Sickle cell disease: Renal manifestations and mechanisms

Nature Reviews Nephrology

Volumn 11, Issue 3, 2015, Pages 161-171

  Nath, Karl A ^a   Hebbel, Robert P ^b  

^a MAYO CLINIC   (United States)

^b UNIVERSITY OF MINNESOTA MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACUTE KIDNEY FAILURE; ARTICLE; CHRONIC KIDNEY DISEASE; ENDOTHELIUM; FOCAL GLOMERULOSCLEROSIS; GLOMERULOPATHY; GLOMERULOSCLEROSIS; HEMATURIA; HEMOLYSIS; HUMAN; KIDNEY DEVELOPMENT; KIDNEY DYSFUNCTION; KIDNEY FIBROSIS; KIDNEY HYPERTROPHY; KIDNEY INJURY; MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS; MICROALBUMINURIA; NONHUMAN; PERICYTE; PODOCYTE; PRIORITY JOURNAL; PROTEINURIA; RENOVASCULAR DISEASE; SICKLE CELL ANEMIA; SICKLE CELL TRAIT; THROMBOTIC THROMBOCYTOPENIC PURPURA; COMPLICATION; DISEASE COURSE; KIDNEY DISEASES; RENAL INSUFFICIENCY, CHRONIC;

ANEMIA, SICKLE CELL; DISEASE PROGRESSION; HUMANS; KIDNEY DISEASES; RENAL INSUFFICIENCY, CHRONIC;

EID: 84923776133     PISSN: 17595061     EISSN: 1759507X     Source Type: Journal    
DOI: 10.1038/nrneph.2015.8     Document Type: Article

References (143)

1. Buckalew, V. M. Jr & Someren, A. Renal manifestations of sickle cell disease. Arch. Intern. Med. 133, 660-669 (1974).
2. Alleyne, G. A. The kidney in sickle cell anemia. Kidney Int. 7, 371-379 (1975).
3. de Jong, P. E. & Statius van Eps, L. W. Sickle cell nephropathy: new insights into its pathophysiology. Kidney Int. 27, 711-717 (1985).
4. Allon, M. Renal abnormalities in sickle cell disease. Arch. Intern. Med. 150, 501-504 (1990).
5. Pham, P. T., Pham, P. C., Wilkinson, A. H. & Lew, S. Q. Renal abnormalities in sickle cell disease. Kidney Int. 57, 1-8 (2000).
6. Ataga, K. I. & Orringer, E. P. Renal abnormalities in sickle cell disease. Am. J. Hematol. 63, 205-211 (2000).
7. Wesson, D. E. The initiation and progression of sickle cell nephropathy. Kidney Int. 61, 2277-2286 (2002).
8. Nath, K. A., Katusic, Z. S. & Gladwin, M. T. The perfusion paradox and vascular instability in sickle cell disease. Microcirculation 11, 179-193 (2004).
9. Scheinman, J. I. Sickle cell disease and the kidney. Nat. Clin. Pract. Nephrol. 5, 78-88 (2009).
10. da Silva, G. B. Jr, Libório, A. B. & Daher Ede, F. New insights on pathophysiology, clinical manifestations, diagnosis, and treatment of sickle cell nephropathy. Ann. Hematol. 90, 1371-1379 (2011).
11. Sharpe, C. C. & Thein, S. L. Sickle cell nephropathy-a practical approach. Br. J. Haematol. 155, 287-297 (2011).
12. Becker, A. M. Sickle cell nephropathy: challenging the conventional wisdom. Pediatr. Nephrol. 26, 2099-2109 (2011).
13. Nath, K. A. & Katusic, Z. S. Vasculature and kidney complications in sickle cell disease. J. Am. Soc. Nephrol. 23, 781-784 (2012).
14. Sharpe, C. C. & Thein, S. L. How I treat renal complications in sickle cell disease. Blood 123, 3720-3726 (2014).
15. Ataga, K. I., Derebail, V. K. & Archer, D. R. The glomerulopathy of sickle cell disease. Am. J. Hematol. 89, 907-914 (2014).
