scholarly journals Orosomucoid As a Biomarker for Chronic Kidney Disease Associated with Sickle Cell Anemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2352-2352
Author(s):  
Ammanuel Taye ◽  
Nathan Smith ◽  
Nowah Kokou Apeadoufia Afangbedji ◽  
Xiaomei Niu ◽  
James G. Taylor ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Research Funding ◽  
Urine Samples ◽  
Cell Disease ◽  
Howard University ◽  
Ckd Stage ◽  
Stage 1

Abstract BACKGROUND: Chronic kidney disease (CDK) is a serious and highly prevalent complication of Sickle cell anemia (SCA). Proteinuria and microalbuminuria can be under-detected in SCA because of the renal concentrating defect. Hence, complementary diagnostic biomarkers are necessary for early detection of CKD in patient with SCA. Our recent study identified alpha 1-acid glycoprotein (orosomucoid, ORM) (1) as potential biomarker of CKD. ORM is a major acute phase inflammatory protein synthesized by the liver and its presence in urine may indicate underlying inflammation in SCA patients. OBJECTIVES: We aimed to validate ORM as biomarker for CKD in a cohort of SCA patients recruited at Howard University. METHODS: We analyzed samples collected from patients enrolled in a sickle cell disease registry study at Center for Sickle Cell Disease, Howard University. Plasma and urine samples were collected and stored at -80°C. Plasma samples were assayed for creatinine and cystatin C. Urine samples were analyzed for albumin, creatinine and ORM. Multistix was used to determine protein, blood, pH and specific gravity (SG) in urine samples. Estimated GFR (eGFR) was calculated using CKD-EPI creatinine-cystatin equation. CKD stages were assigned according to the National Kidney Foundation, Kidney Disease Outcomes Quality Initiatives (K/DOQI) guidelines: stage 0 - eGFR>60 ml/min/1.73m2 and AL/CRE<30 mg/g; stage 1- eGFR>90 ml/min/1.73m2 and AL/CRE≥30 mg/g; stage 2 - eGFR 60-89 ml/min/1.73m2 and AL/CRE≥30 mg/g, stage 3 - eGFR 30 - 59 /1.73m2; stage 4 - eGFR 15 - 29 ml/min/1.73m2 and stage 5 - eGFR < 15 ml/min/1.73m2. Glomerular hyperfiltration was defined as eGFR>130 ml/min/1.73 m2 for females and eGFR>140 ml/min/1.73 m2 for males. RESULTS: The Howard University registry study group consisted of 96 patients (mean age 38.1 years, range 18 - 67 years, 55% females) and included 65.6% HbSS, 21.8% HbSC, 7.2% HbS β+thalassemia, 4.1% HbS β0 thalassemia. Based on urinary dipstick test, proteinurea was detected in 16.5% patient. Hyperfiltration was detected in 45 patients (56.3%). CDK (combined stage 1-4) was detected in 35.8% patients. No difference was found between females and males in CKD prevalence. Prevalence of CKD in HbSC patients was 11% whereas it was 37% in HbSS patients. Prevalence of CDK increased with the age. The overall urinary ORM/CRE levels demonstrated modest correlation with CKD stage (R2=0.22). Next we stratified samples based on the levels of ORM/CRE. The samples were separated into two groups: (i) samples with no or mild inflammation (ORM/CRE<10μg/mg) and (ii) samples that displayed significant inflammation (ORM/CRE>10 μg/mg). We observed strong inverse correlation between the percentage of samples without inflammation and CKD stage (R2=0.996). We also observed strong correlation of CDK progression with number of samples with significant inflammation (R2=0.996). Sensitivity of ORM/CRE was 53.8%, specificity 70.2% and odds ratio OR 2.72 for samples with CKD stages 1-4 compared to the samples without CKD (stage 1). CONCLUSIONS: In our cohort, determination of proteinurea evaluated by dipstick (16%) grossly underestimated CKD prevalence (35%) determined by eGFR and AL/CRE ratios. Subjects with HbSC had 3-fold less prevalence of CKD comparing to the patients with HbSS. ORM/CRE levels correlated with the stages of CKD stages (OR 2.72). Further longitudinal study is needed to determine whether ORM/CRE ratio can be used as a prognostic marker of renal disease development. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants 1P50HL118006, 1R01HL125005 and 5G12MD007597. AT was supported by ASH MMSAP summer program. The content is solely the responsibility of the authors and does not necessarily represent the official view of NHLBI, NIMHD or NIH. REFERENCES: Jerebtsova, M., Saraf, S. L., Soni, S., Afangbedji, N., Lin, X., Raslan, R., Gordeuk, V. R., and Nekhai, S. (2018) Urinary orosomucoid is associated with progressive chronic kidney disease stage in patients with sickle cell anemia. American journal of hematology93, E107-E109 Disclosures Taylor: Pfizer: Research Funding; NHLBI: Research Funding. Nekhai:NIAID, NIH: Research Funding; NIMHD, NIH: Research Funding; NHLBI, NIH: Research Funding.

