Longitudinal study of glomerular hyperfiltration and normalization of estimated glomerular filtration in adults with sickle cell disease

2021 ◽  
Author(s):  
Vimal K. Derebail ◽  
Qingning Zhou ◽  
Emily J. Ciccone ◽  
Jianwen Cai ◽  
Kenneth I. Ataga
Keyword(s):  
Longitudinal Study ◽  
Sickle Cell Disease ◽  
Glomerular Filtration ◽  
Sickle Cell ◽  
Glomerular Hyperfiltration ◽  
Cell Disease

scholarly journals Glomerular Hyperfiltration and Albuminuria in Adolescents with Sickle Cell Disease: Retrospective Cross-Sectional Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Baba PD Inusa ◽  
Caroline Booth ◽  
Nosa Iduoriyekemwen
Keyword(s):  
Sickle Cell Disease ◽  
Haemoglobin Level ◽  
Glomerular Filtration ◽  
Sickle Cell ◽  
Research Funding ◽  
Steering Committee ◽  
Glomerular Hyperfiltration ◽  
Creatinine Ratio ◽  
Cell Disease ◽  
Participation Research

Background:Renal abnormalities in sickle cell disease commence early in childhood. Glomerular hyperfiltration and albuminuria are the most prevalent renal abnormalities in sickle cell disease. However, these renal abnormalities of SCD have not been considered exclusively in the adolescent age group. Objective:To determine the prevalence of glomerular hyperfiltration and albuminuria as well as identify the determinants for glomerular hyperfiltration in adolescents with SCD. Patients and Methods:Ethical permission was through the Trust audit and service evaluation governance review board to implement quality assessment of clinical service. Electronic patient records (charts) of 153 adolescents with SCD aged 10->19 years, attending the Paediatrics Haematology Clinic at Evelina children Hospital, London, United Kingdom. Clinical information obtained included demographics age, gender sickle cell type, as well as history of acute event, treatment history, anthropometric indices and blood pressure. The laboratory parameters obtained were urine albumin-creatinine ratio or protein-creatinine ratio, haemoglobin level, white blood cell count, red blood cell count, platelet count, reticulocyte count, foetal haemoglobin level, lactate dehydrogenase level, serum creatinine and serum ferritin level. The glomerular filtration rate was derived using the Bedside Schwartz's method. Grouping of the adolescents was based on present and absence of glomerular hyperfiltration, which was defined as glomerular filtration rate > 140ml/min/m2. The presence of albuminuria was defined as urine albumin-to-creatinine ratio >3mg/mmol or protein- to- creatinine ratio of > 15mg/mmol. Investigated were the clinical and laboratory determinants of glomerular hyperfiltration in the total study population. Result:Prevalence of glomerular hyperfiltration was 33.3% in the adolescents studied (age bracket please) , and that of albuminuria was 15.7% amongst the adolescents with SCD studies (microalbuminuria 14.4%, and 1.3% overt proteinuria) of which 13.7% of those with glomerular hyperfiltration also had albuminuria. The mean eGFR of the adolescents with SCD who had glomerular hyperfiltration was 160.2 ± 20.0 ml/min/1.73m2, and that of those with no glomerular hyperfiltration was 109.9 ± 19.3ml/min/m2. A significantly higher proportion of the adolescents with SCD who had glomerular hyperfiltration had the haemoglobin SS disease (47 (92.2%) versus 68 (66.7%);P=0.007). On univariable analysis, the adolescent with glomerular hyperfiltration had significantly lower weight (48.0 ± 18.0 versus 54.8 ± 17.0 kg;p= 0.02), height (155.1 ± 13.1 versus 160.6 ± 13.1 cm;p= 0.01), body mass index (19.4 ± 5.0 versus 21.0 ± 4.3 ;p= 0.04), haemoglobin level (88.7 ± 13.3 versus 98.1 ± 21.7 g/L;p= 0.001), and serum creatinine level (0.4 ± 0.1 versus 0.6 ± 0.2mg/dl;p= 0.0001) as compared to those with no glomerular hyperfiltration. The adolescents with glomerular hyperfiltration also had significantly higher lactate dehydrogenase level (525.9 ± 180.3 versus 449.6 ± 170.3 IU/L;p= 0.01) as compared to those with no glomerular hyperfiltration. However, no association was found on multivariable analysis. Conclusion:This study revealed that the prevalence of glomerular hyperfiltration in the adolescent age group was high, and the high glomerular filtration rates begin to decline toward normal values in middle adolescent age not before. Figure Disclosures Inusa: AstraZeneca:Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau;Vertex:Research Funding;Global Blood Therapeutics:Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau;Bluebird bio:Research Funding;Novartis:Honoraria, Other: Steering committee participation, Research Funding, Speakers Bureau.

