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Non-invasive urinary biomarkers of renal function in sickle cell disease: an overview

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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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References

  1. Reddy KS (2016) Global Burden of Disease Study 2015 provides GPS for global health 2030. Lancet 388(10053):1448–1449

    PubMed  Google Scholar 

  2. Sundaram N, Bennett M, Wilhelm J, Kim MO, Atweh G, Devarajan P, Malik P (2011) Biomarkers for early detection of sickle nephropathy. Am J Hematol 86(7):559–566

    PubMed  PubMed Central  CAS  Google Scholar 

  3. Hamideh D, Raj V, Harrington T, Li H, Margolles E, Amole F, Garcia-Buitrago M, Ruiz P, Zilleruelo G, Alvarez O (2014) Albuminuria correlates with hemolysis and NAG and KIM-1 in patients with sickle cell anemia. Pediatr Nephrol 29(10):1997–2003

    PubMed  Google Scholar 

  4. Peres LA, Cunha Júnior AD, Schäfer AJ, Silva AL, Gaspar AD, Scarpari DF, Alves JB, Girelli Neto R, Oliveira TF (2013) Biomarkers of acute kidney injury. J Bras Nefrol 35(3):229–236

    PubMed  Google Scholar 

  5. Vaidya VS, Ferguson MA, Bonventre JV (2008) Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol 48:463–493

    PubMed  PubMed Central  CAS  Google Scholar 

  6. Santos TE, Gonçalves RP, Barbosa MC et al (2015) Monocyte chemoatractant protein-1: a potential biomarker of renal lesion and its relation with oxidative status in sickle cell disease. Blood Cells Mol Dis 54(3):297–301

    PubMed  Google Scholar 

  7. Sanjeevani S, Pruthi S, Kalra S, Goel A, Kalra OP (2014) Role of neutrophil gelatinase-associated lipocalin for early detection of acute kidney injury. Int J Crit Illn Inj Sci 4(3):223–228

    PubMed  PubMed Central  Google Scholar 

  8. Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P (2003) Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 14(10):2534–2543

    PubMed  CAS  Google Scholar 

  9. Soni SS, Cruz D, Bobek I, Chionh CY, Nalesso F, Lentini P, de Cal M, Corradi V, Virzi G, Ronco C (2010) NGAL: a biomarker of acute kidney injury and other systemic conditions. Int Urol Nephrol 42(1):141–150

    PubMed  CAS  Google Scholar 

  10. Devarajan P (2010) Review: Neutrophil gelatinase-associated lipocalin: a troponin-like biomarker for human acute kidney injury. Nephrology (Carlton) 15(4):419–428

    Google Scholar 

  11. Serjeant GR (2010) One hundred years of sickle cell disease. Br J Haematol 151(5):425–429

    PubMed  Google Scholar 

  12. Sundd P, Gladwin MT, Novelli EM (2019) Pathophysiology of sickle cell disease. Annu Rev Pathol 14:263–292

    PubMed  CAS  Google Scholar 

  13. Zago MA, Pinto ACS (2007) Fisiopatologia das doenças falciformes: da mutação genética à insuficiência de múltiplos órgãos. Rev. Bras Hematol. Hemoter. Set 29(3):207–214

    Google Scholar 

  14. Adekile AD (2013) What’s new in the pathophysiology of sickle cell disease? Med Princ Pract 22(4):311–312

    PubMed  PubMed Central  Google Scholar 

  15. Kato GJ, Gladwin MT, Steinberg MH (2007) Deconstructing sickle cell disease: reappraisal of the role of hemolysis in the development of clinical subphenotypes. Blood Rev 21(1):37–47

    PubMed  Google Scholar 

  16. Kato GJ, Hebbel RP, Steinberg MH, Gladwin MT (2009) Vasculopathy in sickle cell disease: Biology, pathophysiology, genetics, translational medicine, and new research directions. Am J Hematol 84(9):618–625

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Rees DC, Gibson JS (2012) Biomarkers in sickle cell disease. Br J Haematol 156(4):433–445

    PubMed  CAS  Google Scholar 

  18. Damanhouri GA, Jarullah J, Marouf S, Hindawi SI, Mushtaq G, Kamal MA (2015) Clinical biomarkers in sickle cell disease. Saudi J Biol Sci 22(1):24–31

