Sickle Cell Disease - Semantic Scholar · 4 Sickle Cell Disease H errick [1] was the first to discover sickle cell hemoglobin (2 S 2) with sickle-shaped erythrocytes. In 1910, he

4

Sickle Cell Disease

Herrick [1] was the first to discover sickle cell hemoglobin (�2�S

2) with sickle-shaped erythrocytes. In 1910, he describedthe case of a young black student from the West Indies with

severe anemia characterized by “peculiar elongated and sickle-shapedred blood corpuscles.” Herrick also noted a slightly increased volumeof urine of low specific gravity and thus observed the most frequentfeature of sickle cell nephropathy: inability of the kidney to concen-trate urine normally.

L.W. Statius van Eps

C H A P T E R

4.2 Systemic Diseases and the Kidney

Sickle Cell Nephropathy

The term sickle cell nephropathy encompasses all the structuraland functional abnormalities of the kidneys seen in sickle celldisease. These renal defects are most pronounced in homozy-gous sickle cell anemia (Hb SS), double heterozygous sickle cellhemoglobin C disease (Hb SC), sickle cell hemoglobin D dis-

ease, sickle cell hemoglobin E disease (SE) disease, and sicklecell �-thalassemia. Identification of this familial autosomalcodominant disorder as an abnormality of the hemoglobin mol-ecule 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 molecularstructure, “a molecular disease” based on one point mutation. Itis 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 ofsickle cell disease. The structural and functional abnormalities inthe kidneys of patients with sickle cell disease, all resulting fromthat one point mutation, are described and discussed.

When sickle hemoglobin (Hb S) is deoxygenated the replace-ment of �6 glutamic acid with valine has as a consequence ahydrophobic interaction with another hemoglobin molecule(reproduced schematically in Fig. 4-3). One of the two � sub-units forms a hydrophobic contact with an acceptor site on a �subunit of a neighboring � chain. An aggregation into largepolymers is triggered. The twisted ropelike structure to the rightis a polymer composed of 14 strands.

In a concentrated solution of deoxygenated Hb S, large poly-mers 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 asimple crystal solution equilibrium [4].

As a rule, renal hemodynamics are either normal or super-normal in patients with Hb SS and who are less than 30 yearsof age. The filtration fraction (glomerular filtration rate/effec-tive renal plasma flow) has been found to be decreased (mean,14% to 18%; normal, 19% to 22%). It has been suggested thatselective damage of the juxtamedullary glomeruli might resultin a lower filtration fraction because these nephrons appear tohave the highest filtration fractions. Microradioangiographicstudies lend support to this suggestion [5].

Speculation exists as to the possible mechanisms responsi-ble for the decline in renal hemodynamics with age, some-times ending in renal failure with shrunken end-stage kidneys.This decline could be the result of the loss of medullary circu-lation, as suggested by the microradioangiographic studies.Another possible mechanism is the relationship betweensupernormal hemodynamics, hyperfiltration, and glomeru-losclerosis [6].

An inability to achieve maximally concentrated urine hasbeen the most consistent feature of sickle cell nephropathy.

4.3Sickle Cell Disease

C7

C3

C5C3

B11

C5

G9

E7H9

F8

FG3

C

G1

FG4

G2

B14

EB

A

F

G1G

H

F

H'

G'

G'

C'

H'

E' A'

F'

H23

E '

A'

F'

E1CD5

C6

EF1EF

F1

C4

H15

A9

A

BB1

G19 E

D1

G

H

H9

G9

B9

EF

C

C3

C6CD5

E1

E7

FG4F8

FG3

EF1

A1

A12H15

E7

G19

FG4

β2

β1

α2

α1

G3

FG5

FIGURE 4-1

Three-dimensional drawing of a hemoglo-bin molecule. Shown are the interrelation-ship of the two � and two � chains, local-ization of the helices, amino acids in thechains, and iron molecules in the porphyriastructure. Of the �1 and �2 chains the heli-cal and nonhelical segments can be identi-fied easily. The individual amino acids aremarked as circles and connected to eachother. The dark rectangles represent theheme group, and within their center is theiron molecule. These heme groups are local-ized between the E and F helices. The helicesin a hemoglobin molecule are designated byletters from A to H, starting from theamino end. The whole molecule has aspherical form with a three-dimensionalmeasurement of 64 by 55 by 50 Å.(Adapted from Dickerson and Geis [7];with permission.)

