Optimizing energy use in the kidney is critical for normal kidney function. Here, we investigate the effect of hyperglycemia and sodium-glucose cotransporter 2 (SGLT2) inhibition on urinary amino acid excretion in individuals with type 1 diabetes (T1D). The open-label ATIRMA trial assessed the impact of 8 weeks of 25 mg empagliflozin orally once per day in 40 normotensive normoalbuminuric young adults with T1D. A consecutive 2-day assessment of clamped euglycemia and hyperglycemia was evaluated at baseline and posttreatment visits. Principal component analysis was performed on urinary amino acids grouped into representative metabolic pathways using MetaboAnalyst. At baseline, acute hyperglycemia was associated with changes in 25 of the 33 urinary amino acids or their metabolites. The most significant amino acid metabolites affected by acute hyperglycemia were 3-hydroxykynurenine, serotonin, glycyl-histidine, and nicotinic acid. The changes in amino acid metabolites were reflected by the induction of four biosynthetic pathways: aminoacyl-tRNA; valine, leucine, and isoleucine; arginine; and phenylalanine, tyrosine, and tryptophan. In acute hyperglycemia, empagliflozin significantly attenuated the increases in aminoacyl-tRNA biosynthesis and valine, leucine, and isoleucine biosynthesis. Our findings using amino acid metabolomics indicate that hyperglycemia stimulates biosynthetic pathways in T1D. SGLT2 inhibition may attenuate the increase in biosynthetic pathways to optimize kidney energy metabolism. 

Interactive effects of Empagliflozin and Hyperglycemia on Urinary Amino Acids in Individuals with Type 1 Diabetes.

Diabetic kidney disease (DKD) can lead to end-stage kidney disease (ESKD) and mortality, however, few mechanistic biomarkers are available for high risk patients, especially those without macroalbuminuria. Urine from participants with diabetes from Chronic Renal Insufficiency Cohort (CRIC), Singapore Study of Macro-Angiopathy and Reactivity in Type 2 Diabetes (SMART2D), and the Pima Indian Study determined if urine adenine/creatinine ratio (UAdCR) could be a mechanistic biomarker for ESKD. ESKD and mortality were associated with the highest UAdCR tertile in CRIC (HR 1.57, 1.18, 2.10) and SMART2D (HR 1.77, 1.00, 3.12). ESKD was associated with the highest UAdCR tertile in patients without macroalbuminuria in CRIC (HR 2.36, 1.26, 4.39), SMART2D (HR 2.39, 1.08, 5.29), and Pima Indian study (HR 4.57, CI 1.37-13.34). Empagliflozin lowered UAdCR in non-macroalbuminuric participants. Spatial metabolomics localized adenine to kidney pathology and transcriptomics identified ribonucleoprotein biogenesis as a top pathway in proximal tubules of patients without macroalbuminuria, implicating mammalian target of rapamycin (mTOR). Adenine stimulated matrix in tubular cells via mTOR and stimulated mTOR in mouse kidneys. A specific inhibitor of adenine production was found to reduce kidney hypertrophy and kidney injury in diabetic mice. We propose that endogenous adenine may be a causative factor in DKD.

/pdf/role-of-endogenous-adenine-in-kidney-failure-and-mortality-1va1oppr.pdf

Role of endogenous adenine in kidney failure and mortality with diabetes

<h3>Purpose/Objective(s)</h3> There is substantial controversy about the benefit of prostate-specific antigen (PSA) screening. PSA screening rates have declined since 2008 due to changing practice guidelines and conflicting clinical trial results regarding the benefit of screening. Since then, the incidence of metastatic prostate cancer (mPCa) has risen; however, there is no direct epidemiologic evidence of a correlation between population PSA screening rates and subsequent mPCa rates. <h3>Materials/Methods</h3> We used data from the United States Veterans Healthcare Administration (VHA) to calculate yearly PSA screening rates, long-term non-screening rates (no PSA measured in prior three years), and age-adjusted mPCa incidence rates from 2005 to 2019. Rates are reported per 100,000 men and were aggregated by race, age group, and VHA facility (128 facilities). We used random effects linear regression to examine the influence of yearly facility-level PSA screening rates from 2010-2013 on subsequent facility-level mPCa incidence from 2014-2019, adjusting for population demographics. <h3>Results</h3> The cohort included 4.7 million men in 2005 and increased to 5.4 million in 2019. PSA screening rates declined from a high of 50.8% in 2008 to 37% in 2019, with declines in all age and race groups; the long-term non-screening rate similarly increased in this period. mPCa incidence increased from a low of 4.6 in 2008 to 7.9 in 2019, driven by increases in the 55-69 and 70+ year old age groups. Lower facility-level PSA screening rates were associated with higher subsequent mPCa incidence (0.87 unit increase in 2014-2019 mPCa incidence rate per 10% decrease in 2010-2013 PSA screening rate, 95% confidence interval [CI] 0.58 to 1.15, p<0.001). Similarly, higher long-term non-screening rates were associated with higher subsequent mPCa incidence (1.61 unit increase in 2014-2019 mPCa incidence rate per 10% increase in 2010-2013 long-term non-screening rate, 95% CI 1.14 to 2.08, p<0.001). <h3>Conclusion</h3> From 2008 to 2019, PSA screening rates declined and long-term non-screening rates increased in the national VHA system. Lower facility-level PSA screening rates were associated with higher subsequent rates of mPCa. These data can be used to inform shared decision making about the potential benefits of PSA screening in men who wish to reduce their risk of prostate cancer metastases. 

Association of Prostate-Specific Antigen Screening Rates and Subsequent Metastatic Prostate Cancer Incidence in a National Healthcare System

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Role of endogenous adenine in kidney failure and mortality with diabetes

Association of Prostate-Specific Antigen Screening Rates and Subsequent Metastatic Prostate Cancer Incidence in a National Healthcare System