    PubMed  CAS  Google Scholar 

  19. Moreira JA, Laurentino MR, Machado RP, Barbosa MC, Gonçalves RP, Mota Ade M, Rocha LB, Martins AM, de Lima Arruda AB, de Souza IP, Gonçalves RP (2015) Pattern of hemolysis parameters and association with fetal hemoglobin in sickle cell anemia patients in steady state. Rev Bras Hematol Hemoter 37(3):167–171

    PubMed  PubMed Central  Google Scholar 

  20. Nath KA, Katusic ZS, Gladwin MT (2004) The perfusion paradox and vascular instability in sickle cell disease. Microcirculation 11(2):179–193

    PubMed  CAS  Google Scholar 

  21. Lamarre Y, Hardy-Dessources MD, Romana M, Lalanne-Mistrih ML, Waltz X, Petras M, Doumdo L, Blanchet-Deverly A, Martino J, Tressières B, Maillard F, Tarer V, Etienne-Julan M, Connes P (2014) Relationships between systemic vascular resistance, blood rheology and nitric oxide in children with sickle cell anemia or sickle cell-hemoglobin C disease. Clin Hemorheol Microcirc 58(2):307–316

    PubMed  CAS  Google Scholar 

  22. Steinberg MH (2009) Genetic etiologies for phenotypic diversity in sickle cell anemia. Sci World J 9:46–67

    Google Scholar 

  23. Orkin SH, Higgs DR (2010) Sickle cell disease at 100 years. Science. 329(5989):291–292

    PubMed  CAS  Google Scholar 

  24. Maigne G, Ferlicot S, Galacteros F, Belenfant X, Ulinski T, Niaudet P, Ronco P, Godeau B, Durrbach A, Sahali S, Lang P, Lambotte O, Audard V (2010) Glomerular lesions in patients with sickle cell disease. Medicine (Baltimore) 89(1):18–27

    Google Scholar 

  25. Kormann R, Jannot AS, Narjoz C, Ribeil JA, Manceau S, Delville M, Joste V, Prié D, Pouchot J, Thervet E, Courbebaisse M, Arlet JB (2017) Roles of APOL1 G1 and G2 variants in sickle cell disease patients: kidney is the main target. Br J Haematol 179(2):323–335

    PubMed  CAS  Google Scholar 

  26. Bundy JL, Anderson BR, Francescatto L, Garrett ME, Soldano KL, Telen MJ, Davis EE, Ashley-Koch AE (2019) RNA sequencing of isolated cell populations expressing human APOL1 G2 risk variant reveals molecular correlates of sickle cell nephropathy in zebrafish podocytes. PLoS One 14(6):e0217042

    PubMed  PubMed Central  CAS  Google Scholar 

  27. Haymann JP, Stankovic K, Levy P, Avellino V, Tharaux PL, Letavernier E, Grateau G, Baud L, Girot R, Lionnet F (2010) Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis associated feature. Clin J Am Soc Nephrol 5(5):756–761

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Becker AM (2011) Sickle cell nephropathy: challenging the conventional wisdom. Pediatr Nephrol 26(12):2099–2109

    PubMed  Google Scholar 

  29. Da Silva GB, Libório AB, Daher EF (2011) New insights on pathophysiology, clinical manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann Hematol 90(12):1371–1379

    PubMed  Google Scholar 

  30. Nath KA, Hebbel RP (2015) Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol 11(3):161–171

    PubMed  PubMed Central  CAS  Google Scholar 

  31. Aban I, Baddam S, Hilliard LM, Howard TH, Feig DI, Lebensburger JD (2017) Severe anemia early in life as a risk factor for sickle-cell kidney disease. Blood. 129(3):385–387

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Tsaras G, Owusu-Ansah A, Boateng FO, Amoateng-Adjepong Y (2009) Complications associated with sickle cell trait: a brief narrative review. Am J Med 122(6):507–512

    PubMed  Google Scholar 

  33. Miller ST, Wang WC, Iyer R, Rana S, Lane P, Ware RE, Li D, Rees RC, BABY-HUG Investigators (2010) Urine concentrating ability in infants with sickle cell disease: baseline data from the phase III trial of hydroxyurea (BABY HUG). Pediatr Blood Cancer 54(2):265–268