Urinary Kringle Domain-Containing Protein HGFL: A Validated Biomarker of Early Sickle Cell Anemia-Associated Kidney Disease

2021 ◽  
pp. 1-6
Author(s):  
Sergei Nekhai ◽  
Xionghao Lin ◽  
Simran Soni ◽  
Ammanuel Taye ◽  
Nathan Smith ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Glomerular Filtration ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Early Stage ◽  
Kringle Domain ◽  
Additional Information ◽  
Howard University ◽  
Ckd Stage ◽  
Stage 1

<b><i>Introduction:</i></b> Chronic kidney disease (CKD) is a prevalent complication of sickle cell anemia (SCA). Hyperfiltration that delayed detection of CKD is common in SCA patients. Identification of novel urinary biomarkers correlating with glomerular filtration rates may help to detect and predict progression of renal disease. <b><i>Methods:</i></b> Reanalysis of mass spectra of urinary samples obtained from University of Illinois at Chicago identified kringle domain-containing protein HGFL. <b><i>Results:</i></b> HGFL levels correlated with hyperfiltration, were significantly reduced at CKD stage 1 compared to stage 0, negatively correlated with progression of CKD and were suitable for differentiation of stage 1. Better prediction of CKD progression to stage 2 was observed for HGFL-based risk prediction compared to the estimated glomerular filtration rate (eGFR)-based prediction. Results from a Howard University patient cohort supported the utility of HGFL-based test for the differentiation of stage 1 of CKD. <b><i>Conclusion:</i></b> Urinary HGFL may contribute additional information beyond eGFR and improve diagnosis of early-stage CKD in SCA patients.

scholarly journals Genetic Modifiers Influencing the Development of Albuminuria in Children with Sickle Cell Anemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3393-3393
Author(s):  
Beverly A Schaefer ◽  
Jonathan M Flanagan ◽  
Banu Aygun ◽  
Ofelia A. Alvarez ◽  
Stephen C Nelson ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Renal Disease ◽  
Candidate Genes ◽  
Genetic Polymorphisms ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Genetic Variants ◽  
Research Funding ◽  
Increased Risk

