Sickle cell disease (SCD), first discovered in West Africa is an autosomal recessive hemoglobin disorder, predominantly affecting persons of African, Mediterranean, Indian, and Middle Eastern descent. It results from the replacement of glutamate for valine at the sixth amino acid of the beta-globin chain. The mutation results in hemoglobin S (HbS) tetramers that accumulate during tissue hypoxia, oxidative stress or dehydration. The accumulation leads to red blood cell sickling, early destruction of erythrocytes, and widespread vaso-occlusive episodes (VOC), subsequently resulting in multiorgan damage. Some of the renal complications, collectively known as sickle cell nephropathy (SCN), include hematuria, hyposthenuria, renal papillary necrosis, proteinuria, renal tubular disorders, acute and chronic kidney injury, sickle cell glomerulopathy, and renal medullary carcinoma. Clinically significant renal involvement occurs more frequently in sickle cell disease than in sickle cell trait or in combined hemoglobinopathies, except renal medullary carcinoma, which appears to be more common among sickle cell trait patients. 
Natural history of SCD is highly variable with reduced life expectancy with multiorgan damage in symptomatic patients. In general, all patients have a reduced lifespan. Median survival in the United States and Jamaica is 45 to 55 years. 
Natural history by age in SCD is as follows:
The primary cause of death in younger patients is usually infection; whereas, in older patients, the primary cause of death is mostly irreversible organ damage.
The sickle hemoglobin mutation (hemoglobin S or HbS) results in the replacement of the glutamate for valine in the sixth amino acid position of the beta-globin chain, thereby changing the arrangement of the Hb tetramer molecule in the homozygous person from A2B2 to A2BS2. SCD occurs in those homozygous for HbS (referred to as sickle cell anemia) or in heterozygotes when HbS coexists with another abnormal or missing beta-chain, for example, HbC (A2SC) or HbS beta thalassemia (A2SBthal). Sickle cell trait occurs in those heterozygous for HbS when the other Hb molecule is normal HbAS (A2SB). ,
Some of the risk factors associated with progression of chronic kidney disease (CKD) in SCN include:
Coinheritance with alpha-thalassemia apart from higher fetal hemoglobin is protective factors.
The high prevalence of SCD in West Africa and parts of Asia represents a probable survival advantage because the presence of the sickle cell gene protects against malaria. SCD is now a worldwide health problem because the carrier state has spread throughout Africa, Mediterranean, Middle East and South Asia, the Caribbean, North America, and Northern Europe. SCD affects anywhere from 70,000 to 100,000 people in the United States and accounts for less than 1% of all new cases of end-stage renal disease (ESRD). In a 25-year observational study of 725 SCD patients, 4% developed CKD at a median age of 23 years, most of them requiring dialysis within a few years. When the study was extended by 15 years, the incidence was 12% (median age of 37 years). Proteinuria is common in SCD, occurring in about 30% of patients. Sickle cell gene prevalence is about 8% in African Americans and about 25% in adult Nigerians.
HbS polymerization is the key pathophysiological event, and it occurs during cellular or tissue hypoxia, oxidative stress, or dehydration. The mutated beta-globin chains of the HbS molecule tend to form a tetramer resulting in the change in the shape of red blood cell (RBC) to a crescent or sickle, with increased rigidity. Local oxygen tension, acidosis, and hyperosmolarity are some factors that influence the tetramerization. Repeated cycles of tetramer formation make the sickle RBCs exhibit high adhesion to the activated endothelium resulting in increased microvascular transit time, leading to further sickling. The whole process ultimately results in the early destruction of the RBCs and frequent, widespread vaso-occlusive episodes with consequent acute and chronic organ damage.