Molecular Pathogenic Mechanisms and Sickling

Respiratory Movement of the Hemoglobin Molecule

F'

C

H

G

GH

G'

A

E

F

B

H

GGH

F'

F'

B'

H'

AE

BC

C

F'

B'A'

G'

H'

H

G

GH

A

B

H

GGH

BC

F

D

AE

F

DE

F

Oxyhemoglobin Deoxyhemoglobin

β2

β1

α2

α1

β2

β1

α2

α1

Shift ofβ chains

FIGURE 4-2

Respiratory movement of a hemoglobinmolecule. From a functional point of viewthe so-called respiratory movement of thehemoglobin molecule is of great impor-tance. When the four oxygen atoms bind tooxyhemoglobin, the firmly bound �1-�1and �1-�2 move away from each otherslightly. After full oxygenation the hemegroups of the � chains are 7 Å closer toeach other (R configuration). After deoxy-genation the opposite occurs (T configura-tion). This “respiratory movement” (R indi-cates the relaxed and T the tense configura-tion) is of great importance in ourunderstanding of the pathogenesis of sick-ling: polymerization occurs when the Tconfiguration takes place. (Adapted fromDickerson and Geis [7]; with permission.)


Polymer

O2

Cell

α β

α β

α

α

β

β

α

α

β

α

α

ββ

α

α

β

α

α

β

β

α

α

β

β

α

α

β

β

β

β

FIGURE 4-3

Schematic representation of the interactionsof sickle red cells. Sickle red cells (dark circles)traverse the microcirculation, releasing oxy-gen from oxyhemoglobin, and change intodeoxyhemoglobin (light circles).Deoxygenation of hemoglobin S induces achange in conformation in which the � sub-units move away from each other. Thehydrophobic patch at the site of the �6where the valine replacement has occurred(shown as a projection) can bind to a com-plementary hydrophobic site of the �6 valinereplacement (shown as an indentation). Thismechanism is important for the formation ofa polymer (see Fig. 4-4). The diagram to theright shows the assembly of deoxyhemoglo-bin S into a helical 14-strand fiber: a poly-mer is formed (see Fig. 4-5). As the deoxyhe-moglobin S polymerizes and fibers align, theerythrocyte is transformed into a “sickle”shape, observed at the bottom by scanningelectron micrography. (Adapted from Bunn[4]; with permission).

Nucleation

GrowthAlignment

FIGURE 4-4

Polymerization of sickle cell hemoglobin. This polymerization occurs in three stages: 1)nucleation, 2) fiber growth, and 3) fiber alignment. The end stage is a complicated structurefor a helical fiber: four inner fibers surrounded by 10 outer filaments. Sickling, the process ofpolymerization, occurs under three different circumstances: 1) deoxygenation, 2) acidosis,and 3) extracellular hyperosmolality. These circumstances produce shrinking of the erythro-cytes that causes elevation of the intracellular hemoglobin concentration. This mechanismoccurs in the inner medulla of the kidney and renal papillae as a result of countercurrentmultiplication. Extracellular osmolality increases with the results previously mentioned [8].


Electron Microscopy and Three-Dimensional Reconstruction of a Polymerized Fiber of Hemoglobin

FIGURE 4-5

Structures of polymerized fibers. A, Electron microscopy of a polymerizedfiber of hemoglobin S. B–D, Structures of a three-dimensional reconstructionof such a fiber. Each small sphere represents a Hb S tetramer. B, A completefiber, consisting of 14 grouped filaments in helical structure. C, The innercore of four filaments. D, A combination of inner and outer filaments. (FromEdelstein [9]; with permission.)

