RATIONALE & OBJECTIVE Plasma kidney injury molecule-1 (KIM-1) is a sensitive marker of proxim... more RATIONALE & OBJECTIVE Plasma kidney injury molecule-1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown. STUDY DESIGN Prospective, observational cohort study. SETTING & PARTICIPANTS 524 individuals undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histopathology by two kidney pathologists enrolled into the Boston Kidney Biopsy Cohort (BKBC) Study and 3,800 individuals with common forms of chronic kidney disease (CKD) enrolled into the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE Histopathologic lesions and clinicopathologic diagnosis in cross-sectional analyses, baseline plasma KIM-1 in prospective analyses. OUTCOMES Baseline plasma KIM-1 in cross-sectional analyses, kidney failure (defined as initiation of kidney replacement therapy) and death in prospective analyses. ANALYTICAL APPROACH Multivariable-adjusted linear regression models tested associations of plasma KIM-1 with histopathologic lesions and clinicopathologic diagnoses. Cox proportional hazards models tested associations of plasma KIM-1 with future kidney failure and death. RESULTS In the BKBC Study, higher plasma KIM-levels were associated with more severe acute tubular injury, tubulointerstitial inflammation, and more severe mesangial expansion after multivariable adjustment. Participants with diabetic nephropathy, glomerulopathies, and tubulointerstitial disease had significantly higher plasma KIM-1 levels after multivariable adjustment. In the BKBC Study, 124 participants progressed to kidney failure and 85 participants died during a median follow-up time of 5 years. In the CRIC Study, 1153 participants progressed to kidney failure and 1356 participants died during a median follow-up time of 11.5 years. In both cohorts, each doubling of plasma KIM-1 was associated with an increased risk of kidney failure after multivariable adjustment (BKBC: HR 1.19, 95% CI 1.03 to 1.38 and CRIC: HR 1.10, 95% CI 1.06 to 1.15). There was no statistically significant association of plasma KIM-1 with death in either cohort. LIMITATIONS Generalizability and unmeasured confounding. CONCLUSIONS Plasma KIM-1 is associated with underlying tubulointerstitial and mesangial lesions and progression to kidney failure in two cohort studies of individuals with kidney diseases.
Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/c... more Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3β (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.
Journal of The American Society of Nephrology, Jul 1, 1993
The two major hypotheses for the pathogenesis of amphotericin nephrotoxicity are direct interacti... more The two major hypotheses for the pathogenesis of amphotericin nephrotoxicity are direct interaction with epithelial cell membranes and vasoconstriction. Studies indicating the special vulnerability of the medullary ray and medulla to hypoxia led to a reexamination of amphotericin nephrotoxicity. Twenty-four rats were divided into four groups: amphotericin injection (5 mg/kg daily for 3 wk), amphotericin plus salt depletion, vehicle, and salt depletion and vehicle. The amphotericin group had polyuria (P < 0.01) but normal serum creatinine. In contrast, amphotericin plus salt depletion rats exhibited renal failure (creatinine of 1.49 +/- 0.05 versus amphotericin alone 0.98 +/- 0.01; P < 0.01). Semiquantitative histologic analysis of cortical and medullary injury correlated with functional impairment. Cortical changes in the amphotericin group were largely restricted to the medullary ray, where focal rupture and calcification of thick ascending limbs were noted. The S2/S3 tubules in the medullary rays showed focally diminished cell complexity with histiocytic/lymphocytic infiltration. However, calcification was also seen in the area of the macula densa. Morphometry revealed that the thick ascending limbs in the medulla were hypertrophied (1,420 +/- 63 versus 1,195 +/- 48 microns 2 for vehicle; P < 0.05). In contrast, in the amphotericin and salt depletion group, the changes in the medullary ray extended to the labyrinth and the thick ascending limbs in the inner stripe showed atrophic changes (772 +/- 23 microns 2; P < 0.01 versus vehicle). Thus, changes as a result of amphotericin toxicity take place both in areas known to be most vulnerable to hypoxia (medullary ray and medulla), and in areas rich in oxygen (adjacent to glomerulus). Salt depletion potentiates the cortical changes and converts medullary hypertrophy to atrophy. These findings support a dual pathogenesis for amphotericin nephropathy (direct toxicity and vasoconstriction).
