 30]. Lysozyme is produced in low levels by granulocytes, monocytes and histiocytes. In the kidney, it is stored in proximal tubules within lysosomes. The enzyme is excessively produced in pathologic conditions such as the myelomonocytic cells of chronic myelogenous leukemia (CML).
与恶性肿瘤相关的一种特殊类型的 ATI 是溶菌酶肾病，这是由于溶菌酶从恶性细胞中释放引起的 [29， 30]。溶菌酶由粒细胞、单核细胞和组织细胞以低水平产生。在肾脏中，它储存在溶酶体内的近端小管中。该酶在慢性粒细胞白血病 （CML） 的骨髓单核细胞等病理条件下过量产生。

It is also associated with high macrophage turnover and secretion of lysozyme in the serum (such as in patients with sarcoidosis). Lysozyme filters through the glomeruli and is absorbed by tubular epithelial cells, which hold high affinity for lysozyme. Plasma levels decrease after treatment of CML and perhaps other conditions so that lysozyme-induced AKI may not be clinically apparent or with blood tests. A renal biopsy may then be performed. The unique constellation of histopathological findings includes intensely eosinophilic and silver-negative protein droplets in proximal tubules. On electron microscopy, membrane-bound lysosomal inclusions are identified. Staining with lysozyme confirms the diagnosis (Figure 2M and N). Nonspecific staining for Congo red may be seen.
它还与高巨噬细胞更新率和血清中溶菌酶的分泌有关（例如在结节病患者中）。溶菌酶通过肾小球过滤并被肾小管上皮细胞吸收，肾小管上皮细胞对溶菌酶具有高亲和力。CML 治疗后血浆水平下降，可能还有其他疾病，因此溶菌酶诱导的 AKI 可能在临床上不明显，也可能无法进行血液检查。然后可以进行肾活检。独特的组织病理学发现包括近端肾小管中的强烈嗜酸性粒细胞和银阴性蛋白飞沫。在电子显微镜下，鉴定出膜结合的溶酶体包涵体。溶菌酶染色可确认诊断（图 2M 和 N）。可能可见刚果红的非特异性染色。

ISOMETRIC VACUOLIZATION, OSMOTIC NEPHROSIS, CONTRAST MEDIA AND MITOCHONDRIAL INJURY-INDUCED ATI
等长空泡化、渗透性肾病、造影剂和线粒体损伤诱导的 ATI

