皮肤和肾小球血管病变

王帆

皮肤和肾小球血管病变

目前我们知道什么?

Cutaneous and Renal Glomerular Vasculopathy

What Do We Know so Far?

作者：

Rosanne E. Jepson, BVSc, MVetMed, PhD, FHEA, MRCVSa,*,

Jacqueline M. Cardwell, MA, VetMB, MScVetEd, PhD, FHEA, MRCVSb,

Stefano Cortellini, DMV, MVetMed, FHEA, MRCVSa,

Laura Holm, BVM&S, CertSAM, MRCVSc,

Kim Stevens, PhD, MScAgric, PGCAPb, David Walker, MRCVSc

翻译：王帆

关键词

•皮肤和肾小球血管病变•血栓性微血管病变•特发性肾小球血管病变•急性肾损伤•皮肤病变

重点

•皮肤型肾小球血管病变是一种导致血栓性微血管病变的疾病，自2012年以来在英国的发病率明显上升。

•迄今尚未确定感染原因。

•病例的临床进展通常包括存在溃疡性皮肤病变，通常病变部位在四肢远端，随后出现少尿型急性肾损伤。然而，该病患病个体亚临床表现很少有严重表现。

•患有急性少尿型肾功能衰竭的犬的死亡率非常高，然而有报道称少数犬能在重症监护下存活。

KEYWORDS

•CRGV
• Thrombotic microangiopathy
•Alabama rot
•Acute kidney injury
•Skin lesion

KEY POINTS

•Cutaneous renal glomerular vasculopathy is a condition resulting in thrombotic microangiopathy recognized with apparently increasing prevalence in the United Kingdom since 2012.

•An infectious cause has not been identified to date.

•Clinical progression of cases usually involves identification of ulcerated skin lesions, typically affecting the distal limb and progression to oligoanuric acute kidney injury. However, subclinical manifestations of this condition with less severely affected individuals are thought to occur.
•Mortalities for dogs that develop oligoanuric acute renal failure are very high, although a limited number of dogs have been reported to survive with intensive supportive care.

介绍

INTRODUCTION

皮肤型肾小球血管病变(CRGV)或俗称“阿拉巴马病”，自2012年以来在英国得到了越来越多的认可。这种情况的发病机制尚不完全清楚。虽然对已确诊病例进行了推测和初步的传染病检测，但是尚未确定感染原因。然而，病变分布的年代、诊断测试和样本数量少是其限制性因素。此病引起了广泛的关注，因为据报道，发展为急性少尿性肾功能衰竭的CRGV患犬死亡率很高。由于缺乏明确的尸检诊断检查，仅凭肾组织病理学来确诊此病，这意味着CRGV在犬中真实的流行性和发病率仍然未知。为了更好地了解CRGV的流行病学，明确个体差异、遗传因素、环境因素或传染性对犬发生CRGV的患病风险的影响，还需要进一步调查。最终，只有更好理解CRGV的发病机制，才能开发出有助于进行早期诊断和提高生存率的诊断测试。

Cutaneous renal glomerular vasculopathy (CRGV) or the condition that has colloquially been termed “Alabama rot” has been recognized with apparently increasing frequency in the United Kingdom since 2012. The etiopathogenesis of this condition remains incompletely understood. Despite speculation and preliminary infectious disease testing of confirmed cases, an infectious cause has not been identified. However, the chronology of presentation, diagnostic testing, and small sample size are limiting factors. The condition has gained much attention because of the high mortality reported in dogs that develop oligoanuric acute renal failure associated with CRGV. Lack of a definitive antemortem diagnostic test and reliance on renal histopathology for confirmation of this condition mean that the true prevalence and incidence of CRGV within the canine population remains unknown. Continued work is required to better understand the epidemiology of CRGV and to explore individual, genetic, environmental, or infectious associations that underpin the risk of dogs developing CRGV. Ultimately it is likely that only through a better understanding of the pathogenesis of CRGV, that diagnostic tests can be developed that may facilitate early diagnosis and intervention that improves survival.

皮肤型肾小球血管病变和“阿拉巴马”病的病史调查

HISTORY OF CUTANEOUS RENAL GLOMERULAR VASCULOPATHY AND “ALABAMA ROT”

在20世纪80年代末，在美国兽医文献中首次报道了灵缇犬的与CRGV相似的疾病。这些病例与皮肤病变和急性肾损伤(AKI)均有不同程度的相关性，且其潜在病因尚不明确。自2012年以来，英国已经认可了CRGV的一种形式。目前尚不清楚这些英国病例的病因是否与以往病例相同，但病例的临床表现和组织病理学表现相似。CRGV患犬通常表现为溃疡性皮肤病变，在出现皮肤病变后平均4天发生AKI。在犬上很少报道出现皮肤病变表现，伴有其他病因的AKI使CRGV患犬临床表现很独特。所有CRGV患犬的组织病理学常见表现是肾组织血栓性微血管病变(TMA)。犬TMA的鉴别诊断包括CRGV和溶血性尿毒症(HUS)。此前曾有5只犬出现过HUS症状，包括几种不同的犬种，如约克夏㹴、迷你贵宾犬、拉布拉多犬和德国牧羊犬。在文献报道的溶血性尿毒综合征病例中，没有皮肤病变的报道。

Conditions compatible with CRGV were first reported in the veterinary literature in greyhounds from the United States in the late 1980s. These cases were variably associated with both skin lesions and acute kidney injury (AKI), and an underlying cause was not identified. Since 2012, a form of CRGV has been recognized in the United Kingdom. It is unclear whether the cause for these UK cases is the same as historical cases, but the clinical progression of cases and histopathologic manifestations are similar. Dogs that develop CRGV commonly present with ulcerated skin lesions, with development of AKI a median of 4 days after skin lesions are noted.The presence of skin lesions is rarely reported in dogs, with other causes of AKI making the clinical presentation of dogs with CRGV unique. The common feature of all dogs with CRGV is the histopathologic finding of thrombotic microangiopathy (TMA) in renal tissue. Differential diagnoses for TMA in dogs include CRGV but also hemolytic uremic syndrome (HUS). HUS has previously been reported in 5 dogs, including several different breeds, such as the Yorkshire terrier, miniature poodle, Labrador retriever, and German shepherd dog. Of the HUS cases reported in the literature, skin lesions were not reported.

人血栓性微血管病变

THROMBOTIC MICROANGIOPATHIES IN HUMANS

TMA是一个术语，用来描述内皮细胞损伤和微血管内血栓形成的病理过程，高压导致血小板聚集，血小板减少，红细胞破裂，导致微血管溶血性贫血。这些特征会导致缺血和梗死，尤其会影响肾脏。TMA是一种组织病理学诊断，其特征可在几种特定临床疾病中存在，包括溶血性尿毒症(HUS)、非典型溶血性尿毒症综合征(a-HUS)和血栓性血小板减少性紫癜(TTP)。TMA可能与潜在疾病相关，如恶性肿瘤、化疗和其他药物的使用、器官移植、败血症和弥漫性血管内凝血。

TMA is a term used to describe a pathologic process that includes endothelial damage and thrombosis within the microvasculature, with high stress leading to platelet aggregation, a consumptive thrombocytopenia, and red cell shearing, resulting in a microangiopathic hemolytic anemia. These features lead to ischemia and infarction, which particularly affect the kidney. TMA is a histopathologic diagnosis, and features of this are identified in several specific clinical conditions, including HUS, atypical hemolytic uremic syndrome (a-HUS), and thrombotic thrombocytopenic purpura (TTP). TMA may be associated with underlying conditions, such as malignancy, administration of chemotherapy and other drugs, transplantation, sepsis, and disseminated intravascular coagulation.