Polymerization of Hemoglobin S

FIGURE 4-6

Polymerization of hemoglobin S. Polymerization of deoxygenatedhemoglobin S is the primary event in the molecular pathogenesis ofsickle cell disease, resulting in a distortion of the shape of the erythro-cyte and a marked decrease in its deformability. These rigid cells areresponsible for the vaso-occlusive phenomena that are the hallmark ofthe disease [4]. Interesting shapes of variable forms result depending

on the localization of the polymers in the cell. A collection of electronmicroscopy scans of sickle cells undergoing intracellular polymeriza-tion is shown here. The slides were created in different laboratories. A, Characteristic peripheral blood smear from a patient with sickle cellanemia. Extreme sickled forms and target cells are seen. B, Electronmicroscopy scan of normal erythrocytes.

(Continued on next page)

A B

A B C D


D

G

I J

K L

C E

F

H

FIGURE 4-6 (Continued)

C, Electron microscopy scan of a normalerythrocyte and a sickle cell. D–L, Thisseries of sickle cells show many possibleformations of sickled erythrocytes. Thevariety of shapes results from the intracellu-lar localization of the polymers. In banana-or sickle-shaped cells the polymers haveformed bundles of fibers oriented along thelong axis of the cell. In cells with a holly-leaf shape (panel E), the hemoglobin fiberspoint in different directions.


Types of Sickle Cells and Released Membrane Structures

C D

A B

E

FIGURE 4-7

Types of sickle cells and released membrane structures. Franck andcoworkers [10] reported that the normal membrane phospholipidorganization is altered in sickled erythrocytes. These authors present-ed evidence of enhanced trans-bilayer movement of phosphatidyl-choline in deoxygenated reversibly sickled cells and put forward thehypothesis that these abnormalities in phospholipid organization areconfined to the characteristic protrusions of these cells. Scanningelectron micrographs of various types of sickle cells and releasedmembrane structures are shown. A, Deoxygenated despicular redsickle cells (RSC). B, Deoxygenated native RSC. C, Oxygenated irre-versibly sickled cell. D, Spicules. E, Purified microvesicles. The freespicules released from RSC by repeated sickling and unsickling aswell as the remnant despicular cells were studied by following thefate of 14C-labeled phosphatidylcholine. The results are shown inFigure 4-8. The free spicules have the same lipid composition as dothe native cell but are deficient in spectrin. These spicules markedlyenhance the rate of thrombin and prothrombin formation, explain-ing the prethrombotic state of the patient with sickle cell disease andthe tendency toward the occurrence of crises. The prethromboticstate, also present in the renal circulation, stimulates sickle cell for-mation occurring in the inner renal medulla and papillae wherehyperosmosis also contributes to sickling and microthrombi formationin the vasa recta. (From Franck and coworkers. [10]; with permission.)


Penetration and Deconstruction of the Erythrocyte Membrane

A

Spicule formation in sickled erythrocyte

B

Spicule formation insickled erythrocyte

Band 3 Spectrin AnkyrinActin Band 4.1

C

FIGURE 4-8

Penetration and destruction of the erythrocyte membrane. A, Themembrane is penetrated and destroyed by the intracellular forma-tion of polymers, resulting in spicule formation. B, Interruptionof the binding between the membrane and protein skeletonresults in a massive exchange of lipids between the inside andoutside of the cell. This process is called flip-flop. An abnormalmembrane skeleton causes an increased flip-flop. The result in thespicule is a change of the chemical structure, increasing the ten-dency toward coagulation of sickle cell blood (prethromboticstate). C, The relationship between the protein skeleton of theerythrocyte and lipid membrane is shown. (Adapted from Franck[11]; with permission.)


B

D

E

A

C

FIGURE 4-9

Macroscopy and microradioangiographs of sickle cell kidneys. The kidneys of patients with sickle cell disease usuallyare of near normal size, and most kidneys show no significant gross alterations. Abnormalities can be expected in therenal medulla as erythrocytes form sickles more readily in the relatively hypoxic and hyperosmotic renal medulla than inother capillary circulations. Formation of microthrombi causes further impairment of the vasa recta circulation. A andB, Injection microradioangiographs of the kidney in a person without hemoglobinopathy are shown: the entire kidney(panel A) and a detailed view (panel B). C and D, Injection microradioangiographs of the kidney in a patient with sicklecell disease are shown: the entire kidney (panel C) and a detailed view (panel D). E, Injection microradioangiograph of akidney in a patient with sickle cell hemoglobin C disease . In the normal kidney (panel A), vasa recta are visible radiat-ing into the renal papilla. In sickle cell anemia (panel D), vasa recta are virtually absent. Those vessels that are presentshow abnormalities: they are dilated, form spirals, end bluntly, and many appear to be obliterated. In the patient withhemoglobin SC (panel E) changes are seen intermediately between patients with hemoglobin SC and normal persons.(From van Eps et al. [5]; with permission.)


