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Jirasomprasert T, Tian LY, You DP, Wang YK, Dong L, Zhang YH, Hao GX, van den Anker J, Wu YE, Tang BH, Zhao W, Zheng Y. Population Pharmacokinetics and Dose Optimization of Piperacillin in Infants and Children with Pneumonia. Paediatr Drugs 2025; 27:91-102. [PMID: 39602006 DOI: 10.1007/s40272-024-00664-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/20/2024] [Indexed: 11/29/2024]
Abstract
OBJECTIVE We aimed to determine the piperacillin disposition and optimize the dosing regimens for infants and children with pneumonia. METHODS An opportunistic sampling strategy was used in this pharmacokinetic study. High-performance liquid chromatography was used to measure the concentrations of piperacillin in plasma samples. A population pharmacokinetic model was conducted using NONMEM. RESULTS The pharmacokinetic data of 90 samples from 64 infants and children with pneumonia (age range: 0.09-1.72 years for infants and 2.12-11.10 years for children) were available. A two-compartment model with first-order elimination was the most suitable model to describe the population pharmacokinetics of piperacillin. A covariate analysis indicated that body weight and age were significant factors affecting clearance. Monte Carlo simulations showed that a 50-mg/kg every 8 h or every 12 h dosing regimen results in underdosing. Results both in infants and children showed that an extended infusion (3 h) of various dosing regimens (80, 100, or 130 mg/kg) three times daily or a 300-mg/kg continuous infusion can reach a therapeutic level based on the chosen target for the probability of target attainment threshold of 70%, 80%, and 90% at minimum inhibitory concentration breakpoints of 8 mg/L and 16 mg/L. CONCLUSIONS A population pharmacokinetic model was obtained to evaluate the disposition of piperacillin, and the optimal dosing regimens were provided for use in infants and children with pneumonia.
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Affiliation(s)
- Totsapol Jirasomprasert
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Li-Yuan Tian
- Department of Respiratory Care, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Dian-Ping You
- Pediatric Research Institute, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Ya-Kun Wang
- Department of Respiratory Care, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Lei Dong
- Department of Pharmacy, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Ya-Hui Zhang
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Pharmacy, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Guo-Xiang Hao
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - John van den Anker
- Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, USA
- Departments of Pediatrics, Pharmacology & Physiology, Genomics & Precision Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
- Department of Pediatric Pharmacology and Pharmacometrics, University of Basel Children's Hospital, Basel, Switzerland
| | - Yue-E Wu
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Bo-Hao Tang
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Wei Zhao
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
- Department of Pharmacy, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
| | - Yi Zheng
- Department of Clinical Pharmacy, Institute of Clinical Pharmacology, Key Laboratory of Chemical Biology (Ministry of Education), NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China.
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Engole Mompango Y, Bukabau Busanga J, Makulo Rissassy JR, Nlandu Mayamba Y, Makanzu B, Nkodila A, Tshiswaka T, Mokoli Momeme V, Longo Luzayadio A, Mboliasa Ingole MF, Kajingulu Musungayi F, Fwana S, Ilunga Kabemba C, Nkondi Nsenga C, Zinga Vuvu C, Nseka Mangani N, Sumaili Kiswaya E. Prevalence and associated factors of glomerular hyperfiltration among adult stable sickle cells in Kinshasa, DR Congo. Ren Fail 2024; 46:2407888. [PMID: 39329176 PMCID: PMC11441020 DOI: 10.1080/0886022x.2024.2407888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 09/18/2024] [Accepted: 09/18/2024] [Indexed: 09/28/2024] Open
Abstract
INTRODUCTION Glomerular hyperfiltration is highly frequent, theoretically dependent on cardiac output, low systemic vascular resistance and hemolysis markers. In sickle cell disease (SCD), hyperfiltration is an extremely common phenomenon and occurred in young and early adult patients. Despite the fact that the glomerular hyperfiltration is known as the early manifestations of sickle cell nephropathy, its burden among adult sickle cell disease in sub-Saharan is poor studied. This study aimed to determine the prevalence and associated factors of hyperfiltration. METHODS This was an analytical multicentric cross-sectional study involving stable adult sickle cell patients in Kinshasa, recruited between March and October 2023. Parameters of interest encompasses demographic, clinical, biological, echocardiographic and pulse wave measurement data. Hyperfiltration was defined using the CDK-EPI equation based on cystatin C; eGFR >130 for women and >140 ml/min/1.73m2 for men. We used multivariate logistic regression analysis to search determinants of glomerular hyperfiltration. RESULTS Two hundred and fourty six (246) patients with SCD were enrolled. The prevalence of hyperfiltration was 20.7%. In multiple logistic regression analysis, hyperfiltration status was independently associated with age (< 25 years) [3.57 (1.78-7.49); p = 0.027)], female sex [4.36 (2.55-5.62); p = 0.031), CRP (< 6 mg/l) [0.77 (0.61-0.97); p = 0.028)], central systolic pressure (< 100 mmHg) and central diastolic pressure (< 60 mmHg) [0.86(0.74-0.98), p = 0.028)], [(0.83 (0.71-0.98); p = 0.032)]. CONCLUSION One out of five SS adults exhibits hyperfiltration, which is associated with young age and female sex, whereas low CRP and blood pressure were negative risk factors.
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Affiliation(s)
- Yannick Engole Mompango
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
- Specialized Clinics in Kinshasa, Kinshasa, Democratic Republic of the Congo
| | - Justine Bukabau Busanga
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
| | | | - Yannick Nlandu Mayamba
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
- Specialized Clinics in Kinshasa, Kinshasa, Democratic Republic of the Congo
| | - Brady Makanzu
- Specialized Clinics in Kinshasa, Kinshasa, Democratic Republic of the Congo
- Cardiology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
| | - Aliocha Nkodila
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
| | - Tresor Tshiswaka
- Cardiology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
| | - Vieux Mokoli Momeme
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
| | | | | | | | - Shekinah Fwana
- Specialized Clinics in Kinshasa, Kinshasa, Democratic Republic of the Congo
| | - Cedric Ilunga Kabemba
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
| | - Clarisse Nkondi Nsenga
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
| | - Chantal Zinga Vuvu
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
| | - Nazaire Nseka Mangani
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
| | - Ernest Sumaili Kiswaya
- Nephrology Unit, Kinshasa University Hospital, Kinshasa, XI, Democratic Republic of the Congo
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Briggs DC, Okechukwu C, Apollus J, Amadi I, Omunakwe H, Dublin-Green LA, Okoh D. Factors Associated with Microalbuminuria among Children with Sickle Cell Disease in a Tertiary Centre in South-South Nigeria. Niger Med J 2024; 65:885-898. [PMID: 39877489 PMCID: PMC11770667 DOI: 10.60787/nmj-v65i6.493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025] Open
Abstract
Background Microalbuminuria, an early indicator of kidney damage in Sickle Cell Disease (SCD) patients, is linked to a heightened risk of chronic kidney disease (CKD) in adulthood. This study investigates the determinants of microalbuminuria in paediatric SCD patients in South-South Nigeria. Methodology This cross-sectional study was conducted over six months at the Rivers State University Teaching Hospital, Nigeria, involving 60 children with [HbSS genotype, SCD] in a steady state. Data collection included demographics, past medical history, clinical measurements, and laboratory assessments of urine and blood samples. 'Steady state' was defined as SCD with a known 'steady state' haemoglobin level and stable clinical state for ≥ 3 months. Microalbuminuria was defined spot urine albumin-creatinine ratio of 30mg/g to <300 mg/g. Results Of the 60 children recruited, 31 children (51.7%) were males. The mean age was 9.6 ± 4.3 years. The prevalence of microalbuminuria was 16.7% (CI: 8.29 - 28.5%) and associated risk factors were hypertension (p = 0.017), use of Hydroxyurea (p = 0.008), and Ciklavit (p = 0.025), but not NSAIDs (p = 0.046). There was a significant negative correlation (ɼ = -0.28; p = 0.032) between haemoglobin level and microalbuminuria. Conclusion This study provides insights into the factors associated with microalbuminuria in children with SCD in our setting and highlights the need for early screening for markers of CKD among children with SCD. Further research is needed to ascertain the potential benefits of addressing anaemia and reducing haemolysis in mitigating the occurrence of microalbuminuria among children with SCD.
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Affiliation(s)
- Datonye Christopher Briggs
- Paediatric Nephrology division, Department of Paediatrics, Rivers State University Teaching Hospital & Faculty of Clinical Sciences, Rivers State University, Nigeria
| | - Chioma Okechukwu
- Paediatric Haemato-oncology unit, Department of Paediatrics, Rivers State University Teaching Hospital & Faculty of Clinical Sciences, Rivers State University, Nigeria
| | - Josiah Apollus
- Paediatric Haemato-oncology unit, Department of Paediatrics, Rivers State University Teaching Hospital & Faculty of Clinical Sciences, Rivers State University, Nigeria
| | - Ijeoma Amadi
- Paediatric Haemato-oncology unit, Department of Paediatrics, Rivers State University Teaching Hospital & Faculty of Clinical Sciences, Rivers State University, Nigeria
| | - Hannah Omunakwe
- Paediatric Nephrology division, Department of Paediatrics, Rivers State University Teaching Hospital & Faculty of Clinical Sciences, Rivers State University, Nigeria
| | - Linda Anucha Dublin-Green
- Department of Haematology and Blood Transfusion, Rivers State University Teaching Hospital & Faculty of Basic Clinical Sciences, Rivers State University, Nigeria
| | - Dorathy Okoh
- Department of Haematology and Blood Transfusion, Rivers State University Teaching Hospital & Faculty of Basic Clinical Sciences, Rivers State University, Nigeria
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Nkoy AB, Mumaka FM, Ngonde A, Mafumba SK, Matoka TT, Kitenge R, Talu FM, Nkolomoni B, Tshilolo L, van den Heuvel LP, Ekulu PM, Levtchenko EN, Labarque V. Relevance of repeated analyses of albuminuria and glomerular filtration rate in African children with sickle cell anaemia. Br J Haematol 2024; 205:1137-1146. [PMID: 38934404 DOI: 10.1111/bjh.19603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024]
Abstract
Glomerular hyperfiltration and albuminuria are frequent kidney abnormalities in children with sickle cell anaemia (SCA). However, little is known about their persistence in African SCA children. This prospective study included 600 steady-state SCA children aged 2-18 years from the Democratic Republic of Congo. Participants were genotyped for apolipoprotein L1 (APOL1) risk variants (RVs) and haem oxygenase-1 (HMOX1) GT-dinucleotide repeats. Kidney abnormalities were defined as albuminuria, hyperfiltration or decreased estimated creatinine-based glomerular filtration rate (eGFRcr). At baseline, 247/600 (41.2%) participants presented with kidney abnormalities: 82/592 (13.8%) with albuminuria, 184/587 (31.3%) with hyperfiltration and 15/587 (2.6%) with decreased eGFRcr. After a median follow-up of 5 months, repeated testing was performed in 180/247 (72.9%) available participants. Persistent hyperfiltration and persistent albuminuria (PA) were present in 29.2% (38/130) and 39.7% (23/58) respectively. eGFR normalized in all participants with a baseline decreased eGFRcr. Haemoglobinuria (p = 0.017) and male gender (p = 0.047) were significantly associated with PA and persistent hyperfiltration respectively. APOL1 RVs (G1G1/G2G2/G1G2) were borderline associated with PA (p = 0.075), while HMOX1 long repeat was not associated with any persistent kidney abnormality. This study reveals that a single screening can overestimate the rate of kidney abnormalities in children with SCA and could lead to overtreatment.