Isometric tubular vacuolization is a distinct form of ATI characterized by focal or diffuse bubbly appearing tubules (Figure 2O). The isometric-appearing vacuoles in most cases are due to swollen lysosomes (seen by electron microscopy) or swollen mitochondria (see below) [31]. This is typically an acute toxicity of calcineurin inhibitors (CNIs), particularly in renal allografts [32]. Cyclosporine, tacrolimus, intravenous IgG, dextran and osmotically active substances can cause similar pathology. Low-osmolar and iso-osmolar radiographic (contrast) media such as iotrolan and iodixanol (but also high-osmolality agents) cause intracellular vacuolization in tubular epithelial cells. It is hypothesized that these agents may interfere with physiologic protein reabsorption and are facilitated by hypoxia (patients with diabetes, atherosclerosis, CKD) [33]. The finding of isometric tubular vacuolization is nonspecific, but important to recognize, in order to prompt identification of a triggering agent and drug discontinuation, possibly reversing ATI. Recovery from the tubular injury will wean the patient off dialysis in many cases. The vacuoles may fade away or persist due to poorly understood mechanisms. Background disease such as diabetes and kidney ischemia may contribute to persistent vacuolization. Cyclosporine toxicity causes mitochondrial swelling (megamitochondria). Mitochondrial enlargement is responsible for the vacuolated cytoplasmic appearance as evidenced by electron microscopy. It was more common in the early era of cyclosporine therapy, but since regular drug monitoring was established, acute cyclosporine toxicity has become rare. The most common mitochondrial toxicity currently seen is with antiretroviral medications (tenofovir and related drugs) [34]. On renal biopsy, mitochondrial toxicity manifests with either isometric vacuolization or more rarely with giant mitochondria with abnormal cristae (dysmorphic), appearing as eosinophilic cytoplasmic inclusions in tubular epithelial cells on H&E (Figure 2P).
等长肾小管空泡化是 ATI 的一种独特形式，其特征是局灶性或弥漫性气泡状小管（图 2O）。大多数病例呈等长状空泡是由于溶酶体肿胀（通过电子显微镜观察）或线粒体肿胀（见下文）所致[31]。这通常是钙调磷酸酶抑制剂（calcineurin inhibitor， CNI）的急性毒性，尤其是在同种异体肾移植物中[32]。环孢菌素、他克莫司、静脉注射 IgG、右旋糖酐和渗透活性物质可引起类似的病理。低渗和等渗放射学（造影剂）介质，如碘罗兰和碘克沙醇（以及高渗剂）会导致肾小管上皮细胞的细胞内空泡化。据推测，这些药物可能会干扰生理性蛋白质重吸收，并因缺氧而促进（糖尿病、动脉粥样硬化、CKD 患者）[33]。等长肾小管空泡化的发现是非特异性的，但识别很重要，以便及时识别触发因素和停药，从而可能逆转 ATI。在许多情况下，从肾小管损伤中恢复将使患者停止透析。由于对机制知之甚少，液泡可能会消失或持续存在。糖尿病和肾缺血等背景疾病可能导致持续空泡化。环孢素中毒会导致线粒体肿胀（巨线粒体）。线粒体增大是导致空泡细胞质外观的原因，电子显微镜检查证明了这一点。在环孢素治疗的早期更为常见，但自从建立了定期药物监测后，急性环孢素毒性已变得罕见。 目前最常见的线粒体毒性是抗逆转录病毒药物（替诺福韦和相关药物）[34]。在肾活检中，线粒体毒性表现为等长空泡化，或者更罕见地表现为巨大线粒体伴异常嵴（畸形），表现为嗜酸性细胞质包涵体在肾小管上皮细胞中（图 2P）。

ATI ASSOCIATED WITH CRYSTALLOPATHIES
ATI 与晶体病相关

Calcium oxalate is the most common type of crystal nephropathy on renal biopsy (Helen Liapis,unpublished results). The extent of oxalate crystals varies from a few foci to massive amounts. Acute presentation shows colorless crystals in tubules and/or the interstitium associated with varying degrees of tubular injury, usually ATI without necrosis. Oxalate crystals, colorless on H&E, polarize under dark-field microscopy (Figure 2Q and R). Under normal conditions, calcium and oxalate form a complex in the colon and are excreted in the feces. In the absence of or with reduced luminal calcium, free oxalate increases, leading to enhanced absorption by the colonic epithelium and ultimately calcium oxalate crystals deposit in the kidney. Fat and/or bile acid malabsorption also facilitate oxalate uptake by colonic epithelial cells.
草酸钙是肾活检中最常见的晶体肾病类型（Helen Liapis，未发表的结果）。草酸盐晶体的范围从几个病灶到大量不等。急性表现显示小管和/或间质中的无色晶体，与不同程度的肾小管损伤相关，通常为 ATI 无坏死。草酸盐晶体，在 H&E 上无色，在暗场显微镜下偏振（图 2Q 和 R）。在正常情况下，钙和草酸盐在结肠中形成复合物，并通过粪便排泄。在缺乏或减少管腔钙的情况下，游离草酸盐增加，导致结肠上皮吸收增强，最终草酸钙晶体沉积在肾脏中。脂肪和/或胆汁酸吸收不良也促进结肠上皮细胞对草酸盐的摄取。