溶血性尿毒症综合征

Hemolytic Uremic Syndrome

人的溶血性尿毒症是由感染微生物和/或其毒素引起的，例如，产生志贺毒素的细菌(如大肠杆菌[STEC]和痢疾志贺氏杆菌1型)或肺炎链球菌感染(肺炎球菌溶血性尿毒症)。然而，在一些个体中，溶血性尿毒综合征不是感染或毒素引起的，因此被称为“非典型”(a-HUS)。在人STEC-HUS患者中，肾功能衰竭通常与之前出血性腹泻症状有关，最常见的是儿童。在这种情况下，志贺毒素与肾小球内皮细胞上表达的球形三酰神经受体具有高亲和力。肾小球内皮细胞的损伤会引起血栓前级联反应，导致微血栓的形成。这些患者的诊断调查通常包括粪便培养和大肠杆菌内毒素抗体(免疫球蛋白M)的评估。

HUS in humans is triggered by infectious organisms and/or their toxins, for example, shiga toxin–producing bacteria (eg, Escherichia coli [STEC] and Shigella dysenteriae type 1) or infection with Streptococcus pneumoniae (pneumococcal HUS). However, in some individuals, HUS is not infection or toxin triggered and is therefore referred to as “atypical” (a-HUS). In human patients with STEC-HUS, renal failure is commonly associated with prodromal hemorrhagic diarrhea and is most commonly recognized in children. In this condition, shiga toxin binds with high affinity to globotriaosylceramide 3 receptors expressed on glomerular endothelial cells. Injury to the glomerular endothelium precipitates a prothrombotic cascade leading to microthrombi formation. Diagnostic investigations in these patients typically include fecal culture and evaluation for E coli endotoxin antibodies (immunoglobulin M).

非感染相关的触发因素，包括遗传或获得的风险因素，有缺陷的调节替代补体途径(AP)，在a- HUS的发病机制中发挥作用。a-HUS的临床特征与其他TMA病因难以区分，以肾损伤为主。据报道，多达25%最终确诊为a-HUS患者之前有腹泻病史。AP补体失调是由于缺乏或功能受损的调节蛋白或C3转化酶活性过高而导致补体活化失控。虽然微血栓形成的确切机制尚不明确，但推测肾小球内皮细胞可能特别容易受到补体失调的影响。家族发病可以推定认为此病遗传，这在大约50%到60%的a-HUS患者中已确定。遗传变异已在补体调节因子(H因子、I因子、CD46和血栓调节蛋白)和补体活化因子(C3和B因子)中得以确定。获得性自身抗体产生H抑制因子，可能也会产生a-HUS相似的表现型,含有和不含有诱发基因变异的H 因子。血浆中C3的低浓度与a- HUS的诊断一致，但既没有特异性也敏感，因为H补体因子中最常见的变异导致循环中C3和H因子浓度正常。因此，对人a- HUS的诊断通常基于免疫学和基因检测相结合。当一名人医患者出现与a- HUS相容的临床症状时，最初的调查将包括评估补体浓度(C3、C4、H因子和I因子)、突变筛查(CFH、CF1、CD46、C3、CFB、THBD和DGKE)，以及检测因子H自身抗体。

Noninfection-associated triggers, including genetic or acquired risk factors for defective regulation of the alternative complement pathway (AP), play a role in the pathogenesis of a-HUS. Clinical features of a-HUS can be indistinguishable from other causes of TMA, with renal involvement predominating. Prodromal diarrhea is reported in up to 25% of patients ultimately considered to have a-HUS. AP complement dysregulation involves uncontrolled complement activation as a result of deficient or functionally impaired regulatory proteins or hyperactive C3 convertase components. It is hypothesized that the glomerular endothelium may be particularly susceptible to complement dysregulation, although the exact mechanism by which microthrombi formation ensues is not fully elucidated. Identification of familial associations leads to the recognition of genetic predispositions, which are identified in approximately 50% to 60% of individuals with a-HUS. These genetic variants have been identified in complement regulators (factor H, factor I, CD46, and thrombomodulin) and complement activators (C3 and factor B). Acquired autoantibody production against factor H may also give a similar a-HUS phenotype, both with and without predisposing genetic variability in factor H. Low plasma concentrations of C3 are consistent with a diagnosis of a-HUS but are neither specific nor sensitive, given the most common variants in complement factor H result in normal circulating C3 and factor H concentrations. Diagnosis of a-HUS in humans is therefore usually based on a combination of immunologic and genetic testing. When a human patient presents with clinical signs compatible with a-HUS, initial investigations will include assessment of complement concentrations (C3, C4, factor H, and factor I), mutation screening (CFH, CF1, CD46, C3, CFB, THBD, and DGKE), and detection of factor H autoantibodies.

血栓性血小板减少性紫癜

Thrombotic Thrombocytopenic Purpura     

TTP是一种罕见的TMA，通常与ADAMTS13的后天缺陷或基因突变有关。ADAMTS13是von Willebrand 因子 (vWF)的裂解蛋白。vWF用于原发性止血、促进血小板聚集和内皮损伤部位血栓形成。在健康状态下，受剪切应力的影响，ADAMTS13将vWF逐渐降解为较小的循环形式。自20世纪80年代以来，人们已经知道TTP与vWF的高血栓性“超大型”多聚体之间存在关联，直到后来才认识到这是由于ADAMTS13缺乏或缺乏功能所致。虽然已经报道了ADAMTS13基因突变，但这些突变只占TTP病例的少数，而ADAMTS13缺陷更常见的原因是后天抑制自身抗体。TTP需要非常低的ADAMTS13活性，通常低于正常蛋白酶活性的5%到10%。然而，在个体中，如果TTP与同时存在的TMA危险因素同时存在，例如脓毒症、恶性肿瘤或移植，则ADAMTS13活性可能不会被显著抑制，因此ADAMTS13的量化并不是一个完美的诊断测试。

TTP is an uncommon TMA, which has been most commonly associated with acquired deficiency or genetic mutations in ADAMTS13. ADAMTS13 is the cleaving protein of von Willebrand factor (vWF). vWF is required for primary hemostasis, facilitating platelet aggregation, and thrombus formation at sites of endothelial injury. In health, vWF is gradually degraded into progressively smaller circulating forms by ADAMTS13 with the influence of shear stress. Since the 1980s, it has been known that there is an association between TTP and highly thrombogenic “ultralarge” multimers of vWF, which was only later recognized to be due to deficiency or lack of functionality of ADAMTS13. Although genetic mutations in ADAMTS13 have been reported, these account for the minority of TTP cases, and it is more common for ADAMTS13 deficiency to be the result of an acquired inhibitory autoantibody. Very low ADAMTS13 activities are required for TTP, typically less than 5% to 10% of normal protease activity. However, in individuals where TTP is present in conjunction with coexisting TMA risk factors, for example, sepsis, malignancy, or transplantation, then ADAMTS13 activity may not be markedly suppressed, so that quantification of ADAMTS13 is not a perfect diagnostic test.

有趣的是，这三种情况都有不同的外显率。例如，据报道，一些遗传性TTP患者直到20岁以上该疾病才表现出来;并非所有感染STEC的患者都会出现STEC- hus，只有40% - 50%的已识别CFH、膜辅因子蛋白和CFI突变携带者会出现疾病。因此，TMA的发病机制是复杂的和多因素的，遗传易感性、环境因素和其他疾病条件之间的相互作用决定了一个人临床是否出现疾病表现。在人医中，为了区分TMA的病因，通常需要对病史进行广泛调查，并结合先进的免疫学和遗传学诊断测试。

Interestingly, all 3 conditions have variable penetrance. For example, it is reported that some patients with hereditary forms of TTP do not manifest the disease until greater than 20 years of age; not all patients infected with STEC will develop STEC-HUS, and only 40% to 50% of carriers of the recognized CFH, membrane cofactor protein, and CFI mutations will manifest disease. The pathogenesis of TMA is therefore complex and multifactorial, with interplay between genetic predispositions, environmental factors, and other disease conditions determining whether an individual clinically manifests a disease phenotype. In humans, extensive exploration of clinical history, combined with advanced immunologic and genetic diagnostic testing, is usually required in order to differentiate between causes of TMA.