The Prevalence of Renal Dysfunction in Young Adults with Sickle Cell Disease.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3804-3804
Author(s):  
Raymond U. Osarogiagbon ◽  
Laura M. McHugh ◽  
Lori E. Kronish ◽  
Elisabeth A. Chismark
Keyword(s):  
Sickle Cell Disease ◽  
Renal Dysfunction ◽  
Glomerular Filtration ◽  
Sickle Cell ◽  
Renal Injury ◽  
Healthcare Providers ◽  
Early Death ◽  
Cell Disease ◽  
Early Screening ◽  
Stage Renal Disease

Abstract Sickle cell disease is typified by dramatic acute painful episodes, which consume the majority of patients’ and healthcare providers’ attention. However, the cumulative damage to vital organs that occurs in this disease is often the determinant of early death. The kidneys are a major target organ in sickle cell disease and renal failure is a highly morbid event. It is also strongly associated with early death. Glomerular hyperfiltration is often the earliest sign of renal injury. This is followed by return to apparently normal filtration rates, then successively lower rates, culminating in end-stage renal disease. Microalbuminuria follows hyperfiltration and progresses to frank proteinuria. We evaluated the prevalence of renal dysfunction in a cohort of patients with sickle cell disease managed at the University of Tennessee Cancer Institute’s adult sickle cell program. At entry into the program, patients underwent a routine battery of tests, including 24 hour urine collection for measurement of creatinine clearance and urine protein. Our findings are summarized in the table below. By the age of 25 years, almost 80% of patients with sickle cell disease showed significant abnormality of glomerular filtration and 40% had significant proteinuria. This worsens with age. By a median of 37 years, 2 in 3 patients have developed significant proteinuria and hypofiltration has become the predominant pattern of glomerular filtration abnormality. Since renal injury is reversible in the early stages, more emphasis needs to be placed on aggressive early screening, surveillance and intervention. Intervention at the stage of hyperfiltration and microalbuminuria is easier and much more likely to be successful. Patients and their healthcare providers need to be educated on the high prevalence of renal damage. Efforts at education, screening, surveillance and, where necessary, treatment should begin well before adolescence.

In Vivo Modeling Of Genetic Mechanisms Associated With Sickle Cell Disease Nephropathy

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2224-2224
Author(s):  
Blair R Anderson ◽  
Erica E Davis ◽  
Marilyn J. Telen ◽  
Allison E Ashley-Koch
Keyword(s):  
At Risk ◽  
Sickle Cell Disease ◽  
Glomerular Filtration ◽  
Sickle Cell ◽  
Organ Damage ◽  
Strong Linkage Disequilibrium ◽  
Wild Type ◽  
Cell Disease ◽  
Gene Suppression ◽  
End Organ Damage

