Sickle cell nephropathy: challenging the conventional wisdom


This review explores the current model of sickle cell nephropathy and the limitations of the model. Renal abnormalities are common complications of sickle cell disease (SCD). Beginning in childhood, patients with SCD develop a urinary concentrating defect resulting in polyuria and a predisposition to nocturnal enuresis and dehydration. The current model of sickle cell nephropathy suggests that destruction of the renal medulla induces production of renal vasodilating substances that feedback to the glomerulus causing hyperfiltration. Hyperfiltration leads to glomerulosclerosis and proteinuria, with eventual reduction in kidney function. The crucial steps of vasodilating substance production and hyperfiltration in children with SCD have not been proven. Treatment of sickle cell nephropathy is aimed at the reduction of proteinuria with angiotensin converting enzyme inhibitors or angiotensin receptor blockers. Hydroxyurea and chronic transfusion therapy may also alter the progression of sickle cell nephropathy in children. Further studies are needed to identify an accurate model and effective treatments for sickle cell nephropathy.

This is a preview of subscription content, access via your institution.

Fig. 1


  1. 1.

    Allon M (1990) Renal abnormalities in sickle cell disease. Arch Intern Med 150:501–504

    CAS  PubMed  Google Scholar 

  2. 2.

    Wesson DE (2002) The initiation and progression of sickle cell nephropathy. Kidney Int 61:2277–2286

    PubMed  Google Scholar 

  3. 3.

    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 115:614–620

    CAS  PubMed  Google Scholar 

  4. 4.

    Powars DR, Chan LS, Hiti A, Ramicone E, Johnson C (2005) Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Med Baltim 84:363–376

    Google Scholar 

  5. 5.

    Statius van Eps LW, Pinedo-Veels C, de Vries GH, de Koning J (1970) Nature of concentrating defect in sickle-cell nephropathy. Microradioangiographic studies. Lancet 1:450–452

    CAS  PubMed  Google Scholar 

  6. 6.

    Allon M, Lawson L, Eckman JR, Delaney V, Bourke E (1988) Effects of nonsteroidal antiinflammatory drugs on renal function in sickle cell anemia. Kidney Int 34:500–506

    CAS  PubMed  Google Scholar 

  7. 7.

    de Jong PE, Saleh AW, de Zeeuw D, Donker AJ, van der Hem GK, Pratt JJ, Sewrajsingh GS, Statius van Eps LW (1984) Urinary prostaglandins in sickle cell nephropathy: a defect in 9-ketoreductase activity? Clin Nephrol 22:212–213

    PubMed  Google Scholar 

  8. 8.

    Etteldorf JN, Tuttle AW, Clayton GW (1952) Renal function studies in pediatrics. 1. Renal hemodynamics in children with sickle cell anemia. AMA Am J Dis Child 83:185–191

    CAS  PubMed  Google Scholar 

  9. 9.

    Wigfall DR, Ware RE, Burchinal MR, Kinney TR, Foreman JW (2000) Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease. J Pediatr 136:749–753

    CAS  PubMed  Google Scholar 

  10. 10.

    Dharnidharka VR, Dabbagh S, Atiyeh B, Simpson P, Sarnaik S (1998) Prevalence of microalbuminuria in children with sickle cell disease. Pediatr Nephrol 12:475–478

    CAS  PubMed  Google Scholar 

  11. 11.

    McBurney PG, Hanevold CD, Hernandez CM, Waller JL, McKie KM (2002) Risk factors for microalbuminuria in children with sickle cell anemia. J Pediatr Hematol Oncol 24:473–477

    PubMed  Google Scholar 

  12. 12.

    McKie KT, Hanevold CD, Hernandez C, Waller JL, Ortiz L, McKie KM (2007) Prevalence, prevention, and treatment of microalbuminuria and proteinuria in children with sickle cell disease. J Pediatr Hematol Oncol 29:140–144

    CAS  PubMed  Google Scholar 

  13. 13.

    Diabetic Nephropathy (2008) In: Brenner BM (ed) Brenner & Rector's the kidney. 8th edn. Saunders, pp 1265–1290

  14. 14.

    Turgut F, Bolton WK (2010) Potential new therapeutic agents for diabetic kidney disease. Am J Kidney Dis 55:928–940

    CAS  PubMed  Google Scholar 

  15. 15.