英国皮肤肾小球血管病变的临床表现

CLINICAL PRESENTATION OF UNITED KINGDOM CASES OF CUTANEOUS RENAL GLOMERULAR VASCULOPATHY

许多不同品种的犬(>25，数据由Anderson Moores兽医专家有限公司提供)都被鉴定出患有CRGV，这与美国的数据形成了鲜明对比，在美国，这种疾病似乎只影响灵缇赛犬。

Many different breeds of dog (>25, data courtesy of Anderson Moores Veterinary Specialists Ltd) have been identified with CRGV, which is in contrast to American data, where the disease appeared to affect only racing greyhounds.

确诊为CRGV的犬最初会被送到兽医那里评估皮肤病变，包括四肢(77%)、机体(20%)、面部/口鼻(7%)和舌头(4%)。有时也会出现全身症状(表1)，但很少在皮肤病变发生前注意到(1%的病例;n = 102，数据由安德森摩尔兽医专家有限公司提供)。

Dogs diagnosed with CRGV are initially presented to veterinarians for assessment of skin lesions, affecting the limbs (77%), body (20%), face/muzzle (7%), and tongue (4%). Systemic signs are also sometimes present (Table 1), but rarely noted before the development of skin lesions (1% of cases; n = 102, data courtesy of Anderson Moores Veterinary Specialists Ltd).

皮肤病变外观变化多样，小到表面擦伤(0.5 cm)，大到大面积的全层溃疡和坏死(>30 cm)，周围有挫伤和水肿。病变通常为圆形和红斑。随后发生中央坏死和溃疡。影响手指的病变常表现为类似爪部皮炎或甲沟炎。口腔病变通常影响舌头为圆形糜烂/溃疡，而影响嘴周的病变可表现为糜烂/溃疡或水疱。面部病变通常与急性湿性皮炎相似(图1)。

Skin lesion appearance is variable, ranging from small, superficial abrasions (0.5 cm), to large areas of full-thickness ulceration and necrosis (>30 cm), with surrounding bruising and edema. Lesions are commonly circular and erythematous. Central necrosis and ulceration develop subsequently. Lesions affecting digits frequently appear similar to pododermatitis or paronychia. Oral cavity lesions generally affect the tongue as circular erosions/ulcers, whereas lesions affecting the muzzle can be erosive/ulcerative or vesicular in appearance. Facial lesions commonly appear similar to acute moist dermatitis (Fig. 1).

CRGV可能导致没有全身症状的皮肤病变，而一些犬会发展成AKI，可能出现或不出现氮质血症。目前，在英国，氮质血症和非氮质血症的CRGV的相对比例仍然未知，因为病例报告的自愿性和难以获得最终的尸检诊断。一个病例分析(n = 160只犬)报告了74%为非氮质血症。但是，这些患犬的确诊方法是完全依赖于临床症状和专家意见。在另一个病例分析(n = 12)中，通过光学和电子显微镜对有氮质血症和无氮质血症病例进行了肾组织病理学检查，并证实所有犬均存在肾小球TMA。无氮质血症组的变化比氮质血症组更轻，范围更广。在另一份报告(n = 18)中，56%的患者出现氮质血症，44%的患者无氮质血症，但所有病例的确诊方法均由专家根据临床症状、血液和尿液检测结果得出，没有皮肤或肾脏组织病理学。

CRGV may cause skin lesions without systemic illness, whereas some dogs develop AKI that may or may not lead to azotemia. Currently, in the United Kingdom, the relative proportion of azotemic versus nonazotemic CRGV remains unknown, because of the voluntary nature of case reporting and the difficulties in achieving a definitive antemortem diagnosis. One case series (n = 160 dogs) reported that 74% were nonazotemic; however, diagnosis in these canine patients relied solely on clinical signs and expert opinion. In a further case series (n = 12), renal histopathology was performed in both azotemic and nonazotemic cases, via light and electron microscopy, and confirmed the presence of glomerular TMA in all dogs. The changes observed in the nonazotemic group were less severe and widespread than in the azotemic group. In another report (n = 18), 56% developed azotemia, whereas 44% remained nonazotemic, but diagnosis for all cases was reached by expert opinion based on clinical signs, blood and urine test results, without dermal or renal histopathology.

将CRGV分为非氮质血症组或氮质血症组可能过于简单。美国最大的病例分析(n = 160)1报道了以下4种可能出现的临床表现:

1.无全身症状的皮肤病变，无氮质血症。(数值见英国)

2.发热和皮肤病变，随后迅速出现氮质血症性AKI。(这种表现似乎在英国确诊病例的比例偏低[102例中19%;未发表数据，2018，由安德森摩尔兽医专家有限公司提供])

3.10天内出现皮肤病变和氮质血症性AKI。（占102例的60%;未发表数据，2018，安德森摩尔兽医专家有限公司）

4. 皮肤病变后出现氮质血症。(在英国很少见;102宗个案中的1%;未发表数据，2018，安德森摩尔兽医专家有限公司)

Classification of CRGV into either nonazotemic or azotemic groups may be overly simplistic. The largest case series from the United States (n = 160)1 reported the following 4 possible clinical manifestations:

1、Skin lesions with no systemic signs, remaining nonazotemic (a population potentially seen in the United Kingdom)

2、Pyrexia and skin lesions, followed rapidly by azotemic AKI (this presentation appears to account for a low number of confirmed UK cases [19% of 102 cases; unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd])

3、Skin lesions with development of azotemic AKI within 10 days (60% of 102 cases; unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd)

4、 Azotemia before development of skin lesions (which appears rare in the United Kingdom; 1% of 102 cases; unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd)

在英国，3%的犬在出现皮肤病变10天后(11、20和21天后)才检测到氮质血症性AKI。这一发现可能表明另一种迟发性氮质血症性CRGV的临床表现存在。但是，也有可能这些病例在进行生化和尿液分析之前就已发生AKI。

In the United Kingdom, in 3% of dogs, azotemic AKI was detected more than 10 days after development of skin lesions (11, 20, and 21 days later). This finding could suggest that another, delayed, clinical manifestation of azotemic CRGV exists; however, it is also possible that these cases developed AKI before biochemistry and urinalysis was performed.

疑似病例的处理方法及临床病理结果

Approach to Suspected Cases and Clinicopathologic Findings   

尸检诊断CRGV很有难度。目前还没有一种单一的、无创的、具有高敏感性和特异性的诊断试验。

Antemortem diagnosis of CRGV can be challenging. There is no single, noninvasive diagnostic test available with high sensitivity and specificity.

•肾组织病理学:TMA在肾组织病理学上的表现被认为是诊断的参考标准。影响肾小球小动脉的纤维蛋白样坏死和血栓形成是肾小球小动脉充血最常见的表现，肾小管变性和坏死也有报道。不幸的是，考虑到犬肾脏活组织检查的风险是相对的禁忌症，或确诊为AKI和有时出现血小板减少症，这一检查通常是通过回顾性进行尸检确诊的CRGV。

•Renal histopathology: Demonstration of TMA on renal histopathology is considered the reference standard for diagnosis. Fibrinoid necrosis and thrombosis, affecting the glomerular arterioles, are the most commonly reported findings with congestion of the glomerular tufts, and tubular degeneration and necrosis also reported. Unfortunately, given the relative contraindication for renal biopsyin dogs at risk of, or diagnosed with,AKI and sometimes thrombocytopenia, this is usually obtained postmortem with retrospective confirmation of CRGV.

•当对犬进行皮肤病变评估时，如果皮肤病变可能与CRGV相对应，则应进行全血细胞计数、生物化学和尿液分析的基础检查以评估是否异常，这可能进一步提示CRGV。这也为进一步监测提供了基线。监测AKI发展的频率和持续时间取决于许多因素，包括临床症状程度、主人诉求、犬的情绪和经济顾虑。

•When presented with a dog for evaluation of skin lesions, which could be compatible with CRGV, baseline complete blood cell count, biochemistry, and urinalysis should be performed to assess for abnormalities, which may further suggest CRGV. This also provides a baseline for ongoing monitoring. The frequency and duration of monitoring for development of AKI will depend on many factors, including the level of clinical concern, owner preferences, dog temperament, and any financial considerations.