16. Darbari, D. S. et al. Severe painful vaso-occlusive crises and mortality in a contemporary adult sickle cell anemia cohort study. PLoS ONE 8, e79923 (2013).
17. Gladwin, M. T. et al. Risk factors for death in 632 patients with sickle cell disease in the United States and United Kingdom. PLoS ONE 9, e99489 (2014).
18. Elmariah, H. et al. Factors associated with survival in a contemporary adult sickle cell disease cohort. Am. J. Hematol. 89, 530-535 (2014).
19. Platt, O. S. et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N. Engl. J. Med. 330, 1639-1644 (1994).
20. Hamideh, D. & Alvarez, O. Sickle cell disease related mortality in the United States (1999-2009). Pediatr. Blood Cancer 60, 1482-1486 (2013).
21. McClellan, A. C. et al. High one year mortality in adults with sickle cell disease and end-stage renal disease. Br. J. Haematol. 159, 360-367 (2012).
22. Piel, F. B. et al. Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. Lancet 381, 142-151 (2013).
23. Piel, F. B., Hay, S. I., Gupta, S., Weatherall, D. J. & Williams, T. N. Global burden of sickle cell anaemia in children under five, 2010-2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 10, e1001484 (2013).
24. Hebbel, R. P. Beyond hemoglobin polymerization: the red blood cell membrane and sickle disease pathophysiology. Blood 77, 214-237 (1991).
25. Hebbel, R. P. Perspectives series: cell adhesion in vascular biology. Adhesive interactions of sickle erythrocytes with endothelium. J. Clin. Invest. 99, 2561-2564 (1997).
26. Hebbel, R. P. Ischemia-reperfusion injury in sickle cell anemia: relationship to acute chest syndrome, endothelial dysfunction, arterial vasculopathy, and inflammatory pain. Hematol. Oncol. Clin. North Am. 28, 181-198 (2014).
27. Prohovnik, I. et al. Cerebral hyperemia, stroke, and transfusion in sickle cell disease. Neurology 39, 344-348 (1989).
28. Etteldorf, J. N., Smith, J. D., Tuttle, A. H. & Diggs, L. W. Renal hemodynamic studies in adults with sickle cell anemia. Am. J. Med. 18, 243-248 (1955).
29. Hatch, F. E. Jr, Azar, S. H., Ainsworth, T. E., Nardo, J. M. & Culbertson, J. W. Renal circulatory studies in young adults with sickle cell anemia. J. Lab. Clin. Med. 76, 632-640 (1970).
30. Ware, R. E. et al. Renal function in infants with sickle cell anemia: baseline data from the BABY HUG trial. J. Pediatr. 156, 66-70.e1 (2010).
31. Bank, N. et al. Renal nitric oxide synthases in transgenic sickle cell mice. Kidney Int. 50, 184-189 (1996).
32. Hostetter, T. H. Hyperfiltration and glomerulosclerosis. Semin. Nephrol. 23, 194-199 (2003).
33. Schmitt, F. et al. Early glomerular dysfunction in patients with sickle cell anemia. Am. J. Kidney Dis. 32, 208-214 (1998).
34. Guasch, A., Cua, M. & Mitch, W. E. Early detection and the course of glomerular injury in patients with sickle cell anemia. Kidney Int. 49, 786-791 (1996).
35. Statius van Eps, L. W., Schouten, H., La Porte-Wijsman, L. W. & Struyker Boudier, A. M. The influence of red blood cell transfusions on the hyposthenuria and renal hemodynamics of sickle cell anemia. Clin. Chim. Acta 17, 449-461 (1967).
36. Bradley, S. E. & Bradley, G. P. Renal function during chronic anemia in man. Blood 2, 192-202 (1947).
37. Bergmann, S., Zheng, D., Barredo, J., Abboud, M. R. & Jaffa, A. A. Renal kallikrein: a risk marker for nephropathy in children with sickle cell disease. J. Pediatr. Hematol. Oncol. 28, 147-153 (2006).
