Bennington Julie, Lankford Shannon, Magalhaes Renata S, Shankle Douglas, Fanning Jason, Kartini Cucu, Suparto Irma, Kusumawardhani Winda, Putra M ArRaniri, Mariya Silmi, Badlani Gopal, Williams J Koudy
Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, United States.
Department of Health and Exercise Science, Wake Forest University, Winston-Salem, NC, United States.
Front Vet Sci. 2021 Mar 4;8:646087. doi: 10.3389/fvets.2021.646087. eCollection 2021.
Chronic tubulointerstitial fibrosis is a common final pathway leading to end stage kidney disease in cats and has no effective treatment. The use of cell-based molecules to treat kidney fibrosis may be a promising approach. The objectives were to test the effects of intra-renal chemokine CXCL12 injection in a pre-clinical cat model of unilateral ischemia/reperfusion (I/R)-induced kidney fibrosis and then, within a clinical pilot study, test the safety/feasibility of CXCL12 injection in cats that might have early chronic kidney disease (CKD). : Thirty cats received intra-renal injection of 100, 200, or 400 ng of recombinant human CXCL12, or sterile saline, into the I/R kidney 70 days post-injury, or were non-injured, non-injected controls ( = 6/group). Kidney collagen content was quantified 4 months post-treatment using Masson's Trichrome and Picrosirius Red (PSR) stained tissues. In a separate study ( = 2) exploring short-term effects of CXCL12, 200 ng CXCL12 was injected into I/R kidneys and then harvested either 30 min ( = 1) or 1 month ( = 1) post-injection. Kidney concentrations of CXCL12, matrix metalloproteinase 1 (MMP-1), and lysyl oxidase-like enzyme 2 (LOXL-2) were quantified ELISA. : 14 client-owned cats with potential early kidney disease received a single-treatment, bilateral intra-renal injection of 200 ng CXCL12 ( = 7), or received no injection ( = 7). Blood/urine samples were collected monthly for 9 months to assess renal function and CKD staging. : I/R increased the affected kidney collagen content, which both mid and high doses of CXCL12 restored to normal ( < 0.05 vs. untreated). I/R increased collagen fiber width, which both mid and high doses of CXCL12 restored to normal ( < 0.001 vs. untreated). Early changes in kidney MMP-1, associated with collagen breakdown, and subsequent decreases in LOXL-2, associated with collagen cross-linking, in response to CXCL12 treatment may contribute to these findings. : Bilateral intra-renal injection of CXCL12 using ultrasound guidance in cats with CKD was feasible and safe in a general practice clinical setting with no obvious side effects noted during the 9-month follow-up period. Intra-renal injection of CXCL12 may prove to be an effective treatment for kidney fibrosis in cats with CKD. Additional mechanistic and clinical evaluations are needed.
慢性肾小管间质纤维化是猫终末期肾病常见的最终途径，且尚无有效治疗方法。使用基于细胞的分子治疗肾纤维化可能是一种有前景的方法。本研究目的是在单侧缺血/再灌注（I/R）诱导的肾纤维化临床前猫模型中测试肾内注射趋化因子CXCL12的效果，然后在一项临床初步研究中，测试在可能患有早期慢性肾病（CKD）的猫中注射CXCL12的安全性/可行性。：30只猫在损伤后70天接受肾内注射100、200或400 ng重组人CXCL12，或无菌生理盐水至I/R肾，或作为未损伤、未注射的对照（每组 = 6只）。在治疗后4个月，使用Masson三色染色法和苦味酸天狼星红（PSR）染色组织对肾胶原含量进行定量分析。在另一项探索CXCL12短期效应的研究中（每组 = 2只），将200 ng CXCL12注射到I/R肾中，然后在注射后30分钟（每组 = 1只）或1个月（每组 = 1只）采集样本。通过酶联免疫吸附测定法（ELISA）对肾中CXCL12、基质金属蛋白酶1（MMP-1）和赖氨酰氧化酶样酶2（LOXL-2）的浓度进行定量分析。：14只可能患有早期肾病的客户拥有的猫接受单次双侧肾内注射200 ng CXCL12（每组 = 7只），或不进行注射（每组 = 7只）。每月采集血液/尿液样本，持续9个月，以评估肾功能和CKD分期。：I/R增加了受影响肾的胶原含量，中剂量和高剂量的CXCL12均可将其恢复至正常水平（与未治疗组相比，P < 0.05）。I/R增加了胶原纤维宽度，中剂量和高剂量的CXCL12均可将其恢复至正常水平（与未治疗组相比，P < 0.001）。肾MMP-1的早期变化与胶原分解有关，随后LOXL-2的降低与胶原交联有关，对CXCL12治疗的反应可能是导致这些结果的原因。：在慢性肾病猫中，在超声引导下双侧肾内注射CXCL12在普通临床实践环境中是可行且安全的，在9个月的随访期内未观察到明显副作用。肾内注射CXCL12可能被证明是治疗慢性肾病猫肾纤维化的有效方法。还需要进行更多的机制和临床评估。