Entities leading to renal oxalosis include enteric hyperoxaluria (e.g. Crohn’s disease, celiac sprue, pancreatic insufficiency, gastric/small intestine bypass or resection, chronic pancreatitis or malabsorption syndromes), vitamin B6 deficiency, ethylene glycol toxicity, excess ingestion of vitamin C, a plethora of dietary products rich in oxalic acid (e.g. dark leafy vegetables, rhubarb, star fruit, tea, spinach, sesame seeds, almonds, beets, buckwheat flour, chocolate soy milk; www.OHF.org/docs/Oxalate2008.pdf), hereditary hyperoxalurias and ATI itself (Table 1). Other risk factors include the absence of enteric oxalate-degrading bacteria (i.e. Oxalobacter formigenes), aspergillosis and drugs (Orlistat, Praxilene). The insults can be irreversible and may be fatal in a fraction of patients [35, 36].
导致肾性草酸中毒的实体包括肠道高草酸尿症（例如 克罗恩病、乳糜泻、胰腺功能不全、胃/小肠旁路或切除术、慢性胰腺炎或吸收不良综合征）、维生素 B6 缺乏症、乙二醇中毒、过量摄入维生素 C、大量富含草酸的膳食产品（例如深色叶蔬菜、大黄、杨桃、茶、菠菜、芝麻、 杏仁、甜菜、荞麦粉、巧克力豆浆;www.OHF.org/docs/Oxalate2008.pdf）、遗传性高草酸尿症和 ATI 本身（表 1）。其他风险因素包括缺乏肠道草酸盐降解细菌（即 产酸草酸杆菌）、曲霉病和药物（奥利司他、普拉西林）。这种侮辱可能是不可逆的，并且在一小部分患者中可能是致命的[35,36]。

In transplant renal biopsies, secondary causes of renal oxalosis include prolonged tubular injury, chronic pancreatic allograft rejection in kidney–pancreas recipients, hypocitraturia secondary to CNIs and mycophenolate mofetil (MMF)-induced malabsorption syndrome secondary to prolonged diarrhea. The anesthetic methoxyflurane is also reported to cause AKI secondary to oxalate nephropathy.
在移植肾活检中，肾草酸中毒的继发性原因包括长期肾小管损伤、肾胰受者慢性同种异体移植物排斥反应、继发于 CNI 的低枸杞酸尿症和继发于长期腹泻的吗替麦考酚酯 （MMF） 诱导的吸收不良综合征。据报道，麻醉剂甲氧氟烷也可引起继发于草酸盐肾病的 AKI。

Other drugs can cause ATI with unique crystalline deposits beyond oxalate; for example, indinavir (not shown here).
其他药物可引起 ATI，除草酸盐外，还存在独特的结晶沉积物;例如，Indinavir（此处未显示）。

Calcium phosphate is the second most common crystallopathy seen on renal biopsy. The deposits are usually focal and stain blue on H&E (Figure 2S) and black with von Kossa stain. Heavy deposits (nephrocalcinosis) are seen with primary or secondary hypercalcemia, including sarcoidosis, vitamin D intoxication, milk-alkali syndrome, ingestion of phosphate-containing medications [antacids, soft drinks, bowel preparations (e.g. oral sodium phosphate)—also called phosphate nephropathy] and stone disease [37]. Once again, drugs may be the culprit causing phosphate crystal deposits (bisphosphonates, ganciclovir and others).
磷酸钙是肾活检中第二常见的晶体病。沉积物通常是焦点的，在 H&E 上呈蓝色（图 2S），黑色带有 von Kossa 染色。原发性或继发性高钙血症可见大量沉积物（肾钙质沉着症），包括结节病、维生素 D 中毒、乳碱综合征、摄入含磷酸盐的药物 [抗酸剂、软饮料、肠道制剂（如口服磷酸钠）——也称为磷酸盐肾病]和结石病 [37]。再一次，药物可能是导致磷酸盐晶体沉积的罪魁祸首（双膦酸盐、更昔洛韦等）。

Some unique causes of crystal deposition associated with AKI will be briefly mentioned here. These include cholesterol embolism presenting with AKI and cystinosis, a defective transport of cystine across lysosomal membranes resulting in systemic accumulation of cystine crystals, including in the kidney (glomeruli, tubules and interstitium). Cysteine crystals are difficult to identify in tissue because they dissolve during formalin processing.
这里将简要提及与 AKI 相关的晶体沉积的一些独特原因。这些包括表现为 AKI 和胱氨酸病的胆固醇栓塞，胱氨酸跨溶酶体膜的转运缺陷导致胱氨酸晶体的全身积累，包括在肾脏（肾小球、肾小管和间质）中。半胱氨酸晶体很难在组织中识别，因为它们在福尔马林加工过程中会溶解。

