1. THE KIDNEY IN SICKLETHE KIDNEY IN SICKLE
CELL DISEASECELL DISEASE
2. SICKLE CELL ANEMIASICKLE CELL ANEMIA
Genetic defect of Hb polymerization resulting in RBCGenetic defect of Hb polymerization resulting in RBC
deformation when deoxygenateddeformation when deoxygenated
ROBERT HERRICK (1910) – first description of clinicalROBERT HERRICK (1910) – first description of clinical
findings and red cell morphology (including urinaryfindings and red cell morphology (including urinary
sediments and low urine specific gravity)sediments and low urine specific gravity)
SYDENSTRICKER ET AL. (1923) - first to report autopsySYDENSTRICKER ET AL. (1923) - first to report autopsy
evidence of gross and microscopic renal alterationsevidence of gross and microscopic renal alterations
LINUS PAULING (1949)– SCD due to abnormal hemoglobinLINUS PAULING (1949)– SCD due to abnormal hemoglobin
moleculemolecule
INGRAM (1956) - b-chain of the sickle cell globin moleculeINGRAM (1956) - b-chain of the sickle cell globin molecule
differed by substitution of valine for glutamic acid at thediffered by substitution of valine for glutamic acid at the
sixth residuesixth residue
Hb S geneHb S gene
– Homozygous – sickle cell anemiaHomozygous – sickle cell anemia
3.
4. Worldwide distribution of the Hb S genotype and the reservoirs of
falciparum malaria infection show striking congruence.
Restriction enzyme techniques have allowed identification of five major
bS haplotypes,
Benin,
Bantu (formerly Central African Republic or CAR),
Senegal,
Cameroon, and
Arab–Indian ( It is the most common haplotype of the tribal peoples of
India)
5. EpidemiologyEpidemiology
25% babies in the West Africa carry25% babies in the West Africa carry
the gene, compared to 8 % of Afro-the gene, compared to 8 % of Afro-
AmericansAmericans
1 in 600 Afro-Americans are1 in 600 Afro-Americans are
homozygoushomozygous
Clinical manifestations in AfricanClinical manifestations in African
homozygotes are more severe thanhomozygotes are more severe than
those in Asian or New Worldthose in Asian or New World
populations.populations.
The Bantu haplotype is mostThe Bantu haplotype is most
associated with severe organ failureassociated with severe organ failure
syndromes, including chronic renalsyndromes, including chronic renal
failurefailure
6.
7. SCD – NATURAL HISTORYSCD – NATURAL HISTORY
childhood – steady statechildhood – steady state
Severe anaemia is the rule in homozygotes
Sickle cell anaemia Hb - >=80 % is HbS, rest
being HbF
Normocytic red blood cell indices
Chronic, low-grade haemolysis - reticulocytosis
of up to 20% - RBC survival of about 30 days
9. SCD – NATURAL HISTORYSCD – NATURAL HISTORY
Childhood- Immune defectsChildhood- Immune defects
Splenic infarction – functional asplenia –
predisposition to severe pneumococcal infection
and sepsis
Other abnormalities include
low circulating levels of IgM,
chronic activation of the complement
system,
a deficiency of tuftsin, a splenic derived
cytokine which activates granulocytes,
monocytes, and tissue macrophages
Common bacterial infections and intermittent
low-grade bacteraemias are life threatening.
The greatest risk of death occurs between the
ages of 1 and 3 years, with pneumococcal
sepsis, being the single most common cause of
death
10. Micro-organism Type of infection Comments
Streptococcus pneumoniae Septicaemia Common despite prophylactic
penicillin and pneumococcal vaccine
Meningitis Less frequent than in years past
Pneumonia Rarely documented except in infants and
young children
Septic arthritis Uncommon
Haemophilus influenzae, Septicaemia, meningitis,
pneumonia
Much less common in recent years
because of immunization with
conjugate vaccine
Salmonella species Osteomyelitis,
septicaemia
Most common cause of bone and
joint infection
Escherichia coli and other
Gram-negative enteric pathogens
Septicaemia,
urinary tract infection,
osteomyelitis
Focus sometimes inapparent
Staphylococcus aureus Osteomyelitis Uncommon
Mycoplasma pneumonia Pneumonia Pleural effusions; multilobe involvement
Chlamydia pneumonia Pneumonia
Parvovirus B19 Bone marrow suppression
(aplastic crisis)
High fever common; rash and other
organ involvement infrequent
Hepatitis viruses (A, B, and C) Hepatitis Marked hyperbilirubinaemia
11. SCD – NATURAL HISTORYSCD – NATURAL HISTORY
Childhood – vaso-occlusiveChildhood – vaso-occlusive
complicationscomplications
Commonly affect bone, muscle, brain, lungs,
spleen, kidneys, and bone marrow
Common sequelae include
aseptic necrosis of bone – hand foot syndrome
rhabdomyolysis,
Stroke –before 3rd
year of life (6%)
Splenic infarction – auto splenectomy
renal infarction
the acute chest syndrome – pulmonary vaso-
occlusion
priapism
12. SCD – NATURAL HISTORY –SCD – NATURAL HISTORY –
The adult patientThe adult patient
Painful and hemolytic crisis continue
Thrombotic cerebral infarctions less common
Bone - Progressive osteonecrosis
Recurrent acute chest syndrome- cor pulmonale
Renal - haematuria, papillary necrosis, nephrotic
syndrome, and chronic renal failure
Liver - transfusional iron overload, viral hepatitis,
hepatic infarction, hepatic sequestration, or
gallstone-associated cholangitis.
