DNA Damage in Chronic Kidney Disease: Evaluation of Clinical Biomarkers.
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ABSTRACT:
SUBMITTER: Schupp N
PROVIDER: S-EPMC4897719 | biostudies-other | 2016
REPOSITORIES: biostudies-other
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Project description:BackgroundWhether the increased incidence of chronic kidney disease (CKD) during intensive systolic blood pressure (SBP) lowering is accompanied by intrinsic kidney injury is unknown.ObjectiveTo compare changes in kidney damage biomarkers between incident CKD case participants and matched control participants as well as between case participants in the intensive (<120 mm Hg) versus the standard (<140 mm Hg) SBP management groups of SPRINT (Systolic Blood Pressure Intervention Trial).DesignNested case-control study within SPRINT.SettingAdults with hypertension without baseline kidney disease.ParticipantsCase participants (n = 162), who developed incident CKD during trial follow-up (128 in the intensive and 34 in the standard group), and control participants (n = 162) without incident CKD, who were matched on age, sex, race, baseline estimated glomerular filtration rate, and randomization group.Measurements9 urinary biomarkers of kidney damage were measured at baseline and at 1 year. Linear mixed-effects models were used to estimate 1-year biomarker changes.ResultsHigher concentrations of urinary albumin, kidney injury molecule-1, and monocyte chemoattractant protein-1 at baseline were significantly associated with greater odds of incident CKD (adjusted odds ratio per doubling: 1.50 [95% CI, 1.14 to 1.98], 1.51 [CI, 1.05 to 2.17], and 1.70 [CI, 1.13 to 2.56], respectively). After 1 year of blood pressure intervention, incident CKD case participants in the intensive group had significantly greater decreases in albumin-creatinine ratio (ACR), interleukin-18, anti-chitinase-3-like protein 1 (YKL-40), and uromodulin than the matched control participants. Compared with case participants in the standard group, those in the intensive group had significantly greater decreases in ACR, β2-microglobulin, α1-microglobulin, YKL-40, and uromodulin.LimitationBiomarker measurements were available only at baseline and 1 year.ConclusionIncident CKD in the setting of intensive SBP lowering was accompanied by decreases, rather than elevations, in levels of kidney damage biomarkers and thus may reflect benign changes in renal blood flow rather than intrinsic injury.Primary funding sourceNational Institute for Diabetes and Digestive and Kidney Diseases.
| S-EPMC6953744 | biostudies-literature
Project description:Mesenchymal stem cells (MSCs) are promising source of cell-based regenerative therapy. In consideration of the risk of allosensitization, autologous MSC-based therapy is preferred over allogenic transplantation in patients with chronic kidney disease (CKD). However, it remains uncertain whether adequate cell functionality is maintained under uremic conditions. As chronic inflammation and oxidative stress in CKD may lead to the accumulation of senescent cells, we investigated cellular senescence of CKD MSCs and determined the effects of metformin on CKD-associated cellular senescence in bone marrow MSCs from sham-operated and subtotal nephrectomized mice and further explored in adipose tissue-derived MSCs from healthy kidney donors and patients with CKD. CKD MSCs showed reduced proliferation, accelerated senescence, and increased DNA damage as compared to control MSCs. These changes were significantly attenuated following metformin treatment. Lipopolysaccharide and transforming growth factor β1-treated HK2 cells showed lower tubular expression of proinflammatory and fibrogenesis markers upon co-culture with metformin-treated CKD MSCs than with untreated CKD MSCs, suggestive of enhanced paracrine action of CKD MSCs mediated by metformin. In unilateral ureteral obstruction kidneys, metformin-treated CKD MSCs more effectively attenuated inflammation and fibrosis as compared to untreated CKD MSCs. Thus, metformin preconditioning may exhibit a therapeutic benefit by targeting accelerated senescence of CKD MSCs.