Cholesterol crystals appear as empty spindle-shaped spaces (clefts) within vascular lumens surrounded by inflammatory cells. AKI and diffuse ATI are invariably present.
胆固醇晶体表现为血管腔内被炎症细胞包围的空纺锤形空间（裂隙）。AKI 和弥漫性 ATI 始终存在。

The mechanisms of crystallopathy-associated AKI remains an enigma [38, 39]. The fate of crystal deposition may be dependent on recruitment of phagocytes enabling crystal clearance from the interstitium, while intratubular deposits may dissolve or clear with urinary flow. Studies show that renal crystal deposits may be a transient phenomenon and disappear at a later time. For example, in rat and human kidneys, calcium oxalate and calcium phosphate crystals translocate into the interstitial space where infiltrating mononuclear cells contribute to crystal disintegration and clearance [36–38]. Recently the NLRP3 inflammasome was shown to trigger inflammation and AKI in oxalate nephropathy, raising the hypothesis of innate immunity possibly involved in this and other crystallopathies [38]. Resolution of inflammation and crystal removal may halt the deleterious chronic effects of crystal deposition within the kidney. There is clinical evidence from AKI recovery in humans that repair of injury is possible via a macrophage phenotype switch toward anti-inflammatory M2 macrophages [39].
晶体病相关AKI的机制仍然是一个谜[38,39]。 晶体沉积的命运可能取决于吞噬细胞的募集，使晶体能够从间质中清除，而肾小管内沉积物可能随着尿流溶解或清除。研究表明，肾晶体沉积可能是一种短暂现象，并在以后消失。例如，在大鼠和人类肾脏中，草酸钙和磷酸钙晶体转移到间质空间，浸润的单核细胞有助于晶体的崩解和清除[36–38]。最近，NLRP3 炎性小体被证明可在草酸盐肾病中触发炎症和 AKI，这提出了先天免疫可能与这种疾病和其他晶体病有关的假设 [38]。炎症的消退和晶体的去除可能会阻止肾脏内晶体沉积的有害慢性影响。人类 AKI 恢复的临床证据表明，可以通过巨噬细胞表型转变为抗炎 M2 巨噬细胞来修复损伤 [39]。

AKI due to adenine phosphoribosyltransferase (APRT) deficiency is characterized by excessive production of 2,8-dihydroxyadenine (DHA). This is an autosomal recessive disorder due to complete loss of APRT. It manifests with AKI episodes, progressive CKD and nephrolithiasis. Renal biopsy reveals round, brown DHA crystals that polarize, mimicking oxalate. The diagnosis is confirmed by the absence of APRT enzyme activity in red cell lysates or identification of biallelic pathogenic variants. A low-purine diet, ample fluid intake and allopurinol therapy improve outcomes [40, 41].
腺嘌磷酸核糖转移酶 （APRT） 缺陷引起的 AKI 的特征是 2,8-二羟基腺嘌呤 （DHA） 的过量产生。这是由于 APRT 完全丢失引起的常染色体隐性遗传病。表现为 AKI 发作、进行性 CKD 和肾结石。肾活检显示圆形、棕色的 DHA 晶体，极化，类似于草酸盐。通过红细胞裂解物中不存在 APRT 酶活性或鉴定双等位基因致病性变异来确诊。低嘌呤饮食、充足的液体摄入和别嘌呤醇治疗可改善结局 [40， 41]。

Acute uric acid nephropathy typically presents with oliguric or anuric AKI and is most frequently associated with massive tumor lysis [42]. The chronic effects of uric acid nephropathy are known for granuloma formation (gouty nephropathy) and interstitial fibrosis.
急性尿酸性肾病通常表现为少尿性或无尿性AKI，最常与大量肿瘤溶解相关[42]。尿酸肾病的慢性影响以肉芽肿形成（痛风肾病）和间质纤维化而闻名。

INFECTION–RELATED AKI 感染相关 AKI

Infections can cause obstructive AKI and ATI/ATN through white cell tubular cast formation or direct invasion of the microorganisms into the tubular epithelia. An associated interstitial nephritis is invariably present [35]. Examples include ATI in the setting of polyomavirus, cytomegalovirus, coronaviruses (including influenza and coronavirus disease 2019 (COVID-19) or adenovirus nephropathy in transplant or immunocompromised patients (Table 1) [43].
感染可通过白细胞肾小管管型形成或微生物直接侵入肾小管上皮细胞引起梗阻性 AKI 和 ATI/ATN。总是存在相关的间质性肾炎[35]。例如，多瘤病毒、巨细胞病毒、冠状病毒（包括流感和COVID-19）或移植或免疫功能低下患者出现腺病毒肾病的ATI（表 1）[43]。