•全血细胞计数:在疑似非氮质血症性CRGV患犬中，通常表现正常，而大多数发生AKI的病例(95%)可表现为，中性粒细胞增多、非再生性贫血或再生性贫血或血小板减少(表2)。在这些病例中，血涂片检查可鉴别微血管病溶血(刺细胞、棘红细胞或红细胞破裂:13例中占38%，Holm及其同事;7例中占29%，Carpenter及其同事;9例中占78%，Cowan及其同事)。

•Complete blood cell count: This is normally unremarkable in dogs suspected to have nonazotemic CRGV, whereas most cases that develop AKI (95%) have some combination of neutrophilia, nonregenerative anemia or preregenerative anemia, or thrombocytopenia (Table2).In these cases, blood smear examination may identify evidence of microangiopathic hemolysis(Burr cells, acanthocytes,or schistocytes:38% of 13 cases,Holm and colleagues;29% of 7 cases,Carpenter and colleagues; 78% of 9 cases, Cowan and colleagues).

•生化检查:在疑似非氮质血症性CRGV病例中，血清生化分析一般不显著。但血清肝酶轻度升高(51/102例，丙氨酸氨基转移酶[ALT]中间值50 m/L，范围35-117;参考范围<25 m/L)。在AKI患犬中，87%到96%的犬初期的生化检查出现血清尿素氮和/或肌酐浓度异常。氮质血症最常发生在皮肤病变出现后3天(n=102，范围:3天前至21天后)。其他异常生化指标包括高磷血症、高胆红素、血清肝酶升高、血清肌酶轻度升高和轻度低白蛋白血症(表3)。犬胰脂肪酶结果异常。(14例中占79%,未发表数据,2018年,由安德森摩尔兽医专家)。

•Biochemistry: Serum biochemical analysis is generally unremarkable in suspected nonazotemic CRGV cases; however, mildly elevated serum liver enzyme activity has been identified (51/102 cases, median alanine aminotransferase [ALT] activity 50 m/L, range 35–117; reference range <25 m/L). Of the dogs developing AKI, 87% to 96% have abnormal serum urea and/or creatinine concentrations at the time of initial biochemistry. Azotemia has most frequently been documented 3 days after the development of skin lesions (n = 102, range: 3 days before to 21 days later). Other biochemical abnormalities include hyperphosphatemia, hyperbilirubinemia, elevated serum liver enzyme activity, mildly elevated serum muscle enzyme activity, and mild hypoalbuminemia (Table 3). Abnormal canine pancreatic lipase results have also been identified (79% of 14 cases, unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd).

•国际肾脏爱好协会(IRIS) AKI分级:IRIS分级有助于记录AKI的严重程度，但尚未显示对CRGV病例的预后有显著意义。英国CRGV病例(n = 102)的 IRIS AKI分级的中间值为III级，范围包括I- V级。

•International Renal Interest Society (IRIS) AKI grading: IRIS grading can be helpful to document severity of AKI but has not yet been shown to be prognostically significant for CRGV cases. Median IRIS AKI grade for UK CRGV cases (n = 102) was III, range I--V.

•尿液分析:虽然有轻度蛋白尿的报道，但在非氮质血症病例中通常并不显著(6例非氮质血症病例中有2例尿蛋白/肌酐比值(UP:Cr) >1.0, Cowan及其同事;13例中有14%的病例UP:Cr的中位值为0.85，范围是0.56-1.14，参考范围<0.5,Holm,和Walker)。在氮质血症病例中通常是异常的，这与由于各种病因导致的AKI患犬相似,包括蛋白尿(n = 5: Cr 1.19 - -7.0,Cowan及其同事; n = 102,UP:Cr平均值为3.42 ，范围是1.81 - -7.64,参考值< 0.5)，血尿/血红蛋白尿(95%)、糖尿(32%)，以及颗粒管型或透明管型(n = 102)。

•Urinalysis: This is generally unremarkable in nonazotemic cases, although mild proteinuria has been reported (2 of 6 nonazotemic cases had Urine protein to creatinine ratio (UP:Cr) >1.0, Cowan and colleagues; 14% of 13 cases had elevated UP:Cr, median value 0.85, range 0.56–1.14, reference range <0.5, Holm and Walker). Commonly identified abnormalities in azotemic cases are similar to those seen in dogs with AKI of any cause and include proteinuria (n = 5, UP:Cr 1.19–7.0, Cowan and colleagues;n= 102, median UP:Cr 3.42, range 1.81–7.64, reference <0.5), hematuria/hemoglobinuria (95%), glycosuria (32%), and granular or hyaline casts (n = 102).

•少尿:有AKI的CRGV患犬通常出现少尿或无尿(102例中61例的尿量数据显示，70%为少尿或无尿(61例中39例少尿和61中13例无尿;未发表数据，2018，安德森摩尔兽医专家有限公司;10例氮质血症中8例为少尿或无尿，Cowan及其同事)。作者注意到有9例发展为严重AKI的疑似CRGV病例(IRIS分级中间值为III级;范围是II-V级)，但通过强化管理得以恢复。这些病例中有7例有尿量数据:3例尿量正常，4例为少尿，没有无尿病例(未发表数据，2018年，由安德森摩尔兽医专家有限公司提供)。

•Oligoanuria: Reduced or absent urine production is common in dogs with CRGV that developed AKI (urine output data available for 61 of 102 cases revealed 70% were oliguric or anuric (30/61 oliguric and 13/61 anuric; unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd; 8 of 10 azotemic cases were oliguric or anuric; Cowan and colleagues). The authors are aware of 9 cases suspected to have had CRGV, which developed severe AKI (median IRIS grade III; range II–V), but recovered with intensive management. Urine output data were available for 7 of these cases: 3 had normal urine output,4 were oliguric, and none were anuric (unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd).

•腹部超声检查:在氮质血症犬中，腹部超声检查有助于进一步评估肾脏结构，并排除其他肾后性氮质血症病因。在CRGV病例中，这些发现通常不显著。有时可发现肾皮质高回声影像(约三分之一的病例;未发表数据，2018年，由安德森摩尔兽医专家有限公司)，以及有些犬出现少量腹腔积液(由于出血或液量超负荷)。

•Abdominal ultrasonography: In azotemic dogs, abdominal ultrasonography is useful to further assess renal architecture and exclude other postrenal causes of azotemia. Findings tend to be largely unremarkable in CRGV cases. Hyperechoic renal cortices are sometimes identified (approximately one-third of cases; unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd), and some dogs have small-volume abdominal effusions (because of hemorrhage or volume overloading).

•皮肤组织病理学:皮肤活检进行皮肤组织病理学检查，有助于确诊，对于疑似病例可以考虑此检查。但是，通常表现为非特异性的缺血性改变，包括表皮溃疡伴有真皮深层凝固性坏死。仅在超过三分之一的病例中，皮肤组织病理学作为尸检的一部分进行检查(89例中占39%,未发表数据,2018年,由安德森摩尔兽医专家),在小的真皮动脉中发现了纤维样坏死和血栓形成，证明是TMA的过程,支持CRGV的诊断。

•Dermal histopathology: Skin biopsy, with dermal histopathology, may help to confirm the diagnosis and can be considered for suspected cases. However, it commonly reveals nonspecific, ischemic changes, including ulceration of the epidermis with coagulative necrosis of the subjacent dermis. In just more than one-third of cases with dermal histopathology performed as part of a postmortem examination (39% of 89 cases, unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd), fibrinoid necrosis and thrombosis were identified in the small dermal arterioles, demonstrating a TMA process, supporting the diagnosis of CRGV.

目前对于发病机理的研究

ETIOPATHOGENESIS EXPLORED TO DATE

目前，CRGV的病因尚不明确。当CRGV在20世纪80年代和90年代首次在灵缇犬中被发现时，人们假定它与食用未煮熟的碎牛肉有关，并且从携带CRGV的灵缇犬粪便中分离出的STEC菌株比从健康的灵缇犬粪便中分离的更频繁。但是，并没有从所有诊断为CRGV的灵缇犬身上分离出STEC菌株。

At this time, the cause of CRGV remains unknown. When CRGV was first recognized in greyhounds in the 1980s and 1990s, it was postulated that it was associated with the ingestion of uncooked ground beef, and STEC strains have been isolated more frequently from the feces of greyhounds with CRGV than from healthy greyhounds. However, STEC strains were not isolated from all greyhounds diagnosed with CRGV.

