Since the discovery of Hemoglobin S (HbS) by Linus Pauling and colleagues in 1949 and identification of the abnormality in the amino acid sequence by Vernon Ingram in 1956 (replacement of the hydrophilic glutamic acid at position 6 in the β-globin chain by the hydrophobic valine residue), it has been known that the abnormal polymerization of deoxy-HbS is the main cause for vaso-occlusive crisis involving many organs including the kidneys in sickle cell disease (SCD).
Advances in understanding of RBC dehydration, role of nitric oxide, adenosine, and changes in RBC and plasma membrane proteins during sickling have advanced our current understanding of SCD.
Medullary renal carcinoma (MRC) is a rare and fatal cancer that occurs primarily in patients with sickle cell trait (SCT) and sickle cell disease (SCD). The typical patient with MRC is a young male (mean age of 22 years) of African or Mediterranean descent. Most patients with this disease present initially with gross hematuria, weight loss, or abdominal pain.
In symptomatic patients, 80% will have retroperitoneal lymphadenopathy and visceral metastasis. The disease is uniformly fatal, with a life expectancy from the time of initial diagnosis of only 15 weeks. There are no known effective radiation or chemotherapy treatments for the disease.
The renal manifestations of SCD are not limited to MRC. The hypertonic, acidic and hypoxic environment in the inner medulla favors RBC sickling, leading to occlusion and necrosis of the vasarecta. The resulting ischemia leads to release of vasodilators such as prostaglandin.
This, in turn, increases the glomerular filtration rate (GFR), leading to microalbuminuria, proteinuria, and eventually low GFR, particularly among patients in the fourth decade of life. Sickle cell patients can have supranormal proximal tubular function resulting in increased creatinine secretion and hyperphosphatemia. Such patients can also have impaired distal hydrogen ion potassium secretion.
Diminished urinary concentrating ability is one of the early renal involvements in SCD and this is often irreversible after age 10. Less severe, impaired urinary concentrating ability is also seen in patients with SCT, which is a benign carrier condition in which one sickle cell beta globulin gene is inherited along with a normal beta globulin gene.
The prevalence of SCT is as high as 8%-10% in African Americans. Hematuria is common in both patients with SCD and SCT and could be from papillary necrosis, renal infarct, or medullary renal carcinoma, which is seen more often in those with the trait.
Investigation has focused on why MRC behaves so aggressively. Data support that chronic renal medullary hypoxia may play a role in tumorigenesis. Conditions in the renal medulla, including low oxygen tension, high acidity, and high osmolarity, promote sickling of red cells in patients with SCT. Sickled cells conglomerate and occlude capillaries.
This leads to tubular epithelial hypertrophy and hyperproliferation. The nature and extent of mutations in MRC are variable, but the net result is activation of the hypoxia-inducible factor 1 pathway.
Clinical strategies are limited currently to prevention and early detection. Medullary hypoxia in these patients may be lessened with daily bicarbonate supplementation and increased fluid hydration. General screening for MRC would be difficult to justify given the high cost of imaging and the low incidence of disease.
Patient selection for screening plays a clear role. Most young males with SCT have gross hematuria with associated papillary necrosis or hypertrophy.
Cross-sectional imaging with and without contrast is mandatory in these patients as part of their formal hematuria evaluation. It could be argued that these patients be placed on a surveillance protocol involving annual renal US. There is no current data to support that early detection impacts survival of MRC.
Indeed, there are no data that describe outcomes of curative-intent surgery for low-stage localized MRC. Nonetheless, in young patients with SCT and gross hematuria, surveillance seems a prudent course of action.
Matthew Simmons, MD, is in the Department of Urology and Surafel Gebreselassie, MD, is in the Department of Nephrology at the Cleveland Clinic’s Glickman Urological and Kidney Institute.