1 5 10 50 100 500

Urine arginine vasopressin, pg min–1 C–1A osm

0

400

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Uri

ne

osm

ola

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mos

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Renal Concentrating Mechanism in a Normal Person

B

Med

ulla

Co

rtex

Thinsegment

Vasarecta

Juxtamedullary nephron

FIGURE 4-10

A–H, Models to demonstrate the principle of countercurrent multi-plier in creating high urine concentration. The first panel illustratesthe relation between urine osmolality and arginine vasopressinexcretion. The long loops of Henle and their accompanying vasarecta reaching the papillae comprise only 15% of the total nephronpopulation but are necessary for producing concentrated urine[12]. As seen, the mechanisms of countercurrent multiplication andcountercurrent exchange create an increase in osmolality in thekidney from 280 mOsm at the cortex to about 1200 mOsm/kgH2O in the inner medulla and papillae. Reabsorption in the collect-ing ducts results in production of highly concentrated urine.



385

285 285

1

C

185

385 185

385 185

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Urine concentration and dilution: countercurrent multiplier

2 3 4

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185

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385 485

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Urea

H2O

H2O

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Urine

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Urine concentration and dilution: countercurrent multiplier

6



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100285

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775 975975

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Na+Cl–UreaH2O

Na+Cl–UreaH2O

Na+Cl–UreaH2O

Na+Cl–UreaH2O

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Na+Cl–UreaH2O

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SoluteH2O

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Urine concentration and dilution: countercurrent diffusion (exchange)

315285

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H2O

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H2O

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H2O

Na+Cl–

H2O

Na+Cl–

H2O

Na+Cl–

H2O

Na+Cl–

H2O

Na+Cl–

Na+Cl–H2O

280

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300

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350

375

20% of filtrate

Na+Cl–

Na+Cl–

Na+Cl–Na+Cl–

H2O

Na+Cl–H2O

Na+Cl–H2O

Na+Cl–H2O

Na+Cl–H2O

Na+Cl–

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100H2O

Na+Cl–

H2O

Urea

H2O Urea

Urea

100%o

f fi ltrate

3 0% of filtrate

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of filtrate

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Urine concentration and dilution: diluting kidney

G

Med

ulla

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rtex

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1200 10001200 1200

UreaNa+Cl–

H2O

UreaH2O

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H2O

UreaNa+Cl–

Na+Cl–H2O

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Na+Cl–

Na+Cl–

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H2O

UreaNa+Cl–

H2O

UreaNa+Cl–

H2O

UreaNa+Cl–

H2O

Na+Cl–

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325

550

775

225300

525750

975750

525375

975

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Na+Cl–Na+Cl–

285

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H2O

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f fi ltrate

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Urine concentration and dilution: concentrating kidney

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Hemoglobin AA AS SS SC ACo CCo

0 20 40 60 0 20 40 60 0 20 40 60 0 20 40 60 800 20 40 60

Age, y

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imu

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heterozygotous hemoglobin disease (Hb AS),sickle cell hemoglobin C disease (SC), hemo-globin C trait (AC), and hemoglobin C disease(Hb CC). Normal persons have a mean maxi-mal urinary osmolality of 1058 ±SD 128mOsm/kg H2O. The most marked impairmentin concentrating capacity occurs in Hb SS dis-ease. Maximal urinary osmolality decreasessignificantly in the first decade of life and sta-bilizes in patients over 10 years of age at amean of 434 ±SD 21 mOsm/kg H2O. Themeasurement has been designated the fixedmaximum of sickle cell nephropathy. Inpatients with Hb AS and Hb SC, a progressivedecrease in maximal urinary osmolality can beobserved with age. C hemoglobin alone (ACor CC) does not impair the concentrating abil-ity of the kidneys. The renal concentratingcapacity of the heterozygote (Hb AS) also isaffected, but only later in life. (Adapted fromvan Eps et al. [13]; with permission.)