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Affiliation(s)
- Agathe B Nkoy
- Division of Nephrology, Department of Pediatrics, University Hospital of Kinshasa, Faculty of Medicine, University of Kinshasa, Kinshasa, Democratic Republic of Congo
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
| | - Floreen M Mumaka
- Division of Nephrology, Department of Pediatrics, University Hospital of Kinshasa, Faculty of Medicine, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Ange Ngonde
- REZODREPANO SS, Kinshasa, Democratic Republic of Congo
| | - Samuel K Mafumba
- Hôpital Général de Référence de Kinkole, Kinshasa, Democratic Republic of Congo
| | - Therance T Matoka
- Division of Nephrology, Department of Pediatrics, University Hospital of Kinshasa, Faculty of Medicine, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Robert Kitenge
- Centre de Formation et d'Appui Sanitaire (CEFA)/Monkole, Kinshasa, Democratic Republic of Congo
| | - Flore M Talu
- Division of Nephrology, Department of Pediatrics, University Hospital of Kinshasa, Faculty of Medicine, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Blaise Nkolomoni
- Centre de Médecine Mixte et Anémie SS (CMMASS), Kinshasa, Democratic Republic of Congo
| | - Léon Tshilolo
- Centre de Formation et d'Appui Sanitaire (CEFA)/Monkole, Kinshasa, Democratic Republic of Congo
| | - Lambertus P van den Heuvel
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
- Department of Pediatric Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Pépé M Ekulu
- Division of Nephrology, Department of Pediatrics, University Hospital of Kinshasa, Faculty of Medicine, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Elena N Levtchenko
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Veerle Labarque
- Department of Pediatric Hematology, University Hospital Leuven, Leuven, Belgium
- Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, KU Leuven, Leuven, Belgium
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Sparkenbaugh EM. EPCR shedding light on sickle nephropathy. Blood 2024; 144:472-474. [PMID: 39088231 PMCID: PMC11307264 DOI: 10.1182/blood.2024025479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024] Open
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Borgey M, Genty I, Habibi A, Arlet JB, Dhedin N, Lionnet F, Bernit E, Julan ME, Loko G, Arnaud C, Kamdem A, Pissard S, Guémas E, Noizat C, Pondarré C. High risk of progression for chronic major organ complications of sickle cell disease in adolescents and young adults: A long-term neonatal cohort study. Am J Hematol 2024; 99:1601-1605. [PMID: 38686944 DOI: 10.1002/ajh.27346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/09/2024] [Accepted: 04/15/2024] [Indexed: 05/02/2024]
Affiliation(s)
- Marion Borgey
- Pediatric Department, Sickle Cell Disease Referral Center, Centre Hospitalier Intercommunal de Créteil, Créteil, France
- Sorbonne University, Paris, France
| | - Isabelle Genty
- Adult Department, Sickle Cell Disease Referral Center, Centre Hospitalier Intercommunal de Créteil, Créteil, France
| | - Anoosha Habibi
- Internal Medicine Department, Sickle Cell Disease Referral Center, Groupe Hospitalo-Universitaire Henri Mondor, INSERM U955, IMRB, Paris XII University, Créteil, France
| | - Jean-Benoit Arlet
- Internal Medicine Department, Sickle Cell Disease Referral Center, hôpital européen Georges Pompidou, Paris, France
| | - Nathalie Dhedin
- Hematologic Department, Sickle Cell Disease Referral Center, hôpital Saint Louis, Paris, France
| | - François Lionnet
- Hematologic Department, Sickle Cell Disease Referral Center, hôpital Tenon, Paris, France
| | - Emmanuelle Bernit
- Sickle Cell Unit Referral Center, Centre Hospitalier Universitaire de Guadeloupe, Pointe-à-Pitre, Guadeloupe, France
| | - Maryse Etienne Julan
- Sickle Cell Unit Referral Center, Centre Hospitalier Universitaire de Guadeloupe, Pointe-à-Pitre, Guadeloupe, France
| | - Gylna Loko
- Sickle Cell Unit Referral Center, Centre Hospitalier Universitaire de Martinique, Fort-de-France, Martinique, France
| | - Cécile Arnaud
- Internal Medicine Department, Sickle Cell Disease Referral Center, Groupe Hospitalo-Universitaire Henri Mondor, Créteil, France
| | - Annie Kamdem
- Pediatric Department, Sickle Cell Disease Referral Center, Centre Hospitalier Intercommunal de Créteil, Créteil, France
| | - Serge Pissard
- Genetics Department, Groupe Hospitalo-Universitaire Henri Mondor, INSERM U955, IMRB, Team 2, Paris XII University, Créteil, France
| | - Eric Guémas
- BIOSSEC Clinical Biostatistics, Paris, France
| | - Clara Noizat
- APHP (Assistance Publique des Hôpitaux de Paris), Paris, France
| | - Corinne Pondarré
- Pediatric Department, Sickle Cell Disease Referral Center, Centre Hospitalier Intercommunal de Créteil, Créteil, France
- INSERM U955, IMRB, Paris XII University, Créteil, France
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Ilonze C, Rai P, Galadanci N, Zahr R, Okhomina VI, Kang G, Padmanabhan D, Lebensburger J, Alishlash AS. Association of elevated tricuspid regurgitation velocity with cerebrovascular and kidney disease in children with sickle cell disease. Pediatr Blood Cancer 2024; 71:e31002. [PMID: 38644595 DOI: 10.1002/pbc.31002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 03/07/2024] [Accepted: 03/21/2024] [Indexed: 04/23/2024]
Abstract
BACKGROUND Tricuspid regurgitation velocity (TRV), measured by echocardiography, is a surrogate marker for pulmonary hypertension. Limited pediatric studies have considered the association between TRV and surrogate markers of end-organ disease. METHODS We conducted a cross-sectional study that evaluated the prevalence of elevated TRV ≥2.5 m/s and its associations with renal and cerebrovascular outcomes in children with sickle cell disease (SCD) 1-21 years of age in two large sickle cell cohorts, the University of Alabama at Birmingham (UAB) sickle cell cohort, and the Sickle Cell Clinical Research and Intervention Program (SCCRIP) cohort at St. Jude Children's Research Hospital. We hypothesized that patients with SCD and elevated TRV would have higher odds of having either persistent albuminuria or cerebrovascular disease. RESULTS We identified 166 children from the UAB cohort (mean age: 13.49 ± 4.47 years) and 325 children from the SCCRIP cohort (mean age: 13.41 ± 3.99 years) with echocardiograms. The prevalence of an elevated TRV was 21% in both UAB and SCCRIP cohorts. Elevated TRV was significantly associated with cerebrovascular disease (odds ratio [OR] 1.88, 95% confidence interval [CI]: 1.12-3.15; p = .017) and persistent albuminuria (OR 1.81, 95% CI: 1.07-3.06; p = .028) after adjusting for age, sex, treatment, and site. CONCLUSION This cross-sectional, multicenter study identifies associations between surrogate markers of pulmonary hypertension with kidney disease and cerebrovascular disease. A prospective study should be performed to evaluate the longitudinal outcomes for patients with multiple surrogate markers of end-organ disease.
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Affiliation(s)
- Chibuzo Ilonze
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Parul Rai
- Division of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Najibah Galadanci
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rima Zahr
- Division of Pediatric Nephrology and Hypertension, Department of Pediatrics, University of Tennessee Health Science Center (UTHSC), Memphis, Tennessee, USA
| | - Victoria I Okhomina
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Guolian Kang
- Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Dakshin Padmanabhan
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jeffrey Lebensburger
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Ammar Saadoon Alishlash
- Division of Pediatric Pulmonology and Sleep Medicine, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Dovern E, Aydin M, DeBaun MR, Alizade K, Biemond BJ, Nur E. Effect of allogeneic hematopoietic stem cell transplantation on sickle cell disease-related organ complications: A systematic review and meta-analysis. Am J Hematol 2024; 99:1129-1141. [PMID: 38517255 PMCID: PMC11730142 DOI: 10.1002/ajh.27297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/31/2024] [Accepted: 03/11/2024] [Indexed: 03/23/2024]
Abstract
Sickle cell disease (SCD)-related organ complications are a major cause of morbidity and mortality in patients with SCD. We sought to assess whether hematopoietic stem cell transplantation (HSCT) stabilizes, attenuates, or exacerbates organ decline. We performed a systematic review and meta-analysis of trials investigating organ function before and after HSCT in patients with SCD. We searched MEDLINE/PubMed and EMBASE up to September 21, 2023. Continuous data were expressed as standardized mean difference (SMD) and pooled in a weighted inverse-variance random-effects model; binomial data were expressed as risk ratio (RR) using the Mantel-Haenszel random-effects meta-analyses. Of 823 screened studies, 34 were included in this review. Of these, 17 (774 patients, 23.6% adults, 86.3% HLA-identical sibling donor, 56.7% myeloablative conditioning regimen) were included in the meta-analyses. Pulmonary function remained stable. Mean tricuspid regurgitant jet velocity decreased but did not reach statistical significance. In children, estimated glomerular filtration rate decreased (SMD -0.80, p = .01), and the presence of proteinuria increased (RR 2.00, p = <.01), while splenic uptake and phagocytic function improved (RR 0.31, p = <.01; RR 0.23, p = <.01). Cerebral blood flow improved (SMD -1.39, p = <.01), and a low incidence of stroke after transplantation in high-risk patients was found. Retinopathy and avascular osteonecrosis were investigated in only one study, showing no significant changes. While HSCT can improve some SCD-related organ dysfunctions, transplantation-related toxicity may have an adverse effect on others. Future research should focus on identifying individuals with SCD who might benefit most from HSCT and which forms of organ damage are more likely to exacerbate post-transplantation.
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Affiliation(s)
- Elisabeth Dovern
- Department of Hematology, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, The Netherlands
| | - Mesire Aydin
- Department of Hematology, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, The Netherlands
| | - Michael R. DeBaun
- Department of Pediatrics, Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Komeil Alizade
- Department of Hematology, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, The Netherlands
| | - Bart J. Biemond
- Department of Hematology, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, The Netherlands
| | - Erfan Nur
- Department of Hematology, Amsterdam University Medical Centers, location University of Amsterdam, Amsterdam, The Netherlands
- Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands
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Garrett ME, Foster MW, Telen MJ, Ashley-Koch AE. Nontargeted Plasma Proteomic Analysis of Renal Disease and Pulmonary Hypertension in Patients with Sickle Cell Disease. J Proteome Res 2024; 23:1039-1048. [PMID: 38353026 PMCID: PMC11938347 DOI: 10.1021/acs.jproteome.3c00748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2024]
Abstract
Sickle cell disease (SCD) is characterized by red blood cell sickling, vaso-occlusion, hemolytic anemia, damage to multiple organ systems, and, as a result, shortened life expectancy. Sickle cell disease nephropathy (SCDN) and pulmonary hypertension (pHTN) are common and frequently co-occurring complications of SCD; both are associated with markedly accelerated mortality. To identify candidate circulating biomarkers of SCDN and pHTN, we used mass spectrometry to quantify the relative abundance of >1000 proteins in plasma samples from 189 adults with SCD from the Outcome Modifying Genes in SCD (OMG-SCD) cohort (ProteomeXchange identifier PXD048716). Forty-four proteins were differentially abundant in SCDN, most significantly cystatin-C and collagen α-1(XVIII) chain (COIA1), and 55 proteins were dysregulated in patients with SCDN and pHTN, most significantly insulin-like growth factor-binding protein 6 (IBP6). Network analysis identified a module of 133 coregulated proteins significantly associated with SCDN, that was enriched for extracellular matrix proteins, insulin-like growth factor binding proteins, cell adhesion proteins, EGF-like calcium binding proteins, and several cadherin family members. Collectively, these data provide a comprehensive understanding of plasma protein changes in SCDN and pHTN which validate numerous studies of chronic kidney disease and suggest shared profiles of protein disruption in kidney dysfunction and pHTN among SCD patients.
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Affiliation(s)
- Melanie E. Garrett
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27701, USA
| | - Matthew W. Foster
- Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Duke University Medical Center, Durham, NC, 27701, USA
- Duke Proteomics and Metabolomics Core Facility, Duke University School of Medicine, Durham, NC, 27701, USA
| | - Marilyn J. Telen
- Department of Medicine, Division of Hematology and Duke Comprehensive Sickle Cell Center, Duke University Medical Center, Durham, NC, 27701, USA
| | - Allison E. Ashley-Koch
- Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, 27701, USA
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10
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Belisário AR, Costa JDA, Simões e Silva AC. Natural history of albuminuria in a large cohort of children and adolescents with sickle cell anemia from Brazil. Blood Adv 2024; 8:365-368. [PMID: 38055923 PMCID: PMC10820287 DOI: 10.1182/bloodadvances.2023011765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 11/27/2023] [Accepted: 12/06/2023] [Indexed: 12/08/2023] Open
Affiliation(s)
- André Rolim Belisário
- Centro de Tecidos Biológicos de Minas Gerais, Fundação Centro de Hematologia e Hemoterapia de Minas Gerais, Lagoa Santa, Brazil
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Jéssica de Almeida Costa
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ana Cristina Simões e Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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11
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Yu X, Majumdar S, Pollard JD, Jackson E, Knudson J, Wolfe D, Kato GJ, Maher JF. Clinical and Laboratory Correlates of QTc Duration in Adult and Pediatric Sickle Cell Disease. AMERICAN JOURNAL OF MEDICINE OPEN 2023; 10:100045. [PMID: 38222852 PMCID: PMC10785202 DOI: 10.1016/j.ajmo.2023.100045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/16/2024]
Abstract
Background Sickle cell disease, a common genetic disorder in African Americans, manifests an increased risk of sudden death, the basis of which is incompletely understood. Prolongation of heart rate-corrected QT (QTc) interval on the electrocardiogram, a standard clinical measure of cardiac repolarization, may contribute to sudden death by predisposing to torsades de pointes ventricular tachycardia. Methods We established a cohort study of 293 adult and 121 pediatric sickle cell disease patients drawn from the same geographic region as the Jackson Heart Study (JHS) cohort, in which significant correlates of QT duration have been characterized and quantitatively modeled. Herein, we establish clinical and laboratory correlates of QTc duration in our cohort using stepwise multivariate linear regression analysis. We then compared our adult sickle cell disease data to effect-size predictions from the published JHS statistical model of QT interval duration. Results In adult sickle cell disease, gender, diuretic use, QRS duration, serum ALT levels, anion gap, and diastolic blood pressure show positive correlation; hemoglobin levels show inverse correlation; in pediatric sickle cell disease, age, hemoglobin levels, and serum bicarbonate and creatinine levels show inverse correlation. The mean QTc in our adult sickle cell disease cohort is 7.8 milliseconds longer than in the JHS cohort, even though the JHS statistical model predicts that the mean QTc in our cohort should be > 11 milliseconds shorter than in the much older JHS cohort, a differential of > 18 milliseconds. Conclusion Sickle cell disease patients have substantial QTc prolongation relative to their age, driven by factors some overlapping, in adult and pediatric sickle cell disease, and distinct from those that have been defined in the general African American community.