Abstract Background: Nephropathy in sickle cell anemia (SCA) begins in childhood and portends chronic kidney disease, renal failure, and early mortality among affected adults. Individuals of African descent have disproportionately higher rates of developing non-diabetic renal disease. Several candidate genetic variants have been identified, including some specific to African Americans, which are associated with the development of albuminuria and renal disease. The influence of genetic polymorphisms on albuminuria and elevated glomerular filtration rate (GFR) in children with SCA, both early signs of sickle nephropathy, has not been investigated. Objectives: To determine the influence of selected single nucleotide polymorphisms (SNPs) on the development of albuminuria and elevated GFR in children with SCA; to identify novel genetic variants influencing albuminuria and GFR by whole exome sequencing (WES). Design/Methods: Genomic DNA was collected on children with SCA enrolled in two prospective studies with pre-hydroxyurea renal assessments (n=185): (1) Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175, n=79) with no prior disease-modifying therapy; and (2) Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH, NCT 01425307, n=106) on chronic transfusions for abnormal TCD velocities. Albuminuria was defined as ≥30mg albumin/gm creatinine on the pre-hydroxyurea urine specimen. GFR was measured in HUSTLE using plasma DTPA (technetium 99m-labeled diethylenetriaminepentaacetic acid) clearance, and estimated GFR (eGFR) in TWiTCH based on serum creatinine. DNA samples were genotyped for 8 candidate SNPs previously associated with renal disease, using PCR-based allelic discrimination, bidirectional Sanger sequencing, and analysis of variable number tandem repeats (VNTR). Associations between albuminuria and genetic polymorphisms were tested using an additive model and correlation trend test. Linked WES data from the same patients were analyzed to identify other variants associated with albuminuria and GFR. Results: Albuminuria was present in 13.1% of patients, including 16.3% in HUSTLE and 11.0% in TWiTCH. APOL1 genetic variants were common (G1 allele frequency = 21.9%, G2 allele = 16.0%, Table) and similar to published cohorts. Children with two APOL1 G1 alleles had an increased risk of albuminuria that approached statistical significance (p=0.053). Conversely, the presence of the DARC SNP that confers Duffy antigen expression had a protective effect (p=.038). WES analysis did not identify additional non-synonymous APOL1 variants linked with albuminuria. However, 93 non-synonymous variants were associated with DTPA GFR (p<0.001). Using patients with eGFR as a validation cohort, 7 variants in FUBP1, ZFAND4, CD163, GMFG and HLA-E maintained their association with kidney filtrative function (p<0.05). In particular, two variants in CD163, which is a macrophage scavenger receptor for hemoglobin-haptoglobin complexes, were strongly associated with increased GFR in both patient cohorts. Table 1. Candidate genes associated with microalbuminuria. All SNPs were tested with either an additive or recessive genetic model. *The eNOS VNTR was analyzed by the chi-square method. Gene SNP Location MAF Albuminuria (Additive) Variant frequency Cases Controls APOL1 G1 rs73885319 22q12 21.9% 0.053 32.0% 20.3% APOL1 G2 rs71785313 22q12 16.0% 0.445 10.0% 16.0% DARC rs2814778 1q23 13.6% 0.038 4.2% 15.7% eNOS 4a VNTR 7q35 31.2% 0.333* 31.5% 22.7% eNOS rs1799983 7q35 12.5% 0.663 14.6% 12.2% eNOS rs2070744 7q35 15.6% 0.299 10.4% 16.3% CUBN rs7918972 10p12 16.2% 0.457 12.5% 16.8% CUBN rs1801239 10p12 2.7% 0.199 0.0% 3.1% Conclusion: Genetic polymorphisms associated with chronic kidney disease in African American adults may influence the development of early-onset albuminuria among children with SCA, including an increased risk among children with ≥1 APOL1 G1 alleles and a decreased risk associated with the DARC SNP. Previously published eNOS and CUBN variants had no measureable effects. WES analysis suggests novel genetic variants including CD163 SNPs may influence the development of elevated GFR in children with SCA, and provide candidate genes for future research. Disclosures Off Label Use: Hydroxyurea is FDA approved for the treatment of sickle cell anemia in adults, but has not yet been approved in children. . Nottage:Janssen Pharmaceuticals: Employment. Ware:Biomedomics: Research Funding; Bristol Myers Squibb: Research Funding; Bayer Pharmaceuticals: Consultancy; Eli Lilly: Other: DSMB membership.

scholarly journals Chronic Kidney Disease Is Under-Screened in SCD and Mild Albuminuria Is Associated with a Drop in Hemoglobin: A Report from the Grndad Sickle Cell Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2284-2284
Author(s):  
Elizabeth Williams ◽  
Elizabeth Brown ◽  
Deepa Manwani ◽  
Payal Desai ◽  
Joshua J. Field ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Sickle Cell Disease ◽  
Kidney Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