FIGURE 4-11

Relationship between maximal urinary osmolality and age in normal subjects and in patientswith hemoglobinopathies. Results of an investigation into a large group of normal persons andthose with homozygotous hemoglobin disease (Hb SS; Hb SS + Hb F),

Relationship Between Nephron with Long Loops and Those with Short Loops of Henle

Cortex

Subcortex

Outer medulla

Inner medulla

FIGURE 4-12

Relationship between nephron with long loops and those with shortloops of Henle. In the normal human kidney, approximately 85% ofthe nephrons have short loops of Henle restricted to the outermedullary zone. These nephrons may be largely responsible for achiev-ing the interstitial osmolality of about 450 mOsm/kg H2O that exists atthe transition of the outer and inner medulla. The remaining 15% ofhuman nephrons are juxtamedullary nephrons with long loops ofHenle, extending into the inner medullary zone and renal papillae.Together with the parallel hairpin vasa recta, these units are responsiblefor further increasing interstitial osmolality during antidiuresis to about1200 mOsm/kg H2O at the tip of the papillae. In experiments withrats, selectively removing the papillae destroys only nephrons originat-ing in the juxtamedullary cortex. In such animal preparations, a severeloss of concentrating capacity during fluid deprivation has beenobserved. Thus, juxtamedullary nephrons are necessary for achieving amaximal urine osmolality. These pathophysiologic mechanisms helpclarify the abnormal findings in sickle cell nephropathy. On the basis ofthese mechanisms, the concentrating defect in sickle cell disease can beexplained as a consequence of the sickling process per se and the resul-tant ischemic changes in the medullary microcirculation [5]. It has beendemonstrated that Hb SS erythrocytes form sickle erythrocytes withinseconds when placed in surroundings as hyperosmotic as is the renalmedulla during hydropenia [8]. Sickling of renal blood cells causes asignificant increase in blood viscosity that could interfere with the nor-mal circulation through the vasa recta, preventing both active and pas-sive accumulation of solute in the papillae necessary to achieve maxi-mally concentrated urine. Increased viscosity of blood and intravascularaggregations of Hb SS erythrocytes could also produce local hypoxiaand eventually infarction of the renal papillae.

Relationship Between Maximal Urinary Osmolality and Age


FIGURE 4-13

A–E, Relationship between concentratingcapacity and patient age. Over a prolongedperiod, we investigated the effect of multi-ple transfusions of hemoglobin A erythro-cytes into children and adults with sicklecell anemia (4, 7, 11, 15, and 40 years). Inthe first panel, the effects of multiple trans-fusions of normal blood given to a 4-year-old boy with homozygotic sickle cell ane-mia. A significant improvement in concen-trating capacity can be observed. Thisdiminishes in older patients.

Relationship Between Concentrating Capacity and Patient Age

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min

50

200

CC

reat

inin

e,

mL/

min

50

200

5

15

0

100

E

ASF



Relationship Between Age and Ability to Reverse the Defect in Urinary Concentration by Blood Transfusions

0

B

A

10 20 30 40 50

Time, y

0

20

40

60

80

100

Incr

ease

in m

axim

al u

rin

ary

osm

ola

lity,

%M

axim

al u

rin

ary

osm

ola

lity,

mos

m

200

500

800

1100 8 patients; van Eps [12]

6 patients; Keitel [13]

FIGURE 4-14

Relationship between age and ability to reverse the defect in urinary concentration byblood transfusions in patients with sickle cell disease. A, The maximal urinary osmolalityachieved before transfusion (lower point of each vertical line) and after multiple transfu-sions with normal blood (upper point of each vertical line) in 14 patients with sickle celldisease, ranging in age from 2 to 40 years. B, The percentage of increase in maximal uri-nary osmolality resulting from transfusion. Maximal urinary osmolality before transfusionis depressed at all ages; significant improvement after transfusion occurs only in childrenand adolescents. (From van Eps et al. [13]; with permission.)