    PubMed  PubMed Central  Google Scholar 

  34. Hariri E, Mansour A, El Alam A et al (2018) Sickle cell nephropathy: an update on pathophysiology, diagnosis, and treatment. Int Urol Nephrol 50(6):1075–1083

    PubMed  CAS  Google Scholar 

  35. Le Joncour A, Mesnard L, Hertig A, Robert T et al (2018) Red urine, updated for the nephrologist: a case report. BMC Nephrol 19(1):133

    PubMed  PubMed Central  Google Scholar 

  36. Pegelow CH, Colangelo L, Steinberg M, Wright EC, Smith J, Phillips G, Vichinsky E (1997) Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med 102(2):171–177

    PubMed  CAS  Google Scholar 

  37. Nath KA, Katusic ZS, Gladwin MT (2004) The perfusion paradox and vascular instability in sickle cell disease. Microcirculation. 11(2):179–193

    PubMed  CAS  Google Scholar 

  38. Gladwin MT (2016) Cardiovascular complications and risk of death in sickle-cell disease. Lancet. 387(10037):2565–2574

    PubMed  Google Scholar 

  39. Novelli EM, Hildesheim M, Rosano C, Vanderpool R, Simon M, Kato GJ, Gladwin MT (2014) Elevated pulse pressure is associated with hemolysis, proteinuria and chronic kidney disease in sickle cell disease. PLoS One 9(12):e114309

    PubMed  PubMed Central  Google Scholar 

  40. Gordeuk VR, Sachdev V, Taylor JG, Gladwin MT, Kato G, Castro OL (2008) Relative systemic hypertension in patients with sickle cell disease is associated with risk of pulmonary hypertension and renal insufficiency. Am J Hematol 83(1):15–18

    PubMed  PubMed Central  CAS  Google Scholar 

  41. Benneh-Akwasi Kuma A, Owusu-Ansah AT, Ampomah MA, Sey F, Olayemi E, Nouraie M, Ofori-Acquah SF (2018) Prevalence of relative systemic hypertension in adults with sickle cell disease in Ghana. PLoS One 13(1):e0190347

    PubMed  PubMed Central  Google Scholar 

  42. Lebensburger JD, Aban I, Pernell B, Kasztan M, Feig DI, Hilliard LM, Askenazi DJ (2019) Hyperfiltration during early childhood precedes albuminuria in pediatric sickle cell nephropathy. Am J Hematol 94(4):417–423

    PubMed  CAS  Google Scholar 

  43. Bartolucci P, Habibi A, Stehlé T, di Liberto G, Rakotoson MG, Gellen-Dautremer J, Loric S, Moutereau S, Sahali D, Wagner-Ballon O, Remy P, Lang P, Grimbert P, Audureau E, Godeau B, Galacteros F, Audard V (2016) Six months of hydroxyurea reduces albuminuria in patients with sickle cell disease. J Am Soc Nephrol 27(6):1847–1853

    PubMed  CAS  Google Scholar 

  44. Powars DR, Elliott-Mills DD, Chan L, Niland J, Hiti AL, Opas LM, Johnson C (1991) Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med 115(8):614–620

    PubMed  CAS  Google Scholar 

  45. Sl Y, Paul Y, Oneal P, Nouraie M (2016) Renal failure in sickle cell disease: prevalence, predictors of disease, mortality and effect on length of hospital stay. Hemoglobin 40(5):295–299

    Google Scholar 

  46. Koyner JL, Vaidya VS, Bennett MR, Ma Q, Worcester E, Akhter SA, Raman J, Jeevanandam V, O'Connor MF, Devarajan P, Bonventre JV, Murray PT (2010) Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury. Clin J Am Soc Nephrol 5(12):2154–2165 Epub 2010 Aug 26

    PubMed  PubMed Central  CAS  Google Scholar 

  47. Iannone R, Ohene-Frempong K, Fuchs EJ, Casella JF, Chen AR (2005) Bone marrow transplantation for sickle cell anemia: progress and prospects. Pediatr Blood Cancer 44(5):436–440

    PubMed  Google Scholar 

  48. Kohne E (2011) Hemoglobinopathies: clinical manifestations, diagnosis, and treatment. Dtsch Arztebl Int 108(31-32):532–540