The Globin Research Network for Data and Discovery (GRNDaD) is a combined effort, from 6 US clinical sites (Baltimore, Cleveland, Columbus OH, Milwaukee, Oakland, and The Bronx) that care for people with sickle cell disease (SCD), to improve care through shared data collection and review and quality improvement. Using a single IRB-Reliant protocol, we have assembled harmonized baseline and annual data on 758 adults with sickle cell disease (41.7% male and 58.3% female, mean age 35.5), collected on a REDCap server housed at Johns Hopkins. For this study, we reviewed adherence to the 2014 NHLBI Guidelines on the management of SCD -- which recommends annual screening for chronic kidney disease (CKD) by testing for albuminuria or proteinuria in anyone over the age of 10 with sickle cell disease. To evaluate whether subjects had an annual visit in any given year we used the recording of a well visit hemoglobin. Of the 758 adults in the study 411 had at least one year of follow up data marked as completed. Among these 411 adults there were 826 distinct observations. Of these 826 observations, 137 observations among 85 subjects did not have any hemoglobin lab drawn, suggesting that they did not have a well outpatient visit during that year. Amongst the observation years, where a well hemoglobin was performed, yearly screening for albuminuria occurred in 37.4% (258/689) of annual observations. There was an association between having screening for CKD and site of care (p<.0001), with some sites having adhered to guidelines in 34.2% of observation years and others having adhered 75.9% of years. There was no association between adherence and genotype or sex. Albuminuria was associated with a clinical phenotype. A multi-variable linear mixed effects model controlling for age and gender with a randomly varying intercept based on the subject, excluding chronically transfused subjects, and stratified by sickle cell anemia (HbSS or HbSB0, SCA) or variant genotypes was used. There was a significant association in those with SCA between the presence of albuminuria between 30 and 300, level (A2) and hemoglobin. Hemoglobin levels were, on average, 0.79 g/dL lower in those with albuminuria between 30-300 when compared to those with no albuminuria (A1, P=0.005). For those with SCA and albuminuria greater than 300 (A3), the sample size was small (n=28) and hemoglobin levels were 0.61 g/dl lower compared to those without albuminuria but this was not statistically significant (p=0.12). For those with variant compound heterozygous SCD and A2 albuminuria, hemoglobin levels were not statistically significantly different from those without albuminuria. However, high-grade albuminuria (A3) was associated with hemoglobin levels which were, on average, 1.86 g/dL lower than those in group A1 (P=0.004). Interestingly, the association between reduced hemoglobin and albuminuria was seen in both variant and SCA genotypes in the context of a preserved creatinine (<1.0 mg/dL). Using a multisite registry we demonstrate the need to develop strategies to assist providers and patients with adherence to guideline based recommendations for routine screening for chronic kidney disease in adults with SCD. The early association of albuminuria with worsening anemia, even in the absence of elevated creatinine levels, suggests an added urgency to screening. The causality of the association remains unclear but emphasizes the need for longitudinally followed cohorts that might help us understand the relationship between anemia and the development of CKD. Figure Disclosures Manwani: Novartis: Consultancy; Pfizer: Consultancy; GBT: Consultancy, Research Funding. Desai:Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Pittsburgh: Research Funding; Ironwood: Other: Adjudication Board; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Potomac: Speakers Bureau. Field:Ironwood: Consultancy, Research Funding; Rigel: Research Funding; Prolong: Research Funding; Incyte: Research Funding. Neumayr:La Jolla Pharmaceuticals: Research Funding; Pfizer: Consultancy, Research Funding; Bayer: Consultancy; CTD Holdings: Consultancy; CDC: Research Funding; Celgene: Research Funding; Imara: Research Funding; NHLBI: Research Funding; Sangamo: Research Funding; HRSA: Research Funding; GBT: Research Funding; Emmaus: Consultancy; Apopharma: Consultancy; Sancillo: Research Funding; Novartis: Research Funding; Bluebird Bio: Research Funding; Silarus: Research Funding; Terumo: Research Funding; PCORI: Research Funding; Doris Duke Foundation: Research Funding; Seattle Children's Research Grants: Research Funding. Clay:Novartis: Speakers Bureau. Cong:Global Blood Therapeutics: Employment, Equity Ownership. Agodoa:Global Blood Therapeutics: Employment, Equity Ownership. Hoppe:Global Blood Therapeutics: Employment, Equity Ownership. Lanzkron:PCORI: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Research Funding; Ironwood: Research Funding; HRSA: Research Funding; NIH: Research Funding. Little:Hemex Health, Inc.: Patents & Royalties; GBT: Research Funding.