Others - Acute gouty arthritis, chronic skin ulcers,
most characteristically over the malleolar areas,
cardiomyopathy, and retinal neovascularization
with haemorrhage
13. The frequency of major organ failure in sickle cell anaemiaThe frequency of major organ failure in sickle cell anaemia
patientspatients. (Reprinted from Powars (1994). (Reprinted from Powars (1994)
14. Epidemiology of RenalEpidemiology of Renal
involvement in SCDinvolvement in SCD
26% of SCD patients have proteinuria26% of SCD patients have proteinuria
while 5-18% have renal failurewhile 5-18% have renal failure
Renal failure is the major risk factorRenal failure is the major risk factor
for early mortality in adult SCDfor early mortality in adult SCD
patientspatients
30% of patients who die early of SCD30% of patients who die early of SCD
have chronic renal failurehave chronic renal failure
Proteinuria, hypertension, severeProteinuria, hypertension, severe
anemia and hematuria are predictorsanemia and hematuria are predictors
of renal failureof renal failure
16. Epidemiology contd…Epidemiology contd…
Clinical heterogenity inClinical heterogenity in
manifestations is due to:manifestations is due to:
Fetal Hb levelsFetal Hb levels
2,3-DPG levels2,3-DPG levels
Linked mutationsLinked mutations
ββs-haplotypess-haplotypes
Coexistence ofCoexistence of αα-Thalassemia-Thalassemia
Environmental factorsEnvironmental factors
18. Pathophysiology contd…Pathophysiology contd…
Basic defect is the polymerization ofBasic defect is the polymerization of
deoxygenated Hb Sdeoxygenated Hb S
HbS undergo a spatial molecularHbS undergo a spatial molecular
rearrangement leading to chain-likerearrangement leading to chain-like
formations.formations.
This process changes the shape of theThis process changes the shape of the
normally biconcave RBCs to sickle shapenormally biconcave RBCs to sickle shape
This imparts rigidity to the distorted redThis imparts rigidity to the distorted red
blood cell, making it likely to occludeblood cell, making it likely to occlude
small vesselssmall vessels
Slowing of passage of RBCs potentiatesSlowing of passage of RBCs potentiates
this processthis process
19.
20.
21.
22.
23. Pathophysiology contdPathophysiology contd……
SCD RBC Hb has increased auto- oxidation
resulting in increased generation of superoxide,
peroxide, hydroxyl and lipid peroxidation
products.