    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 83:15–18

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Rincon-Choles H, Kasinath BS, Gorin Y, Abboud HE (2002) Angiotensin II and growth factors in the pathogenesis of diabetic nephropathy. Kidney Int Suppl S8-11

  17. 17.

    McCrory WW, Goren N, Gornfeld D (1953) Demonstration of impairment of urinary concentration ability, or pitressin-resistance, in children with sickle-cell anemia. AMA Am J Dis Child 86:512–515

    CAS  PubMed  Google Scholar 

  18. 18.

    Kunz HW, Pratt EL, Mellin GW, Cheung MW (1954) Impairment of urinary concentration in sickle cell anemia. Pediatrics 13:352–356

    CAS  PubMed  Google Scholar 

  19. 19.

    Itano HA, Keitel HG, Thompson D (1956) Hyposthenuria in sickle cell anemia: a reversible renal defect. J Clin Invest 35:998–1007

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    de Jong PE, de Jong-van Den Berg LT, De Zeeuw D, Donker AJ, Schouten H, Statius van Eps LW (1982) The influence of indomethacin on renal concentrating and diluting capacity in sickle cell nephropathy. Clin Sci Lond 63:53–58

    PubMed  Google Scholar 

  21. 21.

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

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Zins GR (1975) Renal prostaglandins. Am J Med 58:14–24

    CAS  PubMed  Google Scholar 

  23. 23.

    de Jong PE, de Jong-Van Den Berg, Sewrajsingh GS, Schouten H, Donker AJ, Statius van Eps LW (1980) The influence of indomethacin on renal haemodynamics in sickle cell anaemia. Clin Sci Lond 59:245–250

    PubMed  Google Scholar 

  24. 24.

    Bank N, Aynedjian HS, Qiu JH, Osei SY, Ahima RS, Fabry ME, Nagel RL (1996) Renal nitric oxide synthases in transgenic sickle cell mice. Kidney Int 50:184–189

    CAS  PubMed  Google Scholar 

  25. 25.

    Bank N, Kiroycheva M, Ahmed F, Anthony GM, Fabry ME, Nagel RL, Singhal PC (1998) Peroxynitrite formation and apoptosis in transgenic sickle cell mouse kidneys. Kidney Int 54:1520–1528

    CAS  PubMed  Google Scholar 

  26. 26.

    Bank N, Kiroycheva M, Singhal PC, Anthony GM, Southan GJ, Szabo C (2000) Inhibition of nitric oxide synthase ameliorates cellular injury in sickle cell mouse kidneys. Kidney Int 58:82–89

    CAS  PubMed  Google Scholar 

  27. 27.

    Filler G, Lepage N (2003) Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol 18:981–985

    PubMed  Google Scholar 

  28. 28.

    Zappitelli M, Parvex P, Joseph L, Paradis G, Grey V, Lau S, Bell L (2006) Derivation and validation of cystatin C-based prediction equations for GFR in children. Am J Kidney Dis 48:221–230

    CAS  PubMed  Google Scholar 

  29. 29.

    Thompson BW, Miller ST, Rogers ZR, Rees RC, Ware RE, Waclawiw MA, Iyer RV, Casella JF, Luchtman-Jones L, Rana S, Thornburg CD, Kalpatthi RV, Barredo JC, Brown RC, Sarnaik S, Howard TH, Luck L, Wang WC (2010) The pediatric hydroxyurea phase III clinical trial (BABY HUG): challenges of study design. Pediatr Blood Cancer 54:250–255

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Ware RE, Rees RC, Sarnaik SA, Iyer RV, Alvarez OA, Casella JF, Shulkin BL, Shalaby-Rana E, Strife CF, Miller JH, Lane PA, Wang WC, Miller ST (2010) Renal function in infants with sickle cell anemia: baseline data from the BABY HUG trial. J Pediatr 156:66–70

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Wang W, Thompson B, BABY HUG Investigators (2010) Hydroxyurea Treatment of Infants with Sickle Cell Anemia: Results of the BABY HUG Study. Pediatr Blood Cancer 54:787

    Google Scholar 

  32. 32.

    Thornburg CD, Dixon N, Burgett S, Mortier NA, Schultz WH, Zimmerman SA, Bonner M, Hardy KK, Calatroni A, Ware RE (2009) A pilot study of hydroxyurea to prevent chronic organ damage in young children with sickle cell anemia. Pediatr Blood Cancer 52:609–615

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Aygun B, Mortier NA, Smeltzer MP, Hankins JS, Ware RE (2009) Glomerular hyperfiltration and microalbuminuria in children with sickle cell anemia. Blood 114: Abstract 263

  34. 34.