在最大的CRGV患犬病例分析中，对7只犬进行粪便培养，产生大肠杆菌。但是，在所有犬中，大肠杆菌毒力基因(eaeA、stx 1和2、LT1和ST1和2)的多重聚合酶链反应(pcr)均为阴性。虽然志贺毒素已在不同物种中得以鉴定，但在HUS患犬上未被鉴定，并且用荧光原位杂交（FISH;n = 6）和PCR (n = 4)两种方法检查英国CRGV犬肾组织志贺毒素均为阴性。未能识别毒素或致病菌的原因可能包括以前使用过抗生素、样品处理不当或样品采集较晚。在人医中，大肠杆菌重新产生毒素高度依赖于腹泻开始后6天内的粪便培养。

In the largest case series of dogs with CRGV to date, fecal culture was performed in 7 dogs and yielded E coli. However, multiplex polymerase chain reactions (PCRs) for E coli virulence genes (eaeA, stx 1 and 2, LT1, and ST1 and 2) were negative in all of these dogs. Although shiga toxin has been identified in various species, it has not been identified in dogs with HUS, and both fluorescent in situ hybridization (FISH; n = 6) and PCR (n = 4) for shiga toxin on renal tissue in the UK CRGV dogs were negative. Reasons for failing to identify toxin, or causative bacteria, may have included previous antibiotic administration, inappropriate sample handling, or late collection of samples. In humans, recovery of toxin producing E coli is highly dependent on fecal culture being performed within 6 days of the onset of diarrhea.

其他革兰氏阴性细菌，包括立克氏立克氏体和钩端螺旋体，被假定为灵缇犬的致病因子;然而，血清学并没有给出一个明确的诊断。认为可能是钩端螺旋体病，并已进一步探索，虽然犬钩端螺旋体病的肾组织病理学与CRGV不一致。对15例钩端螺旋体病患者进行显微凝集试验。10只犬的滴度呈阴性，在出现全身症状后平均3天(1-8天)，但没有恢复期滴度资料。5只犬的滴度呈阳性，尽管浓度较低(1:100-1:800)，而且所有这些犬在测试前不到一年都接种了疫苗。虽然接种疫苗后疫苗滴度通常会下降4个月，但有时会持续更长时间，导致假阳性结果。此外，只有单滴度大于1:1600时才被认为是表明接种疫苗的犬感染的重要指标。在证实患有CRGV的犬中，对少量的犬进行了FISH和钩端螺旋体PCR检测，但结果并不一致。

Other gram-negative bacteria, including Rickettsia rickettsii and the leptospirae, were postulated as causative agents in greyhounds; however, serology did not yield a definitive diagnosis.Leptospirosis was considered possible and has been explored further, although renal histopathology in dogs with leptospirosis would not be compatible with CRGV. Leptospirosis microscopic agglutination testing was performed in 15 cases. Ten dogs had negative titers, obtained a median of 3 days (1–8 days) after the development of systemic signsbut without available convalescent titers. Five dogs had positive titers, albeit at a low concentration (1:100–1:800), and all of these dogs had been vaccinated less than 1 year before testing. Although vaccinal titers often decline by 4 months after vaccination, they can sometimes persist for longer, leading to false positive results. In addition, only single titers greater than 1:1600 are considered significant for indicating infection in vaccinated dogs. FISH and Leptospira PCR have been performed in low numbers of dogs confirmed to have CRGV, but have yielded discordant results.

在英国病例分析中，通过对新鲜肾组织(n = 2)、肝脏(n = 1)和淋巴结(n = 1)进行随机核酸扩增，进行病毒宏基因组学研究。所有结果均为阴性，并且组织病理学检查未发现任何组织存在病毒细胞病变效应(细胞质包涵体)。脾脏组织(n = 4)、血液(n = 3)进行PCR检测犬圆环病毒，使用FISH检测肾组织(n = 6)，所有结果均为阴性。病毒宏基因组学的阴性结果并不完全排除病毒原因。这些结果可能表明病毒复制量较低，或者该病毒与用于序列比对的已知病毒关系过远，或者使用的样本太过自溶，无法保存该病毒。

In the UK case series, viral metagenomics was performed on fresh kidney tissue (n = 2), liver (n = 1), and lymph node (n = 1), by random nucleic acid amplification. All results were negative, and histopathologically there was no evidence of viral cytopathic effect (cytoplasmic inclusion bodies) in any of the tissues examined. PCR for canine circovirus was also performed on splenic tissue (n = 4) and blood (n = 3), and FISH was performed on renal tissue (n = 6); all results were negative. Negative results for viral metagenomics do not completely exclude a viral cause. These results could indicate that virus was present in low copy numbers, or that the virus was too remotely related to known viruses used for sequence alignment, or that the sample used was too autolyzed to preserve the virus.

来自2只犬的肾组织分别送到2个单独的实验室，两个实验室都收到相同的样本，用广谱组的16S核糖体RNA定向探针进行评估。其中一个实验室在1只犬的组织中发现了一个清晰的16S条带，另一个在组织中发现了一个微弱的条带，两个样本中都发现了葡萄球菌科;然而，这被认为是共生皮肤细菌污染的结果。尿和肾组织培养结果均为阴性。第二个实验室只在两个样本中发现了钩端螺旋体。

Renal tissue from 2 dogs was submitted to 2 separate laboratories, with both laboratories receiving identical samples for evaluation with a broad spectrum set of 16S ribosomal RNA–directed probes. One laboratory identified a clear 16S band in the tissue of 1 dog and a faint band in the other, and Staphylococcaceae were identified in both samples; however, this was thought to be the result of contamination with commensal skin bacteria. Urine and renal tissue culture results were negative in both dogs. The second laboratory only identified leptospires in both samples.

在英国病例分析中还考虑了其他几个原因。疏螺旋体属PCR (n=5)和血清学(n=2)为阴性，肾脏重金属浓度(n=3);铅、砷和镉)均低于报道的参考区间。一名自然历史博物馆的植物学家,发病前几周曾访问过一只患犬经过的伦敦某地，,且不认为CRGV病因或诱因与植物种类有关。(大卫•沃克2018,个人意见)。唯一一种在英国有很长的历史的真菌，被认为不太可能是这种新出现的疾病的病因。在6只尿液毒理学检测的犬中，有5只呈阴性。1只犬检出戊乙二醇(微量)。棕色隐士蜘蛛叮咬被认为是一个可能的病因，叮咬引发坏死性皮炎，随后出现血管炎和肾坏死,但这种蜘蛛不是英国特有物种，并且在英国蛛形纲动物毒液中毒与此病季节性无关。在7例通过组织病理学确诊的病例尿液中，没有发现蓖麻碱。(未发表数据，2018年，由安德森摩尔兽医专家有限公司提供)。

Several other causes were considered in the UK case series; Borrelia PCR (n = 5) and serology (n 5=2) were negative, and renal heavy metal concentrations (n =3; lead, arsenic and cadmium) were below reported reference intervals in all 3. A botanist from the Natural History Museum, London visited one of the sites that an affected dog had walked over the weeks before developing disease, and no plant species observed were considered likely to be either causal or a cofactor in the development of CRGV (David Walker, 2018, personal communication). The only fungi identified have a long history in the United Kingdom and were considered unlikely to be the cause of this emerging disease. Urine toxicology was negative in 5 of 6 dogs tested. Pentaethylene glycol (trace) was detected in 1 dog. A brown recluse spider bite was considered a possible cause with a bite eliciting a pattern of necrotizing dermatitis with subsequent vasculitis and necrosis in the kidney, but this spider is not endemic in the United Kingdom and arachnid envenomation would not correlate with the seasonality of the disease in the United Kingdom. No evidence of ricinine was found in the urine of 7 histopathologically confirmed cases (unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd).