The oxidized Hb gets irreversibly precipitated as
Heinz Bodies and the iron is in the ferric
statewhich further initiates lipid peroxidation
Reactive species will divert vasoactive nitric oxide
from mechanisms of vascular relaxation to agents
of inflammation and constriction
Superoxide combines with NO to formSuperoxide combines with NO to form
peroxynitritesperoxynitrites induces the enzyme NO synthaseinduces the enzyme NO synthase
in the tubular epithelial cellsin the tubular epithelial cells induce apoptosisinduce apoptosis
24. PathophysiologyPathophysiology
Chronic sickling underlies severalChronic sickling underlies several
mechanisms for kidney injurymechanisms for kidney injury
Sickling promoted in vasa rectae by:Sickling promoted in vasa rectae by:
– Postglomerular arteriolar vasculature has lowPostglomerular arteriolar vasculature has low
oxygen tensionoxygen tension
– Medullary hypertonicityMedullary hypertonicity
– Acidic environment in the medullaAcidic environment in the medulla
Increase in blood viscosityIncrease in blood viscosity
Venous engorgementVenous engorgement
Interstitial edemaInterstitial edema
Predispostion of renal microcirculation toPredispostion of renal microcirculation to
edema and infarctionedema and infarction
25. Pathophysiology –Renal involvementPathophysiology –Renal involvement
Renal hypertrophy in the setting of prominentRenal hypertrophy in the setting of prominent
hemodynamic and vascular alterationshemodynamic and vascular alterations
Hematuria may be due to sickling in the vasa rectaHematuria may be due to sickling in the vasa recta
stasis and ischemiastasis and ischemia extravasation of blood into theextravasation of blood into the
renal parenchyma and collecting system, or in somerenal parenchyma and collecting system, or in some
cases to micropapillary or macropapillary necrosiscases to micropapillary or macropapillary necrosis
Cortical circulation – increased GFR and RPF ;Cortical circulation – increased GFR and RPF ;
Medullary perfusion diminished by vaso-occlusiveMedullary perfusion diminished by vaso-occlusive
diseasedisease increases the vasoactive PGs which furtherincreases the vasoactive PGs which further
increase the RPF and GFRincrease the RPF and GFR
Due to distal vaso-occlusion and efferent arteriolarDue to distal vaso-occlusion and efferent arteriolar
vaso-constriction, the intraglomerular pressure goesvaso-constriction, the intraglomerular pressure goes
up and this results in hyperfiltration,up and this results in hyperfiltration,
glomerulomegaly and FSGS.glomerulomegaly and FSGS.
Increased NO synthase induction accentuates theIncreased NO synthase induction accentuates the
GFR elevationGFR elevation
26. Pathophysiology –RenalPathophysiology –Renal
involvement contd..involvement contd..
Direct endothelial damage + hyperfiltrationDirect endothelial damage + hyperfiltration
endothelial hyperplasia and Interstitial fibrosisendothelial hyperplasia and Interstitial fibrosis
efferent glomerular capillary obstructionefferent glomerular capillary obstruction
intraglomerular pressure further goes upintraglomerular pressure further goes up
progressive reactive sclerosisprogressive reactive sclerosis
Medullary fibrosis >> cortical fibrosisMedullary fibrosis >> cortical fibrosis
juxtamedullary nephrons are most affected byjuxtamedullary nephrons are most affected by
FSGSFSGS
Collapsing pattern of FSGS due to capillaryCollapsing pattern of FSGS due to capillary
collapse secondary to sickling and ischemiacollapse secondary to sickling and ischemia
whereas expansive form is due to mesangialwhereas expansive form is due to mesangial
reaction to capillary collapsereaction to capillary collapse
27.
28. Injection micrograph of kidneys from:Injection micrograph of kidneys from:
A- patient with no hemoglobinopathyA- patient with no hemoglobinopathy – dense uniform cortical– dense uniform cortical
vasculature and normal vasa rectaevasculature and normal vasa rectae
B- Sickle cell traitB- Sickle cell trait – cortical vasculature decreased and vasa rectae– cortical vasculature decreased and vasa rectae
attenuated and distortedattenuated and distorted
C- Sickle cell diseaseC- Sickle cell disease – cortical vasculature markedly decreased and– cortical vasculature markedly decreased and
vasa rectae virtually abent.vasa rectae virtually abent.
29. Sickle cell crisis results from sickling particularly within vasa recta within
the kidney, as seen in this case of a patient who died in sickle cell crisis.
Glomeruli are occluded by sickled cells, and there is extensive congestion
and sickling in peritubular capillaries (Hematoxylin and eosin, X100).
30. Marked congestion filling up capillary loopsMarked congestion filling up capillary loops is evidentis evident
in this case of sickle cell crisis, with occasional sickledin this case of sickle cell crisis, with occasional sickled
RBCs discernible (right) (Hematoxylin and eosin, X400).RBCs discernible (right) (Hematoxylin and eosin, X400).
31. Marked sickling in vasa rectaMarked sickling in vasa recta is illustrated in this patientis illustrated in this patient
who died in acute sickle cell crisis (Hematoxylin andwho died in acute sickle cell crisis (Hematoxylin and
eosin, X400).eosin, X400).
32.
33. Pathophysiology –RenalPathophysiology –Renal
involvement contd..involvement contd..
Anemia potentiates glomerulomegalyAnemia potentiates glomerulomegaly
Iron deposition in tubular cells due to ironIron deposition in tubular cells due to iron
overload may have additional role in theoverload may have additional role in the
chronic nephropathy of SCDchronic nephropathy of SCD
Parvovirus infection in SCD patients not onlyParvovirus infection in SCD patients not only
causes aplastic crises but also acceleratecauses aplastic crises but also accelerate
renal diseaserenal disease
Uric acid nephropathy also can contribute toUric acid nephropathy also can contribute to
some renal damagesome renal damage
34. Pathophysiology –RenalPathophysiology –Renal
involvement contd..involvement contd..