International Journal of Gynecological Pathology, Jul 18, 2023
Mallory-Denk bodies (MBD), described in alcoholic hepatitis, are composed of intermediate filamen... more Mallory-Denk bodies (MBD), described in alcoholic hepatitis, are composed of intermediate filaments admixed with other proteins. These cytoplasmic inclusions are irregularly shaped and eosinophilic as seen under the light microscope. MBD-like inclusions have rarely been described outside the hepatobiliary tree. Though rare, intracytoplasmic inclusions have been reported in ovarian fibromas. This study evaluates a series of torsed ovarian fibromas with intracytoplasmic inclusions resembling MDBs. Forty-three ovarian fibromas were retrieved from the pathology archives. The H&E slides were evaluated for the presence of MBD-like inclusions and histologic evidence of torsion. The cases with histologic features of torsion were included in the study group while the nontorsed fibromas formed the control group. Among the 15 cases of fibromas with torsion, MBD-like intracytoplasmic inclusions were seen in 5 cases, predominantly in the interface between necrotic areas and viable stroma. None of the cases from the control group showed any inclusions. There was no significant difference in the size of the fibroma or patient demographics between cases with and without inclusions. The inclusions were positive for cytokeratin and ubiquitin while being negative for per acidic Schiff and periodic acid-Schiff with diastase reaction, in the 3 cases selected for immunohistochemistry and special stains. Electron microscopy of the index case revealed a predominance of type 3 Mallory hyaline. This is the first report describing MDB-like inclusions in ovarian fibromas. These MDB-like inclusions appear to be limited to a fraction of ovarian fibromas that underwent torsion, suggesting that these inclusions likely result from subacute hypoxic damage to the cells.
Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pat... more Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway and the principal source of NADPH, a major cellular reductant, and is central to cell survival. Our previous work showed that diabetes and increased aldosterone are acquired forms of G6PD deficiency, leading to decreased G6PD activity and NADPH levels and damage to kidney tissue and endothelial cells. In this study, G6PD-deficient mice were studied to test the hypothesis that decreased G6PD activity per se can cause changes similar to those seen in the acquired conditions of G6PD deficiency. Results show that as compared with control mice, G6PD-deficient mice had increased oxidative stress, as manifested by decreased NADPH levels and decreased GSH levels, and increased markers of lipid peroxidation. G6PD-deficient mice had increased protein kinase C activity, increased nuclear factor-kappaB activity, and increased urinary albumin levels, all of which is similar to changes seen in diabetic mice. Changes persisted as the mice aged, as old G6PD-deficient mice (17-20 mo) had higher urine albumin levels and also had evidence for increased apoptosis in the renal cortex. These results show that decreased G6PD activity per se is sufficient to cause changes similar to those seen in diabetic mice.
The T cell–specific adaptor protein (TSAd), encoded by the SH2D2A gene, is an intracellular molec... more The T cell–specific adaptor protein (TSAd), encoded by the SH2D2A gene, is an intracellular molecule that binds Lck to elicit signals that result in cytokine production in CD4+ T effector cells (Teff). Nevertheless, using Sh2d2a knockout (KO; also called TSAd−/−) mice, we find that alloimmune CD4+ Teff responses are fully competent in vivo. Furthermore, and contrary to expectations, we find that allograft rejection is accelerated in KO recipients of MHC class II–mismatched B6.C-H-2bm12 heart transplants versus wild-type (WT) recipients. Also, KO recipients of fully MHC-mismatched cardiac allografts are resistant to the graft-prolonging effects of costimulatory blockade. Using adoptive transfer models, we find that KO T regulatory cells (Tregs) are less efficient in suppressing Teff function and they produce IFN-γ following mitogenic activation. In addition, pyrosequencing demonstrated higher levels of methylation of CpG regions within the Treg-specific demethylated region of KO vers...