scholarly journals The Effect of Crizanlizumab Plus Standard of Care (SoC) Versus Soc Alone on Renal Function in Patients with Sickle Cell Disease and Chronic Kidney Disease: A Randomized, Multicenter, Open-Label, Phase II Study (STEADFAST)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1018-1018
Author(s):  
Kenneth I. Ataga ◽  
Santosh L. Saraf ◽  
Vimal K. Derebail ◽  
Claire C. Sharpe ◽  
Adlette Inati ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Ace Inhibitors ◽  
Research Funding ◽  
Standard Of Care ◽  
Creatinine Ratio ◽  
Cell Disease ◽  
Advisory Committees

Background: Sickle cell disease (SCD) is an inherited genetic disorder that results in the formation of sickle hemoglobin (HbS). HbS polymerizes when deoxygenated, deforming erythrocytes and leading to chronic hemolysis, anemia and vaso-occlusion. Sickle cell nephropathy (SCN) is the term used to describe the renal complications of SCD. Renal vaso-occlusion and hemolysis contribute to the manifestations of SCN which include hyperfiltration and progressive renal impairment. Chronic kidney disease (CKD) is diagnosed if abnormalities in kidney structure or function are present for >3 months. The prevalence of CKD in patients with SCD increases with age, and ~12% of patients progress to end-stage renal disease (Gosmanova et al. J Investig Med 2014; Powars et al. Medicine 2005). There are no treatments approved for CKD caused by SCD. Standard of care (SoC) typically consists of angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs) and/or hydroxyurea (HU). Evidence for the clinical effectiveness of ARBs and ACE inhibitors has been generated mainly from trials in other causes of kidney disease or short-term studies in SCD. P-selectin contributes to vaso-occlusion by mediating adhesion of sickled erythrocytes and leukocytes to the endothelium. Crizanlizumab is a humanized monoclonal antibody that binds to P-selectin with high affinity and specificity. In SUSTAIN, crizanlizumab significantly reduced the median annual rate of vaso-occlusive crises compared with placebo (Ataga et al. N Engl J Med 2017). Preclinical data show P-selectin expression in the kidneys and upregulation in response to renal ischemia-reperfusion injury (Singbartl et al. FASEB J 2000; Zizzi et al. J Pediatr Surg 1997). Crizanlizumab may have a beneficial effect in patients with SCD and CKD by blocking P-selectin-mediated multicellular adhesion, reducing the effects of vaso-occlusion in the renal vasculature and slowing the decline in renal function. The aim of the STEADFAST study is to determine if crizanlizumab can slow the progression of CKD due to SCD (EUDRACT no. 2018-003608-38). Methods: Approximately 170 patients aged ≥16 years with CKD due to SCD will be enrolled. Eligible patients will have HbSS or HbSβ0-thalassemia genotypes, an estimated glomerular filtration rate (eGFR) ≥45 to ≤120 mL/min/1.73 m2, an albumin-to-creatinine ratio (ACR) ≥100 to <2000 mg/g and be receiving SoC (which includes HU, ACE inhibitors and/or ARBs) for SCD and/or CKD. Patients must have been receiving SoC for ≥6 months and plan to continue at the same dose and schedule until study end. Exclusion criteria include history of stem cell transplant, chronic red blood cell transfusion therapy, acute kidney injury (AKI) within 3 months of study entry, and patients undergoing hemodialysis. Patients will be randomized to receive crizanlizumab 5.0 mg/kg plus SoC or SoC alone. Patients in the combination arm will receive crizanlizumab 5.0 mg/kg by IV infusion over 30 minutes on day 1 of week 1, followed by a second dose 2 weeks later, after which it will be administered every 4 weeks. The total treatment period is 12 months. Primary endpoint: proportion of patients with a ≥30% decrease from baseline in ACR at 12 months, based on the intent-to-treat population. A logistic regression model including treatment effects and stratification factors will be utilized and the test (based on the log-odds ratio estimated by the model) will be carried out at the 1-sided significance level of 0.025. Secondary endpoints include mean change in ACR from baseline to 3, 6, 9, and 12 months, proportion of patients with ≥30% decrease in ACR at 6 months, proportion of patients with ≥20% improvement of protein-to-creatinine ratio (PCR) at 12 months, percentage change in eGFR from baseline to 3, 6, 9, and 12 months, and the proportion of patients with progression of CKD (based on decline in eGFR category accompanied by a ≥25% drop in eGFR from baseline) from baseline to 12 months. Exploratory endpoints include improvement in renal and cardiac biomarkers at 3, 6, 9, and 12 months and tricuspid regurgitation velocity (TRV) <2.5 m/s at 12 months among patients with abnormal TRV at baseline. Conclusion: CKD is a common complication of SCD. The STEADFAST study will evaluate whether crizanlizumab, in combination with SoC, can reduce albuminuria and slow CKD progression, thus providing evidence of a reno-protective effect of crizanlizumab. Figure Disclosures Ataga: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Modus Therapeutics: Honoraria. Saraf:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Derebail:RTI: Honoraria; Novartis: Consultancy; Retrophin: Consultancy. Sharpe:Novartis: Consultancy. Inati:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Global Blood Therapeutics: Research Funding. Lebensburger:Pfizer: Research Funding; Novartis: Consultancy. DeBonnett:Novartis Pharmaceuticals Corporation: Employment. Zhang:Novartis: Employment. Bartolucci:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Use of Multiple Urinary Biomarkers for Early Detection of Chronic Kidney Disease in Sickle Cell Anemia Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-30
Author(s):  
Yagahira E. Castro-Sesquen ◽  
Santosh L. Saraf ◽  
Victor R. Gordeuk ◽  
Sergei Nekhai ◽  
Marina Jerebtsova
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Early Detection ◽  
Research Funding ◽  
Urinary Biomarkers ◽  
Complete Model ◽  
Advisory Committees ◽  
Ckd Stage ◽  
Stage 1 ◽  
Hepatocyte Growth

