Sickle cell disease and sickle cell trait are associated with several kidney abnormalities. The inner medullary environment of the kidney with low oxygen tension, hyperosmolarity, and acidemia is an ideal setup for hemoglobin polymerization and sickling. Repeated hemolysis, vaso-occlusive episodes, subsequent reperfusion injury, oxidative stress, and inflammation lead to acute and chronic kidney disease (CKD) (1, 2). The various kidney manifestations of sickle cell disease are summarized in Table 1.
Kidney manifestations of sickle cell disease
Glomerular hyperfiltration and lower mean arterial pressure occur in early years of life. With advancing age, a decline in glomerular filtration rate (GFR) is noted (1−3). Approximately 60% of all patients with sickle cell disease over the age of 45 have some amount of albuminuria. There is a steeper decline in kidney function among adults with albuminuria compared with those without (4).
CKD in sickle cell disease is highly influenced by genetic factors. Coinheritance of alpha-thalassemia is associated with a reduced risk of hemolysis and protection from albuminuria (5). The presence of haplotypes of the APOL1 gene, MYH9 gene, and polymorphism in the bone morphogenic protein receptor 1B promotes albuminuria and CKD in patients with sickle cell disease (6).
The occurrence of nephrotic syndrome due to sickle cell disease is uncommon and is associated with a poor kidney outcome. Human parvovirus B19 infection is an important cause of nephrotic syndrome in this population (7). Sickle cell disease-related end stage kidney disease accounts for 0.1% of the dialysis population in the United States (8). These patients are younger and have high mortality (9). Acute kidney injury (AKI) may occur in approximately 2.3%−13.6% of patients with sickle cell disease who are admitted for vaso-occlusive episodes or acute chest syndrome. Figure 1 describes the pathophysiology of AKI in sickle cell disease (10).
Patients with sickle cell disease should be screened for proteinuria annually starting at age 10. A combination of cystatin C-creatinine-based GFR, a trend rather than an absolute value of creatinine and trend in albuminuria, is preferred to diagnose and follow kidney disease in sickle cell disease. Albuminuria >300 mg/g, decline in kidney function, nephrotic syndrome, persistent hematuria, and hypertension must prompt referral to nephrology (11, 12). Hemodialysis and peritoneal dialysis are well tolerated (13).
Increased incidence of APOL1 risk alleles, higher infection risk, blood group incompatibility, pulmonary hypertension, and inability to tolerate side effects of immunosuppressive drugs are some reasons for lower rates of transplantation in sickle cell disease. Even with these limitations, patients have significantly better outcomes after kidney transplant compared with dialysis (14).
There is no specific treatment for sickle cell disease-related kidney disease. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers remain the mainstay therapy. With patients living longer, the burden of CKD is increasing in this population. Thus, a multidisciplinary approach with hematologists and nephrologists is needed to manage these patients. At our institution, Emory University School of Medicine, we have successfully implemented a CKD clinic for sickle cell disease patients. This clinic has improved access and timeliness to nephrology care. It serves as a great platform for epidemiological, clinical, and basic science research and helps deliver comprehensive care to patients with sickle cell disease. We hope to collaborate with other centers to improve care for this vulnerable population.
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Naik RP, Derebail VK. The spectrum of sickle hemoglobin-related nephropathy: From sickle cell disease to sickle trait. Expert Rev Hematol 2017; 10:1087–1094. doi: 10.1080/17474086.2017.1395279
Nath KA, Hebbel RP. Sickle cell disease: Renal manifestations and mechanisms. Nat Rev Nephrol 2015; 11:161–171. doi: 10.1038/nrneph.2015.8
Guasch A, et al. Glomerular involvement in adults with sickle cell hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure. J Am Soc Nephrol 2006; 17:2228–2235. doi: 10.1681/ASN.2002010084
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 1999; 10:1014–1019. doi: 10.1681/ASN.V1051014
Ashley-Koch AE, et al. MYH9 and APOL1 are both associated with sickle cell disease nephropathy. Br J Haematol 2011; 155:386–394. doi: 10.1111/j.1365-2141.2011.08832.x
Quek L, et al. Acute human parvovirus B19 infection and nephrotic syndrome in patients with sickle cell disease. Br J Haematol 2010; 149:289–291. doi: 10.1111/j.1365-2141.2009.08062.x
Abbott KC, et al. Sickle cell nephropathy at end-stage renal disease in the United States: Patient characteristics and survival. Clin Nephrol 2002; 58:9–15. doi: 10.5414/cnp58009
McClellan AC, et al. High one year mortality in adults with sickle cell disease and end-stage renal disease. Br J Haematol 2012; 159:360–367. doi: 10.1111/bjh.12024
Cecchini J, et al. Outcomes of adult patients with sickle cell disease admitted to the ICU: A case series*. Crit Care Med 2014; 42:1629–1639. doi: 10.1097/CCM.0000000000000316
Yawn BP, et al. Management of sickle cell disease: Summary of the 2014 evidence-based report by expert panel members. JAMA 2014; 312:1033–1048. doi: 10.1001/jama.2014.10517 [Erratums in JAMA 2014; 312:1932; JAMA 2015; 313:729].
National Heart, Lung, and Blood Institute, National Institutes of Health. Evidence-based management of sickle cell disease. Expert panel report, 2014. 2014. https://www.nhlbi.nih.gov/sites/default/files/publications/56-364NFULL.pdf
Sharpe CC, Thein SL. How I treat renal complications in sickle cell disease. Blood 2014; 123:3720–3726. doi: 10.1182/blood-2014-02-557439
Ojo AO, et al. Renal transplantation in end-stage sickle cell nephropathy. Transplantation 1999; 67:291–295. doi: 10.1097/00007890-199901270-00018