Sickle Cell Nephropathy

Herrick [1] was the first to discover sickle cell hemoglobin ( 2 2) with sickle-shaped erythrocytes. In 1910, he described the case of a young black student from the West Indies with severe anemia characterized by “peculiar elongated and sickle-shaped red blood corpuscles.” Herrick also noted a slightly increased volume of urine of low specific gravity and thus observed the most frequent feature of sickle cell nephropathy: inability of the kidney to concentrate urine normally. L.W. Statius van Eps


Sickle Cell Nephropathy
The term sickle cell nephropathy encompasses all the structural and functional abnormalities of the kidneys seen in sickle cell disease.These renal defects are most pronounced in homozygous sickle cell anemia (Hb SS), double heterozygous sickle cell hemoglobin C disease (Hb SC), sickle cell hemoglobin D dis-ease, sickle cell hemoglobin E disease (SE) disease, and sickle cell ␤-thalassemia.Identification of this familial autosomal codominant disorder as an abnormality of the hemoglobin molecule was made in 1949 by Pauling and coworkers [2].

Sickle Cell Anemia
In 1959, Ingram [3] discovered the exact nature of the defect: substitution of valine for glutamic acid at the sixth residue of the ␤ chain, establishing sickle cell anemia as a disease of molecular structure, "a molecular disease" based on one point mutation.It is most fascinating that one substitution in the gene encoding, with the resulting replacement of ␤ 6 glutamic acid by valine, leads to the protean and devastating clinical manifestations of sickle cell disease.The structural and functional abnormalities in the kidneys of patients with sickle cell disease, all resulting from that one point mutation, are described and discussed.
When sickle hemoglobin (Hb S) is deoxygenated the replacement of ␤ 6 glutamic acid with valine has as a consequence a hydrophobic interaction with another hemoglobin molecule (reproduced schematically in Fig. 4-3).One of the two ␤ subunits forms a hydrophobic contact with an acceptor site on a ␤ subunit of a neighboring ␤ chain.An aggregation into large polymers is triggered.The twisted ropelike structure to the right is a polymer composed of 14 strands.
In a concentrated solution of deoxygenated Hb S, large polymers and free tetramers are demonstrated readily.However, species of intermediate size cannot be detected.This means polymerization of Hb S occurs easily and can be regarded as a simple crystal solution equilibrium [4].
As a rule, renal hemodynamics are either normal or supernormal in patients with Hb SS and who are less than 30 years of age.The filtration fraction (glomerular filtration rate/effective renal plasma flow) has been found to be decreased (mean, 14% to 18%; normal, 19% to 22%).It has been suggested that selective damage of the juxtamedullary glomeruli might result in a lower filtration fraction because these nephrons appear to have the highest filtration fractions.Microradioangiographic studies lend support to this suggestion [5].
Speculation exists as to the possible mechanisms responsible for the decline in renal hemodynamics with age, sometimes ending in renal failure with shrunken end-stage kidneys.This decline could be the result of the loss of medullary circulation, as suggested by the microradioangiographic studies.Another possible mechanism is the relationship between supernormal hemodynamics, hyperfiltration, and glomerulosclerosis [6].
An inability to achieve maximally concentrated urine has been the most consistent feature of sickle cell nephropathy.

4.3
Respiratory movement of a hemoglobin molecule.From a functional point of view the so-called respiratory movement of the hemoglobin molecule is of great importance.When the four oxygen atoms bind to oxyhemoglobin, the firmly bound ␣ 1 -␤ 1 and ␣ 1 -␤ 2 move away from each other slightly.After full oxygenation the heme groups of the ␤ chains are 7 Å closer to each other (R configuration).After deoxygenation the opposite occurs (T configuration).This "respiratory movement" (R indicates the relaxed and T the tense configuration) is of great importance in our understanding of the pathogenesis of sickling: polymerization occurs when the T configuration takes place.(Adapted from Dickerson and Geis [7]; with permission.) FIGURE 4-1 Three-dimensional drawing of a hemoglobin molecule.Shown are the interrelationship of the two ␣ and two ␤ chains, localization of the helices, amino acids in the chains, and iron molecules in the porphyria structure.Of the ␣ 1 and ␤ 2 chains the helical and nonhelical segments can be identified easily.The individual amino acids are marked as circles and connected to each other.The dark rectangles represent the heme group, and within their center is the iron molecule.These heme groups are localized between the E and F helices.The helices in a hemoglobin molecule are designated by letters from A to H, starting from the amino end.The whole molecule has a spherical form with a three-dimensional measurement of 64 by 55 by 50 Å.(Adapted from Dickerson and Geis [7]; with permission.)