期刊
NEPHROLOGY DIALYSIS TRANSPLANTATION
卷 33, 期 8, 页码 1292-1304出版社
OXFORD UNIV PRESS
DOI: 10.1093/ndt/gfx219
关键词
dialysis; fibrosis; hyperfiltration; hypertension; streptozotocin
资金
- European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA)
- China Scholarship Council
- European Union [305736, 634086]
Curing 'diabetic nephropathy' is considered an unmet medical need of high priority. We propose to question the concept of 'diabetic nephropathy' that implies diabetes as the predominant cause of kidney disease, which may not apply to the majority of type 2 diabetics approaching end-stage kidney disease. With the onset of diabetes, hyperglycaemia/sodium-glucose cotransporter-2-driven glomerular hyperfiltration promotes nephron hypertrophy, which, however, on its own, causes proteinuria not before a decade later, probably because podocyte hypertrophy can usually accommodate an increase in the filtration surface. In contrast, precedent chronic kidney disease (CKD), that is, few nephrons per body mass, e.g. due to poor nephron endowment from birth, obesity, pregnancy, or renal ageing or injury-related nephron loss, usually precedes the onset of type 2 diabetes. This applies in particular in older adults, and each on its own, but especially in combination, further aggravates single nephron hyperfiltration and glomerular hypertrophy. Whenever this additional hyperglycaemia-driven enlargement of the glomerular filtration surface exceeds the capacity of podocytes for hypertrophy, podocytes detachment leads to glomerulosclerosis and nephron loss, i.e. CKD progression. Animal models of 'diabetic nephropathy' based only on hyperglycaemia do not mimic this aspect and therefore poorly predict outcomes of clinical trials usually performed on elderly CKD patients with type 2 diabetes. Thus, we advocate the use of renal mass (nephron) ablation in type 2 diabetic animals to better mimic the pathophysiology of 'CKD with diabetes' in the target patient population and the use of the glomerular filtration rate as a primary endpoint to more reliably predict trial outcomes.
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