| S-EPMC7884040 | biostudies-literature
Project description:Chronic kidney disease (CKD), defined as the presence of albuminuria and/or reduction in estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, is considered a growing public health problem, with its prevalence and incidence having almost doubled in the past three decades. The implementation of novel biomarkers in clinical practice is crucial, since it could allow earlier diagnosis and lead to an improvement in CKD outcomes. Nevertheless, a clear guidance on how to develop biomarkers in the setting of CKD is not yet available. The aim of this review is to report the framework for implementing biomarkers in observational and intervention studies. Biomarkers are classified as either prognostic or predictive; the first type is used to identify the likelihood of a patient to develop an endpoint regardless of treatment, whereas the second type is used to determine whether the patient is likely to benefit from a specific treatment. Many single assays and complex biomarkers were shown to improve the prediction of cardiovascular and kidney outcomes in CKD patients on top of the traditional risk factors. Biomarkers were also shown to improve clinical trial designs. Understanding the correct ways to validate and implement novel biomarkers in CKD will help to mitigate the global burden of CKD and to improve the individual prognosis of these high-risk patients.
| S-EPMC7461617 | biostudies-literature
Project description:Uremic cardiomyopathy (UC), the peculiar cardiac remodeling secondary to the systemic effects of renal dysfunction, is characterized by left ventricular (LV) diffuse fibrosis with hypertrophy (LVH) and stiffness and the development of heart failure and increased rates of cardiovascular mortality. Several imaging modalities can be used to obtain a non-invasive assessment of UC by different imaging biomarkers, which is the focus of the present review. Echocardiography has been largely employed in recent decades, especially for the determination of LVH by 2-dimensional imaging and diastolic dysfunction by pulsed-wave and tissue Doppler, where it retains a robust prognostic value; more recent techniques include parametric assessment of cardiac deformation by speckle tracking echocardiography and the use of 3D-imaging. Cardiac magnetic resonance (CMR) imaging allows a more accurate assessment of cardiac dimensions, including the right heart, and deformation by feature-tracking imaging; however, the most evident added value of CMR remains tissue characterization. T1 mapping demonstrated diffuse fibrosis in CKD patients, increasing with the worsening of renal disease and evident even in early stages of the disease, with few, but emerging, prognostic data. Some studies using T2 mapping highlighted the presence of subtle, diffuse myocardial edema. Finally, computed tomography, though rarely used to specifically assess UC, might provide incidental findings carrying prognostic relevance, including information on cardiac and vascular calcification. In summary, non-invasive cardiovascular imaging provides a wealth of imaging biomarkers for the characterization and risk-stratification of UC; integrating results from different imaging techniques can aid a better understanding of the physiopathology of UC and improve the clinical management of patients with CKD.
| S-EPMC10216582 | biostudies-literature
Project description:The interrelationship of multiple endothelial biomarkers and chronic kidney disease (CKD) has not been well studied. We measured asymmetric dimethylarginine (ADMA), L-arginine, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), von Willebrand factor (vWF), flow-mediated dilation (FMD), and nitroglycerin-induced dilation (NID) in 201 patients with CKD and 201 community-based controls without CKD. Multivariable analyses were used to examine the interrelationship of endothelial biomarkers with CKD. The multivariable-adjusted medians (interquartile ranges) were 0.54 (0.40, 0.75) in patients with CKD vs. 0.25 (0.22, 0.27) μmol /L in controls without CKD (p<0.0001 for group difference) for ADMA; 67.0 (49.6, 86.7) vs. 31.0 (27.7, 34.2) μmol/L (p<0.0001) for L-arginine; 230.0 (171.6, 278.6) vs. 223.9 (178.0, 270.6) ng/mL (p=0.55) for sICAM-1; 981.7 (782.6, 1216.8) vs. 633.2 (507.8, 764.3) ng/mL (p<0.0001) for sVCAM-1; 47.9 (35.0, 62.5) vs. 37.0 (28.9, 48.0) ng/mL (p=0.01) for sE-selectin; 1320 (1044, 1664) vs. 1083 (756, 1359) mU/mL (p=0.008) for vWF; 5.74 (3.29, 8.72) vs. 8.80 (6.50, 11.39)% (p=0.01) for FMD; and 15.2 (13.5, 16.9) vs. 19.1 (17.2, 21.0)% (p=0.0002) for NID, respectively. In addition, the severity of CKD was positively associated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF and inversely associated with FMD and NID. Furthermore, FMD and NID were significantly and inversely correlated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF. In conclusion, these data indicate that multiple dysfunctions of the endothelium were present among patients with CKD. Interventional studies are warranted to test the effects of treatment of endothelial dysfunction on CKD.
