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.)
4.4 Systemic Diseases and the Kidney
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].
4.5Sickle Cell Disease
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
4.6 Systemic Diseases and the Kidney
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.
4.7Sickle Cell Disease
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.)
4.8 Systemic Diseases and the Kidney
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.)
4.9Sickle Cell Disease
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.)
4.10 Systemic Diseases and the Kidney
1 5 10 50 100 500
Urine arginine vasopressin, pg min–1 C–1A osm
0
400
600
1200
Uri
ne
osm
ola
lity,
mos
mol
/kg
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.
(Continued on next page)
4.11Sickle Cell Disease
385
285 285
1
C
185
385 185
385 185
385 185
385 185
285 185
Urine concentration and dilution: countercurrent multiplier
2 3 4
385
185 285
185
385 185
385 185
385 185
485 285
385 485
385
285
185
385 185
385 185
385 285
585 385
485
285
285
685 485
885 685
1085 885
1285 1085
100
325
550
1000
300
525
750
1200
1200
1200
975
300
525
750
975
1200
300
525
750
975
300
525
750
975
D
285 100
5
285 100
Descendinglimb
Ascendinglimb
Loop of Henle
300
525
750
12001200
975
300
525
750
975
Na+Cl–UreaH2O
H2O
Na+Cl–UreaH2O
Na+Cl–UreaH2O
Na+Cl–
Na+Cl–
Urea
Urea
H2O
H2O
100
325
550
1000
775
285
Collectingduct
Urine
300Urea
525
750
1200
975
300
525
750
1200
975
H2OUrea
H2OUrea
H2OUrea
H2OUrea
ADH
ADH
ADH
ADH
ADH
775
Urine concentration and dilution: countercurrent multiplier
6
FIGURE 4-10 (Continued)
4.12 Systemic Diseases and the Kidney
100
1000120012001200
300
E
Loop of Henle(countercurrent multiplier system)
300
100285
Na+Cl–UreaH2O
325 525525Na+Cl–UreaH2O
550 750750Na+Cl–UreaH2O
775 975975
300
525
750
975Na+Cl–UreaH2O
Na+Cl–Urea
H2O
Vasa recta(countercurrent exchange system)
285 315
300
525
750
975
Na+Cl–UreaH2O
Na+Cl–UreaH2O
Na+Cl–UreaH2O
Na+Cl–UreaH2O
Na+Cl–UreaH2O
Na+Cl–UreaH2O
Na+Cl–UreaH2O
Na+Cl–UreaH2O
Na+Cl–UreaH2O
525
750
1200
975
300
525
750
1200
975
Urine concentration and dilution: countercurrent diffusion (exchange)
F
2
285
300
525
750
975
1200
SoluteH2O
SoluteH2O
SoluteH2O
SoluteH2O
1200 SoluteH2O
300
525
750
975
SoluteH2O
SoluteH2O
SoluteH2O
SoluteH2O
1200SoluteH2O
1
300
525
750
975
Urine concentration and dilution: countercurrent diffusion (exchange)
315285
300
525
750
300
525
750
975
1200
SoluteH2O
SoluteH2O
SoluteH2O
SoluteH2O
SoluteH2O
525
750
975
300
525
750
950
SoluteH2O
SoluteH2O
SoluteH2O
SoluteH2O
1200
FIGURE 4-10 (Continued)
4.13Sickle Cell Disease
400400
Na+Cl–
H2O
Na+Cl–
H2O
Na+Cl–
H2O
Na+Cl–
H2O
Na+Cl–
H2O
Na+Cl–
H2O
Na+Cl–
H2O
Na+Cl–
Na+Cl–H2O
280
280
280
300
325
350
375
300
325
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–
100
125
150
175
280300
325350
375350
325300
375
400
Na+Cl–Na+Cl–
280
280
280
100
100H2O
Na+Cl–
H2O
Urea
H2O Urea
Urea
100%o
f fi ltrate
3 0% of filtrate
20% of filtrate
25%
of filtrate
280
400
Na+Cl–
100
100
100
100
10% offiltrate
100
280
280
280
300
325
350
375
H2O
Na+Cl–
H2O
Na+Cl–
H2O
Na+Cl–
H2O
Urine concentration and dilution: diluting kidney
G
Med
ulla
Co
rtex
280
FIGURE 4-10 (Continued)
4.14 Systemic Diseases and the Kidney
1200 10001200 1200
UreaNa+Cl–
H2O
UreaH2O
UreaNa+Cl–
H2O
UreaNa+Cl–
H2OUrea