Tubular damage results in mild acidification andTubular damage results in mild acidification and
potassium secreting defectpotassium secreting defect
H+ and K+ ion secretion is by intercalated duct cellsH+ and K+ ion secretion is by intercalated duct cells
seen predominantly in the cortical collecting ducts –seen predominantly in the cortical collecting ducts –
since SCD does not typically involve this cortical areasince SCD does not typically involve this cortical area
severe acidification defect is unusual in SCDsevere acidification defect is unusual in SCD
Titrable acid and ammonium generation in responseTitrable acid and ammonium generation in response
to an ammonium chloride challenge in SCD patientsto an ammonium chloride challenge in SCD patients
is slightly decreased, but maximal stimulus producesis slightly decreased, but maximal stimulus produces
normal acidificationnormal acidification
Potassium excretion is impaired but hyperkalemia isPotassium excretion is impaired but hyperkalemia is
rare without renal failurerare without renal failure
35. Pathophysiology –RenalPathophysiology –Renal
involvement contd..involvement contd..
Even though there is defective acidificationEven though there is defective acidification
and potassium excretion it is not due toand potassium excretion it is not due to
aldosterone deficiency as evidenced by theiraldosterone deficiency as evidenced by their
normal levels and normal response tonormal levels and normal response to
volume depletionvolume depletion
Electrolyte abnormalities may resemble typeElectrolyte abnormalities may resemble type
IV RTA but are actually a consequence ofIV RTA but are actually a consequence of
medullary fibrosismedullary fibrosis
ACE inhibitors and potassium sparingACE inhibitors and potassium sparing
diuretics should be used cautiously in SCDdiuretics should be used cautiously in SCD
patientspatients
36. RENAL PATHOLOGY IN SCDRENAL PATHOLOGY IN SCD
Distinctive findings–Distinctive findings–
– medullary / papillary fibrosis with inflammation and scarringmedullary / papillary fibrosis with inflammation and scarring
– FSGS with glomerular hypertrophyFSGS with glomerular hypertrophy
– MPGNMPGN
– Tubular hemosiderin depositsTubular hemosiderin deposits
Obliteration of medullary vasculatureObliteration of medullary vasculature segmental scarringsegmental scarring
and interstitial fibrosisand interstitial fibrosis dilated renal pelvic capillaries anddilated renal pelvic capillaries and
veinsveins
RPN – initial dilatation of vasa rectaeRPN – initial dilatation of vasa rectae engorgementengorgement
destruction of vasa rectae with medullary fibrosisdestruction of vasa rectae with medullary fibrosis smallsmall
focal infarctions of the papilla.focal infarctions of the papilla.
The calyces are affected separately and sequentially andThe calyces are affected separately and sequentially and
therefore acute obstruction and renal failure is uncommontherefore acute obstruction and renal failure is uncommon
RPN – focal – few surviving collecting ducts within area ofRPN – focal – few surviving collecting ducts within area of
diffuse fibrosis, destroyed vasa rectaediffuse fibrosis, destroyed vasa rectae (as against in analgesic(as against in analgesic
RPN where the vasa rectae are spared but most lesions occur inRPN where the vasa rectae are spared but most lesions occur in
peritubular capillaries)peritubular capillaries)
37. PATHOLOGY contd..PATHOLOGY contd..
Glomerular hypertrophy associated withGlomerular hypertrophy associated with
FSGS –glomerulomegaly is very commonFSGS –glomerulomegaly is very common
Earliest distinctive lesion in SCDEarliest distinctive lesion in SCD
glomerulopathy - sub endothelial zoneglomerulopathy - sub endothelial zone
lucency in the glomerular capillary looplucency in the glomerular capillary loop
followed by capillary collapse orfollowed by capillary collapse or
mesangial proliferative processmesangial proliferative process
FSGS – expansive or collapsing patternFSGS – expansive or collapsing pattern
Proteinuria with no immune complexProteinuria with no immune complex
deposition – non immune MPGNdeposition – non immune MPGN
Focal tubulointerstitial fibrosis is presentFocal tubulointerstitial fibrosis is present
adjacent to the sclerotic glomeruliadjacent to the sclerotic glomeruli
Hemosiderin granules in cytoplasmHemosiderin granules in cytoplasm
38. In patients with sickle cell disease, who present with chronic renal disease andIn patients with sickle cell disease, who present with chronic renal disease and
proteinuria,proteinuria, marked glomerular enlargementmarked glomerular enlargement is present, often withis present, often with mesangial expansionmesangial expansion
and segmental sclerosisand segmental sclerosis. This glomerulus shows. This glomerulus shows glomerulomegaly and mesangialglomerulomegaly and mesangial
expansionexpansion. There is. There is abundant brown pigmentabundant brown pigment, representing broken down hemoglobin, in, representing broken down hemoglobin, in
surrounding tubules, andsurrounding tubules, and interstitial fibrosis and vascular sclerosisinterstitial fibrosis and vascular sclerosis (Hematoxylin and(Hematoxylin and
eosin, X100).