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Affiliation(s)
- Xue Yu
- Departments of Data Science, University of Mississippi Medical Center, Jackson, MS
| | - Suvankar Majumdar
- Division of Hematology, Children’s National Hospital, Washington, DC
| | - J. Daryl Pollard
- Medicine/Division of Cardiology, University of Mississippi Medical Center, Jackson, MS
| | - Erin Jackson
- Pediatrics/Division of Hematology-Oncology, University of Mississippi Medical Center, Jackson, MS
| | - Jarrod Knudson
- Pediatrics/Division of Cardiology, University of Mississippi Medical Center, Jackson, MS
| | - Douglas Wolfe
- Medicine/Division of Cardiology, University of Mississippi Medical Center, Jackson, MS
| | - Gregory J. Kato
- Hematology Therapeutic Area, Clinical Research and Development, CSL Behring, King of Prussia, Pa
| | - Joseph F. Maher
- Medicine/Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Miss
- Cancer Genetics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
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12
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Nwosu CS, Nri-Ezedi CA, Okechukwu C, Ulasi TO, Umeh EO, Ebubedike UR, Aronu ME, Obi-Nwosu AL, Odita AO, Agu NV, Ngonadi SC, Emedike NC, Uke KM, Emegoakor AC. Two-Dimensional Ultrasound Assessment of Long-Term Intra-Abdominal Organ Changes in Children with Sickle Cell Anemia during Steady State: A Comparative Study. Niger J Clin Pract 2023; 26:1861-1867. [PMID: 38158354 DOI: 10.4103/njcp.njcp_411_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/18/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND Sickle cell anemia (SCA) is a hereditary blood disorder with global prevalence, including in Nigeria. Despite advancements in SCA care management, understanding the long-term impact on organs during steady state has remained inconclusive. AIM This study aimed to investigate the long-term changes in intra-abdominal organs of SCA children compared with non-SCA children during steady state using two-dimensional ultrasound assessment. MATERIALS AND METHODS A total of 116 children (58 SCA and 58 controls) were enrolled between June 2021 and July 2022. Clinico-demographic data were collected through an interviewer-administered questionnaire. Two-dimensional ultrasound was used to measure the liver, spleen, kidneys, and inferior vena cava in all subjects. Age-matched controls had AA or AS genotypes. RESULTS Of the 58 patients with SCA, 65.5% were males with an overall mean age of 8.1 ± 3.4 years, while among the non-SCA cohort (n = 58), 48.3% were males with an overall mean age of 8.7 ± 3.9 years. There was no statistically significant difference in the age and gender distribution between the SCA and non-SCA cohorts (P = 0.390 and P = 0.091, respectively). SCA subjects had a larger mean hepatic size than non-SCA subjects (12.09 cm ± 2.23 vs. 11.67 cm ± 1.96; P = 0.276) but smaller mean splenic size (8.01 cm ± 1.89 vs. 8.19 cm ± 1.61; P = 0.577) and inferior vena cava diameter (1.16 cm ± 0.29 vs. 1.25 cm ± 0.33; P = 0.100). Left kidney length and breadth were significantly greater in SCA patients (8.91 ± 1.16 vs. 8.27 ± 1.30; P = 0.006 and 4.15 ± 0.92 vs. 3.79 ± 0.48; P = 0.008, respectively). CONCLUSION This study highlights the utility of two-dimensional ultrasound assessment in monitoring intra-abdominal organ changes in SCA children, suggesting its cost-effective benefits in monitoring health outcomes in SCA patients.
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Affiliation(s)
- C S Nwosu
- Department of Radiology, Faculty of Medicine, Nnamdi Azikiwe University Awka, Anambra State, Nigeria
| | - C A Nri-Ezedi
- Department of Paediatrics, Faculty of Medicine, Nnamdi Azikiwe University Awka, Anambra State, Nigeria
| | - C Okechukwu
- Department of Paediatrics and Child Health, Rivers State University Teaching Hospital, Port-Harcourt, Rivers State, Nigeria
| | - T O Ulasi
- Department of Paediatrics, Faculty of Medicine, Nnamdi Azikiwe University Awka, Anambra State, Nigeria
| | - E O Umeh
- Department of Radiology, Faculty of Medicine, Nnamdi Azikiwe University Awka, Anambra State, Nigeria
| | - U R Ebubedike
- Department of Radiology, Faculty of Medicine, Nnamdi Azikiwe University Awka, Anambra State, Nigeria
| | - M E Aronu
- Department of Radiology, Faculty of Medicine, Nnamdi Azikiwe University Awka, Anambra State, Nigeria
| | - A L Obi-Nwosu
- Department of Family Medicine, Faculty of Medicine, Nnamdi Azikiwe University Awka, Anambra State, Nigeria
| | - A O Odita
- Department of Paediatrics, Faculty of Medicine, Nnamdi Azikiwe University Awka, Anambra State, Nigeria
| | - N V Agu
- Department of Paediatrics, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria
| | - S C Ngonadi
- Department of Paediatrics, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria
| | - N C Emedike
- Department of Radiology, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria
| | - K M Uke
- Department of Radiology, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria
| | - A C Emegoakor
- Department of Radiology, Nnamdi Azikiwe University Teaching Hospital, Nnewi, Anambra State, Nigeria
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13
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Babatunde HE, Bello AO, Adeboye MAN, Folayan OS, Ojewole OE, Abubakar U. Cystatin C-derived estimated glomerular filtration rate in children with sickle cell anaemia. BMC Nephrol 2023; 24:349. [PMID: 38031035 PMCID: PMC10688062 DOI: 10.1186/s12882-023-03393-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 11/08/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Sickle cell disease is the most common inherited blood disorder in humans and constitutes a major public health burden. It is a multisystemic condition with long-term renal complications. Early detection of sickle cell nephropathy and initiation of appropriate interventions are associated with improved survival and quality of life. This study aimed to compare the cystatin C-derived estimated glomerular filtration rate (GFR) of the study groups and also, to correlate the clinical features of chronic kidney disease (CKD) with decreased GFR in children with sickle cell anaemia (SCA). METHODS This hospital-based cross-sectional analytic study recruited 86 SCA subjects in steady-state and 86 age and sex-matched healthy HbAA controls aged 1-14 years who attended the Paediatric Haematology and Outpatient clinics of Federal Medical Centre Bida over six months. Data were collected using a semi-structured questionnaire, and participants' length/height, weight, and blood pressure were measured using standard procedures. Blood samples were drawn for serum cystatin C assay via the sandwich enzyme-linked immunosorbent assay (ELISA) technique. Filler's equation was used to calculate the glomerular filtration rate. RESULTS There was a significant difference in the mean cystatin C-derived GFR between the two groups, i.e. 116 ± 30mL/min/1.73m2 vs. 106 ± 24mL/min/1.73m2 for the SCA and control groups, respectively (p = 0.017). The prevalence of supernormal GFR (i.e. GFR > 140mL/min/1.73m2) and decreased GFR (i.e. GFR < 90mL/min/1.73m2) was 19.8% and 22.1%, respectively, in children with SCA. There was no significant association between the age at diagnosis of SCA, blood transfusions, blood pressure, packed cell volume and presence of peripheral oedema with decreased GFR in the study subjects. CONCLUSIONS Supernormal GFR is common in children with SCA and there is no significant association between clinical features of CKD with decreased GFR. Regular evaluation of renal function is, however, recommended in children with SCA for early detection and treatment of renal complications in order to halt the progression to end-stage kidney disease (ESKD).
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Affiliation(s)
- Hakeem Edun Babatunde
- Department of Disease Control and Elimination, Medical Research Council Unit, The Gambia at London School of Hygiene and Tropical Medicine, Atlantic Boulevard, P. O. Box 273, Banjul, The Gambia.
| | - Afeez Oyesola Bello
- Department of Paediatrics, Federal Medical Centre, Bida, Niger State, Nigeria
| | | | | | | | - Usman Abubakar
- Department of Paediatrics, Federal Medical Centre, Bida, Niger State, Nigeria
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14
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Kasztan M, Aban I, Baker K, Ho M, Ilonze C, Lebensburger J. Natural history and variability in albuminuria in pediatric and murine sickle cell anemia. Blood Adv 2023; 7:6850-6858. [PMID: 37428862 PMCID: PMC10685147 DOI: 10.1182/bloodadvances.2023010101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 05/26/2023] [Accepted: 06/19/2023] [Indexed: 07/12/2023] Open
Abstract
It is critical to characterize the natural history of albuminuria in patients with sickle cell anemia (SCA); however, these data are currently lacking and affecting evidence-based guidelines. We performed a natural history study of the development of pediatric albuminuria. We identified participants with hemoglobin SS/SB0 thalassemia ≥5 years with albumin to creatinine ratio (ACR) measurements performed at a steady-state clinic visit. Participants were characterized as either persistent, intermittent, or never albuminuria. We determined the prevalence of persistent albuminuria, use of ACR ≥100 mg/g as a predictor, and variation in ACR measurements. We mirrored this study to determine the variation in albuminuria measurements in the SCA murine model. Among 355 participants with HbSS/SB0 thalassemia with 1728 ACR measurements, we identified 17% with persistent and 13% with intermittent albuminuria. Thirteen percent of participants with persistent albuminuria developed an abnormal ACR before 10 years of age. A single ACR measurement ≥100 mg/g was associated with 55.5 times (95% confidence interval, 12.3-527) higher odds of having persistent albuminuria. Among participants with ACR ≥100 mg/g, we identified significant variability in the results of repeated measurements. The median ACR at the initial and next measurements were 175.8 mg/g (interquartile range [IQR], 135-242) and 117.3 mg/g (IQR, 64-292). The human variability in ACR was mirrored by ∼20% variability in albuminuria in murine model. This evidence suggests adopting standards for repeating ACR measurements, consider screening for ACR before 10 years of age, and using an ACR >100 mg/g as a risk factor for progression. Pediatric and murine renoprotective clinical trials need to consider the high variability in repeated ACR measurements.
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Affiliation(s)
- Malgorzata Kasztan
- Division of Pediatric Hematology Oncology, The University of Alabama at Birmingham, Birmingham, AL
| | - Inmaculada Aban
- Department of Biostatistics, The University of Alabama at Birmingham, Birmingham, AL
| | - Kayla Baker
- Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL
| | - Michael Ho
- Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL
| | - Chibuzo Ilonze
- Division of Pediatric Hematology Oncology, The University of Alabama at Birmingham, Birmingham, AL
| | - Jeffrey Lebensburger
- Division of Pediatric Hematology Oncology, The University of Alabama at Birmingham, Birmingham, AL
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15
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Zahr RS, Saraf SL. Sickle Cell Disease and CKD: An Update. Am J Nephrol 2023; 55:56-71. [PMID: 37899028 PMCID: PMC10872505 DOI: 10.1159/000534865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 10/25/2023] [Indexed: 10/31/2023]
Abstract
BACKGROUND Sickle cell disease is an inherited red blood cell disorder that affects approximately 100,000 people in the USA and 25 million people worldwide. Vaso-occlusion and chronic hemolysis lead to dysfunction of vital organ systems, with the kidneys being among the most commonly affected organs. SUMMARY Early renal manifestations include medullary ischemia with the loss of urine-concentrating ability and hyperfiltration. This can be followed by progressive damage characterized by persistent albuminuria and a decline in the estimated glomerular filtration rate. The risk of sickle nephropathy is greater in those with the APOL1 G1 and G2 kidney risk variants and variants in HMOX1 and lower in those that coinherit α-thalassemia. Therapies to treat sickle cell disease-related kidney damage focus on sickle cell disease-modifying therapies (e.g., hydroxyurea) or those adopted from the nonsickle cell disease kidney literature (e.g., renin-angiotensin-aldosterone system inhibitors), although data on their clinical efficacy are limited to small studies with short follow-up periods. Kidney transplantation for end-stage kidney disease improves survival compared to hemodialysis but is underutilized in this patient population. KEY MESSAGES Kidney disease is a major contributor to early mortality, and more research is needed to understand the pathophysiology and develop targeted therapies to improve kidney health in sickle cell disease.
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Affiliation(s)
- Rima S. Zahr
- Division of Pediatric Nephrology and Hypertension, University of Tennessee Health Science Center, Memphis, TN
| | - Santosh L. Saraf
- Division of Hematology & Oncology, University of Illinois Chicago, Chicago, IL
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16
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Adebayo OC, Nkoy AB, van den Heuvel LP, Labarque V, Levtchenko E, Delanaye P, Pottel H. Glomerular hyperfiltration: part 2-clinical significance in children. Pediatr Nephrol 2023; 38:2529-2547. [PMID: 36472656 DOI: 10.1007/s00467-022-05826-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 10/27/2022] [Accepted: 11/10/2022] [Indexed: 12/12/2022]
Abstract
Glomerular hyperfiltration (GHF) is a phenomenon that can occur in various clinical conditions affecting the kidneys such as sickle cell disease, diabetes mellitus, autosomal dominant polycystic kidney disease, and solitary functioning kidney. Yet, the pathophysiological mechanisms vary from one disease to another and are not well understood. More so, it has been demonstrated that GHF may occur at the single-nephron in some clinical conditions while in others at the whole-kidney level. In this review, we explore the pathophysiological mechanisms of GHF in relation to various clinical conditions in the pediatric population. In addition, we discuss the role and mechanism of action of important factors such as gender, low birth weight, and race in the pathogenesis of GHF. Finally, in this current review, we further highlight the consequences of GHF in the progression of kidney disease.