| S-EPMC4488859 | biostudies-other
Project description:Fractures across the stages of chronic kidney disease (CKD) could be due to osteoporosis, some form of renal osteodystrophy defined by specific quantitative histomorphometry or chronic kidney disease-mineral and bone disorder (CKD-MBD). CKD-MBD is a systemic disease that links disorders of mineral and bone metabolism due to CKD to either one or all of the following: abnormalities of calcium, phosphorus, parathyroid hormone or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, linear growth or strength; or vascular or other soft-tissue calcification. Osteoporosis, as defined by The National Institutes of Health, may coexist with renal osteodystrophy or CKD-MBD. Differentiation among these disorders is required to manage correctly the correct disorder to reduce the risk of fractures. While the World Health Organization (WHO) BMD criteria for osteoporosis can be used in patients with stages 1-3 CKD, the disorders of bone turnover become so aberrant by stages 4 and 5 CKD that neither the WHO criteria nor the occurrence of a fragility fracture can be used for the diagnosis of osteoporosis. The diagnosis of osteoporosis in stages 4 and 5 CKD is one of the exclusion-excluding either renal osteodystrophy or CKD-MBD as the cause of low BMD or fragility fractures. Differentiations among the disorders of renal osteodystrophy, CKD-MBD or osteoporosis are dependent on the measurement of specific biochemical markers, including serum parathyroid hormone (PTH) and/or quantitative bone histomorphometry. Management of fractures in stages 1-3 CKD does not differ in persons with or without CKD with osteoporosis assuming there is no evidence for CKD-MBD, clinically suspected by elevated PTH, hyperphosphatemia or fibroblast growth factor 23 due to CKD. Treatment of fractures in persons with osteoporosis and stages 4 and 5 CKD is not evidence based, with the exception of post hoc analysis suggesting efficacy and safety of specific osteoporosis therapies (alendronate, risedronate and denosumab) in stage 4 CKD. This review also discusses how to diagnose and manage fragility fractures across the five stages of CKD.
| S-EPMC4078413 | biostudies-other
Project description:BackgroundChronic kidney disease (CKD) has few objective symptoms, and it is difficult to make an early diagnosis by using existing methods. Therefore, new biomarkers enabling diagnosis of renal dysfunction at an early stage need to be developed. Here, we searched for new biomarkers of CKD by focusing on kidney-derived proteins that could sensitively reflect that organ's disease state.MethodsTo identify candidate marker proteins, we performed a proteomics analysis on renal influx and efflux blood collected from the same individual.ResultsProteomics analysis revealed 662 proteins in influx blood and 809 in efflux. From these identified proteins, we selected complement C1q as a candidate; the plasma C1q level was significantly elevated in the renal efflux of donors. Moreover, the plasma concentration of C1q in a mouse model of diabetic nephropathy was significantly increased, in association with increases in blood glucose concentration and urinary protein content. Importantly, we demonstrated that the tendency of C1q to increase in the plasma of CKD patients was correlated with a decrease in their estimated glomerular filtration rate.ConclusionOverall, our results indicate that our approach of focusing on kidney-derived proteins is useful for identifying new CKD biomarkers and that C1q has potential as a biomarker of renal function.