39. Large glomerulusLarge glomerulus
in a patient within a patient with
sickle cell anemiasickle cell anemia
showingshowing
distended,distended,
congestedcongested
capillary loopscapillary loops
(silver(silver
methenamine;methenamine;
magnificationmagnification
×465).×465).
40. Sickle cell anemia. Subendothelial zoneSickle cell anemia. Subendothelial zone
of lucency in the glomerular capillaryof lucency in the glomerular capillary
loop (Jones silver stain).loop (Jones silver stain).
41. GlomerulusGlomerulus
from the samefrom the same
patientpatient
exhibiting aexhibiting a
segmentalsegmental
sclerosingsclerosing
lesionlesion
(arrowheads)(arrowheads)
(silver(silver
methenaminemethenamine
originaloriginal
magnificationmagnification
×385)×385)
42. Sickle cell anemia. Focal segmentalSickle cell anemia. Focal segmental
glomerulosclerosis (Jones silver stainglomerulosclerosis (Jones silver stain
with hematoxylin and eosin counterwith hematoxylin and eosin counter
stain).stain).
43. Sickle cell anemia. MembranoproliferativeSickle cell anemia. Membranoproliferative
lesion (hematoxylin and eosin).lesion (hematoxylin and eosin).
44. Moderate diffuse increase in mesangial matrixModerate diffuse increase in mesangial matrix is evident in this case of sickle cellis evident in this case of sickle cell
nephropathy, withnephropathy, with occasional double contours of the glomerular basement membranesoccasional double contours of the glomerular basement membranes..
This is presumably due to chronic endothelial injury, and does not represent a reaction toThis is presumably due to chronic endothelial injury, and does not represent a reaction to
immune complexes.immune complexes. Overt segmental sclerosis and so-called mesangial sclerosisOvert segmental sclerosis and so-called mesangial sclerosis maymay
also be present in addition to this glomerular basement membrane injury (Jones' silveralso be present in addition to this glomerular basement membrane injury (Jones' silver
stain, X400).stain, X400).
45. There areThere are no depositsno deposits in the injury related to sickle cell nephropathy, butin the injury related to sickle cell nephropathy, but
evidence ofevidence of endothelial injury with mild to moderate expansion of theendothelial injury with mild to moderate expansion of the
lamina rara internalamina rara interna may be present.may be present. Misshapen red blood cellsMisshapen red blood cells are alsoare also
seen in the lumen, and there isseen in the lumen, and there is expanded mesangial matrix withoutexpanded mesangial matrix without
depositsdeposits (Transmission electron microscopy, X8000).(Transmission electron microscopy, X8000).
46. In sickle cell nephropathy,In sickle cell nephropathy, iron deposits may be demonstratediron deposits may be demonstrated
in glomerular cells, as shown by Prussian blue positivity inin glomerular cells, as shown by Prussian blue positivity in
glomerular visceral epithelial cells and also in tubular epithelialglomerular visceral epithelial cells and also in tubular epithelial
cells (top right corner)cells (top right corner) (Prussian blue iron stain, X400).(Prussian blue iron stain, X400).
47. The abundantThe abundant hemoglobin accumulation in tubuleshemoglobin accumulation in tubules with surroundingwith surrounding
tubulointerstitial fibrosis and atrophic tubulestubulointerstitial fibrosis and atrophic tubules is illustrated in this case ofis illustrated in this case of
sickle cell nephropathy, withsickle cell nephropathy, with segmental sclerosis of the glomerulus on thesegmental sclerosis of the glomerulus on the
rightright (Hematoxylin and eosin, X200).(Hematoxylin and eosin, X200).