TMA ASSOCIATED WITH ATYPICAL HEMOLYTIC SYNDROME SYNDROMES, ANTIPHOSPHOLIPID SYNDROME, PREECLAMPSIA, DRUG TOXICITY
TMA 与非典型溶血综合征综合征、抗磷脂综合征、子痫前期、药物毒性相关

TMAs are life-threatening entities and have characteristic pathology of thrombi involving glomerular capillaries and/or arterioles (Figure 2T). Clinically, severe AKI is a frequent presenting symptom, while thrombocytopenia, peripheral schistocytes, elevated lactate dehydrogenase and decreased haptoglobin may be nondiagnostic. causing atypical hemolytic syndrome (aHUS). Antiphospholipid syndrome falls in the category of aHUS and on renal biopsy the findings range from subcortical necrosis to focal TMA. Renal biopsy pathology explains the acute presentation, demonstrating hemorrhagic ATN in severe cases or diffuse ATI adjacent to ‘focal’ thrombotic lesions. The emphasis here is on focal TMA manifesting either as single glomerular capillary thrombosis or endothelial swelling and narrowing of the arterioles, sometimes lacking bona fide thrombi. The main injury in TMA is endothelial and ATI is secondary to ischemia and RBC lysis. Mural fragmented RBCs in small arterioles may be present, but these are sufficient for histopathologic diagnosis of TMA. Preeclampsia, postpartum TMA and other causes of aHUS during or after pregnancy have emerged as significant AKI causes, frequently and definitively diagnosed best with renal biopsy. The nephrologists’ reaction to the renal biopsy findings in these cases, typically young women, may be surprise, followed by ambiguity regarding appropriate and immediate potentially lifesaving patient management [44]. This complex clinical setting requires both hematology and nephrology consultation.
TMA 是危及生命的实体，具有涉及肾小球毛细血管和/或小动脉的血栓特征病理（图 2T）。临床上，重度 AKI 是一种常见的首发症状，而血小板减少、外周裂红细胞、乳酸脱氢酶升高和结合珠蛋白降低可能无诊断意义。引起非典型溶血综合征 （aHUS）。抗磷脂综合征属于 aHUS 类别，肾活检发现范围从皮质下坏死到局灶性 TMA。肾活检病理学解释了急性表现，严重病例显示出血性 ATN 或“局灶性”血栓性病变附近的弥漫性 ATI。这里的重点是局灶性 TMA，表现为单肾小球毛细血管血栓形成或小动脉内皮肿胀和狭窄，有时缺乏真正的血栓。TMA 的主要损伤是内皮损伤，而 ATI 继发于缺血和 RBC 溶解。小动脉中可能存在壁状碎片红细胞，但这些足以对 TMA 的组织病理学诊断。子痫前期、产后 TMA 和妊娠期间或妊娠后 aHUS 的其他原因已成为重要的 AKI 原因，通常最好通过肾活检进行明确诊断。在这些病例中，肾病科医生对肾活检结果的反应可能是意外的，然后对适当和立即可能挽救生命的患者管理感到模糊[44]。这种复杂的临床环境需要血液学和肾脏病学会诊。

The current COVID-19 pandemic brought to light the deleterious effects of viruses to endothelia, manifesting in the kidney as TMA, but also systemically (e.g. strokes) [45].
当前的 COVID-19 大流行揭示了病毒对内皮细胞的有害影响，在肾脏中表现为 TMA，但也表现为全身性（例如中风）[45]。