BACKGROUND : More than 60% of sickle cell anemia (SCA) adults develop chronic kidney disease (CKD). Identification of early stages of CKD in SCA patients at high risk of complications could lead to personalized treatment and better prognosis. Recently we identified several urinary biomarkers that can differentiate CKD stage 1 in SCA patients. These biomarkers reflect pathophysiology of SCA, including iron homeostasis (ceruloplasmin, transferrin, hemoglobin, and ferritin); inflammation (orosomucoid); and glomerular hyperfiltration (hepatocyte growth factor like). HYPOTHESIS: We hypothesized that combination of novel urinary biomarkers might improve the accuracy of early detection of CKD. METHODS : We evaluated spot urine samples of 54 patients with SCA in a steady state from the University of Illinois at Chicago. Patients were classified by the stage of chronic kidney disease (CKD) based on the National Kidney Foundation, Kidney Disease Outcomes Quality Initiatives guidelines. Three groups of CKD stages were compared: Stage 0 (without CKD, n=23), stage 1 (early stage of CKD, n=19), and stages 2 to 5 (moderate to severe CKD, n=12). Urine levels of ceruloplasmin (CP), transferrin (TrF), hemoglobin (Hgb), ferritin (FrT), orosomucoid (ORM), and hepatocyte growth factor like (HGFL) were measured by ELISA and normalized to urinary creatinine (CRE) concentrations. Differences in sensitivity and specificity of biomarker combinations were compared using the McNemar's Test against the simple model, which uses urine Hgb only, and the complete model, with all the biomarkers together. A test for the equality of the Area Under the Curve (AUC) compared to the simple and complete models was done using the algorithm suggested by DeLong, DeLong, and Clarke-Pearson (1988). RESULTS: We tested the ability of each biomarker to distinguish SCA patients without CKD and with CKD stage 1. Receiver operating characteristic (ROC) curves were constructed to determine appropriate cutoffs for each biomarker. Cutoffs that provided the highest Youden Indexes were used. Three biomarkers (Hgb, CP, and ORM) had a sensitivity of 100%; however, specificity was lower than 80% (range: 65.2%-72.7%). Other biomarkers (Frt, Trf, and HGFL) had sensitivities lower than 80%, suggesting that individually these biomarkers are not accurate for early detection of CKD. We compared different combinations to the single biomarker model (Hgb only or model 0) and a complete combination of six biomarkers (model 1) (Table 1). The complete combination significantly improved specificity (from 69.6 to 82.6%) and increased AUC (from 0.86 to 0.96) compared to the single biomarker model. All combinations significantly increased the specificity (from 69.6% to 78.3-82.7%) compared to the single biomarker model. Combinations of four to five biomarkers (models 1-6) significantly increased specificity and AUC values than model 0. Combination of Hgb + CP+ ORM + Frt produced similar specificity and AUC values compared to complete model. CONCLUSION: These results demonstrate that the use of multiple biomarkers can improve the accuracy in the detection of kidney pathology in SCD patients, which has essential value for clinicians and researchers of clinical trials to target high-risk individuals for early treatment and preventive care. LIMITATION: Small cohort of patients from one center. Disclosures Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Boards, Speakers Bureau; Novartis, Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer, Global Blood Therapeutics, Novartis: Research Funding. Gordeuk:Imara: Research Funding; Novartis: Consultancy; Ironwood: Research Funding; CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding.