48. CLINICAL FEATURESCLINICAL FEATURES
Unlike in other organs, vaso-Unlike in other organs, vaso-
occlusive events in kidney areocclusive events in kidney are
surprisingly asymptomaticsurprisingly asymptomatic
except for episodes of grossexcept for episodes of gross
hematuriahematuria
Clinical renal involvement is ageClinical renal involvement is age
dependentdependent
49. Age at onset of renal features of sickle cell diseaseAge at onset of renal features of sickle cell disease
52. CLINICAL FEATURESCLINICAL FEATURES
SECOND DECADESECOND DECADE
– Microscopic papillary necrosisMicroscopic papillary necrosis
– Loss of vasa rectaLoss of vasa recta
– Renal tubular acidosisRenal tubular acidosis
– Renal tubular siderosisRenal tubular siderosis
– Irreversible hyposthenuriaIrreversible hyposthenuria
– Potassium excretion defectPotassium excretion defect
– ProteinuriaProteinuria
– BacteruriaBacteruria
– HematuriaHematuria
53. CLINICAL FEATURESCLINICAL FEATURES
THIRD DECADETHIRD DECADE
– Microscopic papillary necrosisMicroscopic papillary necrosis
– Interstitial nephritisInterstitial nephritis
– MpgnMpgn
– Decreased gfr and rpfDecreased gfr and rpf
– Nephrotic syndromeNephrotic syndrome
– PyelonephritisPyelonephritis
– Decreased urate c;earanceDecreased urate c;earance
– HypertensionHypertension
FOURTH DECADE – Renal failureFOURTH DECADE – Renal failure
54. HematuriaHematuria
Most prevalent renal manifestationMost prevalent renal manifestation
D/D -papillary necrosis, glomerulonephritis,D/D -papillary necrosis, glomerulonephritis,
tuberculosis, tumor, stones, and urinarytuberculosis, tumor, stones, and urinary
tract infectiontract infection
Gross hematuria due to crisisGross hematuria due to crisis
– Absence of signs of extrarenal bleedingAbsence of signs of extrarenal bleeding
– Usually painless except with clot colicUsually painless except with clot colic
– UnilateralUnilateral
– Left (80%) >>right (20%) (long LRV- increasedLeft (80%) >>right (20%) (long LRV- increased
venous pr.)venous pr.)
– Dramatic / prolongedDramatic / prolonged
– Mostly self limitingMostly self limiting
55. HyposthenuriaHyposthenuria
1st clinical evidence of defective medullary1st clinical evidence of defective medullary
tonicitytonicity
Output >=2000ml/day, nocturia andOutput >=2000ml/day, nocturia and
enuresisenuresis
Max concentrating ability falls toMax concentrating ability falls to
400mOsm/Kg H400mOsm/Kg H22O (n = 900 to 1200)O (n = 900 to 1200)
Reversible with transfusion in <10 yrs;Reversible with transfusion in <10 yrs;
irreversible with >15yrsirreversible with >15yrs
No change in ADH production or dilutingNo change in ADH production or diluting
capacity of kidneycapacity of kidney
Increases risk of dehydration –consequentIncreases risk of dehydration –consequent
sicklingsickling
56. Renal Acidification andRenal Acidification and
Potassium excretion defectsPotassium excretion defects
Renal acidification normal in SCTRenal acidification normal in SCT
SCD – greater acidic stimulus isSCD – greater acidic stimulus is
necessary to achieve max. Urine tonecessary to achieve max. Urine to
Blood HBlood H++
ion gradiention gradient
No proximal bicarbonaturia andNo proximal bicarbonaturia and
systemic acidosis is raresystemic acidosis is rare
Impaired KImpaired K++
excretion – but noexcretion – but no
hyperkalemia without renal failure orhyperkalemia without renal failure or
hemolysishemolysis
Hyperuricemia observed in 15%Hyperuricemia observed in 15%
children and 40% adults with SCD –children and 40% adults with SCD –
due to increase in production anddue to increase in production and
decreased renal clearancedecreased renal clearance
57. Glomerular DysfunctionGlomerular Dysfunction
GFR initially rises, thenGFR initially rises, then
normalizes and finally reducesnormalizes and finally reduces
with agewith age
Renal plasma flow is elevated inRenal plasma flow is elevated in
excess of GFR indicating aexcess of GFR indicating a
reduced filtration fractionreduced filtration fraction
GFR maintained in SCD patientsGFR maintained in SCD patients
with prostaglandin mechanismswith prostaglandin mechanisms
– careful use of NSAIDs for pain– careful use of NSAIDs for pain
58. Proteinuria and NephroticProteinuria and Nephrotic
syndromesyndrome
26% SCD patients have proteinuria;26% SCD patients have proteinuria;
increases with age; 13% are in theincreases with age; 13% are in the
nephrotic rangenephrotic range
Nephrotic syndrome is seen in 40% ofNephrotic syndrome is seen in 40% of
patients with sickle cell nephropathypatients with sickle cell nephropathy
Nephrotic syndrome leads to renalNephrotic syndrome leads to renal
failure in 2/3 of patients and death infailure in 2/3 of patients and death in
2 years in 1/2 of these patients2 years in 1/2 of these patients