Abstract End-organ damage in patients with sickle cell disease (SCD) has become an emergent clinical priority over recent decades due to the increased lifespan of affected individuals. Renal failure (ESRD), which occurs in 4-12% of SCD patients and is strongly associated with early mortality, has become a particular concern. The detection of SCD nephropathy (SCDN) relies on relatively late markers of the disease process, namely proteinuria and reduced glomerular filtration rate (GFR). Therefore, at-risk SCD patients cannot be identified prior to end-organ damage. A genomic region on human chromosome 22 containing two genes, MYH9 and APOL1, has been associated with non-SCD nephropathy, although the primary gene responsible has remained elusive due to strong linkage disequilibrium in this region. Our group demonstrated that both MYH9 and APOL1 are strong, independent genetic predictors of risk for proteinuria in SCD and interact to affect GFR (Ashley-Koch et al., 2011). We have now used zebrafish as a model to study the contribution of each gene (myh9 and apol1) to kidney function and filtration. To test independent effects of the knockdown of myh9 or apol1, we injected morpholino (MO) antisense oligonucleotides in wild-type zebrafish embryos; this resulted in generalized edema (64% [myh9-MO] and 58% [apol1-MO], both significantly different compared to 3% of control embryos) and reduced glomerular filtration (as measured by quantitative dextran clearance; myh9-MO p=0.047 and apol1-MO p=0.042 when compared to control embryos) for both gene suppression models. Each morphant phenotype was rescued significantly by co-injection of each respective wild type human MYH9 (p=0.001) and APOL1 (p=0.043) mRNA. Importantly, co-injection of human mRNA corresponding to other APOL gene family members did not significantly rescue the observed apol1-MO phenotype, suggesting that apol1 is indeed the functional ortholog to the human gene. Next, we investigated the possibility of a genetic interaction between MYH9 and APOL1 by co-suppression of each of the zebrafish orthologous genes. We observed no additive or synergistic effects due to the co-suppression. Instead, the double morphants were indistinguishable from the myh9 morpholino alone, and neither single morpholino could be rescued by the human mRNA of the other gene. These data suggest that MYH9 and APOL1 may function independently but converge on the same biological process to affect risk of SCDN. In addition to evaluating the effects of candidate gene suppression in wild-type models, we have begun to utilize anemic zebrafish models described previously (Shah et al., 2012). Our preliminary work suggests that the myh9 knockdown phenotype is exacerbated under anemic stress. Ongoing efforts are aimed at identifying novel genetic contributions to SCDN through genome-wide association analysis and exome sequencing of extreme phenotypes in SCD patients, with functional evaluation of putative genetic candidates in our zebrafish model. By offering new insights into the contribution of genes that regulate renal function, these results further our understanding of the pathogenesis of SCDN and may provide genetic markers for the identification of at-risk SCD patients prior to the onset of kidney dysfunction. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hydroxyurea Reverses Dysfunctional Ubiquitin-Proteasomal System in Sickle CELL Disease and Suppresses Posttranslational Alterations in Hemoglobin and CELL Membranes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4822-4822
Author(s):  
Swee Lay Thein ◽  
Arun S Shet ◽  
Michael Brad Strader ◽  
Fanato Meng ◽  
Michael Heaven ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Longitudinal Study ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Membranes ◽  
Conflicts Of Interest ◽  
Side Reactions ◽  
Cell Disease ◽  
Post Translational Modification ◽  
Oxidative Modifications

HYDROXYUREA REVERSES DYSFUNCTIONAL UBIQUITIN-PROTEASOMAL SYSTEM IN SICKLE CELL DISEASE AND SUPPRESSES POSTTRANSLATIONAL ALTERATIONS IN HEMOGLOBIN AND CELL MEMBRANES Sirsendu Jana, PhD1, Michael Brad Strader, PhD1, Fantao Meng, PhD1,Michael Heaven, PhD2, Arun Shet, MD3, Swee Lay Thein, MD3, and Abdu I. Alayash, PhD1. 1Laboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration (FDA), 2Vulcan Analytical, Birmingham Al, 3Sickle Cell Branch, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH). Introduction: Intracellular oxidative stress and oxidative modifications of sickle cell hemoglobin (HbS) play an important role in the pathogenesis of sickle cell disease (SCD). We recently reported transgenic mice studies revealing microparticles (MP) proteome differences between SCD and control mice expressing human HbS and HbA, respectively. Hb-dependent oxidative reactions and consequent posttranslational modifications of Hb βCys93 were central to red cell membrane changes that included modification of band3, and ubiquitination of proteins (Jana S et al., JCI Insights, 2018 3:120451). Ubiquitination is an important post-translational modification required for several biological functions including degradation by the ubiquitin-proteasomal system (UPS) proteolytic pathway. Proteins susceptible to oxidative damage are therefore likely degraded by UPS machinery. When these animals were treated with hydroxyurea (HU) they were able to reduce oxidative stress by controlling Hb oxidation side reactions. As a follow-up study, we have characterized human RBC derived MP proteomes of control, untreated and HU treated SCD patient samples to identify the mechanistic basis of how HU treatment reduces oxidative stress. Methods: We used a variety of biochemical and hematological methods to investigate a group of sickle cell disease (SCD) patients (n= 22) who are either on HU treatment (n=10) or without HU treatment (n=12) and a group of ethnically matched controls (n=4). We also performed an additional proteomic analysis on a subset of these patients, including a separate longitudinal study in which SCD patients (n=2) were followed before and after treatment with HU. Results: Immunoprecipitation experiments on RBCs obtained from untreated SCD patients revealed the presence of extensive ubiquitination contrary to those samples obtained from HU treated patients and controls. High proteasomal activity was found in SCD RBCs suggesting accumulated polyubiquitinated proteins found in these samples were not a byproduct of proteasomal inhibition but rather due to imbalance in the redox state of SS RBCs. In addition to Hb oxidation and oxidative modifications (including βCys93), our results revealed differences in the SCD proteome (from both control and untreated groups) including upregulation of phosphorylation and ubiquitination of proteins that are known to interact directly with band3 and are functionally involved in MP formation. Ubiquitination of Hb βLys145 and βLys96 were more abundant in SS patient's samples as well as phosphorylation of band3 (a prerequisite process for band3 clustering and MPs release). As revealed by the separate longitudinal study, HU treatment uniformly reversed ubiquination and phosphorylation of proteins involved in SCD induced MP formation. Conclusion: These mechanistic analyses of SCD RBC derived MPs suggest a potential involvement of ubiquitination and phosphorylation in SCD pathogenesis and provide additional insight into the therapeutic mechanisms of HU treatment. Disclosures No relevant conflicts of interest to declare.