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Affiliation(s)
- Oyindamola C Adebayo
- Center of Vascular and Molecular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
| | - Agathe B Nkoy
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Division of Nephrology, Department of Pediatrics, Faculty of Medicine, University Hospital of Kinshasa, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Lambertus P van den Heuvel
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Department of Pediatric Nephrology, Radboud University Medical Centre, 6500 Nijmegen, The Netherlands
| | - Veerle Labarque
- Center of Vascular and Molecular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Department of Pediatric Hematology, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Elena Levtchenko
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, Katholieke Universiteit Leuven, Campus Gasthiusberg, 3000 Leuven, Belgium
- Department of Pediatric Nephrology, University Hospitals Leuven, 3000 Leuven, Belgium
| | - Pierre Delanaye
- Department of Nephrology-Dialysis-Transplantation, University of Liège, CHU Sart Tilman, Liège, Belgium
- Department of Nephrology-Dialysis-Apheresis, Hôpital Universitaire Carémeau, Nîmes, France
| | - Hans Pottel
- Department of Public Health and Primary Care, Katholieke Universiteit Leuven, Campus Kulak, 8500 Kortrijk, Belgium.
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17
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Farris N, Benoit SW, McNinch NL, Bodas P. Urinary Biomarkers for the Assessment of Acute Kidney Injury of Pediatric Sickle Cell Anemia Patients Admitted for Severe Vaso-occlusive Crises. J Pediatr Hematol Oncol 2023; 45:309-314. [PMID: 36898013 DOI: 10.1097/mph.0000000000002642] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/20/2022] [Indexed: 03/12/2023]
Abstract
Sickle cell nephropathy is a progressive morbidity, beginning in childhood, which is incompletely understood partially due to insensitive measures. We performed a prospective pilot study of pediatric and young adult patients with sickle cell anemia (SCA) to assess urinary biomarkers during acute pain crises. Four biomarkers were analyzed with elevations potentially suggesting acute kidney injury: (1) neutrophil gelatinase-associated lipocalin (NGAL), (2) kidney injury molecule-1, (3) albumin, and (4) nephrin. Fourteen unique patients were admitted for severe pain crises and were found to be representative of a larger SCA population. Urine samples were collected at the time of admission, during admission, and at follow-up after discharge. Exploratory analyses compared cohort values to the best available population values; individuals were also compared against themselves at various time points. Albumin was found to be moderately elevated for an individual during admission compared with follow-up ( P = 0.006, Hedge g : 0.67). Albumin was not found to be elevated compared with population values. Neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and nephrin were not found to be significantly elevated compared with population values or comparing admission to follow-up. Though albumin was found to be minimally elevated, further research should focus on alternative markers in efforts to further understand kidney disease in patients with SCA.
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Affiliation(s)
- Nicholas Farris
- Division of Pediatric Hematology Oncology, University of Rochester, Rochester, NY
- Division of Hematology Oncology Akron Children's Hospital
| | - Stefanie W Benoit
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH
| | - Neil L McNinch
- Division of Hematology Oncology Akron Children's Hospital
- Rebecca D. Considine Research Institute at Akron Children's Hospital, Akron
| | - Prasad Bodas
- Division of Hematology Oncology Akron Children's Hospital
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18
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Terracina S, Pallaria A, Lucarelli M, Angeloni A, De Angelis A, Ceci FM, Caronti B, Francati S, Blaconà G, Fiore M, Ferraguti G. Urine Dipstick Analysis on Automated Platforms: Is a Reliable Screening Tool for Proteinuria? An Experience from Umberto I Hospital in Rome. Biomedicines 2023; 11:biomedicines11041174. [PMID: 37189791 DOI: 10.3390/biomedicines11041174] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/07/2023] [Accepted: 04/10/2023] [Indexed: 05/17/2023] Open
Abstract
Urinalysis is commonly used as a screening tool for kidney disease. In many cases, the dipstick urine assay includes the assessment of albumin/protein and creatinine; consequently, the value of their ratio is available on the urine section report. Identification of albuminuria/proteinuria at early stages is an important issue to prevent or at least delay the onset of chronic kidney disease (CKD), kidney failure, and the progression of cardiovascular damage linked to the kidney's loss of function. Sensitive and specific diagnostic methods are required for the assessment of such an important biomarker: urine albumin, creatinine, and their ratio (ACR) measured with quantitative assays are considered the gold standard. Routine dipstick methods (more rapid and at a lower cost) are intended for wide population screening. The aim of our study was to verify the reliability of an automated urinalysis dipstick method by comparing the results with the quantitative test of creatinine and albumin performed on a clinical chemistry platform. The first-morning voids of 249 patients who arrived from different departments were analyzed in the Central Laboratory of the University Hospital Policlinico Umberto I in Rome. We found a good correlation between the two assays, even though we observed that the dipstick assessment tends to overestimate the ACR's value, disclosing a higher number of false positives if compared to the reference method. As an important novelty in this study, we analyzed our data considering age (starting from pediatric to geriatric patients) and sex as variables for a sub-stratification of the participants. Our results show that positive values need to be confirmed with quantitative methods, especially in women and younger people, and that from samples that resulted as diluted at the dipstick assay, the ACR's values can be obtained if they are reanalyzed with quantitative assays. Moreover, patients with microalbuminuria (ACR 30-300 mg/g) or severe albumin urinary excretion (ACR > 300 mg/g) should be reanalyzed using quantitative methods to obtain a more reliable calculation of the ACR.
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Affiliation(s)
- Sergio Terracina
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Antonio Pallaria
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Marco Lucarelli
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Antonio Angeloni
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Annarita De Angelis
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Flavio Maria Ceci
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Brunella Caronti
- Department of Human Neurosciences, Sapienza University Hospital of Rome, 00185 Rome, Italy
| | - Silvia Francati
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Giovanna Blaconà
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology, IBBC-CNR, 00185 Rome, Italy
| | - Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
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19
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Novel insights in classic versus relative glomerular hyperfiltration and implications on pharmacotherapy. Curr Opin Nephrol Hypertens 2023; 32:58-66. [PMID: 36444663 DOI: 10.1097/mnh.0000000000000847] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW Glomerular filtration rate (GFR) assessment and its estimation (eGFR) is a long-lasting challenge in medicine and public health. Current eGFR formulae are indexed for standardized body surface area (BSA) of 1.73 m2, ignoring persons and populations wherein the ratio of BSA or metabolic rate to nephron number might be different, due to increased BSA, increased metabolic rate or reduced nephron number. These equations are based on creatinine, cystatin C or a combination of the two, which adds another confounder to eGFR assessment. Unusually high GFR values, also known as renal hyperfiltration, have not been well defined under these equations. RECENT FINDINGS Special conditions such as solitary kidney in kidney donors, high dietary protein intake, obesity and diabetes are often associated with renal hyperfiltration and amenable to errors in GFR estimation. In all hyperfiltration types, there is an increased intraglomerular pressure that can be physiologic, but its persistence over time is detrimental to glomerulus leading to progressive glomerular damage and renal fibrosis. Hyperfiltration might be underdiagnosed due to BSA standardization embedded in the formula. Hence, timely intervention is delayed. Reducing intraglomerular pressure in diabetes can be achieved by SGLT2 inhibitors or low protein diet to reverse the glomerulopathy process. SUMMARY Accurate identification of glomerular hyperfiltration as a pre-CKD condition needs accurate estimation of GFR in the above normal range should establish a threshold for timely intervention.
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Lebensburger JD, Derebail VK. Sickle Cell Disease and the Kidney. Hematol Oncol Clin North Am 2022; 36:1239-1254. [DOI: 10.1016/j.hoc.2022.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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21
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Afangbedji N, Jerebtsova M. Glomerular filtration rate abnormalities in sickle cell disease. Front Med (Lausanne) 2022; 9:1029224. [PMID: 36341242 PMCID: PMC9633850 DOI: 10.3389/fmed.2022.1029224] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 10/04/2022] [Indexed: 12/03/2022] Open
Abstract
Sickle cell disease (SCD) is a group of inherited blood disorders affecting the β-globin gene, resulting in the polymerization of hemoglobin and subsequent sickling of the red blood cell. Renal disease, the most common complication in SCD, begins in childhood with glomerular hyperfiltration and then progresses into albuminuria, a fast decline of glomerular filtration, and renal failure in adults. This mini-review focuses on glomerular filtration abnormalities and the mechanisms of hyperfiltration, explores genetic modifiers and methods of estimating glomerular filtration rates, and examines novel biomarkers of glomerular filtration in SCD.
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Affiliation(s)
- Nowah Afangbedji
- Department of Physiology and Biophysics, Howard University, Washington, DC, United States
| | - Marina Jerebtsova
- Department of Microbiology, Howard University, Washington, DC, United States
- *Correspondence: Marina Jerebtsova,
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22
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Zahr RS, Ding J, Kang G, Wang WC, Hankins JS, Ataga KI, Lebensburger JD, Porter JS. Enuresis and Hyperfiltration in Children With Sickle Cell Disease. J Pediatr Hematol Oncol 2022; 44:358-362. [PMID: 35180759 PMCID: PMC9385885 DOI: 10.1097/mph.0000000000002426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 01/06/2022] [Indexed: 11/26/2022]
Abstract
Nocturnal enuresis is a common symptom in children with sickle cell disease (SCD). Risk factors for development of enuresis are currently unknown. An early manifestation of SCD-associated kidney damage is glomerular hyperfiltration. We test the hypothesis that in a pediatric SCD cohort, individuals with hyperfiltration are more likely to have nocturnal enuresis when compared to children without hyperfiltration. To assess the relationship between nocturnal enuresis and hyperfiltration, we retrospectively evaluated children with SCD enrolled in the Evaluation of Nocturnal Enuresis and Barriers to Treatment among Pediatric Patients with SCD study and prospectively identified children who reported nocturnal enuresis and were enrolled in the longitudinal cohort study Sickle Cell Clinical Research and Intervention Program. Nocturnal enuresis occurred in 46.5% of Pediatric Patients with Sickle Cell Disease participants and was more frequent in participants with HbSS/HbSβ 0 thalassemia and in male participants. We did not identify an association between hyperfiltration from 3 to 5 years of age with the later development of enuresis. Severe SCD genotypes and male sex were associated with nocturnal enuresis after age 5 years. We could not identify additional renal or hematologic predictors associated with the diagnosis of nocturnal enuresis. Future studies should incorporate nonrenal risk factors into studies that predict development of enuresis.
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Affiliation(s)
- Rima S. Zahr
- Division of Pediatric Nephrology and Hypertension, University of Tennessee Health Science Center, Memphis, TN
| | - Juan Ding
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN
| | - Guolian Kang
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN
| | - Winfred C. Wang
- Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Jane S. Hankins
- Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Kenneth I. Ataga
- Center for Sickle Cell Disease, University of Tennessee Health Science Center, Memphis, TN
| | - Jeffrey D. Lebensburger
- Division of Pediatric Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL
| | - Jerlym S. Porter
- Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN
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Batte A, Menon S, Ssenkusu JM, Kiguli S, Kalyesubula R, Lubega J, Berrens Z, Mutebi EI, Ogwang R, Opoka RO, John CC, Conroy AL. Neutrophil gelatinase-associated lipocalin is elevated in children with acute kidney injury and sickle cell anemia, and predicts mortality. Kidney Int 2022; 102:885-893. [PMID: 35718113 PMCID: PMC7613606 DOI: 10.1016/j.kint.2022.05.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 04/10/2022] [Accepted: 05/09/2022] [Indexed: 11/30/2022]
Abstract
Urine neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury that has been adapted to a urine dipstick test. However, there is limited data on its use in low-and-middle-income countries where diagnosis of acute kidney injury remains a challenge. To study this, we prospectively enrolled 250 children with sickle cell anemia aged two to 18 years encompassing 185 children hospitalized with a vaso-occlusive pain crisis and a reference group of 65 children attending the sickle cell clinic for routine care follow up. Kidney injury was defined using serial creatinine measures and a modified-Kidney Disease Improving Global Outcome definition for sickle cell anemia. Urine NGAL was measured using the NGAL dipstick and a laboratory reference. The mean age of children enrolled was 8.9 years and 42.8% were female. Among hospitalized children, 36.2% had kidney injury and 3.2% died. Measured urine NGAL levels by the dipstick were strongly correlated with the standard enzyme-linked immunosorbent assay for urine NGAL (hospitalized children, 0.71; routine care reference, 0.88). NGAL levels were elevated in kidney injury and significantly increased across injury stages. Hospitalized children with a high-risk dipstick test (300ng/mL and more) had a 2.47-fold relative risk of kidney injury (95% confidence interval 1.68 to 3.61) and 7.28 increased risk of death (95% confidence interval 1.10 to 26.81) adjusting for age and sex. Thus, urine NGAL levels were found to be significantly elevated in children with sickle cell anemia and acute kidney injury and may predict mortality.
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Affiliation(s)
- Anthony Batte
- Child Health and Development Centre, Makerere University College of Health Sciences, Kampala, Uganda
| | - Sahit Menon
- San Diego School of Medicine, University of California, San Diego, California, USA
| | - John M Ssenkusu
- Department of Epidemiology and Biostatistics, Makerere University School of Public Health, Kampala, Uganda
| | - Sarah Kiguli
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - Robert Kalyesubula
- Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | - Joseph Lubega
- Division of Pediatric Hematology and Oncology, Baylor College of Medicine, Houston, Texas, USA
| | - Zachary Berrens
- Department of Pediatrics, Pediatric Critical Care Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Edrisa Ibrahim Mutebi
- Department of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | - Rodney Ogwang
- Kenyan Medical Research Institute (KEMRI)-Wellcome Trust Research Programme, Centre for Geographic Medicine Coast, Kilifi, Kenya
| | - Robert O Opoka
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - Chandy C John
- Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Andrea L Conroy
- Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, Indianapolis, Indiana, USA.