Patients with albuminuria and normalPatients with albuminuria and normal
GFR have a decrease in ultrafiltrationGFR have a decrease in ultrafiltration
coefficient (selectivity for proteinuria)coefficient (selectivity for proteinuria)
60. Renal Papillary NecrosisRenal Papillary Necrosis
Mostly asymptomaticMostly asymptomatic
Often associated with infectionOften associated with infection
Calyceal clubbingCalyceal clubbing
Fornicial extension into medullaFornicial extension into medulla
(sinus tracts)(sinus tracts)
Garland pattern of calcification ofGarland pattern of calcification of
renal pyramids around the renalrenal pyramids around the renal
pelvispelvis
Sonographic echogenicity withoutSonographic echogenicity without
calcification (SCT > SCD)calcification (SCT > SCD)
IVP shows irregularities in theIVP shows irregularities in the
calyceal anatomy - pseudodiverticulaecalyceal anatomy - pseudodiverticulae
of the renal paillary tipsof the renal paillary tips
61. Radiographic pattern of renal papillary necrosis:Radiographic pattern of renal papillary necrosis:
Partial paillary necrosis – medullary typePartial paillary necrosis – medullary type
Total papillary necrosis – papillary typeTotal papillary necrosis – papillary type
Normal calyx
Medullary ring
sinus
Ring shadow
due to
sequestered papilla
caliectasis
62. Renal papillary necrosis. Kidneys are normalRenal papillary necrosis. Kidneys are normal
sized and smooth in contour. Central cavitationsized and smooth in contour. Central cavitation
is present in many papillae, particularly in rightis present in many papillae, particularly in right
interpolar areas (arrows).interpolar areas (arrows).
63. Urinary Tract InfectionsUrinary Tract Infections
Asymptomatic bacteruria and symptomaticAsymptomatic bacteruria and symptomatic
urinary tract infections are commonurinary tract infections are common
frequent urinalyses and periodic urinefrequent urinalyses and periodic urine
cultures with colony counts may be usefulcultures with colony counts may be useful
as a routine surveillance measureas a routine surveillance measure
Associated with renal papillary necrosis andAssociated with renal papillary necrosis and
acute renal failureacute renal failure
Careful long term monitoring and evaluationCareful long term monitoring and evaluation
for structural abnormalities should be donefor structural abnormalities should be done
Patients with persistent or recurrentPatients with persistent or recurrent
pyelonephritis should be considered forpyelonephritis should be considered for
long-term antibiotic therapylong-term antibiotic therapy
64. HypertensionHypertension
Unusual in SCD (incidence varies fromUnusual in SCD (incidence varies from
2-6% compared to 28% in non SCD2-6% compared to 28% in non SCD
patients)patients)
Black > WhiteBlack > White
Associated with renal failureAssociated with renal failure
BP values that could be consideredBP values that could be considered
normal or that represent mildnormal or that represent mild
hypertension in healthy individualshypertension in healthy individuals
should be considered a risk forshould be considered a risk for
important cardiovascularimportant cardiovascular
complications in patients with SCDcomplications in patients with SCD
Positive association betweenPositive association between
hypertension, stroke, heart failurehypertension, stroke, heart failure
and increased mortalityand increased mortality
65. Acute Renal FailureAcute Renal Failure
Acute non-oliguric renal failure –Acute non-oliguric renal failure –
in 10% of hospitalized patientsin 10% of hospitalized patients
with SCDwith SCD
Concomitant infection orConcomitant infection or
rhabdomyolysis or NSAID userhabdomyolysis or NSAID use
83% survival with recovery83% survival with recovery
without progression to ESRDwithout progression to ESRD
66. Chronic Renal FailureChronic Renal Failure
GFR initially rises in the 1GFR initially rises in the 1stst
decade, begins todecade, begins to
fall by 2fall by 2ndnd
decade, normalises and fallsdecade, normalises and falls
progressively with age in the 3progressively with age in the 3rdrd
decade todecade to
ESRD b/w 3ESRD b/w 3rdrd
& 5& 5thth
decadesdecades
Nephrotic syndrome progresses to CRFNephrotic syndrome progresses to CRF
faster in SCD patients compared to thosefaster in SCD patients compared to those
with other causes of proteinuriawith other causes of proteinuria
2/3 patients with SCD nephrotic syndrome2/3 patients with SCD nephrotic syndrome
developed renal failure within 2 yrsdeveloped renal failure within 2 yrs
Renal failure is associated with inadequateRenal failure is associated with inadequate
erythropoiesis and carries a mean survivalerythropoiesis and carries a mean survival
time of 4 years.time of 4 years.