皮肤性肾小球血管病变的流行病学

EPIDEMIOLOGY OF CUTANEOUS RENAL GLOMERULAR VASCULOPATHY

2012年，英国首次报告了犬CRGV的病例，虽然最初的数字非常低(n = 3)，但每年报告的病例频率呈稳步上升趋势，尽管偶尔会出现同比变化。英国CRGV的暴发模式符合一种新出现疾病的定义。然而，这并不意味着这种疾病在英国完全不为人知，因为由于2012年之前英国的发病率非常低，所以它可能根本没有被认识到。

The first known cases of CRGV in UK dogs were reported in 2012, and although initial numbers were very low (n = 3), the annual frequency of reported cases showed a steady increase, albeit exhibiting occasional year-on-year variation. The outbreak pattern of CRGV in the United Kingdom is in accord with the definition of a newly emerging disease. However, that does not mean that the disease was completely unknown in the United Kingdom, because it may simply not have been recognized, owing to a very low incidence in the population before 2012.

品种的风险因素

Breed Risk Factors                        

此前非英国研究表明，CRGV主要与灵缇犬有关，有一个病例报道了德国的一只大丹犬。但是,在2012年11月至2017年5月，将101只诊断CRGV的患犬 ,与来自英国VetCompass数据库的446453只犬的总数相比(VetCompass 2014),诊断CRGV的灵缇犬的比例没有明显升高(优势比[OR]为1.65,P =0.629)，相反与该疾病有关的有多个品种。一般来说，猎犬(OR值为10.68,P<0.001)、枪猎犬(OR值为9.69,P<0.001)和牧养犬(OR值为3.50,P=0.046)被诊断为CRGV的风险最高，而玩具犬则没有出现在病例中。与杂交犬相比，品种犬出现CRGV病例的比例更高，包括平毛猎犬(OR值为84.48)、匈牙利猎犬(OR值为40.98)、曼彻斯特梗(OR值为41.41)、沙克犬(OR值为27.46)、惠比特犬(OR值为22.43)、英国史宾格猎犬(OR值为11.41)和长毛牧羊犬(OR值为10.85)。发病率较低的品种有斯塔福斗牛犬(OR值为0.50)、德国牧羊犬(OR值为0.45)和杰克罗素梗(OR值为0.37)。母犬CRGV(OR值为1.51)以及绝育犬(OR值为3.36)。更有可能被诊断出

Previous non-UK studies have suggested that CRGV is associated primarily with greyhounds, with a single case reported in a great Dane in Germany. However, a comparison of 101 dogs diagnosed with CRGV between November 2012 and May 2017, with a denominator population of 446,453 UK dogs from the VetCompass database (VetCompass 2014), reported that greyhounds did not have a significantly higher odds of CRGV diagnosis (odds ratio [OR] 1.65, P =0.629) and that the disease was instead associated with multiple breeds. In general, hounds (OR 10.68, P<.001), gundogs (OR 9.69, P<.001), and pastoral dogs (OR 3.50, P 5 .046) had the highest risk of being diagnosed with CRGV, whereas toy dogs were absent from the case population. Compared with crossbreds, specific breeds with increased odds of being a CRGV case included the flat-coated retriever (OR 84.48), Hungarian Vizsla (OR 40.98), Manchester terrier (OR 41.41), Saluki (OR 27.46), Whippet (OR 22.43), English springer spaniel (OR 11.41), and bearded collie (OR 10.85). Breeds with decreased odds of being a case were the Staffordshire bull terrier (OR 0.50), German shepherd dog (OR 0.45), and Jack Russell terrier (OR 0.37). Female dogs were more likely to be diagnosed with CRGV (OR 1.51), as were neutered dogs (OR 3.36).

英国的时空分布

Spatiotemporal Distribution in the United Kingdom   

英国CRGV的特点是每年爆发一次，表现出明显的季节性模式。2012年至2017年间，90%以上的病例发生在11月至5月之间，Kuldorff的季节性扫描统计数据显示，12月至4月期间存在一个显著的时间间期(P =0.001;金姆·史蒂文斯，2018，未出版作品，2018)。一般来说，夏季报告的病例数量可忽略不计。

CRGV in the United Kingdom has been characterized by annual outbreaks, which display a distinct seasonal pattern. More than 90% of cases between 2012 and 2017 occurred between November and May, and Kuldorff’s seasonal scan statistics identified a significant temporal cluster from December to April (P =0.001; Kim Stevens, 2018, unpublished work, 2018). In general, negligible numbers of cases are reported during the summer months.

病例数量从2012年的3例逐渐增加到2017/2018“时期”的60例以上。英格兰南部海岸的新林区是该病最初起源，尽管随后在英格兰南部和西部的大部分地区都发现了病例。然而，英格兰东部地区相对来说没有这种疾病，因此被预测为低风险地区。小的、局部的时空集中性表现该病病例数显著高于英国其他地区，在2013年2月和3月之间在新林区(P = 0.004)和2014年1月和4月之间在曼彻斯特(P = 0.087)得以确定,但是在这些区域似乎是一过性的,因为他们不是每年都这么明显。事实上，无论是2016年还是2017/2018年“时期”，新林区都没有病例报告。“有趣的是，在2015年4月至2017年5月期间，新林区以东地区报告的CRGV病例比例显著低于英国其他地区(P =0.002)。

The number of cases has increased incrementally from 3 in 2012 to greater than 60 in the 2017/2018 “season.” The New Forest region on England’s southern coast was the initial focus of the disease, although cases have subsequently been identified across most of southern and western England. The eastern half of England, however, has remained relatively free of the disease and is consequently predicted to be a low-risk region. Small, localized spatiotemporal clusters exhibiting significantly higher proportions of cases than the rest of the United Kingdom were identified between February and March 2013 in the New Forest area (P =0.004) and between January and April 2014 in Manchester (P =0.087), although these clusters appeared to be transient, because they were not apparent every year. In fact, no cases were reported from the New Forest area in either 2016 or the 2017/2018 “season.” Interestingly, between April 2015 and May 2017, the area immediately to the east of the New Forest reported a significantly lower proportion of CRGV cases (P =0.002) than the rest of the United Kingdom.

农业生态的风险因素

Agroecological Risk Factors                        

一个改进的回归树模型确定栖息地，特别是林地和低地的干荒地群落是CRGV发生的相对贡献最大的变改变因素(20.3%)。然而，英国林地高度多样化，每一种林地都有不同类型的树木，而且受地质、土壤、气候和历史的影响很大，因此很难确定该病的潜在来源。牧场是与CRGV发生关联最小的栖息地，这表明CRGV不太可能是一种家畜相关病原体的结果，犬在穿过牧场时接触了这种病原体。除了与特定生境类型相关外，CRGV存在的相对概率增加还与冬季、春季和秋季平均最高气温的增加、冬季和春季平均降雨量的增加以及春季平均气温的增加有关。Stevens及其同事们认为，适当的气候条件本身似乎不足以导致CRGV的发生;与之相伴而来的适宜栖息地似乎是至关重要的，因为威尔士和英格兰西南部的大部分地区(该疾病尚未在这些地区获得任何明显的立足点)主要是牧场。

A boosted regression tree model identified habitat, specifically, woodlands and lowland dry heath communities, as the variable with the highest relative contribution to CRGV occurrence (20.3%). However, UK woodlands are highly diverse, each characterized by different types of trees, and largely influenced by geology, soils, climate, and history, making it difficult to identify a potential source of the disease. Pastures were the habitat least associated with CRGV occurrence, suggesting it is unlikely CRGV is the result of a livestock-related pathogen to which dogs are exposed while walking across pastures. In addition to associations with specific habitat types, increasing relative probability of CRGV presence was associated with increasing mean maximum temperatures in winter, spring, and autumn, increasing mean rainfall in winter and spring, and increasing mean temperature in spring. Stevens and colleagues suggest that appropriate climatic conditions on their own appear to be insufficient for CRGV occurrence; the concomitant presence of suitable habitats appears to be essential, citing the fact that Wales and most of southwest England, where the disease has yet to gain any noticeable foothold, are dominated by pastures.