    Alvarez O, Montane B, Lopez G, Wilkinson J, Miller T (2006) Early blood transfusions protect against microalbuminuria in children with sickle cell disease. Pediatr Blood Cancer 47:71–76

    PubMed  Google Scholar 

  35. 35.

    Bayazit AK, Noyan A, Aldudak B, Ozel A, Anarat A, Kilinc Y, Sasmaz GE, Anarat R, Dikmen N (2002) Renal function in children with sickle cell anemia. Clin Nephrol 57:127–130

    CAS  PubMed  Google Scholar 

  36. 36.

    Stevens LA, Schmid CH, Greene T, Li L, Beck GJ, Joffe MM, Froissart M, Kusek JW, Zhang YL, Coresh J, Levey AS (2009) Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney Int 75:652–660

    CAS  PubMed  Google Scholar 

  37. 37.

    Knight EL, Verhave JC, Spiegelman D, Hillege HL, de Zeeuw D, Curhan GC, de Jong PE (2004) Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int 65:1416–1421

    CAS  PubMed  Google Scholar 

  38. 38.

    Wiesli P, Schwegler B, Spinas GA, Schmid C (2003) Serum cystatin C is sensitive to small changes in thyroid function. Clin Chim Acta 338:87–90

    CAS  PubMed  Google Scholar 

  39. 39.

    White C, Akbari A, Hussain N, Dinh L, Filler G, Lepage N, Knoll GA (2005) Estimating glomerular filtration rate in kidney transplantation: a comparison between serum creatinine and cystatin C-based methods. J Am Soc Nephrol 16:3763–3770

    CAS  PubMed  Google Scholar 

  40. 40.

    Alvarez O, Zilleruelo G, Wright D, Montane B, Lopez-Mitnik G (2006) Serum cystatin C levels in children with sickle cell disease. Pediatr Nephrol 21:533–537

    PubMed  Google Scholar 

  41. 41.

    Schmitt F, Martinez F, Brillet G, Giatras I, Choukroun G, Girot R, Bachir D, Galacteros F, Lacour B, Grunfeld JP (1998) Early glomerular dysfunction in patients with sickle cell anemia. Am J Kidney Dis 32:208–214

    CAS  PubMed  Google Scholar 

  42. 42.

    Hatch FE Jr, Azar SH, Ainsworth TE, Nardo JM, Culbertson JW (1970) Renal circulatory studies in young adults with sickle cell anemia. J Lab Clin Med 76:632–640

    PubMed  Google Scholar 

  43. 43.

    Guasch A, Cua M, You W, Mitch WE (1997) Sickle cell anemia causes a distinct pattern of glomerular dysfunction. Kidney Int 51:826–833

    CAS  PubMed  Google Scholar 

  44. 44.

    Thompson J, Reid M, Hambleton I, Serjeant GR (2007) Albuminuria and renal function in homozygous sickle cell disease: observations from a cohort study. Arch Intern Med 167:701–708

    CAS  PubMed  Google Scholar 

  45. 45.

    Guasch A, Navarrete J, Nass K, Zayas CF (2006) Glomerular involvement in adults with sickle cell hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol 17:2228–2235

    CAS  PubMed  Google Scholar 

  46. 46.

    Bhathena DB, Sondheimer JH (1991) The glomerulopathy of homozygous sickle hemoglobin (SS) disease: morphology and pathogenesis. J Am Soc Nephrol 1:1241–1252

    CAS  PubMed  Google Scholar 

  47. 47.

    Bernstein J, Whitten CF (1960) A histologic appraisal of the kidney in sickle cell anemia. Arch Pathol 70:407–418

    CAS  PubMed  Google Scholar 

  48. 48.

    Voskaridou E, Terpos E, Michail S, Hantzi E, Anagnostopoulos A, Margeli A, Simirloglou D, Loukopoulos D, Papassotiriou I (2006) Early markers of renal dysfunction in patients with sickle cell/beta-thalassemia. Kidney Int 69:2037–2042

    CAS  PubMed  Google Scholar 

  49. 49.