Na+Cl–
H2O
UreaNa+Cl–
H2O
UreaNa+Cl–
H2O
UreaNa+Cl–
H2O
UreaNa+Cl–
Na+Cl–H2O
300
525
750
975
300
525
750
975
525
750
975
285
285
25% of filtrate
Na+Cl–
Na+Cl–
UreaNa+Cl–
Na+Cl–
H2O
UreaNa+Cl–
H2O
UreaNa+Cl–
H2O
UreaNa+Cl–
H2O
Na+Cl–
100
325
550
775
225300
525750
975750
525375
975
1200
Na+Cl–Na+Cl–
285
285
285
100
100H2O
Na+Cl–
H2O
Urea
H2O Urea
Urea
100%o
f fi ltrate
3 0% of filtrate
20% of filtrate
25%
of filtrate
285
Na+Cl–
525
750
975
1200
1% offiltrate
285
200
285
285
Na+Cl–
H2OUrea
Na+Cl–
H2OUrea
H2OUrea
Na+Cl–
H2OUrea
Urine concentration and dilution: concentrating kidney
H
Med
ulla
Co
rtex
ADH
ADH
ADH
H2O
H2O
ADH
ADH
ADH
285
FIGURE 4-10 (Continued)
4.15Sickle Cell Disease
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
0
200
400
600
800
1000
1200
1400
Max
imu
m o
smo
lalit
y, m
osm
/kg
H2O
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
4.16 Systemic Diseases and the Kidney
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
5
15
Filt
rati
on
frac
tio
n, %
Uri
ne
osm
ola
lity,
mos
m/k
g H
2OH
emog
lobi
n,%
Hb
cont
ent,
g %
Red blood cell-suspension
175 mL
W.J. 4 y.
CP
AH
, m
L/m
in
500
1000
1500
500
700
900
CIn
ulin
e,
mL/
min
50
200
CC
reat
inin
e,
mL/
min
50
200
5
20
0
100
A S F
Aug.31
Sept.10
Oct.10
Nov.10
Dec.10
Jan20
Feb10
Mar.1
A
20 30 20 30 20 30 3017 20
(Continued on next page)
4.17Sickle Cell Disease
May31
June10 20 30
July10 20 30
Aug.10 20 30
Sept.10
Mar.3
Jan.6
Red blood cell-suspension
350 mL
F.A. 7 y.
10
20
Filt
rati
on
frac
tio
n, %
Uri
ne
osm
ola
lity,
mos
m/k
g H
2OH
emog
lobi
n,%
Hb
cont
ent,
g %
CP
AH
, m
L/m
in
500
1000
1500
700
900
1100
CIn
ulin
e,
mL/
min
50
200
CC
reat
inin
e,
mL/
min
50
200
5
15
0
100
B
A S F
June10 20 30
July10 20 30
Aug.10 20 30
Sept.10 20
Red blood cell-suspension
350 mL
M.V. 11 y.
51015
Filt
rati
on
frac
tio
n, %
Uri
ne
osm
ola
lity,
mos
m/k
g H
2OH
emog
lobi
n,%
Hb
cont
ent,
g %
CP
AH
, m
L/m
in
1000
1500
2000
400
600
800
CIn
ulin
e,
mL/
min
50
200
CC
reat
inin
e,
mL/
min
50
200
5
15
0
100
C
A S F
FIGURE 4-13 (Continued)
4.18 Systemic Diseases and the Kidney
Dec.
'62
29
Feb.
'65
25
Apr.
22 30 20
May
10 20 30
June
10 20 30
July
10 20 30
Aug.
10 20 30
Sept.
10 20 30
Oct.
10 20 30
Nov.
10
Red blood cell-suspension
350 mL
M.K. 15 y.
10
20
Filt
rati
on
frac
tio
n,
%
Uri
ne
osm
ola
lity,
mos
m/k
g H
2OH
emog
lobi
n,%
Hb
cont
ent,
g %
CP
AH
, m
L/m
in
500
1000
1500
400
600
800
CIn
ulin
e,
mL/
min
50
200
CC
reat
inin
e,
mL/
min
50
200
5
15
0
100
D
ASF
May
1 10 20 30
June
10 20 30
July
10 20 30
Aug.
10 20
Red blood cell-suspension
300 mL
A.P. 40 y.
10
20
Filt
rati
on
frac
tio
n,
%
Uri
ne
osm
ola
lity,
mos
m/k
g H
2OH
emog
lobi
n,%
Hb
cont
ent,
g %
CP
AH
, m
L/m
in
500
1000
1500
400
600
800
CIn
ulin
e,
mL/
min
50
200
CC
reat
inin
e,
mL/
min
50
200
5
15
0
100
E
ASF
FIGURE 4-13 (Continued)
4.19Sickle Cell Disease
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.
(Continued on next page)
4.20 Systemic Diseases and the Kidney
B Beaver Rabbit Psammomys
FIGURE 4-15 (Continued)
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].
(Continued on next page)
4.21Sickle Cell Disease
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
FIGURE 4-16 (Continued)
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.)
4.22 Systemic Diseases and the Kidney
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