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d-serine administration prevents kidney damage in murine models of acute kidney injury, and risperidone inhibits the activity of d-amino acid oxidase, which regulate plasma d-amino acid levels. This pilot randomized controlled trial investigated the effects of risperidone on glucose, amino acid metabolism, and kidney function in healthy adults. Healthy adults with a homeostasis model assessment of insulin resistance (HOMA-IR) of ≥ 1.6 and estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/1.73m2 were randomly assigned to the risperidone and control groups. The risperidone group received 0.5 mg/day risperidone for 4 days. The primary outcome was mean change in HOMA-IR on day 5, and the secondary outcomes were changes in d-amino acid levels, eGFR, and urinary albumin. Seven participants were randomized to the risperidone and control groups. The changes in HOMA-IR, eGFR, and urinary albumin on day 5 were not significantly different between the two groups (all p > 0.05). Mean changes in plasma d-serine level and urinary d-serine/creatinine ratio were significantly higher in the risperidone group than in the control group (0.2 vs. -0.3 nmol/mL, p = 0.03 and 38.2 vs. -25.8 nmol/mL, p = 0.01, respectively). Short-term risperidone affects d-serine metabolism without instigating acute adverse effects on kidney or glucose homeostasis in healthy individuals. Clinical Trial Registry number: This study was registered with the Japan Registry for Clinical Trials (jRCTs041210165).

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.

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.

The imbalance of blood and urine amino acids in renal failure has been studied mostly without chiral separation. Although a few reports have shown the presence of D-serine, an enantiomer of L-serine, in the serum of patients with severe renal failure, it has remained uncertain how serine enantiomers are deranged in the development of renal failure. In the present study, we have monitored serine enantiomers using a two-dimensional HPLC system in the serum and urine of mice after renal ischemia-reperfusion injury (IRI), known as a mouse model of acute kidney injury. In the serum, the level of D-serine gradually increased after renal IRI in parallel with that of creatinine, whereas the L-serine level decreased sharply in the early phase after IRI. The increase of D-serine was suppressed in part by genetic inactivation of a D-serine-degrading enzyme, D-amino acid oxidase (DAO), but not by disruption of its synthetic enzyme, serine racemase, in mice. Renal DAO activity was detected exclusively in proximal tubules, and IRI reduced the number of DAO-positive tubules. On the other hand, in the urine, D-serine was excreted at a rate nearly triple that of L-serine in mice with sham operations, indicating that little D-serine was reabsorbed while most L-serine was reabsorbed in physiological conditions. IRI significantly reduced the ratio of urinary D-/L-serine from 2.82 ± 0.18 to 1.10 ± 0.26 in the early phase and kept the ratio lower than 0.5 thereafter. The urinary D-/L-serine ratio can detect renal ischemia earlier than kidney injury molecule-1 (KIM-1) or neutrophil gelatinase-associated lipocalin (NGAL) in the urine, and more sensitively than creatinine, cystatin C, or the ratio of D-/L-serine in the serum. Our findings provide a novel understanding of the imbalance of amino acids in renal failure and offer a potential new biomarker for an early detection of acute kidney injury.

Introductiond-Serine, present only in trace amounts in humans, is now recognized as a biomarker of chronic kidney disease (CKD). CKD is heterogeneous in its original kidney diseases, whose diagnoses require kidney biopsy. In this study, we examined whether the intra-body dynamics of d-serine, indexed by its blood and urinary levels, reflects the origin of kidney diseases.MethodsPatients with six kinds of kidney disease undergoing kidney biopsy were enrolled in a single center. Levels of d- and l-serine were measured using two-dimensional high-performance liquid chromatography. The associations between the origin of kidney diseases and the intra-body dynamics of d-serine were examined using multivariate cluster analyses.ResultsUnlike the non-CKD profile, patients with CKD showed broadly-distributed profiles of intra-body dynamics of d-serine. The plasma level of d-serine plays a key role in the detection of kidney diseases, whereas a combination of plasma and urinary levels of d-serine distinguished the origin of CKD, especially lupus nephritis.ConclusionIntra-body dynamics of d-serine have the potential to predict the origin of kidney diseases. Monitoring of d-serine may guide specific treatments for the origin of kidney diseases.

Chiral separation has revealed enantio-specific changes in blood and urinary levels of amino acids in kidney diseases. Blood d-/l -serine ratio has been identified to have a correlation with creatinine-based kidney function. However, the mechanism of distinctive behavior in serine enantiomers is not well understood. This study was performed to investigate the role of renal tubules in derangement of serine enantiomers using a mouse model of cisplatin-induced tubular injury. Cisplatin treatment resulted in tubular damage histologically restricted to the proximal tubules and showed a significant increase of serum d-/l -serine ratio with positive correlations to serum creatinine and blood urine nitrogen (BUN). The increased d-/l -serine ratio did not associate with activity of a d -serine degrading enzyme, d -amino acid oxidase, in the kidney. Screening transcriptions of neutral amino acid transporters revealed that Asc-1, found in renal tubules and collecting ducts, was significantly increased after cisplatin-treatment, which correlates with serum d -serine increase. In vitro study using a kidney cell line showed that Asc-1 is induced by cisplatin and mediated influx of d -serine preferably to l -serine. Collectively, these results suggest that cisplatin-induced damage of proximal tubules accompanies Asc-1 induction in tubules and collecting ducts and leads to serum d -serine accumulation.