scholarly journals The Copenhagen chronic kidney disease echo study (COInCYDE)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N Landler ◽  
S Bro ◽  
B Feldt-Rasmussen ◽  
D Hansen ◽  
A.L Kamper ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Cohort Study ◽  
Kidney Disease ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Funding Source ◽  
Ckd Stage ◽  
Significant Difference ◽  
Stage 1

Abstract Background The cardiovascular mortality of patients with chronic kidney disease (CKD) is 2–10 times higher than in the average population. Purpose To estimate the prevalence of abnormal cardiac function or structure across the stages CKD 1 to 5nonD. Method Prospective cohort study. Patients with CKD stage 1 to 5 not on dialysis, aged 30 to 75 (n=875) and age-/sex-matched controls (n=173) were enrolled consecutively. All participants underwent a health questionnaire, ECG, morphometric and blood pressure measurements. Blood and urine were analyzed. Echocardiography was performed. Left ventricle (LV) hypertrophy, dilatation, diastolic and systolic dysfunction were defined according to current ESC guidelines. Results 63% of participants were men. Mean age was 58 years (SD 12.6 years). Mean eGFR was 46.7 mL/min/1,73 m (SD 25.8) for patients and 82.3 mL/min/1,73 m (SD 13.4) for controls. The prevalence of elevated blood pressure at physical exam was 89% in patients vs. 53% in controls. Patients were more often smokers and obese. Left ventricular mass index (LVMI) was slightly, albeit insignificantly elevated at CKD stages 1 & 2 vs. in kontrols: 3.1 g/m2, CI: −0.4 to 6.75, p-value 0.08. There was no significant difference in LV-dilatation between patients and controls. Decreasing diastolic and systolic function was observed at CKD stage 3a and later: LVEF decreased 0.95% (CI: −1.5 to −0.2), GLS increased 0.5 (CI: 0.3 to 0.8), and OR for diastolic dysfunction increased 3.2 (CI 1.4 to 7.3) pr. increment CKD stage group. Conclusion In accordance to previous studies, we observe in the CPHCKD cohort study signs of early increase of LVMI in patients with CKD stage 1 & 2. Significant decline in systolic and diastolic cardiac function is apparent already at stage 3 CKD. Figure 1. Estimated GFR vs. GLS & histogram of GLS Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): The Capital Region of Denmark

scholarly journals FGF-23 and Phosphate in Children with Chronic Kidney Disease: A Cross-Sectional Study in Kazakhstan