The main cause of disease severity is the rate and degree of HbS tetramerization, which leads to 2 major pathophysiologic events:
The renal complications in sickle cell disease originate from the occluded vessels (vasa recta) in the renal medulla, given the low partial pressure of oxygen (10 to 35 mm Hg), acidosis, and high osmolarity, which predisposes to hemoglobin S tetramerization and subsequent sickling of the erythrocytes. Repeated cycles of sickling and sludging lead to microinfarcts and ischemic injury giving rise to chronic microvascular disease which is seen in patients with SCN. The factors which promote the cycles of chronic medullary hypoxia include:
Hyperfiltration injury from a paradoxical increase in the total RBF and GFR in renal medulla ultimately results in proteinuria and glomerulosclerosis, which together with tubulointerstitial fibrosis leads to progressive CKD,. Polyuria, from the decreased concentrating ability, a consequence of tubular injury may be seen in childhood and adolescence. Type IV RTA (hyperkalemia and mild hyperchloremic metabolic acidosis) can be observed in these patients before a significant loss of nephron mass and proteinuria from secondary FSGS (focal segmental glomerulosclerosis). Papillary necrosis may result from ischemia from the sickling of red cells and manifest with gross hematuria and ureteric obstruction from sloughed ischemic papillae.
Possible mechanisms for glomerular abnormalities in HbSS patients include:
No pathognomonic lesion defines SCN, but glomerular hypertrophy, leading to hyperfiltration, is universal and is seen in children as young as 1 to 3 years of age. Given the glomerular hypertrophy, the GFR continues to rise throughout childhood and early adulthood, often exceeding 200 ml/min/1.73 m, but in comparison to diabetic nephropathy, the hyperfiltration is not associated with hypertension, as patients with SCN have lower systemic vascular resistance. Nephrotic syndrome, though uncommon (up to 4% of patients with proteinuria) is associated with a very poor renal prognosis. An infection with human parvovirus B19 (HPV B19), is a rare cause of acute nephrotic syndrome with severe hemolysis and life-threatening anemia. The biopsy in such patients shows collapsing variant of focal segmental glomerulosclerosis (FSGS). Renal papillary necrosis can be seen with complete occlusion of vasa recta and can be complicated by superimposed infection and colic from clots. An aggressive form of renal cell carcinoma, renal medullary carcinoma affects patients with sickle cell hemoglobinopathies, more so in teenagers and young adults. Chronic medullary hypoxia is thought to contribute to its pathogenesis.. Patients with SCN advance through stages of tubular dysfunction and hyperfiltration, microalbuminuria through heavy proteinuria, and ultimately loss of GFR. Single-nephron GFR increases with the loss of other nephrons, leading to progressive damage to the glomeruli and on renal pathology, it is manifested as FSGS and interstitial fibrosis and tubular atrophy. FSGS is the most common lesion in SCN and is associated with proteinuria. Collapsing pattern and expansive pattern of FSGS may be observed. Other renal biopsy lesions that have been reported in SCD comprise thrombotic microangiopathy and membranoproliferative glomerulonephritis, though neither are limited to SCN. The only characteristic interstitial lesion is abundant hemosiderin granules in proximal tubular epithelial cells.
Some of the common findings in patients with sickle cell nephropathy include:
The initial diagnosis is based on the clinical manifestations and is primarily is a diagnosis of exclusion.
The initial investigations in a patient with SCD, who presents with hematuria or proteinuria include:
In a patient with eGFR less than 60 ml/mt/1.73mt2 with a rapid decline in eGFR by greater than 5mls/mt/1.73mt2 or with persistent proteinuria needs a nephrologist referral and evaluation. Especially, SCD patients with urinary protein to creatinine ratio (UPCR) greater than 300 mg/gm should be evaluated for other causes of CKD.
The conservative approach, with bed rest, oral hydration, remains the cornerstone in the management gross hematuria.
Patients with sickle cell are commonly followed by the primary care provider, nurse practitioner, hematologist and the internist. The renal function in these patients needs to be monitored by an interprofessional team because it can lead to end-stage renal disease and a shortened life expectancy. As soon as the renal function starts to decline, a nephrology consult should be made. Many of these patients do require dialysis and some may benefit from a kidney transplant. Without any treatment, the life span is severely limited.
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