    Marouf R, Mojiminiyi O, Abdella N, Kortom M, Al Wazzan H (2006) Comparison of renal function markers in Kuwaiti patients with sickle cell disease. J Clin Pathol 59:345–351

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Datta V, Ayengar JR, Karpate S, Chaturvedi P (2003) Microalbuminuria as a predictor of early glomerular injury in children with sickle cell disease. Indian J Pediatr 70:307–309

    PubMed  Google Scholar 

  51. 51.

    Sesso R, Almeida MA, Figueiredo MS, Bordin JO (1998) Renal dysfunction in patients with sickle cell anemia or sickle cell trait. Braz J Med Biol Res 31:1257–1262

    CAS  PubMed  Google Scholar 

  52. 52.

    Falk RJ, Scheinman J, Phillips G, Orringer E, Johnson A, Jennette JC (1992) Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N Engl J Med 326:910–915

    CAS  PubMed  Google Scholar 

  53. 53.

    Bakir AA, Hathiwala SC, Ainis H, Hryhorczuk DO, Rhee HL, Levy PS, Dunea G (1987) Prognosis of the nephrotic syndrome in sickle glomerulopathy. A retrospective study. Am J Nephrol 7:110–115

    CAS  PubMed  Google Scholar 

  54. 54.

    Abbott KC, Hypolite IO, Agodoa LY (2002) Sickle cell nephropathy at end-stage renal disease in the United States: patient characteristics and survival. Clin Nephrol 58:9–15

    CAS  PubMed  Google Scholar 

  55. 55.

    Ojo AO, Govaerts TC, Schmouder RL, Leichtman AB, Leavey SF, Wolfe RA, Held PJ, Port FK, Agodoa LY (1999) Renal transplantation in end-stage sickle cell nephropathy. Transplantation 67:291–295

    CAS  PubMed  Google Scholar 

  56. 56.

    Warady BA, Sullivan EK (1998) Renal transplantation in children with sickle cell disease: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 2:130–133

    CAS  PubMed  Google Scholar 

  57. 57.

    Cherner M, Isenberg D (2010) The overlap of systemic lupus erythematosus and sickle cell disease: report of two cases and a review of the literature. Lupus 19:875–883

    CAS  PubMed  Google Scholar 

  58. 58.

    Willson RA (1997) Extrahepatic manifestations of chronic viral hepatitis. Am J Gastroenterol 92:3–17

    CAS  PubMed  Google Scholar 

  59. 59.

    Meyers CM, Seeff LB, Stehman-Breen CO, Hoofnagle JH (2003) Hepatitis C and renal disease: an update. Am J Kidney Dis 42:631–657

    PubMed  Google Scholar 

  60. 60.

    Buskin SE, Torno MS, Talkington DF, Zhang M, Jones JL, Butler JC, McNaghten AD, Dworkin MS (2009) Trends in nephropathy among HIV-infected patients. J Natl Med Assoc 101:1205–1213

    PubMed  Google Scholar 

  61. 61.

    Jaffe JA, Kimmel PL (2006) Chronic nephropathies of cocaine and heroin abuse: a critical review. Clin J Am Soc Nephrol 1:655–667

    CAS  PubMed  Google Scholar 

  62. 62.

    Aoki RY, Saad ST (1995) Enalapril reduces the albuminuria of patients with sickle cell disease. Am J Med 98:432–435

    CAS  PubMed  Google Scholar 

  63. 63.

    Foucan L, Bourhis V, Bangou J, Merault L, Etienne-Julan M, Salmi RL (1998) A randomized trial of captopril for microalbuminuria in normotensive adults with sickle cell anemia. Am J Med 104:339–342

    CAS  PubMed  Google Scholar 

  64. 64.

    Fitzhugh CD, Wigfall DR, Ware RE (2005) Enalapril and hydroxyurea therapy for children with sickle nephropathy. Pediatr Blood Cancer 45:982–985

    PubMed  Google Scholar 

  65. 65.

    Batlle D, Itsarayoungyuen K, Arruda JA, Kurtzman NA (1982) Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies. Am J Med 72:188–192

    CAS  PubMed  Google Scholar 

  66. 66.

    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 102:171–177

    CAS  PubMed  Google Scholar 

  67. 67.

    Rodgers GP, Walker EC, Podgor MJ (1993) Is "relative" hypertension a risk factor for vaso-occlusive complications in sickle cell disease? Am J Med Sci 305:150–156

    CAS  PubMed  Google Scholar 

  68. 68.