    PubMed  PubMed Central  Google Scholar 

  49. Orkin SH, Bauer DE (2019) Emerging genetic therapy for sickle cell disease. Annu Rev Med 70:257–271

    PubMed  CAS  Google Scholar 

  50. Nahavandi M, Tavakkoli F, Wyche MQ, Perlin E, Winter WP, Castro O (2002) Nitric oxide and cyclic GMP levels in sickle cell patients receiving hydroxyurea. Br J Haematol 119(3):855–857

    PubMed  CAS  Google Scholar 

  51. Agrawal RK, Patel RK, Shah V, Nainiwal L, Trivedi B (2014) Hydroxyurea in sickle cell disease: drug review. Indian J Hematol Blood Transfus 30(2):91–96

    PubMed  Google Scholar 

  52. Nader E, Grau M, Fort R et al (2018) Hydroxyurea therapy modulates sickle cell anemia red blood cell physiology: impact on RBC deformability, oxidative stress, nitrite levels and nitric oxide synthase signalling pathway. Nitric Oxide 81:28–35

    PubMed  CAS  Google Scholar 

  53. Mckie KT, Hanevold CD, Hernandez C et al (2007) Prevalence, prevention, and treatment of microalbuminuria and proteinuria in children with sickle cell disease. J Pediatr Hematol Oncol 29(3):140–144

    PubMed  CAS  Google Scholar 

  54. Aygun B, Mortier NA, Smeltzer MP, Shulkin BL, Hankins JS, Ware RE (2013) Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia. Am J Hematol 88(2):116–119

    PubMed  CAS  Google Scholar 

  55. Laurin LP, Nachman PH, Desai PC et al (2014) Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease. Nephrol Dial Transplant 29(6):1211–1218

    PubMed  CAS  Google Scholar 

  56. Roy NB, Fortin PM, Bull KR et al (2017) Interventions for chronic kidney disease in people with sickle cell disease. Cochrane Database Syst Rev 7:CD012380

    PubMed  Google Scholar 

  57. Estcourt LJ, Fortin PM, Hopewell S et al (2017) Blood transfusion for preventing primary and secondary stroke in people with sickle cell disease. Cochrane Database Syst Rev 1:CD003146

    PubMed  Google Scholar 

  58. Yawn BP, Buchanan GR, Afenyi-Annan AN et al (2014) Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 312(10):1033–1048

    PubMed  Google Scholar 

  59. Detterich JA (2018) Simple chronic transfusion therapy, a crucial therapeutic option for sickle cell disease, improves but does not normalize blood rheology: what should be our goals for transfusion therapy? Clin Hemorheol Microcirc 68(2-3):173–186

    PubMed  PubMed Central  CAS  Google Scholar 

  60. Ware RE, de Montalembert M, Tshilolo L, Abboud MR (2017) Sickle cell disease. Lancet 390(10091):311–323

    PubMed  Google Scholar 

  61. Wood JC, Cohen AR, Pressel SL, Aygun B, Imran H, Luchtman-Jones L, Thompson AA, Fuh B, Schultz WH, Davis BR, Ware RE, TWiTCH Investigators (2016) Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial. Br J Haematol 172(1):122–130

    PubMed  CAS  Google Scholar 

  62. Gburek J, Verroust PJ, Willnow TE, Fyfe JC, Nowacki W, Jacobsen C, Moestrup SK, Christensen EI (2002) Megalin and cubilin are endocytic receptors involved in renal clearance of hemoglobin. J Am Soc Nephrol 13(2):423–430

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. 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

    Marília Rocha Laurentino & Romélia Pinheiro Gonçalves Lemes

  2. Medical Sciences Post-Graduation Program, Department of Internal Medicine, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil

    Sérgio Luiz Arruda Parente Filho & Elizabeth De Francesco Daher

  3. School of Medicine, Christus University Center (Unichristus), Fortaleza, Ceara, Brazil

    Lívia Leal Chagas Parente

  4. Public Health Post-Graduation Program, School of Medicine, Health Sciences Center, University of Fortaleza, Fortaleza, Ceara, Brazil

    Geraldo Bezerra da Silva Júnior

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  1. Marília Rocha Laurentino
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Correspondence to Marília Rocha Laurentino.

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Laurentino, M.R., Parente Filho, S.L.A., Parente, L.L.C. et al. Non-invasive urinary biomarkers of renal function in sickle cell disease: an overview. Ann Hematol 98, 2653–2660 (2019). https://doi.org/10.1007/s00277-019-03813-9

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