38. Nath, K. A. et al. Oxidative stress and induction of heme oxygenase-1 in the kidney in sickle cell disease. Am. J. Pathol. 158, 893-903 (2001).
39. Jison, M. L. et al. Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease. Blood 104, 270-280 (2004).
40. Sears, D. A., Udden, M. M. & Thomas, L. J. Carboxyhemoglobin levels in patients with sickle-cell anemia: relationship to hemolytic and vasoocclusive severity. Am. J. Med. Sci. 322, 345-348 (2001).
41. Sylvester, K. P. et al. Exhaled carbon monoxide levels in children with sickle cell disease. Eur. J. Pediatr. 164, 162-165 (2005).
42. Haymann, J. P. et al. Glomerular hyperfiltration in adult sickle cell anemia: a frequent hemolysis associated feature. Clin. J. Am. Soc. Nephrol. 5, 756-761 (2010).
43. Statius van Eps, L. W., Pinedo-Veels, C., de Vries, G. H. & de Koning, J. Nature of concentrating defect in sickle-cell nephropathy. Microradioangiographic studies. Lancet 1, 450-452 (1970).
44. Walker, T. M., Beardsall, K., Thomas, P. W. & Serjeant, G. R. Renal length in sickle cell disease: observations from a cohort study. Clin. Nephrol. 46, 384-388 (1996).
45. McCarville, M. B. et al. Abdominal ultrasound with scintigraphic and clinical correlates in infants with sickle cell anemia: baseline data from the BABY HUG trial. AJR Am. J. Roentgenol. 196, 1399-1404 (2011).
46. Fine, L. The biology of renal hypertrophy. Kidney Int. 29, 619-634 (1986).
47. Hostetter, T. H. Progression of renal disease and renal hypertrophy. Annu. Rev. Physiol. 57, 263-278 (1995).
48. Helal, I., Fick-Brosnahan, G. M., Reed-Gitomer, B. & Schrier, R. W. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nature Rev. Nephrol. 8, 293-300 (2012).
49. Brittain, J. E. & Parise, L. V. Cytokines and plasma factors in sickle cell disease. Curr. Opin. Hematol. 14, 438-443 (2007).
50. Pitcock, J. A., Muirhead, E. E., Hatch, F. E., Johnson, J. G. & Kelly, B. J. Early renal changes in sickle cell anemia. Arch. Pathol. 90, 403-410 (1970).
51. Walker, B. R., Alexander, F., Birdsall, T. R. & Warren, R. L. Glomerular lesions in sickle cell nephropathy. JAMA 215, 437-440 (1971).
52. Elfenbein, I. B., Patchefsky, A., Schwartz, W. & Weinstein, A. G. Pathology of the glomerulus in sickle cell anemia with and without nephrotic syndrome. Am. J. Pathol. 77, 357-374 (1974).
53. Tejani, A. et al. Renal lesions in sickle cell nephropathy in children. Nephron 39, 352-355 (1985).
54. Bhathena, D. B. & Sondheimer, J. H. The glomerulopathy of homozygous sickle hemoglobin (SS) disease: morphology and pathogenesis. J. Am. Soc. Nephrol. 1, 1241-1252 (1991).
55. Falk, R. J. et al. Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme. N. Engl. J. Med. 326, 910-915 (1992).
56. Nasr, S. H., Markowitz, G. S., Sentman, R. L. & D'Agati, V. D. Sickle cell disease, nephrotic syndrome, and renal failure. Kidney Int. 69, 1276-1280 (2006).
57. Maigne, G. et al. Glomerular lesions in patients with sickle cell disease. Medicine (Baltimore) 89, 18-27 (2010).
58. Dharnidharka, V. R., Dabbagh, S., Atiyeh, B., Simpson, P. & Sarnaik, S. Prevalence of microalbuminuria in children with sickle cell disease. Pediatr. Nephrol. 12, 475-478 (1998).
59. Guasch, A., Navarrete, J., Nass, K. & Zayas, C. F. Glomerular involvement in adults with sickle cell hemoglobinopathies: prevalence and clinical correlates of progressive renal failure. J. Am. Soc. Nephrol. 17, 2228-2235 (2006).