Sickle cell trait:Progressive loss in 70 y of inner medullary concentrating function

Sickle cell anemia:A. Up to about 15 y: reversible concentrating defectB. Over 15 y: complete and irreversible loss of inner medullary concentrating function

Cortex Medulla

Normal kidney14% juxtamedullary

nephrons with long loops

Ou

ter

Inn

erzo

ne

Sickle cell kidneyBeaver kidney

Long loops of Henlenot functioning

or absent

A

Length of the Loops of Henle in Animals Correlated with Kidney Concentrating Capacity

FIGURE 4-15

Length of the loops of Henle in animalscorrelated with kidney concentrating capac-ity. A, Investigations of animal species [14]with different lengths of the loops of Henleand correlation with the concentratingcapacity of their kidneys reveal their rela-tionship. B, Desert animals with very longloops of Henle can produce highly concen-trated urine; in contrast, beavers living inwater-rich surroundings have only shortloops of Henle and cannot produce urineconcentrate over 450 mOsm.



B Beaver Rabbit Psammomys


In sickle cell disease the long loop of Henle has been obliteratedand the concentrating capacity of the kidney is not higher than

400 mosm, much as in beavers. An overview has been reproduced.(From van Eps and De Jong [15]; with permission.)

Urinary Acidification

72

73

74

75

Blo

od

pH

2 4 6 8 10

Time, hA

4.0

5.0

6.0

7.0

2 4 6 8 10

Time, h

Uri

nar

y p

H

Ammonium chloride Ammonium chloride

Ammonium chloride Ammonium chloride

2 4 6 8 10

SS Anemia

10

30

50

70

90

10

30

50

70

NH

4+, µ

-equ

iv/m

in/1

.73

m2

T.A

., µ-

equi

v/m

in/1

.73

m2

2 4 6 8 10

FIGURE 4-16

A, Urinary acidification. Patients withhemoglobin SS or SC demonstrate anincomplete form of renal tubular acidosis.In response to a short-duration acid load,all of the patients studied by Goossens andcoworkers [16] with otherwise normal renalfunction were unable to decrease urine pHbelow 5.3, whereas normal persons achievea urinary pH of 5.0 or lower. Titrateableacid (TA) and total hydrogen ion excretionare lower in patients with Hb SS or Hb SC;however, in most cases, ammonia excretionis appropriate for the coexisting urine pH.The acidification defect has been classifiedas distal rather than proximal, because noassociated wasting of bicarbonate occurs,and the acidification defect is characterizedby failure to achieve a normal minimal uri-nary pH during acid loading. Investigatorsfrom several centers have found no evi-dence of metabolic acidosis in the absenceof a sickle cell crisis; however, they havefound changes consistent with mild chronicrespiratory alkalosis [15].



4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 6.0

Minimal urinary pHB

400

600

800

1000

1200

Max

imal

uri

nar

y o

smo

lalit

y

Normals

AS

SC

SS


B, Relationship between renal concentrating and acidifying capacityin Hb AS, SC, and SS and in normal persons [16].

Tubular Reabsorption of Phosphate in Sickle Cell Nephropathy

0 1 2 3 4 5 6 7 8

Phosphate, mg/100 mL

0 1.00

0.90

0.80

0.70

0.60

0.50

0.10

0.20

0.30

0.40

0.50

UV

/L

T.R

.P.

Tm

P/GFR 2.5–4.2

+

+

FIGURE 4-17

Relationship between Cp/glomerular filtration rate and serum phos-phate. Closed circles represent values for patients who had fastedfrom food and drink; open circles are values obtained when UpVwas 0.032 mmol/min. The continuous line shows the mean of thevalues in patients with sickle cell anemia, and the hatched areaindicates the range for normal persons. Cp—clearance of phos-phate; TmP/GFR—tubular maximum reabsorption of phosphate/glomerular filtration rate. (Adapted from De Jong and coworkers[17]; with permission.)


15–24 25–34 35–44 45–54 15–24 25–34 35–44 45–54

Male Female

Age, y

60

80

100

120

140

160

180

mm

Hg

<0.01 <0.01 ns ns <0.02 <0.05 <0.05

ns ns

Dia

sto

licSy

sto

lic

ns ns <0.05 <0.01 ns

P

P

1. Herrick JB: Peculiar elongated and sickle shaped red blood corpusclesin a case of severe anemia. Arch Intern Med 1910, 6:517.