    Weir MR, Blantz RC (2003) Blood pressure and cardiovascular risks: implications of the presence or absence of a nocturnal dip in blood pressure. Curr Opin Nephrol Hypertens 12:57–60

    PubMed  Google Scholar 

  69. 69.

    Sayk F, Becker C, Teckentrup C, Fehm HL, Struck J, Wellhoener JP, Dodt C (2007) To dip or not to dip: on the physiology of blood pressure decrease during nocturnal sleep in healthy humans. Hypertension 49:1070–1076

    CAS  PubMed  Google Scholar 

  70. 70.

    Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, Alvarez V, Batlle D (2002) Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 347:797–805

    CAS  PubMed  Google Scholar 

  71. 71.

    Bianchi S, Bigazzi R, Baldari G, Sgherri G, Campese VM (1994) Diurnal variations of blood pressure and microalbuminuria in essential hypertension. Am J Hypertens 7:23–29

    CAS  PubMed  Google Scholar 

  72. 72.

    Fukuda M, Munemura M, Usami T, Nakao N, Takeuchi O, Kamiya Y, Yoshida A, Kimura G (2004) Nocturnal blood pressure is elevated with natriuresis and proteinuria as renal function deteriorates in nephropathy. Kidney Int 65:621–625

    PubMed  Google Scholar 

  73. 73.

    Gabriel A, Przybylski J (2010) Sickle cell anemia: a look at global haplotype distribution. Nat Educ 3:2

    Google Scholar 

  74. 74.

    Kobori H, Nangaku M, Navar LG, Nishiyama A (2007) The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev 59:251–287

    CAS  PubMed  Google Scholar 

  75. 75.

    Saito T, Urushihara M, Kotani Y, Kagami S, Kobori H (2009) Increased urinary angiotensinogen is precedent to increased urinary albumin in patients with type 1 diabetes. Am J Med Sci 338:478–480

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Sharma R, Sharma M, Reddy S, Savin VJ, Nagaria AM, Wiegmann TB (2006) Chronically increased intrarenal angiotensin II causes nephropathy in an animal model of type 2 diabetes. Front Biosci 11:968–976

    CAS  PubMed  Google Scholar 

  77. 77.

    Yamamoto T, Nakagawa T, Suzuki H, Ohashi N, Fukasawa H, Fujigaki Y, Kato A, Nakamura Y, Suzuki F, Hishida A (2007) Urinary angiotensinogen as a marker of intrarenal angiotensin II activity associated with deterioration of renal function in patients with chronic kidney disease. J Am Soc Nephrol 18:1558–1565

    CAS  PubMed  Google Scholar 

  78. 78.

    Kobori H, Alper AB Jr, Shenava R, Katsurada A, Saito T, Ohashi N, Urushihara M, Miyata K, Satou R, Hamm LL, Navar LG (2009) Urinary angiotensinogen as a novel biomarker of the intrarenal renin-angiotensin system status in hypertensive patients. Hypertension 53:344–350

    CAS  PubMed  Google Scholar 

  79. 79.

    Calcagno PL, McLavy J, Kelley T (1950) Glomerular filtration rate in children with sickle cell disease. Pediatrics 5:127–129

    CAS  PubMed  Google Scholar 

  80. 80.

    Etteldorf JN, Smith JD, Tuttle AH, Diggs LW (1955) Renal hemodynamic studies in adults with sickle cell anemia. Am J Med 18:243–248

    CAS  PubMed  Google Scholar 

  81. 81.

    Aparicio SA, Mojiminiyi S, Kay JD, Shepstone BJ, de Ceulaer K, Serjeant GR (1990) Measurement of glomerular filtration rate in homozygous sickle cell disease: a comparison of 51Cr-EDTA clearance, creatinine clearance, serum creatinine and beta 2 microglobulin. J Clin Pathol 43:370–372

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


I would like to thank Dr. George Buchanan for his mentorship. This work was supported in part by the CTSA NIH Grant UL1-RR024982 and the Sickle Cell Scholar Award from NHLBI Grant U54-HL70588.

Author information



Corresponding author

Correspondence to Amy M. Becker.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Becker, A.M. Sickle cell nephropathy: challenging the conventional wisdom. Pediatr Nephrol 26, 2099–2109 (2011).

Download citation


  • Sickle cell anemia
  • Hyperfiltration
  • Proteinuria
  • Chronic kidney disease
  • Prostaglandins