60. Gosmanova, E. O., Zaidi, S., Wan, J. Y. & Adams-Graves, P. E. Prevalence and progression of chronic kidney disease in adult patients with sickle cell disease. J. Investig. Med. 62, 804-807 (2014).
61. Bakir, A. A. et al. Prognosis of the nephrotic syndrome in sickle glomerulopathy. A retrospective study. Am. J. Nephrol. 7, 110-115 (1987).
62. Powars, D. R., Chan, L. S., Hiti, A., Ramicone, E. & Johnson, C. Outcome of sickle cell anemia: a 4-decade observational study of 1056 patients. Medicine (Baltimore) 84, 363-376 (2005).
63. Becker, A. M. et al. Blood pressure abnormalities in children with sickle cell anemia. Pediatr. Blood Cancer 61, 518-522 (2014).
64. Thompson, J., Reid, M., Hambleton, I. & Serjeant, G. R. Albuminuria and renal function in homozygous sickle cell disease: observations from a cohort study. Arch. Intern. Med. 167, 701-708 (2007).
65. Gordeuk, V. R. et al. 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 (2008).
66. Aygun, B., Mortier, N. A., Smeltzer, M. P., Hankins, J. S. & Ware, R. E. Glomerular hyperfiltration and albuminuria in children with sickle cell anemia. Pediatr. Nephrol. 26, 1285-1290 (2011).
67. Faulkner, M. et al. Severe anemia: a risk factor for glomerular injury in sickle cell disease. J. Natl Med. Assoc. 87, 209-213 (1995).
68. Lebensburger, J. et al. Protective role of hemoglobin and fetal hemoglobin in early kidney disease for children with sickle cell anemia. Am. J. Hematol. 86, 430-432 (2011).
69. Gurkan, S., Scarponi, K. J., Hotchkiss, H., Savage, B. & Drachtman, R. Lactate dehydrogenase as a predictor of kidney involvement in patients with sickle cell anemia. Pediatr. Nephrol. 25, 2123-2127 (2010).
70. Day, T. G., Drasar, E. R., Fulford, T., Sharpe, C. C. & Thein, S. L. Association between hemolysis and albuminuria in adults with sickle cell anemia. Haematologica 97, 201-205 (2012).
71. Hamideh, D. et al. Albuminuria correlates with hemolysis and NAG and KIM-1 in patients with sickle cell anemia. Pediatr. Nephrol. 29, 1997-2003 (2014).
72. Wigfall, D. R., Ware, R. E., Burchinal, M. R., Kinney, T. R. & Foreman, J. W. Prevalence and clinical correlates of glomerulopathy in children with sickle cell disease. J. Pediatr. 136, 749-753 (2000).
73. Powars, D. R. et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann. Intern. Med. 115, 614-620 (1991).
74. Ataga, K. I. et al. Urinary albumin excretion is associated with pulmonary hypertension in sickle cell disease: potential role of soluble fms-like tyrosine kinase-1. Eur. J. Haematol. 85, 257-263 (2010).
75. Laurin, L. P., Nachman, P. H., Desai, P. C., Ataga, K. I. & Derebail, V. K. Hydroxyurea is associated with lower prevalence of albuminuria in adults with sickle cell disease. Nephrol. Dial. Transplant. 29, 1211-1218 (2014).
76. Wierenga, K. J. et al. Glomerulonephritis after human parvovirus infection in homozygous sickle-cell disease. Lancet 346, 475-476 (1995).
77. Ashley-Koch, A. E. et al. MYH9 and APOL1 are both associated with sickle cell disease nephropathy. Br. J. Haematol. 155, 386-394 (2011).
78. Guasch, A. et al. Evidence that microdeletions in the alpha globin gene protect against the development of sickle cell glomerulopathy in humans. J. Am. Soc. Nephrol. 10, 1014-1019 (1999).
79. Nolan, V. G. et al. Estimated glomerular filtration rate in sickle cell anemia is associated with polymorphisms of bone morphogenetic protein receptor 1B. Am. J. Hematol. 82, 179-184 (2007).