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Longitudinal Study of Glomerular Hyperfiltration in Adults with Sickle Cell Anemia: A Multicenter Pooled Analysis. Blood Adv 2022; 6:4461-4470. [PMID: 35696734 PMCID: PMC9636315 DOI: 10.1182/bloodadvances.2022007693] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/07/2022] [Indexed: 11/21/2022] Open
Abstract
Glomerular hyperfiltration is common in young sickle cell anemia patients and precedes development of overt kidney disease. In this multicenter pooled cohort, we characterized hyperfiltration and its decline to normal range in adult patients. Glomerular filtration rate (GFR) was estimated using the creatinine-based 2009 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation omitting race adjustment and the 2021 CKD-EPI equation. Using CKD-EPI–2009, 506 patients had baseline estimated GFR (eGFR) ≥90 mL/min per 1.73 m2, median age of 24 (interquartile range [IQR], 19-34) years and 5.17 years of follow-up. The prevalence of hyperfiltration (eGFR ≥140 and ≥130 mL/min per 1.73 m2 for men and women, respectively) was 38.3%. Using CKD-EPI–2009, baseline hyperfiltration was less likely with older age (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.73-0.83; P < .0001), male sex (OR, 0.32; 95% CI, 0.18-0.58; P = .0002), and higher weight (OR, 0.96; 95% CI, 0.94-0.99; P = .001). Using CKD-EPI–2021, hyperfiltration was similarly less likely with older age (OR, 0.75; 95% CI, 0.70-0.81; P < .0001), male sex (OR, 0.24; 95% CI, 0.13-0.44; P < .0001), and higher weight (OR, 0.97; 95% CI, 0.95-0.99; P = .004). In patients with baseline hyperfiltration, eGFR declined to normal values at a median age of 26.2 years. Using CKD-EPI–2009, this decline was associated with male sex (HR, 2.20; 95% CI, 1.26-3.87; P = .006), systolic blood pressure (hazard ratio [HR], 1.02; 95% CI, 1.01-1.04; P = .01), and hydroxyurea use (HR, 1.74; 95% CI, 1.002-3.03; P = .05). Using CKD-EPI–2021, decline of eGFR to normal was only associated with male sex (HR, 3.39; 95% CI, 2.01-5.69; P < .0001). Decline to normal eGFR range from hyperfiltration occurs earlier in males, those on hydroxyurea, and with higher systolic blood pressure.
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25
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Al-Eyadhy A, Al-Jelaify MR. Suboptimal vancomycin levels in critically ill children with sickle cell disease and acute chest syndrome. J Infect Chemother 2022; 28:1304-1309. [DOI: 10.1016/j.jiac.2022.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/24/2022] [Accepted: 05/29/2022] [Indexed: 10/18/2022]
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26
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Ataga KI, Saraf SL, Derebail VK. The nephropathy of sickle cell trait and sickle cell disease. Nat Rev Nephrol 2022; 18:361-377. [PMID: 35190716 PMCID: PMC9832386 DOI: 10.1038/s41581-022-00540-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2022] [Indexed: 01/13/2023]
Abstract
Sickle cell syndromes, including sickle cell disease (SCD) and sickle cell trait, are associated with multiple kidney abnormalities. Young patients with SCD have elevated effective renal plasma flow and glomerular filtration rates, which decrease to normal ranges in young adulthood and subnormal levels with advancing age. The pathophysiology of SCD-related nephropathy is multifactorial - oxidative stress, hyperfiltration and glomerular hypertension are all contributing factors. Albuminuria, which is an early clinical manifestation of glomerular damage, is common in individuals with SCD. Kidney function declines more rapidly in individuals with SCD than in those with sickle cell trait or in healthy individuals. Multiple genetic modifiers, including APOL1, HMOX1, HBA1 and HBA2 variants are also implicated in the development and progression of SCD-related nephropathy. Chronic kidney disease and rapid decline in estimated glomerular filtration rate are associated with increased mortality in adults with SCD. Renin-angiotensin-aldosterone system inhibitors are the standard of care treatment for albuminuria in SCD, despite a lack of controlled studies demonstrating their long-term efficacy. Multiple studies of novel therapeutic agents are ongoing, and patients with SCD and kidney failure should be evaluated for kidney transplantation. Given the high prevalence and severe consequences of kidney disease, additional studies are needed to elucidate the pathophysiology, natural history and treatment of SCD-related nephropathy.
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Affiliation(s)
- Kenneth I Ataga
- Center for Sickle Cell Disease, University of Tennessee Health Scienter Center, Memphis, TN, USA.
| | - Santosh L Saraf
- Division of Hematology/Oncology, University of Illinois, Chicago, IL, USA
| | - Vimal K Derebail
- Division of Nephrology and Hypertension, University of North Carolina, Chapel Hill, NC, USA
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27
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Revisiting anemia in sickle cell disease and finding the balance with therapeutic approaches. Blood 2022; 139:3030-3039. [PMID: 35587865 DOI: 10.1182/blood.2021013873] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 12/05/2021] [Indexed: 11/20/2022] Open
Abstract
Chronic hemolytic anemia and intermittent acute pain episodes are the 2 hallmark characteristics of sickle cell disease (SCD). Anemia in SCD not only signals a reduction of red cell mass and oxygen delivery, but also ongoing red cell breakdown and release of cell-free hemoglobin, which together contribute to a number of pathophysiological responses and play a key role in the pathogenesis of cumulative multiorgan damage. However, although anemia is clearly associated with many detrimental outcomes, it may also have an advantage in SCD in lowering risks of potential viscosity-related complications. Until recently, clinical drug development for SCD has predominantly targeted a reduction in the frequency of vaso-occlusive crises as an endpoint, but increasingly, more attention is being directed toward addressing the contribution of chronic anemia to poor outcomes in SCD. This article aims to explore the complex pathophysiology and mechanisms of anemia in SCD, as well as the need to balance the benefits of raising hemoglobin levels with the potential risks of increasing blood viscosity, in the context of the current therapeutic landscape for anemia in SCD.
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28
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Brandow AM, Liem RI. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol 2022; 15:20. [PMID: 35241123 PMCID: PMC8895633 DOI: 10.1186/s13045-022-01237-z] [Citation(s) in RCA: 75] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 02/15/2022] [Indexed: 12/12/2022] Open
Abstract
Sickle cell disease (SCD), which affects approximately 100,000 individuals in the USA and more than 3 million worldwide, is caused by mutations in the βb globin gene that result in sickle hemoglobin production. Sickle hemoglobin polymerization leads to red blood cell sickling, chronic hemolysis and vaso-occlusion. Acute and chronic pain as well as end-organ damage occur throughout the lifespan of individuals living with SCD resulting in significant disease morbidity and a median life expectancy of 43 years in the USA. In this review, we discuss advances in the diagnosis and management of four major complications: acute and chronic pain, cardiopulmonary disease, central nervous system disease and kidney disease. We also discuss advances in disease-modifying and curative therapeutic options for SCD. The recent availability of L-glutamine, crizanlizumab and voxelotor provides an alternative or supplement to hydroxyurea, which remains the mainstay for disease-modifying therapy. Five-year event-free and overall survival rates remain high for individuals with SCD undergoing allogeneic hematopoietic stem cell transplant using matched sibling donors. However, newer approaches to graft-versus-host (GVHD) prophylaxis and the incorporation of post-transplant cyclophosphamide have improved engraftment rates, reduced GVHD and have allowed for alternative donors for individuals without an HLA-matched sibling. Despite progress in the field, additional longitudinal studies, clinical trials as well as dissemination and implementation studies are needed to optimize outcomes in SCD.
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Affiliation(s)
- A. M. Brandow
- grid.30760.320000 0001 2111 8460Department of Pediatrics, Section of Pediatric Hematology/Oncology/Bone Marrow Transplantation, Medical College of Wisconsin, Milwaukee, WI USA
| | - R. I. Liem
- grid.413808.60000 0004 0388 2248Division of Hematology, Oncology and Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL USA
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29
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Safdar OY, Baghdadi RM, Alahmadi SA, Fakieh BE, Algaydi AM. Sickle cell nephropathy: A review of novel biomarkers and their potential roles in early detection of renal involvement. World J Clin Pediatr 2022; 11:14-26. [PMID: 35096543 PMCID: PMC8771312 DOI: 10.5409/wjcp.v11.i1.14] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 08/12/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Whether the underlying mutations are homozygous, heterozygous, or co-inherited with other hemoglobinopathies, sickle cell disease is known to afflict the kidneys, leading to the clinical entity known as sickle cell nephropathy (SCN). Although common, SCN remains diagnostically elusive. Conventional studies performed in the context of renal disorders often fail to detect early stage SCN. This makes the quest for early diagnosis and treatment more challenging, and it increases the burden of chronic kidney disease-related morbidity among patients. Novel diagnostic tools have been employed to overcome this limitation. In this study, we discuss various biomarkers of SCN, including those employed in clinical practice and others recently identified in experimental settings, such as markers of vascular injury, endothelial dysfunction, tubulo-glomerular damage, and oxidative stress. These include kidney injury molecule-1, monocyte chemoattractant protein-1, N-acetyl-B-D-glucosaminidase, ceruloplasmin, orosomucoid, nephrin, and cation channels, among others. Furthermore, we explore the potential of novel biomarkers for refining diagnostic and therapeutic approaches and describe some obstacles that still need to be overcome. We highlight the importance of a collaborative approach to standardize the use of promising new biomarkers. Finally, we outline the limitations of conventional markers of renal damage as extensions of the pathogenic process occurring at the level of the organ and its functional subunits, with a discussion of the expected pattern of clinical and biochemical progression among patients with SCN.
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Affiliation(s)
- Osama Y Safdar
- Department of Pediatric, King Abdulaziz University, JEDDAH 21414, Saudi Arabia
| | - Rana M Baghdadi
- College of Medicine, King Abdulaziz University, JEDDAH 21422, Saudi Arabia
| | - Sereen A Alahmadi
- College of Medicine, King Abdulaziz University, JEDDAH 21422, Saudi Arabia
| | - Bana E Fakieh
- College of Medicine, King Abdulaziz University, JEDDAH 21422, Saudi Arabia
| | - Amaal M Algaydi
- College of Medicine, King Abdulaziz University, JEDDAH 21422, Saudi Arabia
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30
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Flahault A, Bollée G, El-Jalbout R, Cloutier A, Santos RAS, Lapeyraque AL, Luu TM, Nuyt AM. Plasma copeptin is increased and associated with smaller kidney volume in young adults born very preterm. Clin Kidney J 2021; 15:709-717. [PMID: 35371457 PMCID: PMC8967663 DOI: 10.1093/ckj/sfab226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Indexed: 11/26/2022] Open
Abstract
Background Plasma copeptin, a surrogate marker for vasopressin levels, is increased in neonates born preterm, particularly in those with a more severe neonatal course, as reflected by bronchopulmonary dysplasia. Copeptin levels in adulthood are unknown. Methods In this case–control study of 101 adults born very preterm (<30 weeks of gestation) and 105 control adults born full-term, a comprehensive clinical and biological assessment was performed, including blood pressure measurements, kidney ultrasound and determination of plasma copeptin, renin activity, angiotensin II, aldosterone, apelin, sodium and potassium, serum and morning urine osmolality. Results The median age in the study was 23.1 years [interquartile range (IQR) 21.2–24.8] and 57% were females. In males, the median copeptin levels were 8.2 pmol/L (IQR 6.3–12.4) and 6.1 pmol/L (IQR 4.3–9.0) in the preterm and term groups, respectively (P = 0.022). In females, the median copeptin levels were 5.2 pmol/L (IQR 3.9–7.6) and 4.0 pmol/L (IQR 2.8–5.7) in the preterm and term groups, respectively (P = 0.005). Adults born preterm with a history of bronchopulmonary dysplasia had further increased copeptin levels. The kidney volume, adjusted for height, was smaller and albuminuria was higher in the preterm group, and both were associated with higher plasma copeptin levels. Conclusions Plasma copeptin is higher in young adults born preterm and is related to a more severe neonatal course and smaller kidney volume.