A Cohort Study of Renal Complications in Patients Over the Age of 40 with Sickle Cell Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4789-4789
Author(s):  
Jennifer J Thomson ◽  
Cormac Breen ◽  
Jo Howard
Keyword(s):  
Renal Failure ◽  
Sickle Cell Disease ◽  
Kidney Disease ◽  
Glomerular Filtration ◽  
Sickle Cell ◽  
Filtration Rate ◽  
Ace Inhibitor ◽  
The United States ◽  
Microscopic Haematuria ◽  
Cell Disease

Abstract Survival data from the United States (US) has shown a median age of death of 42 and 48 years for men and women respectively with HbSS disease, with renal failure being a contributory factor in about 18% of adult deaths (Platt, O.S. et al (1994) Mortality in Sickle Cell Disease – Life Expectancy and Risk Factors for Early Death. NEJM 330; 1639–1644). Renal damage begins early in life, with abnormalities of tubular function reflected by hyposthenuria and glomerular damage which results in hyperfiltration and an increased glomerular filtration rate. Microalbuminuria may develop in childhood and can progress to frank proteinuria. In later life, an apparent return to normal glomerular filtration rates often indicates loss of kidney function which may lead to end stage renal failure (ESRF). Although there are no randomised trials in this area it seems likely that, as in patients with other forms of proteinuric kidney disease, renin-angiotensin system blockade might decrease proteinuria and delay progression of kidney disease. The prognosis for patients with sickle cell disease and ESRF is poor despite dialysis, and it is therefore imperative to detect these patients early if we are to slow or halt their progression to ESRF. A retrospective study was performed at St Thomas’ Hospital to provide a snapshot of the prevalence of renal impairment in patients with sickle cell disease aged 40 or over. The sickle cell disease database was reviewed for the year 2007–2008. Kidney disease was defined as either an estimated glomerular filtration rate (eGFR) of <60mL/min (corrected for race), protein creatinine ratio (PCR) of >50 or persistent microscopic haematuria. Patients who were previously started on an ACE inhibitor due to a previously raised PCR were also included even if the most recent results were within the normal range. 80 patients were included in this study, with a median age of 47 (range 40–75 years). 57.1% had HbSS and 31.4% had HbSC disease. 35 patients (43.8%) had kidney disease according to at least one of the criteria above. 33 patients had a PCR of greater than 50 (8), or were on an ACE inhibitor (25) (indicating a previous PCR >50). 12 patients had a corrected eGFR of <60mL/min and 5 patients had microscopic haematuria. The male to female ratio of those included in the study was 1:3 but this did not differ in those with and without kidney disease. 42.6% with HbSS and 42.3% with HbSC had kidney disease. Patients with hypertension (blood pressure (BP) >140/90mmHg) had a relative risk of kidney disease of 1.73 (95% confidence interval; 1.08 – 2.78). A target BP of <130/80mmHg was set for patients with kidney disease (based on evidence from diabetic nephropathy). Only 18 (50%) patients achieved this target. There was an increased tendency towards retinopathy (34.3% cf. 17.8%; relative risk 1.59; range 0.98 – 2.58) but no other associations, in particular, no association with cerebrovascular disease. In conclusion, almost 50% of patients over 40 years with sickle cell disease have kidney disease, which is greater than the background prevalence in all age US adults of 13.1% (Coresh, J. et al (2007) Prevalence of Chronic Kidney Disease in the United States. JAMA 298 (17): 2038–2047). Due to the poor prognosis of ESRF in patients with sickle cell disease and the contributory effect of renal impairment in all cause mortality, early detection and intervention is critical in further improving the quality of life and life expectancy in the increasingly older population of patients with sickle cell disease. Further trials are required to determine the optimal time to intervene and most effective interventions.

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