2. Pauling L, et al.: Sickling cell anemia, molecular disease. Science 1949,110:543.

3. Ingram VM: Gene mutations in human hemoglobin: the chemical difference between normal and sickle cell hemoglobin. Nature 1959,180:326.

4. Bunn HF: Mechanisms of disease: pathogenesis and treatment of sick-le cell disease. N Engl J Med 1997, 337:762–769.

5. Statius van Eps LW, Pinedo Veels C, De Vries H, De Koning J: Natureof concentrating defect in sickle cell nephropathy, microradioangio-graphic studies. Lancet 1970, 1:450.

6. Hostetter TH, et al.: Hyperfiltration in remnant nephrons: a potential-ly adverse response to renal ablation. Am J Physiol 1981, 241:F85.

7. Dickerson RE, Geis I: The Structure and Action of Proteins. NewYork: Harper and Row, 1969, 1971.

8. Perillie PE, Epstein, FH: Sickling phenomenon produced by hyperton-ic solutions: a possible explanation for the hyposthenuria of sicklemia.J Clin Invest 1963, 42:570.

9. Edelstein SJ: Structure of the fibers of hemoglobin S: human hemoglo-bins and hemoglobinopathies: a review to 1981. Galveston: Universityof Texas; 1981.

10. Franck PF, Bevers EM, Lubin BH, et al.: Uncoupling of the membraneskeleton from the lipid bilayer: the cause of accelerated phospholipidflip-flop leading to an enhanced procoagulant activity of sickled cells.J Clin Invest 1985, 75:183–190.

11. Frank PFH: Studies on the phospolid organization in membranes ofabnormal erythrocytes [PhD thesis]. Utrecht: State University ofUtrecht; 1984.

12. Statius van Eps LW, Schouten H, Ter Haar Romeny Wachter CCh, laPorte-Wijsman LW: The relation between age and renal concentratingcapacity in sickle cell disease and hemoglobin C disease. Clin ChimActa 1970, 27:501.

13. Statius van Eps LW, Schouten H, la Porte-Wijsman LW, StruykerBoudier AM: The influence of red blood cell transfusions on thehyposthenuria and renal hemodynamics of sickle cell anemia. ClinChim Acta 1967, 17:449.

14. Schmidt-Nielsen B, O’Dell R: Structure and concentrating mechanismin the mammalian kidney. Am J Physiol 1961, 200:1119.

15. Keitel HG, et al.: Hyposthenuria in sickle cell anemia: a reversiblerenal defect. J Clin Invest 1956, 35:998.

16. Statius van Eps LW, De Jong PE: Sickle cell disease. In Diseases of theKidney, edn 6. Edited by Schrier RW, Gottschalk CW. Boston: Little,Brown; 1997:2201.

17. Goossens JP, Statius van Eps LW, Schouten H, Gieterson AL:Incomplete renal tubular acidosis in sickle cell disease. Clin ChimActa 1972, 41:149.

18. De Jong PE, et al.: The tubular reabsorption of phosphate in sicklecell nephropathy. Clin Sci 1978, 55:429.

19. De Jong PE, Landman H, Statius van Eps LW: Blood pressure in sicklecell disease. Arch Intern Med 1982, 142:1239.

20. De Jong PE, Statius van Eps LW: Sickle cell nephropathy: new insightsinto its pathophysiology. Editorial review. Kidney Int 1985, 27:711.

Blood Pressure in Sickle Cell Disease

FIGURE 4-18

Blood pressure and sickle cell anemia. Mean standard deviation ofsystolic and diastolic blood pressure in control subjects (dottedlines) and patients with sickle cell anemia (closed lines) who arematched for age and gender. (From De Jong and van Eps [20].)

References

Documents

Sickle Cell Disease - Semantic Scholar · 4 Sickle Cell Disease H errick [1] was the first to discover sickle cell hemoglobin (2 S 2) with sickle-shaped erythrocytes. In 1910, he