Last but not least, chemotherapy agents and monoclonal antibodies, e.g. immune checkpoint inhibitors, that target inhibitory receptors expressed on T cells and currently used for solid tumors or hematologic malignances are increasingly reported as causes of TMA-induced AKI. Other side effects to explain AKI in such patients include interstitial nephritis and generic ATI [46].
最后但并非最不重要的一点是，化疗药物和单克隆抗体，例如 免疫检查点抑制剂，靶向 T 细胞上表达的抑制性受体，目前用于实体瘤或血液系统恶性肿瘤，越来越多地报道为 TMA 诱导的 AKI 的原因。解释这类患者AKI的其他副作用包括间质性肾炎和通用性ATI[46]。

AKI pathophysiology AKI 病理生理学

An increased understanding of the pathophysiology underlying AKI was revealed in the last few decades through molecular and animal studies that show oxidative stress [47], endothelial injury [48], mitochondrial injury (best described in the HIV) population treated with antiretroviral medications] [49] and innate immunity as central mechanisms [50], discussed briefly below.
在过去的几十年里，通过分子和动物研究揭示了对 AKI 病理生理学的理解增加，这些研究表明氧化应激 [47]、内皮损伤 [48]、接受抗逆转录病毒药物治疗的线粒体损伤（在 HIV 中描述最好）人群 [49] 和先天免疫是核心机制 [50]，下文将简要讨论。

AKI, previously thought to be a relatively benign process without significant long-term sequelae, is now considered a long-term risk factor for CKD, particularly in older patients with coexisting comorbidities, particularly sepsis, affecting 40–70% of patients in the ICU [51, 52].
AKI 以前被认为是一个相对良性的过程，没有明显的长期后遗症，现在被认为是 CKD 的长期危险因素，特别是对于合并症的老年患者，尤其是脓毒症，影响了 ICU 中 40-70% 的患者 [51， 52]。

Therapeutic or illicit drugs and toxins represent external insults. Numerous drugs can cause ATI/ATN. The most common are antibiotics (e.g. vancomycin), chemotherapeutics, angiotensin-converting enzyme inhibitors, lithium and over-the-counter supplements. Similar patterns of tubular injury have been reported in association with illicit drugs such as opioids and synthetic cannabinoids (Spice, K2, etc.) [49, 53–55]. Drugs are such a common cause of ATI/ATN that, above and beyond any other causes, drug exposure should first and foremost be clinically excluded.
治疗性或非法药物和毒素代表外部侮辱。许多药物可引起 ATI/ATN。最常见的是抗生素（例如万古霉素）、化疗药物、血管紧张素转换酶抑制剂、锂和非处方补充剂。据报道，与阿片类药物和合成大麻素（Spice、K2 等）等非法药物相关的类似肾小管损伤模式也存在。[49， 53–55]。药物是 ATI/ATN 的常见原因，因此，除了任何其他原因之外，首先应在临床上排除药物暴露。

Interesting mechanisms of infection-induced ischemic AKI continue to be found. For example, neutrophil extracellular traps damage the kidney through neutrophil arginine deiminase 4 [56, 57].
感染诱导的缺血性 AKI 的有趣机制不断被发现。例如，中性粒细胞胞外陷阱通过中性粒细胞精氨酸脱亚胺酶4 [56， 57]。