皮肤肾小球血管病变的治疗

MANAGEMENT OF CUTANEOUS RENAL GLOMERULAR VASCULOPATHY CASES

根据目前对CRGV的认识，对许多AKI患犬来说，治疗是一样的。治疗目标旨在限制进一步的肾脏损害和促进细胞恢复。纠正液体、电解质和酸碱紊乱，达到和维持正常张力，建立/维持尿流量是治疗最重要的方面。读者可以阅读有关AKI最佳医疗管理的更具体信息的文章。

On the basis of the current understanding of CRGV, management is as for many dogs with AKI. Treatment goals are aimed at limiting further renal damage and enhancing cellular recovery.Correction of fluid, electrolyte, and acid-base disorders, achieving and maintaining normotension, and establishing/maintaining urine flow are the most important aspects of therapy. Readers are directed to review articles for more specific information on the optimal medical management of AKI.

高血压是AKI常见的一种并发症。在AKI发病时，CRGV犬的血压中间值为176mm Hg(范围是102-280mm Hg)。如果收缩压大于180mm Hg，或有证据表明“末梢器官”损害，应予以治疗。

Hypertension is a common complication of AKI. The median blood pressure in dogs with CRGV was 176 mm Hg (range 102–280 mm Hg) at the time of onset of AKI. Treatment is indicated if systolic blood pressure is greater than 180 mm Hg or if there is evidence of “end-organ” damage.

免疫调节和抗血小板治疗

Immunomodulatory and Antiplatelet Therapy  

治疗人TMA依赖于潜在病因。血浆疗法、抗生素治疗、单克隆志贺毒素抗体和肾移植已被用于治疗STEC-HUS。一种重组的抗c5抗体(eculizumab)是人A - hus的治疗选择。据报道，一只CRGV患犬用免疫抑制疗法治疗无效。单克隆抗体治疗CRGV的疗效还有待评估。

Management of human TMAs is dependent on the underlying cause. Plasma therapy, antibiotic administration, monoclonal shiga toxin antibodies, and renal transplantation have been used in STEC-HUS. A recombinant, anti-C5 antibody (eculizumab) is the treatment of choice for human a-HUS. One dog with CRGV was reportedly ineffectively managed with immunosuppressive therapy. The efficacy of monoclonal antibody therapy has yet to be evaluated in CRGV.

根据CRGV的发病机制，抗血小板治疗似乎被认为是一个潜在治疗方法。阿司匹林是两项最大的TTP血浆交换研究的标准治疗方案的一部分，有报道称，在没有服用血小板抑制剂的情况下，TTP患者在恢复期间突然恶化并死亡。抗血小板药物通常不推荐用于观察出血或伴有严重血小板减少的TTP患者。英国血液学标准委员会建议血小板计数超过每立方毫米50,000个的TTP患者服用低剂量阿司匹林。氯吡格雷与出现TTP密切相关。因此，虽然没有与TTP患犬有关的报道，但是使用阿司匹林治疗可能优于氯吡格雷。

Antiplatelet therapy seems like a potential therapeutic consideration, given the etiopathogenesis of CRGV. Aspirin was part of the standard treatment protocol in the 2 largest studies of plasma exchange in TTP, and there have been reports of sudden deterioration and death among patients with TTP during recovery, when not taking platelet inhibitors. Antiplatelet agents are usually not recommended for patients with TTP when bleeding is observed or when they also have severe thrombocytopenia. Low-dose aspirin is recommended by the British Committee for Standards in Hematology for patients with TTP with platelet counts greater than 50,000 per cubic millimeter. Clopidogrel has been associated with the development of TTP. Therefore, although there is no reported association with TTP in dogs, aspirin therapy may be preferred to clopidogrel.

伤口管理

Wound Management                    

一旦犬临床状态稳定后，应妥善治疗CRGV的皮肤病变;除非绝对必要，否则伤口处理应避免镇静或麻醉，但考虑到肾功能可能受损，应提供镇痛。在CRGV中发生的病变很少需要进行清创手术。应采集细胞学和细菌学样本，最好是在开始局部或全身抗菌治疗之前。即使从病变中分离出微生物，如果没有临床症状表明感染，也禁止开始全身抗菌治疗。如果认为抗菌素的使用是合理的，药物的选择应该首先基于最有可能的病原体及其流行的易感性模式。一旦细菌培养和药敏试验的结果可用，抗菌药物应切换到尽可能窄的抗菌谱。应使用无菌敷料，以提供物理防护，防止污染和感染，并维持加速伤口愈合的伤口环境。

Skin lesions in CRGV should be appropriately managed once the dog is clinically stable; sedation or anesthesia should be avoided for wound management unless deemed absolutely necessary, but analgesia should be provided, taking into account potentially compromised renal function. Debridement is rarely needed for lesions that develop in CRGV. Samples for cytology and bacteriology should be collected, ideally before topical or systemic antimicrobial therapy is initiated. Even if microorganisms are isolated from a lesion, the initiation of systemic antimicrobial treatment is contraindicated if there are no clinical signs that indicate infection. If antimicrobial use is deemed appropriate, drug selection should initially be based on the most likely pathogen and their prevailing susceptibility patterns. Once the results of bacterial culture and sensitivity testing are available, the antimicrobial should be switched to the narrowest spectrum possible. A sterile dressing should be applied to provide a physical barrier to prevent contamination and infection and to maintain a wound environment that accelerates wound healing.

应用先进的治疗方法治疗皮肤性肾小球血管病变的病例

UTILITY OF ADVANCED THERAPIES FOR CUTANEOUS RENAL GLOMERULAR VASCULOPATHY CASES

在人的许多TMA亚型中，该病的严重程度和潜在病因不容易治疗。肾脏替代治疗(RRT)提供持续的支持，以减少氮质血症和维持适当的液体状态和酸碱电解质失衡严重肾功能下降的患者，同时等待AKI恢复或肾移植。

In many subtypes of TMA in people, the severity of the disease and underlying cause are not easily treatable. Renal replacement therapy (RRT) offers ongoing support to reduce azotemia and maintain an appropriate fluid status and acid-base and electrolyte imbalance in patients with severely reduced kidney function, while awaiting either resolution of the AKI or renal transplantation.

RRT已被用于出现严重AKI导致少尿的CRGV患犬，并允许治疗时间延长至数周。然而，在缺乏特异性治疗的情况下，这种单独的治疗方法并没有被证明在改善严重肾损伤患者的生存率方面有效(Rosanne Jepson, 2019, personal communication)。到目前为止，还没有报告使用RRT超过几周的犬;目前还不清楚长期提供RRT是否可以使CRGV引起的肾脏损害完全恢复。

RRT has been used in dogs with CRGV with severe AKI resulting in oligoanuria and has allowed for treatment to be extended for a few weeks. However, this therapy alone, in the absence of specific treatments, has not been shown to be effective in improving survival in cases with severe renal damage (Rosanne Jepson, 2019, personal communication). To date, there are no reports of the use of RRT beyond a few weeks in dogs; it is currently unknown whether providing RRT over a longer period may allow full recovery of the renal lesions induced by CRGV.

考虑到某些类型的TMA在人中的高死亡率，研究工作已经集中于调节与这些疾病相关的免疫系统失调。如本综述所述，为激活a-HUS中出现的补体系统或TTP中存在的抗adamts13自身抗体，有必要实施替代治疗。

Given the high mortality associated with certain types of TMA in people, research efforts have been focused on mediating the dysregulation of the immune system associated with these conditions. Implementation of alternative treatments has been necessary to target the activation of the complement system occurring in a-HUS or the presence of anti-ADAMTS13 autoantibodies in TTP, as previously described in this review.

一种新的免疫调节剂，依库丽单抗（Eculizumab），一种与C5结合的单克隆抗体，阻碍其水解和随后补体通路的激活，与传统的免疫抑制疗法相比，在治疗A - hus方面已被证明是有效的。这种疗法目前被高度推荐用于甲型溶血性尿毒综合征患者，但对兽医患者来说成本过高，而且没有证据表明它对CRGV犬有疗效。

A novel immune modulator, Eculizumab, a monoclonal antibody that binds to C5, impeding its hydrolysis and the subsequent activation of the complement pathway, has proven successful in treating a-HUS compared with traditional immunosuppressive treatment. This therapy, which is currently highly recommended in people with a-HUS, is cost-prohibitive for veterinary patients, and there is no evidence for its efficacy in dogs with CRGV.