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Affiliation(s)
- Adrien Flahault
- Sainte-Justine University Hospital Research Center, Université de Montréal, Montréal, Québec, Canada
| | - Guillaume Bollée
- Division of Nephrology, Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montréal, Québec, Canada
| | - Ramy El-Jalbout
- Sainte-Justine University Hospital Research Center, Université de Montréal, Montréal, Québec, Canada
- Medical Imaging Department, Sainte-Justine University Hospital, Université de Montréal, Montréal, Québec, Canada
| | - Anik Cloutier
- Sainte-Justine University Hospital Research Center, Université de Montréal, Montréal, Québec, Canada
| | - Robson A S Santos
- Department of Physiology and Biophysics, National Institute of Science and Technology in Nanobiopharmaceutics (INCT-Nanobiofar), Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Anne-Laure Lapeyraque
- Sainte-Justine University Hospital Research Center, Université de Montréal, Montréal, Québec, Canada
- Division of Nephrology, Department of Pediatrics, Sainte-Justine University Hospital, Université de Montréal, Montréal, Québec, Canada
| | - Thuy Mai Luu
- Sainte-Justine University Hospital Research Center, Université de Montréal, Montréal, Québec, Canada
- Division of General Pediatrics, Department of Pediatrics, Sainte-Justine University Hospital, Université de Montréal, Montréal, Québec, Canada
| | - Anne Monique Nuyt
- Sainte-Justine University Hospital Research Center, Université de Montréal, Montréal, Québec, Canada
- Division of Neonatology, Department of Pediatrics, Sainte-Justine University Hospital, Université de Montréal, Montréal, Québec, Canada
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31
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Adebayo OC, Betukumesu DK, Nkoy AB, Adesoji OM, Ekulu PM, Van den Heuvel LP, Levtchenko EN, Labarque V. Clinical and genetic factors are associated with kidney complications in African children with sickle cell anaemia. Br J Haematol 2021; 196:204-214. [PMID: 34545573 DOI: 10.1111/bjh.17832] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/19/2021] [Accepted: 09/02/2021] [Indexed: 12/11/2022]
Abstract
Clinical and genetic factors have been reported as influencing the development of sickle cell nephropathy (SCN). However, such data remain limited in the paediatric population. In this cross-sectional study, we enrolled 361 sickle cell disease children from the Democratic Republic of Congo. Participants were genotyped for the beta (β)-globin gene, apolipoprotein L1 (APOL1) risk variants, and haem oxygenase-1 (HMOX1) GT-dinucleotide repeats. As markers of kidney damage, albuminuria, hyperfiltration and decreased estimated glomerular filtration with creatinine (eGFRcr) were measured. An association of independent clinical and genetic factors with these markers of kidney damage were assessed via regression analysis. Genetic sequencing confirmed sickle cell anaemia in 326 participants. Albuminuria, hyperfiltration and decreased eGFRcr were present in 65 (20%), 52 (16%) and 18 (5·5%) patients, respectively. Regression analysis revealed frequent blood transfusions, indirect bilirubin and male gender as clinical predictors of SCN. APOL1 high-risk genotype (G1/G1, G2/G2 and G1/G2) was significantly associated with albuminuria (P = 0·04) and hyperfiltration (P = 0·001). HMOX1 GT-dinucleotide long repeats were significantly associated with lower eGFRcr. The study revealed a high burden of kidney damage among Congolese children and provided evidence of the possible role of APOL1 and HMOX1 in making children more susceptible to kidney complications.
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Affiliation(s)
- Oyindamola Christiana Adebayo
- Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.,Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium
| | - DieuMerci Kabasele Betukumesu
- Division of Nephrology, Department of Paediatrics, Faculty of Medicine, University Hospital of Kinshasa, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Agathe Bikupe Nkoy
- Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium.,Division of Nephrology, Department of Paediatrics, Faculty of Medicine, University Hospital of Kinshasa, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | | | - Pepe Mfutu Ekulu
- Division of Nephrology, Department of Paediatrics, Faculty of Medicine, University Hospital of Kinshasa, University of Kinshasa, Kinshasa, Democratic Republic of Congo
| | - Lambertus P Van den Heuvel
- Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium.,Department of Paediatric Nephrology, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Elena N Levtchenko
- Department of Development and Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium.,Department of Paediatric Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Veerle Labarque
- Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven, Leuven, Belgium.,Department of Paediatric Haemato-Oncology, University Hospitals Leuven, Leuven, Belgium
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Derebail VK, Zhou Q, Ciccone EJ, Cai J, Ataga KI. Longitudinal study of glomerular hyperfiltration and normalization of estimated glomerular filtration in adults with sickle cell disease. Br J Haematol 2021; 195:123-132. [PMID: 34402052 DOI: 10.1111/bjh.17723] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 07/07/2021] [Accepted: 07/09/2021] [Indexed: 01/16/2023]
Abstract
Glomerular hyperfiltration is common in sickle cell disease (SCD) and precedes proteinuria and declining kidney function. We evaluated hyperfiltration in SCD patients and its "normalization." Routine visit data were collected retrospectively from adult SCD patients in a single centre from 2004 to 2013. Baseline was defined as first available serum creatinine and hyperfiltration as estimated glomerular filtration rates (eGFR) >130 ml/min/1·73 m2 for women and >140 ml/min/1·73 m2 for men. Normalization of hyperfiltration was eGFR reduction to 90-130 ml/min/1·73 m2 for women or 90-140 ml/min/1·73 m2 for men. Among 292 patients, median age was 27 years [interquartile range (IQR):20·0-38·0], and 56·8% had baseline hyperfiltration. Baseline hyperfiltration was inversely associated with age [odds ratio (OR):0·86, 95% confidence interval (CI): 0·82-0·90; P < 0·0001], male sex (OR:0·16, 95% CI: 0·07-0·41; P = 0·0001), haemoglobin (OR:0·76, 95% CI 0·61-0·94; P = 0·01), weight (OR:0·96, 95% CI: 0·93-0·99; P = 0·004), and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACE-I/ARB) use (OR:0·08, 95% CI: 0·01-0·75; P = 0·03), and positively with hydroxycarbamide use (OR:2·99, 95% CI: 1·18-7·56; P = 0·02). Of 89 hyperfiltration patients without baseline proteinuria, 10 (11·2%) developed new-onset proteinuria [median 1·05 years (IQR:0·63-2·09)]. Normalization of hyperfiltration was less likely with higher baseline eGFR [hazard ratio (HR):0·90, 95% CI: 0·86-0·95; P < 0·0001] and more likely in males (HR:6·35, 95% CI:2·71-14·86, <0·0001). Hyperfiltration is common in adult SCD patients, particularly when younger. Decline to normal values is more likely in males, possibly representing kidney function loss rather than improvement in hyperfiltration.
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Affiliation(s)
- Vimal K Derebail
- Division of Nephrology and Hypertension, UNC Kidney Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Qingning Zhou
- Department of Mathematics and Statistics, University of North Carolina at Charlotte, Charlotte, NC, USA
| | - Emily J Ciccone
- Division of Infectious Diseases, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jianwen Cai
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
| | - Kenneth I Ataga
- Center for Sickle Cell Disease, University of Tennessee Health Science Center, Memphis, TN, USA
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Belisário AR, S Filha RD, de Almeida JA, Mendes FG, Rezende PV, Vieira ÉL, E Silva AC. Novel kidney injury biomarkers in a large cohort of children with sickle cell anemia. Biomark Med 2021; 15:999-1009. [PMID: 34289712 DOI: 10.2217/bmm-2020-0769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: The aim of this study was to compare novel kidney injury biomarkers in sickle cell anemia (SCA) children with and without albuminuria or glomerular hyperfiltration. Materials & methods: A total of 358 Brazilian children with SCA were studied. Fifteen kidney injury biomarkers in urine were measured. Albuminuria was defined as urine albumin/creatinine ratio >100 mg/g. Glomerular hyperfiltration was defined as estimated glomerular filtration rate ≥140 ml/min/1.73 m2. Results: After adjustment for age, sex and modifying therapies in use, EGF and collagen IV urinary levels were associated with albuminuria. Renin and clusterin levels were associated with hyperfiltration. Conclusion: Levels of novel kidney injury biomarkers were associated with albuminuria and hyperfiltration in Brazilian children with SCA, suggesting concomitant structural and functional abnormalities.
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Affiliation(s)
- André R Belisário
- Centro de Tecidos Biológicos de Minas Gerais, Fundação Hemominas, Lagoa Santa, Minas Gerais, 33400000, Brazil.,Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil.,Faculdade de Medicina/Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), UFMG, Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Roberta da S Filha
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Jéssica A de Almeida
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Fabíola G Mendes
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Paulo V Rezende
- Faculdade de Medicina/Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), UFMG, Belo Horizonte, Minas Gerais, 30130100, Brazil.,Ambulatório do Hemocentro de Belo Horizonte, Fundação Hemominas, Belo Horizonte, Minas Gerais, 30130110, Brazil
| | - Érica Lm Vieira
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Ana Cs E Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
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Thomas CC, Sinha A. Sickle Cell Nephropathy: Screening Provides an Opportunity to Intervene. Indian J Pediatr 2021; 88:540-541. [PMID: 33881744 DOI: 10.1007/s12098-021-03775-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 04/12/2021] [Indexed: 11/29/2022]
Affiliation(s)
| | - Aditi Sinha
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India.
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Allali S, Taylor M, Brice J, Montalembert MD. Chronic organ injuries in children with sickle cell disease. Haematologica 2021; 106:1535-1544. [PMID: 33626864 PMCID: PMC8168494 DOI: 10.3324/haematol.2020.271353] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Indexed: 02/02/2023] Open
Abstract
Median life expectancy of patients with sickle cell disease has increased to up to 55 years but there are still frequent cases of premature death, mostly in patients with pre-existing organ failure such as pulmonary hypertension, kidney injury, and cerebral vasculopathy. Most organ injuries remain asymptomatic for a long time and can only be detected through early systematic screening. Protocols combining assessment of velocities on transcranial Doppler and regular transfusions in patients with abnormal velocities have been demonstrated to dramatically reduce the risk of stroke. In contrast, no consensus has been reached on systematic screening or therapy for silent cerebral infarcts. The prognostic significance of increased tricuspid regurgitant jet velocity on echocardiography has not yet been identified in children, whereas increased albuminuria is a good predictor of kidney injury. Finally, screening for hip and eye disorder is recommended; however, different countries adopt different screening strategies. Hydroxyurea is probably of potential benefit in preventing chronic organ damage but this requires further study in order to be fully demonstrated. Efficacy and safety of the other new drugs available are also under investigation.
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Affiliation(s)
- Slimane Allali
- Department of General Pediatrics and Pediatric Infectious Diseases, Reference Center for Sickle Cell Disease, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris (AP-HP), Université de Paris, Paris; Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, Université de Paris, Imagine Institute, Inserm U1163, Paris; Laboratory of Excellence GR-Ex
| | - Melissa Taylor
- Department of General Pediatrics and Pediatric Infectious Diseases, Reference Center for Sickle Cell Disease, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris (AP-HP), Université de Paris, Paris; Laboratory of Excellence GR-Ex, Paris; Paris-Cardiovascular Research Centre (PARCC), Université de Paris, Inserm U970
| | - Joséphine Brice
- Department of General Pediatrics and Pediatric Infectious Diseases, Reference Center for Sickle Cell Disease, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris (AP-HP), Université de Paris, Paris; Laboratory of Excellence GR-Ex, Paris; Institut National de la Transfusion Sanguine (INTS), Université de Paris, Inserm U1134, Paris
| | - Mariane de Montalembert
- Department of General Pediatrics and Pediatric Infectious Diseases, Reference Center for Sickle Cell Disease, Necker Hospital for Sick Children, Assistance Publique - Hôpitaux de Paris (AP-HP), Université de Paris, Paris; Laboratory of Excellence GR-Ex, Paris; Institut National de la Transfusion Sanguine (INTS), Université de Paris, Inserm U1134, Paris.
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Progression of albuminuria in patients with sickle cell anemia: a multicenter, longitudinal study. Blood Adv 2021; 4:1501-1511. [PMID: 32289161 DOI: 10.1182/bloodadvances.2019001378] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 03/16/2020] [Indexed: 12/28/2022] Open
Abstract
Sickle cell nephropathy results in chronic kidney disease (CKD), which is associated with significant morbidity and mortality in sickle cell anemia (SCA). Albuminuria is an early manifestation of sickle nephropathy; however, little is known about progression of albuminuria or its correlation with glomerular filtration rate (GFR) decline or CKD. We studied nephropathy progression in 303 SCA participants in a prospective, multicenter, longitudinal study. We collected steady-state urine and serum samples yearly and assessed albumin/creatinine ratio (ACR), estimated GFR (eGFR), and SCA and nephropathy biomarkers. Participants with albuminuria (ACR ≥30 mg/g) for ≥2 annual measurements were classified as having persistent albuminuria (PA). At baseline (mean age, 21 years; range, 2-64 years), 32% had albuminuria. In longitudinal multivariate analysis, ACR was associated with sex, anemia, older age, and higher bilirubin and kidney injury molecule-1 levels. Albuminuria increased with age by 3.5 mg/g per year (P < .0001). Of 175 participants with ≥3 annual samples, 81% with baseline albuminuria ≥100 mg/g developed PA. Decreased eGFR and adult CKD were associated with PA (P = .002 and P = .02, respectively), but not with baseline albuminuria. Rate of eGFR decline was steeper among adults (but not children) with albuminuria, compared with those without (P = .02). Participants with PA were more likely to have rapid eGFR decline compared with those without (P = .03). In this longitudinal study, albuminuria progressed with age, and adults with albuminuria had worse eGFR decline than those without. Albuminuria ≥100 mg/g predicted PA, which was associated with rapid eGFR decline and CKD development in adults with SCA. This trial was registered at www.clinicaltrials.gov as #NCT02239016.
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Jain RB. Impact of kidney hyperfiltration on concentrations of selected perfluoroalkyl acids among US adults for various disease groups. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:21499-21515. [PMID: 33411299 DOI: 10.1007/s11356-020-11855-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 11/26/2020] [Indexed: 05/26/2023]
Abstract
Data from the National Health and Nutrition Examination Survey (N = 6141) for the years 2003-2016 for US adults were analyzed to evaluate the impact of glomerular hyperfiltration on the observed concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorodecanoic acid, perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) for several disease groups. Hyperfiltrators were defined as having an estimated glomerular filtration rate (eGFR) ≥ 110 mL/min/1.73 m2, and normal filtrators were defined as those having an eGFR between 90 and 110 mL/min/1.73 m2. The seven disease groups for which the data were analyzed were as follows: those (i) without any diseases; (ii) with hypertension only; (iii) with albuminuria only; (iv) with anemia only; (v) with diabetes only; (vi) with hypertension and one or more of diabetes, anemia, and albuminuria; and (vii) with two or more of diabetes, anemia, and albuminuria without hypertension. For almost every PFAA, for all seven disease groups except the albuminuria only group, hyperfiltrators had lower adjusted geometric means (AGM) than normal filtrators. For example, for the disease group with hypertension only, for PFOS, the AGMs for hyperfiltrators and normal filtrators were 8.3 and 10.6 ng/mL, respectively, for the total population. For the group with albuminuria only, normal filtrators were found to have higher AGMs than hyperfiltrators for the total population and males. For example, for PFHxS, the AGMs for normal and hyperfiltrators were 0.98 and 1.05 ng/mL, respectively, for the total population. For females, these AGMs for normal and hyperfiltrators were 0.96 and 0.86 ng/mL respectively. Males usually had higher AGMs than females, but the reverse was also true occasionally. Usually, male-female differences were substantially narrower for normal filtrators than hyperfiltrators. Irrespective of the filtration status, the disease group with hypertension only had the highest AGMs for every PFAA. AGMs for the anemia only group were the lowest for every PFAA as compared with other disease groups among hyperfiltrators.