Targeted metabolomics requires accurate and precise quantification of candidate biomarkers, often through tandem mass spectrometric (MS/MS) analysis. Differential isotope labeling (DIL) improves mass spectrometric (MS) analysis in metabolomics by derivatizing metabolites with two isotopic forms of the same reagent. Despite its advantages, DIL-liquid chromatographic (LC)-MS/MS can result in substantial increase in workload when fully validated quantitative methods are required. To decrease the workload, we hypothesized that single point calibration or relative quantification could be used as alternative methods. Either approach will result in significant saving in resources and time. To test our hypothesis, six urinary metabolites were selected as model compounds. Urine samples were analyzed using a fully validated multipoint dansyl chloride-DIL-LC-MS/MS method. Samples were reprocessed using single point calibration and relative quantification modes. Our results demonstrated that the performance of single point calibration or relative quantification was inferior, for some metabolites, to multipoint calibration. The lower limit of quantification failed in the quantification of ethanolamine in most of participant samples using single point calibration. In addition, its precision was not acceptable in one participant during serine and ethanolamine quantification. On the other hand, relative quantification resulted in the least accurate data. In fact, none of the data generated from relative quantification for serine was comparable to that obtained from multipoint calibration. Finally, while single point calibration showed an overall acceptable performance for the majority of the model compounds, we cannot extrapolate the findings to other metabolites within the same analytical run. Analysts are advised to assess accuracy and precision for each metabolite in which single point calibration is the intended quantification mean.

Prostate specific antigen (PSA) remains the most used biomarker in the management of early prostate cancer (PCa), in spite of the problems related to false positive results and overdiagnosis. New biomarkers have been proposed in recent years with the aim of increasing specificity and distinguishing aggressive from non-aggressive PCa. The emerging role of the prostate health index and the 4Kscore is reviewed in this article. Both are blood-based tests related to the aggressiveness of the tumor, which provide the risk of suffering PCa and avoiding negative biopsies. Furthermore, the use of urine has emerged as a non-invasive way to identify new biomarkers in recent years, including the PCA3 and TMPRSS2:ERG fusion gene. Available results about the PCA3 score showed its usefulness to decide the repetition of biopsy in patients with a previous negative result, although its relationship with the aggressiveness of the tumor is controversial. More recently, aberrant microRNA expression in PCa has been reported by different authors. Preliminary results suggest the utility of circulating and urinary microRNAs in the detection and prognosis of PCa. Although several of these new biomarkers have been recommended by different guidelines, large prospective and comparative studies are necessary to establish their value in PCa detection and prognosis.

SARS-CoV-2 virus infects cells by engaging with ACE2 requiring protease TMPRSS2. ACE2 is highly expressed in kidneys. Predictors for severe disease are high age and male sex. We hypothesized that ACE2 and TMPRSS2 proteins are more abundant (1) in males and with increasing age in kidney and (2) in urine and extracellular vesicles (EVs) from male patients with COVID-19 and (3) SARS-CoV-2 is present in urine and EVs during infection. Kidney cortex samples from patients subjected to cancer nephrectomy (male/female; < 50 years/˃75 years, n  = 24; ˃80 years, n  = 15) were analyzed for ACE2 and TMPRSS2 protein levels. Urine from patients hospitalized with SARS-CoV-2 infection was analyzed for ACE2 and TMPRSS2. uEVs were used for immunoblotting and SARS-CoV-2 mRNA and antigen detection. Tissue ACE2 and TMPRSS2 protein levels did not change with age. ACE2 was not more abundant in male kidneys in any age group. ACE2 protein was associated with proximal tubule apical membranes in cortex. TMPRSS2 was observed predominantly in the medulla. ACE2 was elevated significantly in uEVs and urine from patients with COVID-19 with no sex difference compared with urine from controls w/wo albuminuria. TMPRSS2 was elevated in uEVs from males compared to female. ACE2 and TMPRSS2 did not co-localize in uEVs/apical membranes. SARS-CoV-2 nucleoprotein and mRNA were not detected in urine. Higher kidney ACE2 protein abundance is unlikely to explain higher susceptibility to SARS-CoV-2 infection in males. Kidney tubular cells appear not highly susceptible to SARS-CoV-2 infection. Loss of ACE2 into urine in COVID could impact susceptibility and angiotensin metabolism.

BACKGROUND : Rosmarinic acid (RA) is a natural polyphenolic substance contained in many Lamiaceae herbs such as Perilla frutescens. Previous studies have shown RA has antioxidative and anti-inflammatory activity. However, little is known on the absorption, metabolism, degradation and excretion of RA. AIM OF THE STUDY : The aim of this study in healthy humans was to determine the absorption, metabolism, and urinary excretion of RA after a single intake of perilla extract (PE). METHOD : Six healthy men (mean age 37.2 ± 6.2 y and mean body mass index 22.0 ± 1.9 kg/m²) were enrolled in the study that was a crossover design involving single intakes of PE containing 200 mg RA and placebo with a 10 day interval between treatments. Blood samples were collected before intake and at designated time intervals, while urine samples were collected over the periods 0-6 h, 6-24 h and 24-48 h after intake. RA and its related metabolites in plasma and urine were measured by LC-MS. RESULTS : RA, methylated RA (methyl-RA), caffeic acid (CAA), ferulic acid (FA) and a trace of m-coumaric acid (COA) were detected in the urine after intake of PE. In plasma, RA, methyl-RA and FA were detected, with maximum levels obtained 0.5, 2 and 0.5 h after intake of PE, respectively. The majority of these components in both plasma and urine were present as conjugated forms (glucuronide and/or sulfated). The proportion of RA and its related metabolites excreted in the urine was 6.3 ± 2.2% of the total dose,with approximately 75% of these components being excreted within 6h after intake of PE. CONCLUSIONS : RA contained in PE was absorbed, conjugated and methylated following intake,with a small proportion of RA being degraded into various components, such as conjugated forms of CAA, FA and COA. These metabolites were then rapidly excreted in the urine.