80. Sundaram, N. et al. Biomarkers for early detection of sickle nephropathy. Am. J. Hematol. 86, 559-566 (2011).
81. Sasongko, T. H., Nagalla, S. & Ballas, S. K. Angiotensin-converting enzyme (ACE) inhibitors for proteinuria and microalbuminuria in people with sickle cell disease. Cochrane Database Syst. Rev. 3, CD009191 (2013).
82. Yawn, B. P. et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA 312, 1033-1048 (2014).
83. Alvarez, O. et al. Effect of hydroxyurea treatment on renal function parameters: results from the multi-center placebo-controlled BABY HUG clinical trial for infants with sickle cell anemia. Pediatr. Blood Cancer 59, 668-674 (2012).
84. Aygun, B. et al. Hydroxyurea treatment decreases glomerular hyperfiltration in children with sickle cell anemia. Am. J. Hematol. 88, 116-119 (2013).
85. Sklar, A. H., Perez, J. C., Harp, R. J. & Caruana, R. J. Acute renal failure in sickle cell anemia. Int. J. Artif. Organs 13, 347-351 (1990).
86. Audard, V. et al. Acute kidney injury in sickle patients with painful crisis or acute chest syndrome and its relation to pulmonary hypertension. Nephrol. Dial. Transplant. 25, 2524-2529 (2010).
87. Cecchini, J. et al. Outcomes of adult patients with sickle cell disease admitted to the ICU: a case series. Crit. Care Med. 42, 1629-1639 (2014).
88. Hassell, K. L., Eckman, J. R. & Lane, P. A. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Am. J. Med. 96, 155-162 (1994).
89. Aderibigbe, A., Arije, A. & Akinkugbe, O. O. Glomerular function in sickle cell disease patients during crisis. Afr. J. Med. Med. Sci. 23, 153-160 (1994).
90. Audard, V. et al. First evidence of subclinical renal tubular injury during sickle-cell crisis. Orphanet J. Rare Dis. 9, 67 (2014).
91. Nath, K. A. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am. J. Kidney Dis. 20, 1-17 (1992).
92. Duffield, J. S. Cellular and molecular mechanisms in kidney fibrosis. J. Clin. Invest. 124, 2299-2306 (2014).
93. Kriz, W. & LeHir, M. Pathways to nephron loss starting from glomerular diseases-insights from animal models. Kidney Int. 67, 404-419 (2005).
94. Garg, P. & Rabelink, T. Glomerular proteinuria: a complex interplay between unique players. Adv. Chronic Kidney Dis. 18, 233-242 (2011).
95. Hebbel, R. P., Osarogiagbon, R. & Kaul, D. The endothelial biology of sickle cell disease: inflammation and a chronic vasculopathy. Microcirculation 11, 129-151 (2004).
96. Kato, G. J., Hebbel, R. P., Steinberg, M. H. & Gladwin, M. T. Vasculopathy in sickle cell disease: biology, pathophysiology, genetics, translational medicine, and new research directions. Am. J. Hematol. 84, 618-625 (2009).
97. Peppiatt-Wildman, C. M. The evolving role of renal pericytes. Curr. Opin. Nephrol. Hypertens. 22, 10-16 (2013).
98. Schein, A., Enriquez, C., Coates, T. D. & Wood, J. C. Magnetic resonance detection of kidney iron deposition in sickle cell disease: a marker of chronic hemolysis. J. Magn. Reson. Imaging 28, 698-704 (2008).
99. Vasavda, N. et al. Renal iron load in sickle cell disease is influenced by severity of haemolysis. Br. J. Haematol. 157, 599-605 (2012).
100. Saraf, S. L. et al. Haemoglobinuria is associated with chronic kidney disease and its progression in patients with sickle cell anaemia. Br. J. Haematol. 164, 729-739 (2014).
101. Nath, K. A., Croatt, A. J., Haggard, J. J. & Grande, J. P. Renal response to repetitive exposure to heme proteins: chronic injury induced by an acute insult. Kidney Int. 57, 2423-2433 (2000).
