Tarak Srivastava1, Wenjun Ju2, Ginger L Milne3, Mohamed H Rezaiekhaligh4, Vincent S Staggs5, Uri S Alon4, Ram Sharma6, Jianping Zhou7, Ashraf El-Meanawy8, Ellen T McCarthy9, Virginia J Savin10, Mukut Sharma11. 1. Division of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, United States; Research and Development, Nephrology, Kansas City VA Medical Center, Kansas City, MO, United States. Electronic address: tsrivastava@cmh.edu. 2. Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States. 3. Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN, United States. 4. Division of Nephrology, Children's Mercy Hospital and University of Missouri at Kansas City, Kansas City, MO, United States. 5. Biostatistics & Epidemiology Core, Children's Mercy Kansas City, Department of Pediatrics, University of Missouri, Kansas City, United States. 6. Research and Development, Nephrology, Kansas City VA Medical Center, Kansas City, MO, United States. 7. Research and Development, Nephrology, Kansas City VA Medical Center, Kansas City, MO, United States; Midwest Biomedical Research Foundation (MBRF), KCVA Medical Center, Kansas City, MO, United States. 8. Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, United States. 9. Kidney Institute, Kansas University Medical Center, Kansas City, KS, United States. 10. Research and Development, Nephrology, Kansas City VA Medical Center, Kansas City, MO, United States; Kidney Institute, Kansas University Medical Center, Kansas City, KS, United States. 11. Research and Development, Nephrology, Kansas City VA Medical Center, Kansas City, MO, United States; Midwest Biomedical Research Foundation (MBRF), KCVA Medical Center, Kansas City, MO, United States; Kidney Institute, Kansas University Medical Center, Kansas City, KS, United States.
Abstract
INTRODUCTION: Hyperfiltration is a major contributor to progression of chronic kidney disease (CKD) in diabetes, obesity and in individuals with solitary functioning kidney (SFK). We have proposed hyperfiltration-induced injury as a continuum of overlapping glomerular changes caused by increased biomechanical forces namely, fluid flow shear stress (FFSS) and tensile stress. We have shown that FFSS is elevated in animals with SFK and, it upregulates prostaglandin E2 (PGE2), cyclooxygenase-2 and PGE2 receptor EP2 in cultured podocytes and in uninephrectomized mice. We conceptualized urinary PGE2 as a biomarker of early effects of hyperfiltration-induced injury preceding microalbuminuria in individuals with SFK. We studied children with SFK to validate our hypothesis. METHODS: Urine samples from children with SFK and controls were analyzed for PGE2, albumin (glomerular injury biomarker) and epidermal growth factor (EGF, tubular injury biomarker). Age, gender, and Z-scores for height, weight, BMI, and blood pressure were obtained. RESULTS: Children with SFK were comparable to controls except for lower BMI Z-scores. The median values were elevated in SFK compared to control for urine PGE2 [9.1 (n = 57) vs. 5.7 (n = 72), p = 0.009] ng/mgCr and albumin [7.6 (n = 40) vs. 7.0 (n = 41), p = 0.085] μg/mgCr, but not for EGF [20098 (n = 44) vs. 18637 (n = 44), p = 0.746] pg/mgCr. Significant increase in urinary PGE2 (p = 0.024) and albumin (p = 0.019) but not EGF (p = 0.412) was observed using additional regression modeling. These three urinary analytes were independent of each other. CONCLUSION: Increased urinary PGE2 from elevated SNGFR and consequently increased FFSS during early stage of CKD precedes overt microalbuminuria and is a biomarker for early hyperfiltration-induced injury in individuals with SFK.
INTRODUCTION: Hyperfiltration is a major contributor to progression of chronic kidney disease (CKD) in diabetes, obesity and in individuals with solitary functioning kidney (SFK). We have proposed hyperfiltration-induced injury as a continuum of overlapping glomerular changes caused by increased biomechanical forces namely, fluid flow shear stress (FFSS) and tensile stress. We have shown that FFSS is elevated in animals with SFK and, it upregulates prostaglandin E2 (PGE2), cyclooxygenase-2 and PGE2 receptor EP2 in cultured podocytes and in uninephrectomized mice. We conceptualized urinary PGE2 as a biomarker of early effects of hyperfiltration-induced injury preceding microalbuminuria in individuals with SFK. We studied children with SFK to validate our hypothesis. METHODS: Urine samples from children with SFK and controls were analyzed for PGE2, albumin (glomerular injury biomarker) and epidermal growth factor (EGF, tubular injury biomarker). Age, gender, and Z-scores for height, weight, BMI, and blood pressure were obtained. RESULTS: Children with SFK were comparable to controls except for lower BMI Z-scores. The median values were elevated in SFK compared to control for urine PGE2 [9.1 (n = 57) vs. 5.7 (n = 72), p = 0.009] ng/mgCr and albumin [7.6 (n = 40) vs. 7.0 (n = 41), p = 0.085] μg/mgCr, but not for EGF [20098 (n = 44) vs. 18637 (n = 44), p = 0.746] pg/mgCr. Significant increase in urinary PGE2 (p = 0.024) and albumin (p = 0.019) but not EGF (p = 0.412) was observed using additional regression modeling. These three urinary analytes were independent of each other. CONCLUSION: Increased urinary PGE2 from elevated SNGFR and consequently increased FFSS during early stage of CKD precedes overt microalbuminuria and is a biomarker for early hyperfiltration-induced injury in individuals with SFK.
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