Medicina ◽  
2020 ◽  
Vol 57 (1) ◽  
pp. 15
Author(s):  
Altynay Balmukhanova ◽  
Kairat Kabulbayev ◽  
Harika Alpay ◽  
Assiya Kanatbayeva ◽  
Aigul Balmukhanova
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Fibroblast Growth Factor 23 ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Cross Sectional ◽  
Ckd Stage ◽  
Advanced Stages ◽  
Fgf 23 ◽  
Stage 1

Background and objectives: Chronic kidney disease (CKD) in children is a complex medical and social issue around the world. One of the serious complications is mineral-bone disorder (CKD-MBD) which might determine the prognosis of patients and their quality of life. Fibroblast growth factor 23 (FGF-23) is a phosphaturic hormone which is involved in the pathogenesis of CKD-MBD. The purpose of the study was to determine what comes first in children with CKD: FGF-23 or phosphate. Materials and Methods: This cross-sectional study included 73 children aged 2–18 years with CKD stages 1–5. We measured FGF-23 and other bone markers in blood samples and studied their associations. Results: Early elevations of FGF-23 were identified in children with CKD stage 2 compared with stage 1 (1.6 (1.5–1.8) pmol/L versus 0.65 (0.22–1.08), p = 0.029). There were significant differences between the advanced stages of the disease. FGF-23 correlated with PTH (r = 0.807, p = 0.000) and phosphate (r = 0.473, p = 0.000). Our study revealed that the elevated level of FGF-23 went ahead hyperphosphatemia and elevated PTH. Thus, more than 50% of children with CKD stage 2 had the elevating level of serum FGF-23, and that index became increasing with the disease progression and it achieved 100% at the dialysis stage. The serum phosphate increased more slowly and only 70.6% of children with CKD stage 5 had the increased values. The PTH increase was more dynamic. Conclusions: FGF-23 is an essential biomarker, elevates long before other markers of bone metabolism (phosphate), and might represent a clinical course of disease.

scholarly journals Comparative analysis of physical development parameters of children with stages 1 to 3 of chronic kidney disease

2017 ◽  
Vol 98 (1) ◽  
pp. 5-9
Author(s):  
T L Nastausheva ◽  
O A Zhdanova ◽  
N S Nastausheva ◽  
L I Stahurlova ◽  
I V Grebennikova
Keyword(s):  
Chronic Kidney Disease ◽  
Comparative Analysis ◽  
Kidney Disease ◽  
Physical Development ◽  
Average Height ◽  
Time Period ◽  
Ckd Stage ◽  
Group 2 ◽  
Stage 1 ◽  
Group 1

Aim. To conduct comparative analysis of height, weight and body mass index in children with stages 1 to 3 of chronic kidney disease (CKD) caused by recurrent urinary tract infection due to congenital anomalies of kidney and urinary tract.Methods. The study was performed on 210 children: 110 patients examined in 2001-2002 (group 1) and 100 children examined in 2011-2012 (group 2). Stage 1 of CKD was observed in 94 (85.4%) children in group 1 and in 93 (93%) in group 2, stage 2 - in 16 (14.6%) and 7 (7%) patients, respectively. From both groups patients matched by sex, age, diagnosis and social status were selected: 20 patients with stage 1, 19 children with stage 2; in addition, 6 children with stage 3 were examined.Results. Nowadays children with CKD stage 1 are taller compared to patients of the beginning of the XXI century (Z-score: -0.14±1.43 and 0.20±0.98 respectively, p=0.01). Significant differences in weight were found in children with stage 1 in 2011-2012 compared to the patients in 2001-2002 (0.18±0.46 and 0.78±1.19 for groups 1 and 2, respectively, р=0.026). A tendency towards decrease of average height in children with stage 3 is observed compared to patients with stage 1, i.e. due to the progression of the disease.Conclusion. The data obtained reflect modern tendencies towards increase of children height and weight. No significant differences were found in physical development parameters of children with stages of chronic kidney disease 1 and 2 examined at the same time period but a tendency towards children’s height decrease from stages 1 to 3 of CKD of non-glomerular etiology was revealed.

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