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Pecker LH, Hussain S, Christianson M, Lanzkron S. Hydroxycarbamide exposure and ovarian reserve in women with sickle cell disease in the Multicenter Study of Hydroxycarbamide. Br J Haematol 2020; 191:880-887. [PMID: 32712966 PMCID: PMC10189607 DOI: 10.1111/bjh.16976] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 06/24/2020] [Indexed: 10/21/2023]
Abstract
The application of modern ovarian reserve measures to women with sickle cell disease (SCD) may help answer longstanding questions about whether SCD or hydroxycarbamide (HC; also known as hydroxyurea) affect women's reproductive lifespan. Anti-Müllerian hormone (AMH), an established marker of ovarian reserve, is used to assess the ovarian follicle pool. We used a standard clinical assay to measure AMH in 285 banked samples from 93 female subjects with haemoglobin SS from the historic Multicenter Study of Hydroxyurea (MSH), which led to the United States Food and Drug Administration approval of HC for adults with SCD. No samples from the randomised portion of the MSH remain, so samples from the decade-long MSH follow-up studies were analysed. Most subjects were exposed to HC (86/93). The median AMH levels were lower in study subjects than in age- and sex-matched reference values. The median AMH levels consistent with diminished ovarian reserve, a risk factor for infertility, occurred in subjects starting at the age of 25-30 years; in healthy women, this occurs after the age of 40 years. In multivariate analysis, taking HC was independently associated with a low AMH (β = 0·001, 95% confidence interval -0·002 to 0·000; P = 0·006). These results suggest that ovarian reserve is prematurely reduced in women with haemoglobin SS and raise the possibility that HC contributes to this finding.
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Affiliation(s)
- Lydia H. Pecker
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sarah Hussain
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Mindy Christianson
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD
- Division of Reproductive Endocrinology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sophie Lanzkron
- Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
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39
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Boucher AA, Dong M, Vinks AA, Marahatta A, Howard TA, Ware RE, Nathan JD, Abu-El-Haija M, Luchtman-Jones L. Hydroxyurea Pharmacokinetics in Pediatric Patients After Total Pancreatectomy With Islet Autotransplantation. J Clin Pharmacol 2020; 61:547-554. [PMID: 33029796 DOI: 10.1002/jcph.1759] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Accepted: 09/15/2020] [Indexed: 12/17/2022]
Abstract
Total pancreatectomy with islet autotransplantation is a complex surgical approach for acute recurrent or chronic pancreatitis that frequently triggers extreme thrombocytosis (platelets ≥ 1000 × 109 /L). Thrombocytosis can be prothrombotic, so cytoreductive hydroxyurea is often initiated after this surgery; however, optimal dosing strategy and efficacy are unknown. This prospective pilot study characterized the pharmacokinetics of hydroxyurea after this procedure in children. It also compared them with previously published pediatric parameters in sickle cell anemia (SCA), the disease in which pediatric hydroxyurea pharmacokinetics have primarily been studied. Plasma hydroxyurea levels were quantified in 14 participants aged 4-19 years using high-performance liquid chromatography. Blood collections were scheduled 20 minutes, 1 hour, and 4 hours after the first dose, on pharmacokinetic day 1 (PK1), and again 2-3 months later if still on hydroxyurea (PK2). Six participants had PK1 and PK2 data at all 3 postdose timed collections, 5 only had PK1 samples, and 3 only had PK2 samples. Total pancreatectomy with islet autotransplantation participants had reduced and delayed absorption compared with sickle cell anemia participant data from the Hydroxyurea Study of Long-Term Effects, regardless of timing or dosing methodology. Total pancreatectomy with islet autotransplantation participants had different pharmacokinetic profiles at PK1 versus PK2, with lower dose-normalized exposures than previously reported in sickle cell anemia. These results suggest variability exists in hydroxyurea absorption and bioavailability in total pancreatectomy with islet autotransplantation patients, suspected to be primarily because of Roux-en-Y reconstruction, and suggest that more pharmacokinetic data are needed for scenarios when hydroxyurea is prescribed to children without sickle cell anemia.
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Affiliation(s)
- Alexander A Boucher
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Min Dong
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Alexander A Vinks
- Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Anu Marahatta
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Thad A Howard
- Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Russell E Ware
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jaimie D Nathan
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Departments of Surgery and Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Maisam Abu-El-Haija
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Lori Luchtman-Jones
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.,Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
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Batte A, Starr MC, Schwaderer AL, Opoka RO, Namazzi R, Phelps Nishiguchi ES, Ssenkusu JM, John CC, Conroy AL. Methods to estimate baseline creatinine and define acute kidney injury in lean Ugandan children with severe malaria: a prospective cohort study. BMC Nephrol 2020; 21:417. [PMID: 32993548 PMCID: PMC7526147 DOI: 10.1186/s12882-020-02076-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 09/18/2020] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is increasingly recognized as a consequential clinical complication in children with severe malaria. However, approaches to estimate baseline creatinine (bSCr) are not standardized in this unique patient population. Prior to wide-spread utilization, bSCr estimation methods need to be evaluated in many populations, particularly in children from low-income countries. METHODS We evaluated six methods to estimate bSCr in Ugandan children aged 6 months to 12 years of age in two cohorts of children with severe malaria (n = 1078) and healthy community children (n = 289). Using isotope dilution mass spectrometry (IDMS)-traceable creatinine measures from community children, we evaluated the bias, accuracy and precision of estimating bSCr using height-dependent and height-independent estimated glomerular filtration (eGFR) equations to back-calculate bSCr or estimating bSCr directly using published or population-specific norms. RESULTS We compared methods to estimate bSCr in healthy community children against the IDMS-traceable SCr measure. The Pottel-age based equation, assuming a normal GFR of 120 mL/min per 1.73m2, was the more accurate method with minimal bias when compared to the Schwartz height-based equation. Using the different bSCr estimates, we demonstrated the prevalence of KDIGO-defined AKI in children with severe malaria ranged from 15.6-43.4%. The lowest estimate was derived using population upper levels of normal and the highest estimate was derived using the mean GFR of the community children (137 mL/min per 1.73m2) to back-calculate the bSCr. Irrespective of approach, AKI was strongly associated with mortality with a step-wise increase in mortality across AKI stages (p < 0.0001 for all). AKI defined using the Pottel-age based equation to estimate bSCr showed the strongest relationship with mortality with a risk ratio of 5.13 (95% CI 3.03-8.68) adjusting for child age and sex. CONCLUSIONS We recommend using height-independent age-based approaches to estimate bSCr in hospitalized children in sub-Saharan Africa due to challenges in accurate height measurements and undernutrition which may impact bSCr estimates. In this population the Pottel-age based GFR estimating equation obtained comparable bSCr estimates to population-based estimates in healthy children.
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Affiliation(s)
- Anthony Batte
- Child Health and Development Center, Makerere University College of Health Sciences, Kampala, Uganda
| | - Michelle C Starr
- Department of Pediatrics, Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Andrew L Schwaderer
- Department of Pediatrics, Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Robert O Opoka
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - Ruth Namazzi
- Department of Paediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda
| | | | - John M Ssenkusu
- Department of Epidemiology and Biostatistics, Makerere University School of Public Health, Kampala, Uganda
| | - Chandy C John
- Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN, 46202, USA
| | - Andrea L Conroy
- Department of Pediatrics, Ryan White Center for Pediatric Infectious Disease and Global Health, Indiana University School of Medicine, 1044 W. Walnut St., Indianapolis, IN, 46202, USA.
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End points for sickle cell disease clinical trials: renal and cardiopulmonary, cure, and low-resource settings. Blood Adv 2020; 3:4002-4020. [PMID: 31809537 DOI: 10.1182/bloodadvances.2019000883] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 10/07/2019] [Indexed: 01/19/2023] Open
Abstract
To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-patient-reported outcomes), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the end-organ considerations, measurement of cure, and low-resource settings panels as well as relevant findings and recommendations from the biomarkers panel.
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Nnaji UM, Ogoke CC, Okafor HU, Achigbu KI. Sickle Cell Nephropathy and Associated Factors among Asymptomatic Children with Sickle Cell Anaemia. Int J Pediatr 2020; 2020:1286432. [PMID: 32908550 PMCID: PMC7474388 DOI: 10.1155/2020/1286432] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 07/11/2020] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Sickle cell nephropathy (SCN) is a serious complication of sickle cell anaemia (SCA) with asymptomatic onset in childhood and possible progression to chronic kidney disease (CKD). In Southeast Nigeria, few studies have evaluated renal function in paediatric SCA patients for early detection of renal impairment and early intervention to reduce morbidity and mortality. Therefore, this study evaluated the renal function of paediatric SCA patients in a steady state based on glomerular filtration rate and urinalysis findings (proteinuria and haematuria). METHODS A cross-sectional study of consecutively recruited sixty haemoglobin SS (HbSS) children in a steady state and sixty age- and sex-matched haemoglobin AA (HbAA) controls aged 2-18 years was done. Renal function of HbSS subjects was evaluated using estimated glomerular filtration rate (eGFR) which was compared with healthy HbAA subjects. The prevalence of significant proteinuria and haematuria, its association with eGFR, and the effect of past sickle cell crisis (in the preceding 24 months) on renal function were also evaluated. RESULTS Mean eGFR was significantly higher in HbSS subjects than in the HbAA subjects (p = 0.001) and decreased with age. Significant proteinuria and haematuria were more prevalent in the HbSS group (3.4% and 6.7%, respectively) compared to the HbAA subjects (0% and 0%, respectively) (p = 0.496 and 0.119, respectively). No significant association was observed between eGFR and proteinuria (p = 1.000) or haematuria (p = 1.000). There was a positive correlation between eGFR and frequency of past painful crisis that required hospitalization (r = 0.138, p = 0.295) and between eGFR and frequency of blood transfusion (r = 0.679, p ≤ 0.001). CONCLUSIONS Asymptomatic paediatric HbSS (SCA) patients had higher mean eGFR indicating an increased risk of nephropathy. There was no association between eGFR and proteinuria or haematuria. Frequent sickle cell crises especially one requiring transfusion were positively correlated with hyperfiltration.