在抗adamts13自身抗体患者中，治疗性血浆置换(TPE，也称为血浆置换)已成功地提高生存率。这种疗法包括在体外循环中转移血液，通过过滤或离心血液去除血浆，然后用健康献血者的同种异体血浆替换。该疗法去除自身抗体，取代ADAMTS-13，并减少凝血系统的进一步激活，从而限制临床症状的进展。目前的人医指南建议每次循环交换1.5倍的血浆容量，每天重复，直到血小板数量恢复正常。因为这个疗法已被证明有效的TTP,导致大幅提高生存如果在疾病的早期阶段进行,最近的一个病例分析研究描述了使用TPE 的6只严重CRGV的犬.虽然2只严重AKI的犬在报告中幸存下来,它仍然是未知的,如果这种疗法优于保守治疗,因为不受控制的研究设计。此外，如果在早期和较长时间内进行治疗，这种疗法通常对TTP患者有效，但本研究中描述的犬已经处于疾病的晚期，总共只接受了1或2次治疗;因此，目前还不清楚如果在疾病早期应用这种疗法是否有用。

In people with anti-ADAMTS13 autoantibodies, therapeutic plasma exchange (TPE, also known as plasmapheresis) has been successful in improving survival rates. This therapy consists of diverting blood in an extracorporeal circuit and removing plasma, either by filtration or by centrifugation of the blood, and then replacing it with allogenic plasma from healthy donors. This therapy removes autoantibodies, replaces ADAMTS-13, and reduces further activation of the coagulation system, thus limiting the progression of clinical signs. Current human guidelines advise the exchange of 1.5 times the plasma volume for each cycle, repeated every day until platelet numbers normalize. Because this therapy has been proven effective in people with TTP, leading to a substantial increase in survival if performed in an early phase of the disease, a recent case series study described the use of TPE in 6 dogs with severe CRGV. Although 2 dogs with severe AKI in the report survived, it still remains unknown if this therapy is superior to conservative management because of the uncontrolled study design. In addition, this therapy is usually effective in people with TTP if performed early and for extended periods, but dogs described in this study were already in an advanced stage of the disease and only received 1 or 2 treatments in total; hence, it remains unclear if this therapy could be useful if applied earlier in the disease.

结果和预后

OUTCOME AND PROGNOSIS

以往的报道表明，犬非氮质血症性CRGV预后良好。在美国，表现为嗜睡、发热和皮肤病变的犬，随着快速出现AKI，在加强治疗下也表现出良好的预后(25/30存活)。也有报道，在皮肤病变前出现氮质血症的犬也完全恢复(7/7存活)。这一发现与犬出现皮肤病变后10天内出现AKI的100%死亡率相比，这是类似于英国的经验,以及后来的美国经验,大多数出现典型氮质血症的犬被安乐死(100%氮质血症病例,Cowan及其同事们;83%的氮质血症病例，Holm及其同事;92%的氮质血症病例，Holm和Walker)。

Previous reports suggest that the prognosis for dogs with nonazotemic CRGV is excellent. In the United States, dogs presenting with lethargy, pyrexia, and skin lesions, with rapid development of AKI, also appeared to have a fair prognosis with intensive management (25/30 survived). Dogs that developed azotemia before skin lesions were also reported to recover fully (7/7 survived). This finding is in contrast with the 100% mortality observed when dogs developed AKI within 10 days of the appearance of skin lesions, which is similar to the experience in the United Kingdom, and also to later experiences in the United States, where most dogs that developed significant azotemia were euthanized (100% of azotemic cases, Cowan and colleagues; 83% of azotemic cases, Holm and colleagues4; 92% of azotemic cases, Holm and Walker).

在英国病例中，从出现皮肤病变发展到安乐死的平均时间为5天(n = 102;范围1-31天，未发表数据，2018年，安德森摩尔兽医专家有限公司)。安乐死的原因包括药物难以治疗的无尿(n = 29)、进行性氮质血症(n = 25)、认为预后不良(n = 15)、癫痫发作(n = 4)、出现疑似急性肺损伤/急性呼吸窘迫综合征(n = 4)、费用限制 (n = 4)、进行性贫血(n = 2)、疑似DIC(n = 2)和疑似败血症(n = 2)。另有2只犬死亡,13例安乐死的原因并没有说明。如果采取加强治疗管理，某些病例的预后可能会更好，但尚不明确。

For UK cases, the median time from the development of skin lesions to euthanasia was 5 days (n = 102; range 1–31 days, unpublished data, 2018, courtesy of Anderson Moores Veterinary Specialists Ltd). Reasons for euthanasia included oligoanuria refractory to medical management (n = 29), progressive azotemia (n = 25), perceived poor prognosis (n = 15), development of seizures (n = 4), development of suspected acute lung injury/acute respiratory distress syndrome (n = 4), financial constraints (n = 4), progressive anemia (n = 2), suspected DIC (n = 2), and suspected sepsis (n = 2). A further 2 dogs died, and the reason for euthanasia was not stated for 13 cases. It is possible that prognosis for some cases could have been more favorable if more intensive management had been pursued, but this is unknown.

作者注意到少数疑似病例(n = 3)出现IRISI级的AKI，静脉输液治疗±速尿效果良好，恢复正常。这些病例要么出现血清肌酐升高(>26.4 mmol/L,高于基础值，但仍在参考范围内)，要么出现少尿(尿量<1 mL/kg/h)。同样，在没有肾脏组织病理学的情况下，很难确诊，这阻碍了在英国更好地了解犬CRGV的真实预后。存活下来的少数严重氮质血症的疑似病例可能表明，经过适当的加强治疗，伴有AKI的CRGV并非都是致命的。

The authors are aware of a small number of suspected cases (n = 3) that developed IRIS grade I AKI, which responded well to intravenous fluid therapy ± furosemide and recovered uneventfully. These cases either developed an increase in serum creatinine concentration (>26.4 mmol/L above baseline, while remaining within the reference range) or oliguria (urine output <1 mL/kg/h). Again, the difficulty of confirming the diagnosis without renal histopathology has hampered efforts to better understand the true prognosis for CRGV in dogs in the United Kingdom. The small number of suspected cases with severe azotemia that survived could suggest that CRGV with AKI is not invariably fatal with appropriate intensive management.

总结

SUMMARY

CRGV在英国是一种新出现的疾病，但其病因和与感染源的任何相关性目前仍不确定。一些非氮质血症的CRGV患犬，对于这些病例，预后可能良好。对于发展为氮质血症的犬，特别是无尿型AKI，预后谨慎，但在这些病例中加强药物治疗被认为能有好的效果。现阶段，进一步工作必须集中在潜在的感染诱因和免疫失调，这与人医相关的TMA类似，以确定这些是否在犬中是风险因素。

CRGV is an emerging disease in the United Kingdom, but the cause and any association with an infectious agent remains uncertain at this time. A population of nonazotemic dogs with CRGV exists, and for such cases, prognosis may be good. For the population of dogs that develop azotemia, and particularly oligoanuric AKI, the prognosis can be guarded, but intensive medical therapy is indicated in these cases because successful outcomes have been achieved. At this stage, further work must focus on the underlying infectious triggers and immune dysregulation, which have been associated with similar TMA conditions in humans, in order to determine whether risk factors can be identified for the canine population.

图1：CRGV患犬的典型皮肤病变。(A) CRGV患犬指间皮肤病变。(B) CRGV患犬的进行性溃疡性皮肤病变。

Fig. 1. Typical skin lesions identified in dogs with CRGV. (A) Interdigital skin lesion identified in dog with CRGV. (B) Progressive ulcerated skin lesions identified in dog with CRGV.

廊坊永鑫罗玄

学习了。