| S-EPMC8903635 | biostudies-literature
Project description:Chronic kidney disease (CKD) patients have an accelerated atherosclerosis, increased risk of thrombotic-ischemic complications, and excessive mortality rates when compared with the general population. There is also evidence of an endothelial damage in which the proinflammatory state, the enhanced oxidative stress, or the accumulation of toxins due to their reduced renal clearance in uremia play a role. Further, there is evidence that uremic endothelial cells are both involved in and victims of the activation of the innate immunity. Uremic endothelial cells produce danger associated molecular patterns (DAMPS), which by binding to specific pattern recognition receptors expressed in multiple cells, including endothelial cells, induce the expression of adhesion molecules, the production of proinflammatory cytokines and an enhanced production of reactive oxygen species in endothelial cells, which constitute a link between immunity and inflammation. The connection between endothelial damage, inflammation and defective immunity in uremia will be reviewed here.
| S-EPMC7354562 | biostudies-literature
Project description:It is well-established that there is a crosstalk between the lung and the kidney, and several studies have reported association between chronic kidney disease (CKD) and pulmonary pathophysiological changes. Experimentally, CKD can be caused in mice by dietary intake of adenine. Nevertheless, the consequence of such intervention on the lung received only scant attention. Here, we assessed the pulmonary effects of adenine (0.2% w/w in feed for 4 weeks)-induced CKD in mice by assessing various physiological histological and biochemical endpoints. Adenine treatment induced a significant increase in urine output, urea and creatinine concentrations, and it decreased the body weight and creatinine clearance. It also increased proteinuria and the urinary levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Compared with control group, the histopathological evaluation of lungs from adenine-treated mice showed polymorphonuclear leukocytes infiltration in alveolar and bronchial walls, injury, and fibrosis. Moreover, adenine caused a significant increase in lung lipid peroxidation and reactive oxygen species and decreased the antioxidant catalase. Adenine also induced DNA damage assessed by COMET assay. Similarly, adenine caused apoptosis in the lung characterized by a significant increase of cleaved caspase-3. Moreover, adenine induced a significant increase in the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) in the lung. We conclude that administration of adenine in mice induced CKD is accompanied by lung oxidative stress, DNA damage, apoptosis, and Nrf2 expression and fibrosis.
| S-EPMC5703828 | biostudies-literature
Project description:BACKGROUND:Growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) are emerging predictors of adverse clinical outcomes. We examined whether circulating concentrations are related to the development of kidney disease in the community. METHODS:Plasma GDF-15, sST2, and hsTnI concentrations were measured in 2614 Framingham Offspring cohort participants (mean age 57 years, 54% women) at the sixth examination cycle (1995-1998). Associations of biomarkers with incident chronic kidney disease [CKD, eGFR <60 mL · min(-1) · (1.73 m(2)) (-1), n = 276], microalbuminuria (urinary albumin to creatinine ratio ?25 mg/g in women and 17 mg/g in men, n = 191), and rapid decline in renal function [decline in eGFR ?3 mL · min(-1) · (1.73 m(2)) (-1) per year, n = 237], were evaluated using multivariable logistic regression; P < 0.006 was considered statistically significant in primary analyses. RESULTS:Participants were followed over a mean of 9.5 years. Higher plasma GDF-15 was associated with incident CKD [multivariable-adjusted odds ratio (OR) 1.9 per 1-U increase in log-GDF-15, 95% CI 1.6-2.3, P < 0.0001] and rapid decline in renal function (OR, 1.6; 95% CI, 1.3-1.8; P < 0.0001). GDF-15, sST2, and hsTnI had suggestive associations with incident microalbuminuria but did not meet the prespecified P-value threshold after multivariable adjustment. Adding plasma GDF-15 to clinical covariates improved risk prediction of incident CKD: the c-statistic increased from 0.826 to 0.845 (P = 0.0007), and categorical net reclassification was 6.3% (95% CI, 2.7-9.9%). CONCLUSIONS:Higher circulating GDF-15 is associated with incident renal outcomes and improves risk prediction of incident CKD. These findings may provide insights into the mechanisms of renal injury.
| S-EPMC3972213 | biostudies-literature