Animal models of AKI AKI 的动物模型

A significant amount of research has been directed at investigating AKI pathophysiology and developing AKI therapeutics in animal models [58, 59]. However, none of these therapies have translated into clinical care to date. One of the most widely used animal models of AKI is the ischemia–reperfusion model. A warm ischemia–reperfusion study is typically performed by unilateral or bilateral clamping of the renal vasculature for 30–45 min followed by reperfusion for 1–2 days [59, 60]. This model was extensively studied in pigs, dogs, rabbits, rats and mice. Toxin exposure is a known cause of AKI and has been used to study AKI pathophysiology in vivo. Cisplatin, folic acid, aristolochic acid and warfarin are common nephrotoxins utilized to induce AKI in animal models [51–65]. Rhabdomyolysis is a specific clinical condition that may be reproduced in animals using a glycerol model of AKI. Glycerol injected into the hind leg muscles of rats produces rapid AKI and rhabdomyolysis [66, 67]. The unilateral ureteral obstruction model is a reproducible animal model whereby a single ureter is ligated, resulting in mechanical stress and inflammation in one kidney. This model is used to study the AKI to CKD transition. Sepsis is another well-documented cause of AKI [51, 68]. Studying this process in animals may be performed by lipopolysaccharide injection or by using the more clinically relevant cecal ligation and puncture (CLP) model [69, 70]. Although the CLP model is more typical of the human condition, it is less reproducible and more technically challenging. Animal models are a useful tool to investigate the pathophysiology of AKI. However, the dearth of new clinically useful therapeutics developed using these animal models highlights the disconnect between human clinical AKI and preclinical studies. This underscores the point that clinical AKI in humans is a diverse process with multiple etiologies and varying pathophysiology such that single treatment options are unlikely to prove effective.
大量研究已针对调查 AKI 病理生理学和在动物模型中开发 AKI 疗法 [58， 59]。然而，迄今为止，这些疗法都没有转化为临床护理。最广泛使用的 AKI 动物模型之一是缺血再灌注模型。温缺血再灌注研究通常通过单侧或双侧夹住肾血管系统30-45分钟，然后再灌注1-2天进行[59,60]。 该模型在猪、狗、兔、大鼠和小鼠中进行了广泛研究。毒素暴露是 AKI 的已知原因，已用于研究体内 AKI 的病理生理学。顺铂、叶酸、马兜铃酸和华法林是动物模型中用于诱导AKI的常见肾毒素[51–65]。横纹肌溶解症是一种特定的临床病症，可以使用 AKI 的甘油模型在动物中重现。将甘油注射到大鼠的后腿肌肉中会产生快速的 AKI 和横纹肌溶解症 [66， 67]。单侧输尿管梗阻模型是一种可重复的动物模型，其中结扎了单个输尿管，导致一个肾脏出现机械应力和炎症。该模型用于研究 AKI 到 CKD 的转变。脓毒症是AKI的另一个有据可查的原因[51,68]。 在动物中研究这一过程可以通过注射脂多糖或使用更具临床相关性的盲肠结扎穿刺 （CLP） 模型进行 [69， 70]。尽管 CLP 模型更典型地反映了人类状况，但它的可重复性较低，并且在技术上更具挑战性。 动物模型是研究 AKI 病理生理学的有用工具。然而，使用这些动物模型开发的临床有用新疗法的缺乏凸显了人类临床 AKI 和临床前研究之间的脱节。这强调了人类临床 AKI 是一个多样化的过程，具有多种病因和不同的病理生理学，因此单一的治疗方案不太可能被证明有效。

AKI biomarkers AKI 生物标志物

Current clinical practice utilizes serum creatinine and urine output to identify patients with AKI, regardless of the underlying etiology. A significant achievement has been standardizing AKI diagnostic criteria by the KDIGO [5, 71, 72]. Serum creatinine may not increase until days following injury, may change in cases without structural kidney damage and may not change despite injury in patients with significant renal reserve [73–75]. Due to these known imperfections, a troponin-like biomarker for AKI is desired. The hope is to facilitate early diagnosis in order to implement current management strategies aimed at preventing further injury. Earlier diagnosis may facilitate reexamination of therapeutics that previously failed clinical trials, possibly due to delayed treatment using creatinine for therapeutic initiation.
目前的临床实践利用血清肌酐和尿量来识别 AKI 患者，而不管潜在的病因如何。一项重大成就是 KDIGO 对 AKI 诊断标准进行了标准化 [5， 71， 72]。血清肌酐在受伤后几天内可能不会增加，在没有结构性肾损伤的情况下可能会发生变化，而在肾储备显著的患者中，即使受伤也可能不会发生变化 [73–75]。由于这些已知的缺陷，需要一种 AKI 的肌钙蛋白样生物标志物。希望促进早期诊断，以便实施旨在防止进一步伤害的当前管理策略。早期诊断可能有助于重新检查以前临床试验失败的治疗，这可能是由于使用肌酐开始治疗延迟。