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Affiliation(s)
| | - Christian Chukwukere Ogoke
- Department of Clinical Neurophysiology & Child Neurology, Mother Healthcare Diagnostics & Hospital, Owerri, Nigeria
| | - Henrietta Uche Okafor
- Department of Paediatrics, University of Nigeria, Enugu Campus & University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria
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Affiliation(s)
- Elissa R Engel
- Department of Pediatrics, University of South Florida Morsani College of Medicine, 2 Tampa General Circle, Tampa, FL 33606, USA
| | - Alexandra L Howard
- Department of Pediatrics, University of South Florida Morsani College of Medicine, 2 Tampa General Circle, Tampa, FL 33606, USA
| | - Emily J Ankus
- University of South Florida Morsani College of Medicine, 2 Tampa General Circle, 5th Floor, Tampa, FL 33606, USA
| | - Juan Felipe Rico
- Division of Hematology/Oncology, Department of Pediatrics, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
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Belisário AR, Almeida JA, Mendes FG, Silva DMM, Planes W, Rezende PV, Silva CM, Brito AC, Sales RR, Viana MB, Simões e Silva AC. Prevalence and risk factors for albuminuria and glomerular hyperfiltration in a large cohort of children with sickle cell anemia. Am J Hematol 2020; 95:E125-E128. [PMID: 32083326 DOI: 10.1002/ajh.25763] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 02/09/2020] [Accepted: 02/13/2020] [Indexed: 12/20/2022]
Affiliation(s)
- André Rolim Belisário
- Centro de Tecidos Biológicos de Minas GeraisFundação Hemominas Lagoa Santa Minas Gerais Brazil
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de MedicinaUniversidade Federal de Minas Gerais (UFMG) Belo Horizonte Minas Gerais Brazil
- Faculdade de Medicina/Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD)UFMG Belo Horizonte Minas Gerais Brazil
| | - Jéssica Alves Almeida
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de MedicinaUniversidade Federal de Minas Gerais (UFMG) Belo Horizonte Minas Gerais Brazil
| | - Fabíola Gomes Mendes
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de MedicinaUniversidade Federal de Minas Gerais (UFMG) Belo Horizonte Minas Gerais Brazil
| | - Déborah Maria Moreira Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de MedicinaUniversidade Federal de Minas Gerais (UFMG) Belo Horizonte Minas Gerais Brazil
| | - Wallysson Planes
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de MedicinaUniversidade Federal de Minas Gerais (UFMG) Belo Horizonte Minas Gerais Brazil
| | - Paulo Val Rezende
- Faculdade de Medicina/Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD)UFMG Belo Horizonte Minas Gerais Brazil
- Ambulatório do Hemocentro de Belo HorizonteFundação Hemominas Belo Horizonte Minas Gerais Brazil
| | - Célia Maria Silva
- Ambulatório do Hemocentro de Belo HorizonteFundação Hemominas Belo Horizonte Minas Gerais Brazil
| | - Andréa Conceição Brito
- Ambulatório do Hemocentro de Belo HorizonteFundação Hemominas Belo Horizonte Minas Gerais Brazil
| | - Rahyssa Rodrigues Sales
- Instituto de Ciências BiológicasUniversidade Federal de Minas Gerais ‐ UFMG Belo Horizonte Minas Gerais Brazil
| | - Marcos Borato Viana
- Faculdade de Medicina/Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD)UFMG Belo Horizonte Minas Gerais Brazil
| | - Ana Cristina Simões e Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de MedicinaUniversidade Federal de Minas Gerais (UFMG) Belo Horizonte Minas Gerais Brazil
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Hyperuricemia is associated with a lower glomerular filtration rate in pediatric sickle cell disease patients. Pediatr Nephrol 2020; 35:883-889. [PMID: 31960140 DOI: 10.1007/s00467-019-04432-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/12/2019] [Accepted: 11/19/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Sickle cell nephropathy (SCN) is a progressive disease that contributes significant morbidity and mortality in sickle cell disease (SCD), yet it remains poorly understood. Hyperuricemia negatively impacts renal function in the non-sickle cell population but is understudied in SCD. METHODS We performed a cross-sectional analysis of the first 78 pediatric SCD patients enrolled in a cohort study. The mechanism of development of hyperuricemia (defined, serum uric acid (UA) ≥ 5.5 mg/dL) was characterized as a result of either UA overproduction or inefficient renal excretion by the Simkin index and fractional clearance of urate (FCU) equations. Associations between hyperuricemia and albuminuria or estimated glomerular filtration rate (eGFR) were determined by linear regression. RESULTS The prevalence of hyperuricemia in this young population (mean age 11.6 ± 3.77 years) was 34.2%. Only 1 hyperuricemic participant overproduced UA by Simkin index, while 62.5% were inefficient renal excretors of UA (FCU < 4%). Hyperuricemia was associated with a significant decrease in average eGFR, -27 ml/min/1.73m2 below normouricemia (mean eGFR 151.6 ± 40.32), p = 0.0122. Notably, the previously accepted association between decline of eGFR with age is significantly modified by hyperuricemia stratification, where hyperuricemia explains 44% of the variance in eGFR by age (R2 = 0.44, p = 0.0004) and is nonsignificant in normouricemia (R2 = 0.07, p = 0.0775). CONCLUSION These findings indicate that hyperuricemia may be associated with early eGFR decline in SCN. This association must be further characterized in prospective cohort studies in SCN, and hyperuricemia must be investigated as a potential therapeutic target for SCN.
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Ataga KI, Gordeuk VR, Agodoa I, Colby JA, Gittings K, Allen IE. Low hemoglobin increases risk for cerebrovascular disease, kidney disease, pulmonary vasculopathy, and mortality in sickle cell disease: A systematic literature review and meta-analysis. PLoS One 2020; 15:e0229959. [PMID: 32243480 PMCID: PMC7122773 DOI: 10.1371/journal.pone.0229959] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 02/17/2020] [Indexed: 12/20/2022] Open
Abstract
Sickle cell disease (SCD) is characterized by deoxygenation-induced polymerization of hemoglobin in red blood cells, leading to hemolytic anemia, vaso-occlusion, and the development of multiple clinical complications. To characterize the clinical burden associated with differences in hemoglobin concentration and hemolysis measures, a systematic literature review of MEDLINE, EMBASE, and related meta-analyses was undertaken. For quantitative analyses related to hemoglobin concentration, pooled results were analyzed using random effects models to control for within-and between-study variability. To derive risk ratios associated with hemoglobin concentration change, we combined ratios of means from select studies, which reported hazard and odds ratios in meta-analyses for hemoglobin concentration-related outcomes and changes between groups. Forty-one studies were identified for inclusion based on relating hemoglobin concentration to clinical outcomes. Meta-analyses demonstrated that mean hemoglobin concentration was significantly lower in patients with cerebrovascular disease (0.4 g/dL), increased transcranial Doppler velocity in cerebral arteries (0.6 g/dL), albuminuria (0.6 g/dL), elevated estimated pulmonary artery systolic pressure (0.9 g/dL), and in patients that subsequently died (0.6 g/dL). In a risk reduction meta-analysis, modeled increased hemoglobin concentrations of 1 g/dL or greater resulted in decreased risk of negative clinical outcomes of 41% to 64%. In conclusion, chronic anemia is associated with worse clinical outcomes in individuals with SCD and even modest increases in hemoglobin concentration may be beneficial in this patient population. This systematic review has been registered on Prospero (Registration number CRD42018096860; https://www.crd.york.ac.uk/prospero/).
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Affiliation(s)
- Kenneth I. Ataga
- University of Tennessee Health Science Center, Memphis, TN, United States of America
| | - Victor R. Gordeuk
- University of Illinois at Chicago College of Medicine, Chicago, IL, United States of America
| | - Irene Agodoa
- GBT, South San Francisco, CA, United States of America
| | | | | | - Isabel E. Allen
- School of Medicine, University of California, San Francisco, San Francisco, CA, United States of America
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Kasztan M, Aban I, Hande SP, Pollock DM, Lebensburger JD. Sex differences in the trajectory of glomerular filtration rate in pediatric and murine sickle cell anemia. Blood Adv 2020; 4:263-265. [PMID: 31951651 PMCID: PMC6988403 DOI: 10.1182/bloodadvances.2019001237] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 12/09/2019] [Indexed: 01/04/2023] Open
Affiliation(s)
| | | | - Suraj P Hande
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL
| | - David M Pollock
- Cardio-Renal Physiology and Medicine, Department of Medicine
| | - Jeffrey D Lebensburger
- Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL
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Liem RI, Lanzkron S, D Coates T, DeCastro L, Desai AA, Ataga KI, Cohen RT, Haynes J, Osunkwo I, Lebensburger JD, Lash JP, Wun T, Verhovsek M, Ontala E, Blaylark R, Alahdab F, Katabi A, Mustafa RA. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv 2019; 3:3867-3897. [PMID: 31794601 PMCID: PMC6963257 DOI: 10.1182/bloodadvances.2019000916] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 11/01/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Prevention and management of end-organ disease represent major challenges facing providers of children and adults with sickle cell disease (SCD). Uncertainty and variability in the screening, diagnosis, and management of cardiopulmonary and renal complications in SCD lead to varying outcomes for affected individuals. OBJECTIVE These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. METHODS ASH formed a multidisciplinary guideline panel that included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews up to September 2017. The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS The panel agreed on 10 recommendations for screening, diagnosis, and management of cardiopulmonary and renal complications of SCD. Recommendations related to anticoagulation duration for adults with SCD and venous thromboembolism were also developed. CONCLUSIONS Most recommendations were conditional due to a paucity of direct, high-quality evidence for outcomes of interest. Future research was identified, including the need for prospective studies to better understand the natural history of cardiopulmonary and renal disease, their relationship to patient-important outcomes, and optimal management.
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Affiliation(s)
- Robert I Liem
- Division of Hematology, Oncology and Stem Cell Transplant, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Sophie Lanzkron
- Division of Adult Hematology, School of Medicine, Johns Hopkins University, Baltimore, MD
| | - Thomas D Coates
- Division of Hematology, Oncology and Blood and Marrow Transplantation, Children's Hospital of Los Angeles, Los Angeles, CA
| | - Laura DeCastro
- Division of Hematology/Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Ankit A Desai
- Krannert Institute of Cardiology, School of Medicine, Indiana University, Indianapolis, IN
| | - Kenneth I Ataga
- Center for Sickle Cell Disease, University of Tennessee Health Science Center, Memphis, TN
| | - Robyn T Cohen
- Division of Pediatric Pulmonary and Allergy, Boston Medical Center, School of Medicine, Boston University, Boston, MA
| | - Johnson Haynes
- Division of Pulmonary Disease, College of Medicine, University of South Alabama, Mobile, AL
| | - Ifeyinwa Osunkwo
- Division of Hematology, The Levine Cancer Institute, Atrium Health, Charlotte, NC
| | - Jeffrey D Lebensburger
- Division of Pediatric Hematology/Oncology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL
| | - James P Lash
- Division of Nephrology, Department of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Theodore Wun
- Division of Hematology and Oncology, School of Medicine, University of California Davis, Sacramento, CA
| | - Madeleine Verhovsek
- Division of Hematology and Thromboembolism, McMaster University, Hamilton, ON, Canada
| | | | | | - Fares Alahdab
- Division of General Internal Medicine, Mayo Medical School, Rochester, MN; and
| | - Abdulrahman Katabi
- Division of General Internal Medicine, Mayo Medical School, Rochester, MN; and
| | - Reem A Mustafa
- Division of Nephrology and Hypertension, School of Medicine, University of Kansas, Kansas City, KS
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Laurentino MR, Parente Filho SLA, Parente LLC, da Silva Júnior GB, Daher EDF, Lemes RPG. Non-invasive urinary biomarkers of renal function in sickle cell disease: an overview. Ann Hematol 2019; 98:2653-2660. [PMID: 31641850 DOI: 10.1007/s00277-019-03813-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 09/26/2019] [Indexed: 12/27/2022]
Abstract
Sickle cell disease (SCD) is a hereditary condition characterized by homozygosis of the hemoglobin S (HbS) gene. Marked morbimortality is observed due to chronic hemolysis, endothelial injury, and episodes of vaso-occlusion, which leads to multi-organ damage. Renal impairment is common and may have different presentations, such as deficiency in urinary acidification or concentration, glomerulopathies, proteinuria, and hematuria, frequently resulting in end-stage renal disease (ESRD). Novel biomarkers of renal function, such as kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein 1 (MCP-1) are being studied in order to enable early diagnosis of kidney damage in SCD.
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Affiliation(s)
- Marília Rocha Laurentino
- Post-Graduation Program in Pharmaceutical Sciences, School of Pharmacy, Federal University of Ceara, Capitão Francisco Pedro, Street, n.1210 - Rodolfo Teófilo, Fortaleza, Ceara, CEP 60430-370, Brazil.
| | - Sérgio Luiz Arruda Parente Filho
- Medical Sciences Post-Graduation Program, Department of Internal Medicine, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | | | - Geraldo Bezerra da Silva Júnior
- Public Health Post-Graduation Program, School of Medicine, Health Sciences Center, University of Fortaleza, Fortaleza, Ceara, Brazil
| | - Elizabeth De Francesco Daher
- Medical Sciences Post-Graduation Program, Department of Internal Medicine, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
| | - Romélia Pinheiro Gonçalves Lemes
- Post-Graduation Program in Pharmaceutical Sciences, School of Pharmacy, Federal University of Ceara, Capitão Francisco Pedro, Street, n.1210 - Rodolfo Teófilo, Fortaleza, Ceara, CEP 60430-370, Brazil
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Belisário AR, da Silva AAS, Silva CVM, de Souza LMG, Wakabayashi EA, Araújo SDA, Simoes-e-Silva AC. Sickle cell disease nephropathy: an update on risk factors and potential biomarkers in pediatric patients. Biomark Med 2019; 13:967-987. [DOI: 10.2217/bmm-2019-0105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
One of the major chronic complications of sickle cell disease (SCD) is sickle cell nephropathy. The aim of this review is to discuss the pathophysiology, natural history, clinical manifestations, risk factors, biomarkers and therapeutic approaches for sickle cell nephropathy, focusing on studies with pediatric patients. The earliest manifestation of renal disease is an increase in the glomerular filtration rate. A finding that may also be observed in early childhood is microalbuminuria. Nephrin, KIM-1, VGFs, chemokines and renin-angiotensin system molecules have emerged as potential early markers of renal dysfunction in SCD. In regards to a therapeutic approach, renin-angiotensin system inhibitors and angiotensin receptor blockers seem to be effective for the control of albuminuria in adults with SCD, although new studies in children are needed. The precise moment to begin renoprotection in SCD patients who should be treated remains to be determined.
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Affiliation(s)
- André R Belisário
- Centro de Tecidos Biológicos de Minas Gerais, Fundação Hemominas, Rua das Goiabeiras, 779, Lagoa Santa, Minas Gerais 33400-000, Brazil
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av Prof. Alfredo Balena, 190, Belo Horizonte, Minas Gerais 30130-100, Brazil
| | - Ariadna AS da Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av Prof. Alfredo Balena, 190, Belo Horizonte, Minas Gerais 30130-100, Brazil
| | - Cristiane VM Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av Prof. Alfredo Balena, 190, Belo Horizonte, Minas Gerais 30130-100, Brazil
| | - Larissa MG de Souza
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av Prof. Alfredo Balena, 190, Belo Horizonte, Minas Gerais 30130-100, Brazil
| | - Eduarda A Wakabayashi
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av Prof. Alfredo Balena, 190, Belo Horizonte, Minas Gerais 30130-100, Brazil
| | - Stanley de A Araújo
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av Prof. Alfredo Balena, 190, Belo Horizonte, Minas Gerais 30130-100, Brazil
| | - Ana C Simoes-e-Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av Prof. Alfredo Balena, 190, Belo Horizonte, Minas Gerais 30130-100, Brazil
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