RATIONALE AND OBJECTIVES Tubular secretion plays an important role in the efficient elimination o... more RATIONALE AND OBJECTIVES Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) was associated with lower tubular secretory clearance in persons undergoing kidney biopsy. STUDY DESIGN Cross sectional. SETTINGS AND PARTICIPANTS The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications. EXPOSURES Semi-quantitive score of IFTA reported by two trained pathologists. OUTCOMES We measured plasma and urine concentrations of nine endogenous secretory solutes using a targeted liquid chromatography mass-spectroscopy assay. We used linear regression to test associations of urine to plasma ratios (UPR) of these solutes with IFTA score after controlling for estimated GFR (eGFR) and albuminuria. RESULTS Among 418 persons, the mean age was 53 years, 51% were women, 64% were White and 18% were Black. The mean eGFR was 50 ml/min/1.73m2 and median albumin/creatinine ratio was 819 mg/g. Compared to individuals with <25% IFTA, those with >50% IFTA had 12 to 37% lower UPR for the all 9 secretory solutes. Adjusting for age, sex, race, eGFR and urinary albumin and creatinine attenuated the associations, yet trend of lower secretion across groups remained statistically significant (p for trend <0.05) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (p for trend <0.05). LIMITATIONS Single time point and spot measures of secretory solutes. CONCLUSIONS Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.
RATIONALE & OBJECTIVE Plasma kidney injury molecule-1 (KIM-1) is a sensitive marker of proxim... more RATIONALE & OBJECTIVE Plasma kidney injury molecule-1 (KIM-1) is a sensitive marker of proximal tubule injury, but its association with risks of adverse clinical outcomes across a spectrum of kidney diseases is unknown. STUDY DESIGN Prospective, observational cohort study. SETTING & PARTICIPANTS 524 individuals undergoing clinically indicated native kidney biopsy with biopsy specimens adjudicated for semiquantitative scores of histopathology by two kidney pathologists enrolled into the Boston Kidney Biopsy Cohort (BKBC) Study and 3,800 individuals with common forms of chronic kidney disease (CKD) enrolled into the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE Histopathologic lesions and clinicopathologic diagnosis in cross-sectional analyses, baseline plasma KIM-1 in prospective analyses. OUTCOMES Baseline plasma KIM-1 in cross-sectional analyses, kidney failure (defined as initiation of kidney replacement therapy) and death in prospective analyses. ANALYTICAL APPROACH Multivariable-adjusted linear regression models tested associations of plasma KIM-1 with histopathologic lesions and clinicopathologic diagnoses. Cox proportional hazards models tested associations of plasma KIM-1 with future kidney failure and death. RESULTS In the BKBC Study, higher plasma KIM-levels were associated with more severe acute tubular injury, tubulointerstitial inflammation, and more severe mesangial expansion after multivariable adjustment. Participants with diabetic nephropathy, glomerulopathies, and tubulointerstitial disease had significantly higher plasma KIM-1 levels after multivariable adjustment. In the BKBC Study, 124 participants progressed to kidney failure and 85 participants died during a median follow-up time of 5 years. In the CRIC Study, 1153 participants progressed to kidney failure and 1356 participants died during a median follow-up time of 11.5 years. In both cohorts, each doubling of plasma KIM-1 was associated with an increased risk of kidney failure after multivariable adjustment (BKBC: HR 1.19, 95% CI 1.03 to 1.38 and CRIC: HR 1.10, 95% CI 1.06 to 1.15). There was no statistically significant association of plasma KIM-1 with death in either cohort. LIMITATIONS Generalizability and unmeasured confounding. CONCLUSIONS Plasma KIM-1 is associated with underlying tubulointerstitial and mesangial lesions and progression to kidney failure in two cohort studies of individuals with kidney diseases.
Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/c... more Transplant glomerulopathy (TG) is a major cause of late allograft loss. Increased urine podocin/creatinine ratio in TG signifies accelerated podocyte loss. The mechanisms that lead to podocyte injury in TG remain unclear. We report that IgG from kidney transplant recipients with TG, but not from those without TG, cause a reduction in the expression of nephrin, significant podocyte actin cytoskeleton, and motility changes. These changes are preceded by increased expression of calcium/calmodulin kinase IV (CAMK4). Mechanistically, we found that CAMK4 phosphorylates GSK3β (glycogen synthase kinase 3 beta), activates the Wnt pathway and stabilizes the nephrin transcriptional repressor SNAIL. Silencing neonatal Fc Receptor (FcRn) or CAMK4 prevented the podocyte-damaging effects of IgG from patients with TG. Furthermore, we show that removal of N-linked glycosyl residues from these IgG did not interfere with its entry into the podocytes but eliminated its ability to upregulate CAMK4 and cause podocyte injury. The translational value of these findings is signified by the fact that CAMK4 is increased in podocytes of patients with TG but not in those without TG despite other forms of renal dysfunction. Our results offer novel considerations to limit podocyte injury in patients with kidney transplants, which may lead to eventual glomerular destabilization and transplant glomerulopathy.
Journal of The American Society of Nephrology, Jul 1, 1993
The two major hypotheses for the pathogenesis of amphotericin nephrotoxicity are direct interacti... more The two major hypotheses for the pathogenesis of amphotericin nephrotoxicity are direct interaction with epithelial cell membranes and vasoconstriction. Studies indicating the special vulnerability of the medullary ray and medulla to hypoxia led to a reexamination of amphotericin nephrotoxicity. Twenty-four rats were divided into four groups: amphotericin injection (5 mg/kg daily for 3 wk), amphotericin plus salt depletion, vehicle, and salt depletion and vehicle. The amphotericin group had polyuria (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01) but normal serum creatinine. In contrast, amphotericin plus salt depletion rats exhibited renal failure (creatinine of 1.49 +/- 0.05 versus amphotericin alone 0.98 +/- 0.01; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). Semiquantitative histologic analysis of cortical and medullary injury correlated with functional impairment. Cortical changes in the amphotericin group were largely restricted to the medullary ray, where focal rupture and calcification of thick ascending limbs were noted. The S2/S3 tubules in the medullary rays showed focally diminished cell complexity with histiocytic/lymphocytic infiltration. However, calcification was also seen in the area of the macula densa. Morphometry revealed that the thick ascending limbs in the medulla were hypertrophied (1,420 +/- 63 versus 1,195 +/- 48 microns 2 for vehicle; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). In contrast, in the amphotericin and salt depletion group, the changes in the medullary ray extended to the labyrinth and the thick ascending limbs in the inner stripe showed atrophic changes (772 +/- 23 microns 2; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01 versus vehicle). Thus, changes as a result of amphotericin toxicity take place both in areas known to be most vulnerable to hypoxia (medullary ray and medulla), and in areas rich in oxygen (adjacent to glomerulus). Salt depletion potentiates the cortical changes and converts medullary hypertrophy to atrophy. These findings support a dual pathogenesis for amphotericin nephropathy (direct toxicity and vasoconstriction).
International Journal of Gynecological Pathology, Jul 18, 2023
Mallory-Denk bodies (MBD), described in alcoholic hepatitis, are composed of intermediate filamen... more Mallory-Denk bodies (MBD), described in alcoholic hepatitis, are composed of intermediate filaments admixed with other proteins. These cytoplasmic inclusions are irregularly shaped and eosinophilic as seen under the light microscope. MBD-like inclusions have rarely been described outside the hepatobiliary tree. Though rare, intracytoplasmic inclusions have been reported in ovarian fibromas. This study evaluates a series of torsed ovarian fibromas with intracytoplasmic inclusions resembling MDBs. Forty-three ovarian fibromas were retrieved from the pathology archives. The H&amp;E slides were evaluated for the presence of MBD-like inclusions and histologic evidence of torsion. The cases with histologic features of torsion were included in the study group while the nontorsed fibromas formed the control group. Among the 15 cases of fibromas with torsion, MBD-like intracytoplasmic inclusions were seen in 5 cases, predominantly in the interface between necrotic areas and viable stroma. None of the cases from the control group showed any inclusions. There was no significant difference in the size of the fibroma or patient demographics between cases with and without inclusions. The inclusions were positive for cytokeratin and ubiquitin while being negative for per acidic Schiff and periodic acid-Schiff with diastase reaction, in the 3 cases selected for immunohistochemistry and special stains. Electron microscopy of the index case revealed a predominance of type 3 Mallory hyaline. This is the first report describing MDB-like inclusions in ovarian fibromas. These MDB-like inclusions appear to be limited to a fraction of ovarian fibromas that underwent torsion, suggesting that these inclusions likely result from subacute hypoxic damage to the cells.
Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pat... more Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway and the principal source of NADPH, a major cellular reductant, and is central to cell survival. Our previous work showed that diabetes and increased aldosterone are acquired forms of G6PD deficiency, leading to decreased G6PD activity and NADPH levels and damage to kidney tissue and endothelial cells. In this study, G6PD-deficient mice were studied to test the hypothesis that decreased G6PD activity per se can cause changes similar to those seen in the acquired conditions of G6PD deficiency. Results show that as compared with control mice, G6PD-deficient mice had increased oxidative stress, as manifested by decreased NADPH levels and decreased GSH levels, and increased markers of lipid peroxidation. G6PD-deficient mice had increased protein kinase C activity, increased nuclear factor-kappaB activity, and increased urinary albumin levels, all of which is similar to changes seen in diabetic mice. Changes persisted as the mice aged, as old G6PD-deficient mice (17-20 mo) had higher urine albumin levels and also had evidence for increased apoptosis in the renal cortex. These results show that decreased G6PD activity per se is sufficient to cause changes similar to those seen in diabetic mice.
The T cell–specific adaptor protein (TSAd), encoded by the SH2D2A gene, is an intracellular molec... more The T cell–specific adaptor protein (TSAd), encoded by the SH2D2A gene, is an intracellular molecule that binds Lck to elicit signals that result in cytokine production in CD4+ T effector cells (Teff). Nevertheless, using Sh2d2a knockout (KO; also called TSAd−/−) mice, we find that alloimmune CD4+ Teff responses are fully competent in vivo. Furthermore, and contrary to expectations, we find that allograft rejection is accelerated in KO recipients of MHC class II–mismatched B6.C-H-2bm12 heart transplants versus wild-type (WT) recipients. Also, KO recipients of fully MHC-mismatched cardiac allografts are resistant to the graft-prolonging effects of costimulatory blockade. Using adoptive transfer models, we find that KO T regulatory cells (Tregs) are less efficient in suppressing Teff function and they produce IFN-γ following mitogenic activation. In addition, pyrosequencing demonstrated higher levels of methylation of CpG regions within the Treg-specific demethylated region of KO vers...
RATIONALE AND OBJECTIVES Tubular secretion plays an important role in the efficient elimination o... more RATIONALE AND OBJECTIVES Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) was associated with lower tubular secretory clearance in persons undergoing kidney biopsy. STUDY DESIGN Cross sectional. SETTINGS AND PARTICIPANTS The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications. EXPOSURES Semi-quantitive score of IFTA reported by two trained pathologists. OUTCOMES We measured plasma and urine concentrations of nine endogenous secretory solutes using a targeted liquid chromatography mass-spectroscopy assay. We used linear regression to test associations of urine to plasma ratios (UPR) of these solutes with IFTA score after controlling for estimated GFR (eGFR) and albuminuria. RESULTS Among 418 persons, the mean age was 53 years, 51% were women, 64% were White and 18% were Black. The mean eGFR was 50 ml/min/1.73m2 and median albumin/creatinine ratio was 819 mg/g. Compared to individuals with <25% IFTA, those with >50% IFTA had 12 to 37% lower UPR for the all 9 secretory solutes. Adjusting for age, sex, race, eGFR and urinary albumin and creatinine attenuated the associations, yet trend of lower secretion across groups remained statistically significant (p for trend <0.05) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (p for trend <0.05). LIMITATIONS Single time point and spot measures of secretory solutes. CONCLUSIONS Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.
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