The last decade has seen a significant effort to identify sensitive and specific urine and plasma AKI biomarkers. AKI biomarkers may be functional (cystatin C), related to damage (myo-inositol oxygenase, N-acetyl-β-glucosaminidase, glutathione S-transferase, alkaline phosphatase), inflammatory (interleukins-18, -6, -10 and -5), upregulated in the proximal tubule following injury (KIM-1), upregulated in the distal tubule following injury (neutrophil gelatinase–associated lipocalin) or cell cycle arrest indicators (tissue inhibitor metalloproteinase-2 and insulin-like growth factor binding protein-7) [76, 77]. Despite extensive research and development of standardized assays for some biomarkers, AKI biomarkers have predominantly been restricted to research use and have not yet permeated clinical practice. One reason for this discrepancy is the use of creatinine as a flawed gold standard for biomarker qualification [76]. Another drawback is their lack of specificity for renal disease [7]. One biomarker, myo-inositol oxygenase, is reportedly restricted to renal tissue and shows promise as a renal-specific proximal tubular damage indicator but has yet to undergo significant investigation [76]. Utilizing other criteria such as need for dialysis and mortality has helped to identify biomarkers that complement clinical assessment [78–80]. Despite these shortcomings, recent studies indicate a possible role for biomarkers in discriminating true AKI from prerenal azotemia, hepatorenal syndrome and cardiorenal syndrome [78]. Future studies will need to assess the ability of AKI biomarkers to improve patient outcomes in order to be widely adopted in clinical practice [77].
过去十年来，人们在鉴定敏感和特异性尿液和血浆 AKI 生物标志物方面做出了重大努力。AKI 生物标志物可能是功能性的（胱抑素 C），与损伤（肌醇加氧酶、N-乙酰-β-氨基葡萄糖苷酶、谷胱甘肽 S-转移酶、碱性磷酸酶）、炎症（白细胞介素-18、-6、-10 和 -5）有关，损伤后在近端肾小管中上调 （KIM-1），在损伤后远端肾小管中上调（中性粒细胞明胶酶相关脂质运载蛋白）或细胞周期停滞指标（组织抑制剂金属蛋白酶-2 和胰岛素样生长因子结合蛋白-7）[76， 77]。尽管对某些生物标志物的标准化检测进行了广泛的研究和开发，但 AKI 生物标志物主要局限于研究使用，尚未渗透到临床实践中。造成这种差异的一个原因是，肌酐作为生物标志物鉴定的金标准存在缺陷[76]。另一个缺点是它们对肾脏疾病缺乏特异性 [7]。据报道，一种生物标志物肌醇加氧酶仅限于肾组织，有望成为肾脏特异性近端肾小管损伤指标，但尚未进行重大研究[76]。利用其他标准，如透析需求和死亡率，有助于确定补充临床评估的生物标志物[78–80]。尽管存在这些缺点，但最近的研究表明，生物标志物可能在区分真性 AKI 与肾前性氮质血症、肝肾综合征和心肾综合征方面发挥作用 [78]。未来的研究需要评估 AKI 生物标志物改善患者预后的能力，以便在临床实践中得到广泛采用 [77]。

CONCLUSIONS 结论

The pathology of AKI is as diverse as the entities causing it. Renal biopsy illuminates this diversity and provides specific diagnoses using available immunohistochemical or histochemical stains to complement routine pathologic evaluation. Interpretation and effective consultation require highly skilled and sophisticated renal pathologists and clear communication with the treating nephrologists. Renal biopsy pathology is frequently the fastest and most accurate procedure in determining the specific cause of AKI, as shown below. Furthermore, in spite of the existing clinical AKI criteria and worldwide validation, there is still inconsistency in the application of criteria confounded by the limitations of serum creatinine and urine output as AKI biomarkers.
AKI 的病理学与导致它的实体一样多样化。肾活检阐明了这种多样性，并使用现有的免疫组织化学或组织化学染色提供特异性诊断，以补充常规病理评估。口译和有效会诊需要技术娴熟、经验丰富的肾脏病理学家，并与治疗肾病学家进行清晰的沟通。肾活检病理学通常是确定 AKI 具体原因的最快、最准确的程序，如下所示。此外，尽管已有临床 AKI 标准和全球验证，但由于血清肌酐和尿量作为 AKI 生物标志物的限制，标准的应用仍然存在不一致。

CONFLICT OF INTEREST STATEMENT
利益冲突声明

None declared. The results presented in this article have not been published previously in whole or part, except in abstract format.
没有人宣布。本文中介绍的结果以前没有全部或部分发表过，只是以摘要形式发表。

REFERENCES 引用