D-Amino acids, long-term undetected enantiomers of L-amino acids, are now emerging as potential biomarkers, especially for kidney diseases. Management of chronic kidney disease (CKD), a global problem with its high prevalence and poor prognosis, is currently unsatisfactory due to the difficulty in estimating kidney function and in early detection of diseases. We now show that intra-body dynamics of D-serine reflect kidney function and diseases. The blood level of D-serine correlated well with the actual glomerular filtration ratio, a key kidney function. This correlation was compatible with those of conventional kidney markers, and blood level of D-serine was relatively unaffected by such clinical factors as body size. The balance between excretion and reabsorption of amino acids by the kidney was controlled with chiral selectivity, and the reabsorption of D-serine was sensitive to the presence of CKD. The combination of blood level and urinary dynamics of D-serine effectively distinguished CKD from non-CKD. These lines of evidence provide new insights into the enantioselective amino acid dynamics in the human body that reflect disease pathophysiology. D-Serine may serve as a vital biomarker that suppress CKD onset through the precise assessment of kidney function and the diagnosis of CKD.

d-Amino acids are the recently detected enantiomers of l-amino acids. Accumulating evidence points their potential in solving the long-standing critical problems associated with the management of both chronic and acute kidney diseases. This includes estimating kidney function, early diagnosis and prognosis of chronic kidney disease, and disease monitoring. Among the d-amino acids, d-serine levels in the blood are strongly correlated with the glomerular filtration rate and are useful for estimating the function of the kidney. Urinary d-serine also reflects other conditions. The kidney proximal tubule reabsorbs serine with chiral-selectivity, with d-serine being reabsorbed much less efficiently than l-serine, and urinary excretion of d-serine is sensitive to the presence of kidney diseases. Therefore, assessing the intra-body dynamics of d-serine by measuring its level in blood and urinary excretion can be used to detect kidney diseases and assess pathophysiology. This new concept, the intra-body dynamics of d-serine, can be useful in the comprehensive management of kidney disease.

BackgroundEvidence of a protective role of autophagy in kidney diseases has sparked interest in autophagy as a potential therapeutic strategy. However, understanding how the autophagic process is altered in each disorder is critically important in working toward therapeutic applications.MethodsUsing cultured kidney proximal tubule epithelial cells (PTECs) and diabetic mouse models, we investigated how autophagic activity differs in type 1 versus type 2 diabetic nephropathy. We explored nutrient signals regulating starvation-induced autophagy in PTECs and used autophagy-monitoring mice and PTEC-specific autophagy-deficient knockout mice to examine differences in autophagy status and autophagy’s role in PTECs in streptozotocin (STZ)-treated type 1 and db/db type 2 diabetic nephropathy. We also examined the effects of rapamycin (an inhibitor of mammalian target of rapamycin [mTOR]) on vulnerability to ischemia-reperfusion injury.ResultsAdministering insulin or amino acids, but not glucose, suppressed autophagy by activating mTOR signaling. In db/db mice, autophagy induction was suppressed even under starvation; in STZ-treated mice, autophagy was enhanced even under fed conditions but stagnated under starvation due to lysosomal stress. Using knockout mice with diabetes, we found that, in STZ-treated mice, activated autophagy counteracts mitochondrial damage and fibrosis in the kidneys, whereas in db/db mice, autophagic suppression jeopardizes kidney even in the autophagy-competent state. Rapamycin-induced pharmacologic autophagy produced opposite effects on ischemia-reperfusion injury in STZ-treated and db/db mice.ConclusionsAutophagic activity in PTECs is mainly regulated by insulin. Consequently, autophagic activity differs in types 1 and 2 diabetic nephropathy, which should be considered when developing strategies to treat diabetic nephropathy by modulating autophagy.