Nephrology Division, Second University of Naples-Med School, Naples, Italy.
Department of Medicine, Veterans Administration San Diego Healthcare System-University of California at San Diego Medical School, San Diego, CA.
Am J Kidney Dis. 2014 Jul;64(1):16-24. doi: 10.1053/j.ajkd.2014.02.010. Epub 2014 Mar 25.
Optimal prevention and treatment of chronic kidney disease in diabetes requires implementing therapies that specifically interfere with the pathogenesis of diabetic nephropathy. In this regard, significant attention has been given to alterations of the proximal tubule and resulting changes in glomerular filtration rate. At the onset of diabetes mellitus, hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport. The increase in proximal reabsorption leads to a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate. Because glomerular hyperfiltration currently is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. The recent introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives for this high-risk patient population. Experimental studies have shown that these new agents attenuate the progressive nature of diabetic nephropathy by blood glucose-dependent and -independent mechanisms. SGLT2 inhibition may prevent glomerular hyperfiltration independent of the effect of lowering blood glucose levels while limiting kidney growth, inflammation, and albuminuria through reductions in blood glucose levels. Clinical data for the potential role of the proximal tubule in the pathophysiology of diabetic nephropathy and the nephroprotective effects of SGLT2 inhibitors currently are limited compared to the more extensive experimental literature. We review the evidence supporting this working hypothesis by integrating the experimental findings with the available clinical data.
优化糖尿病慢性肾脏病的预防和治疗需要实施专门针对糖尿病肾病发病机制的治疗方法。在这方面，人们高度关注近端小管的改变和肾小球滤过率的相应变化。在糖尿病发生的初期，高血糖导致近端小管重吸收增加，这是由于管状生长引起的，同时伴有钠/葡萄糖共转运蛋白的增加。近端重吸收的增加导致向致密斑传递的溶质负荷减少，管球反馈失活，肾小球滤过率增加。由于目前肾小球高滤过被认为是糖尿病患者肾脏病进展的一个危险因素，因此限制近端小管重吸收构成了降低高滤过的一个潜在目标。最近引入的钠/葡萄糖共转运蛋白 2（SGLT2）抑制剂为这一高危患者群体开辟了新的治疗前景。实验研究表明，这些新的药物通过血糖依赖性和非依赖性机制减轻了糖尿病肾病的进行性发展。SGLT2 抑制可能会阻止肾小球高滤过，而不依赖于降低血糖水平的作用，同时通过降低血糖水平来限制肾脏生长、炎症和白蛋白尿。与更广泛的实验文献相比，目前关于近端小管在糖尿病肾病病理生理学中的作用以及 SGLT2 抑制剂的肾脏保护作用的临床数据有限。我们通过将实验结果与现有临床数据相结合，整合支持这一工作假说的证据进行综述。