102. Nath, K. A. et al. Heme protein-induced chronic renal inflammation: suppressive effect of induced heme oxygenase-1. Kidney Int. 59, 106-117 (2001).
103. Nath, K. A. et al. Age sensitizes the kidney to heme protein-induced acute kidney injury. Am. J. Physiol. Renal Physiol. 304, F317-F325 (2013).
104. Belcher, J. D. et al. Heme triggers TLR4 signaling leading to endothelial cell activation and vasoocclusion in murine sickle cell disease. Blood 123, 377-390 (2014).
105. Tracz, M. J., Alam, J. & Nath, K. A. Physiology and pathophysiology of heme: implications for kidney disease. J. Am. Soc. Nephrol. 18, 414-420 (2007).
106. Moraes, J. A. et al. Heme modulates smooth muscle cell proliferation and migration via NADPH oxidase: a counter-regulatory role for heme oxygenase system. Atherosclerosis 224, 394-400 (2012).
107. Chawla, L. S., Eggers, P. W., Star, R. A. & Kimmel, P. L. Acute kidney injury and chronic kidney disease as interconnected syndromes. N. Engl. J. Med. 371, 58-66 (2014).
108. Nath, K. A. et al. Transgenic sickle mice are markedly sensitive to renal ischemia-reperfusion injury. Am. J. Pathol. 166, 963-972 (2005).
109. Juncos, J. P. et al. Early and prominent alterations in hemodynamics, signaling, and gene expression following renal ischemia in sickle cell disease. Am. J. Physiol. Renal Physiol. 298, F892-F899 (2010).
110. Bank, N. et al. Inhibition of nitric oxide synthase ameliorates cellular injury in sickle cell mouse kidneys. Kidney Int. 58, 82-89 (2000).
111. Mimura, I. & Nangaku, M. The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat. Rev. Nephrol. 6, 667-678 (2010).
112. Sun, K. & Xia, Y. New insights into sickle cell disease: a disease of hypoxia. Curr. Opin. Hematol. 20, 215-221 (2013).
113. Fine, L. G. & Norman, J. T. Chronic hypoxia as a mechanism of progression of chronic kidney diseases: from hypothesis to novel therapeutics. Kidney Int. 74, 867-872 (2008).
114. Long, D. A., Norman, J. T. & Fine, L. G. Restoring the renal microvasculature to treat chronic kidney disease. Nat. Rev. Nephrol. 8, 244-250 (2012).
115. Grgic, I. et al. Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis. Kidney Int. 82, 172-183 (2012).
116. Sabaa, N. et al. Endothelin receptor antagonism prevents hypoxia-induced mortality and morbidity in a mouse model of sickle-cell disease. J. Clin. Invest. 118, 1924-1933 (2008).
117. Camus, S. M. et al. Erythrocyte microparticles can induce kidney vaso-occlusions in a murine model of sickle cell disease. Blood 120, 5050-5058 (2012).
118. Zhang, Y. et al. Detrimental effects of adenosine signaling in sickle cell disease. Nat. Med. 17, 79-86 (2011).
119. Nath, K. A., Salahudeen, A. K., Clark, E. C., Hostetter, M. K. & Hostetter, T. H. Role of cellular metabolites in progressive renal injury. Kidney Int. Suppl. 38, S109-S113 (1992).
120. Strauss, J., Pardo, V., Koss, M. N., Griswold, W. & McIntosh, R. M. Nephropathy associated with sickle cell anemia: an autologous immune complex nephritis. I. Studies on nature of glomerular-bound antibody and antigen identification in a patient with sickle cell disease and immune deposit glomerulonephritis. Am. J. Med. 58, 382-387 (1975).
121. McCoy, R. C. Ultrastructural alterations in the kidney of patients with sickle cell disease and the nephrotic syndrome. Lab. Invest. 21, 85-95 (1969).
122. Weber, M. L. et al. Morphine promotes renal pathology in sickle mice. Int. J. Nephrol. Renovasc. Dis. 5, 109-118 (2012).
