Table1_Experimental renal transplantation in rats improves cardiac dysfunction caused by chronic kidney disease while LVH persists.xlsx

BackgroundChronic kidney disease (CKD) causes congestive heart failure (CHF) with systolic dysfunction and left ventricular hypertrophy (LVH), which is a major contributor to increased mortality in CKD patients. It remains unclear whether cardiovascular changes that occur during the course of CKD can be reversed when renal function is restored by transplantation.
MethodsTo investigate this, chronic kidney disease was established in F344 rats by subtotal nephrectomy (SNx) for 8 weeks, followed by transplantation of a functional kidney from an isogenic F344 donor. SNx rats without transplantation and sham-operated animals served as controls. Renal function was assessed before and throughout the experiment. In addition, cardiac ultrasound was performed at weeks 0, 8, 12 and 16. At the end of the experiment, intra-arterial blood pressure was measured and kidneys and hearts were histologically and molecularly examined.
ResultsEight weeks after SNx, rats developed marked renal dysfunction associated with significant glomerulosclerosis and tubulointerstitial fibrosis, but also an increase in left ventricular mass. After transplantation, renal function normalized but relative heart weight and ventricular mass as assessed by ultrasound scans showed no reduction compared with SNx controls. However, left ventricular wall thickness, fractional shortening and ejection fraction was normalized by renal transplantation. At 8 weeks after kidney transplantation, cardiac expression of BNP and FGF23 was also at levels comparable to healthy controls, whereas these factors were significantly increased in SNx rats. Cardiac fibrosis, as measured by fibronectin mRNA expression, was completely normalized, whereas cardiac fibronectin protein was still slightly but not significantly increased in transplanted animals compared to controls. In addition, the myofibroblast marker collagen 1, as assessed by immunohistochemistry, was significantly increased in SNx rats and also normalized by renal transplantation. Interestingly, CD68+ macrophages were significantly reduced in the hearts of SNx rats and in transplanted animals at slightly higher levels compared to controls.
ConclusionRestoration of renal function by kidney transplantation normalized early cardiac changes at most functional and molecular levels, but did not completely reverse LVH. However, further studies are needed to determine whether restoration of renal function can also reverse LVH at a later time point.

【研究背景】慢性肾脏病（Chronic Kidney Disease, CKD）可引发伴收缩功能障碍与左心室肥厚（Left Ventricular Hypertrophy, LVH）的充血性心力衰竭（Congestive Heart Failure, CHF），是导致慢性肾脏病患者死亡率升高的重要危险因素。目前尚不明确，在通过肾脏移植恢复肾功能后，慢性肾脏病病程中出现的心血管改变是否能够逆转。

【研究方法】为探究上述问题，本研究通过次全肾切除术（Subtotal Nephrectomy, SNx）在F344大鼠中构建慢性肾脏病模型，造模周期为8周，随后向模型大鼠移植同基因F344供体的功能性肾脏。将未接受移植的次全肾切除术大鼠与假手术动物设为对照组。于实验前及实验全程评估肾功能。此外，分别于第0、8、12、16周进行心脏超声检测。实验结束时，检测大鼠动脉内血压，并对肾脏与心脏组织进行组织学及分子生物学检测。

【研究结果】次全肾切除术造模8周后，大鼠出现显著肾功能不全，伴随明显的肾小球硬化（Glomerulosclerosis）与肾小管间质纤维化（Tubulointerstitial Fibrosis），同时左心室质量升高。肾脏移植术后，大鼠肾功能恢复正常，但通过超声扫描评估的相对心脏重量与心室质量与次全肾切除术对照组相比无显著降低。然而，肾脏移植使左心室壁厚度、短轴缩短率（Fractional Shortening）与射血分数（Ejection Fraction）恢复至正常水平。肾脏移植术后8周，心脏组织中脑钠肽（Brain Natriuretic Peptide, BNP）与成纤维细胞生长因子23（Fibroblast Growth Factor 23, FGF23）的表达水平也与健康对照组相当，而次全肾切除术大鼠的上述因子表达显著升高。通过纤连蛋白（Fibronectin）mRNA表达水平评估的心脏纤维化程度完全恢复正常，但与对照组相比，移植大鼠的心脏纤连蛋白蛋白水平仍有轻微升高，但差异无统计学意义。此外，通过免疫组织化学（Immunohistochemistry）检测的肌成纤维细胞标志物Ⅰ型胶原（Collagen Type 1）在次全肾切除术大鼠中显著升高，而肾脏移植可使其恢复正常。值得注意的是，次全肾切除术大鼠的心脏组织中CD68+巨噬细胞（CD68+ macrophages）数量显著减少，移植大鼠的该细胞水平略高于对照组，但差异同样无统计学意义。

【研究结论】通过肾脏移植恢复肾功能，可使大多数功能与分子层面的早期心脏改变恢复正常，但无法完全逆转左心室肥厚。然而，仍需开展进一步研究以明确，在更晚的时间节点恢复肾功能是否也能够逆转左心室肥厚。