123. Itano, H. A., Keitel, H. G. & Thompson, D. Hyposthenuria in sickle cell anemia: a reversible renal defect. J. Clin. Invest. 35, 998-1007 (1956).
124. Pallone, T. L., Zhang, Z. & Rhinehart, K. Physiology of the renal medullary microcirculation. Am. J. Physiol. Renal Physiol. 284, F253-F266 (2003).
125. Hakimi, A. A. et al. Renal medullary carcinoma: the Bronx experience. Urology 70, 878-882 (2007).
126. Gatalica, Z. et al. Renal medullary carcinomas: histopathologic phenotype associated with diverse genotypes. Hum. Pathol. 42, 1979-1988 (2011).
127. Shetty, A. & Matrana, M. R. Renal medullary carcinoma: a case report and brief review of the literature. Ochsner J. 14, 270-275 (2014).
128. Maurel, S. et al. Prevalence and correlates of metabolic acidosis among patients with homozygous sickle cell disease. Clin. J. Am. Soc. Nephrol. 9, 648-653 (2014).
129. DeFronzo, R. A., Taufield, P. A., Black, H., McPhedran, P. & Cooke, C. R. Impaired renal tubular potassium secretion in sickle cell disease. Ann. Intern. Med. 90, 310-316 (1979).
130. Batlle, D., Itsarayoungyuen, K., Arruda, J. A. & Kurtzman, N. A. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies. Am. J. Med. 72, 188-192 (1982).
131. Tsaras, G., Owusu-Ansah, A., Boateng, F. O. & Amoateng-Adjepong, Y. Complications associated with sickle cell trait: a brief narrative review. Am. J. Med. 122, 507-512 (2009).
132. Key, N. S. & Derebail, V. K. Sickle-cell trait: novel clinical significance. Hematology Am. Soc. Hematol. Educ. Program 2010, 418-422 (2010).
133. Shaw, C. & Sharpe, C. C. Could sickle cell trait be a predisposing risk factor for CKD? Nephrol. Dial. Transplant. 25, 2403-2405 (2010).
134. Derebail, V. K. et al. High prevalence of sickle cell trait in African Americans with ESRD. J. Am. Soc. Nephrol. 21, 413-417 (2010).
135. Hicks, P. J. et al. Sickle cell trait is not independently associated with susceptibility to end-stage renal disease in African Americans. Kidney Int. 80, 1339-1343 (2011).
136. Ajayi, A. A. & Kolawole, B. A. Sickle cell trait and gender influence type 2 diabetic complications in African patients. Eur. J. Intern. Med. 15, 312-315 (2004).
137. Bleyer, A. J. et al. Sickle cell trait and development of microvascular complications in diabetes mellitus. Clin. J. Am. Soc. Nephrol. 5, 1015-1020 (2010).
138. Naik, R. P. et al. Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. JAMA 312, 2115-2125 (2014).
139. Yium, J., Gabow, P., Johnson, A., Kimberling, W. & Martinez-Maldonado, M. Autosomal dominant polycystic kidney disease in blacks: clinical course and effects of sickle-cell hemoglobin. J. Am. Soc. Nephrol. 4, 1670-1674 (1994).
140. Rosenthal, P. J. Lessons from sickle cell disease in the treatment and control of malaria. N. Engl. J. Med. 364, 2549-2551 (2011).
141. Ferreira, A. et al. Sickle hemoglobin confers tolerance to Plasmodium infection. Cell 145, 398-409 (2011).
142. Roy, S. et al. Increased oxidative stress in sickle cell disease activates the renin-angiotensin-TGF-β pathway to mediate sickle nephropathy. 55th ASH Annual Meeting and Exposition https://ash.confex.com/ash/2013/webprogram/Paper64925.html (2013).
143. Hebbel, R. P., Vercellotti, G. & Nath, K. A. A systems biology consideration of the vasculopathy of sickle cell anemia: the need for multi-modality chemo-prophylaxsis. Cardiovasc. Hematol. Disord. Drug Targets. 9, 271-292 (2009).