Biopsy most often reveals FSGS andBiopsy most often reveals FSGS and
occasionally MPGNoccasionally MPGN
67. Cumulative probability of survival (beginning at age 10 years) ofCumulative probability of survival (beginning at age 10 years) of
patients with sickle cell anaemia. Patients with sickle renal failurepatients with sickle cell anaemia. Patients with sickle renal failure
were compared with a cohort comprising the Los Angeleswere compared with a cohort comprising the Los Angeles
population that had not developed renal failure. After 10 years ofpopulation that had not developed renal failure. After 10 years of
age, endstage renal disease is a significant cause of death duringage, endstage renal disease is a significant cause of death during
young adult life (log-rank test, P = 0.02).young adult life (log-rank test, P = 0.02).
68. RENAL MEDULLARYRENAL MEDULLARY
CARCINOMACARCINOMA
Distinctive renal cell carcinoma inDistinctive renal cell carcinoma in
SCD patientsSCD patients
Very aggressive tumourVery aggressive tumour
<25 yrs M>F; >25 yrs M=F<25 yrs M>F; >25 yrs M=F
Gross hematuria , flank pain, weightGross hematuria , flank pain, weight
loss, palpable massloss, palpable mass
Mean duration of symptoms ~ 8Mean duration of symptoms ~ 8
weeksweeks
Mean survival after surgery ~15Mean survival after surgery ~15
weeksweeks
69. RENAL MEDULLARYRENAL MEDULLARY
CARCINOMA contd..CARCINOMA contd..
Right kidney >> left kidneyRight kidney >> left kidney
Satellite nodules in the cortex, perinephric andSatellite nodules in the cortex, perinephric and
peripelvic soft tissue and Llbulated pattern inperipelvic soft tissue and Llbulated pattern in
renal medullarenal medulla
Reticular or adenoid cystic pattern with regionsReticular or adenoid cystic pattern with regions
of poor differentiation in a stroma with aof poor differentiation in a stroma with a
mucinoid, myxoid or edematous appearancemucinoid, myxoid or edematous appearance
Chromosome 11 anomaly (monosomy orChromosome 11 anomaly (monosomy or
mutation)mutation)
Aggressive tumor – course unmodified byAggressive tumor – course unmodified by
treatmenttreatment
70. TREATMENTTREATMENT
Alleviate frequent serious sickle cell crisesAlleviate frequent serious sickle cell crises
General Care – avoid hypoxia, immunise forGeneral Care – avoid hypoxia, immunise for
capsulated organisms, prophylactic antibiotics,capsulated organisms, prophylactic antibiotics,
transfusional support during stress, increased fluidtransfusional support during stress, increased fluid
intake, iron chelation therapy, treatment of crisesintake, iron chelation therapy, treatment of crises
(pain relief, fluids, steroids, etc…)(pain relief, fluids, steroids, etc…)
Transfusion therapy - to prevent progression ofTransfusion therapy - to prevent progression of
complicationscomplications
NSAIDs carry untoward risk to renal function – sinceNSAIDs carry untoward risk to renal function – since
GFR is maintained by the vasoactive prostaglandins.GFR is maintained by the vasoactive prostaglandins.
Care to be taken while treating pain crises withCare to be taken while treating pain crises with
conventional analgesicsconventional analgesics
Hydroxyurea significantly decreases sickling byHydroxyurea significantly decreases sickling by
myelosuppression of Hb SS cell and therebymyelosuppression of Hb SS cell and thereby
increasing Hb F – trials in adults and children showincreasing Hb F – trials in adults and children show
safe reduction in acute episodes and allowed normalsafe reduction in acute episodes and allowed normal
growth and developmentgrowth and development
71. TREATMENTTREATMENT
Adjuvant antioxidants like alpha –Adjuvant antioxidants like alpha –
tocopherol and ascorbic acid may enhancetocopherol and ascorbic acid may enhance
the safety of Hydroxyureathe safety of Hydroxyurea
Clotrimazole and magnesium have beenClotrimazole and magnesium have been
studied and are proposed to reduce cellularstudied and are proposed to reduce cellular
dehydration that may precipitate sickling –dehydration that may precipitate sickling –
but their clinical value is unknownbut their clinical value is unknown
Bone marrow transplantation is curative –Bone marrow transplantation is curative –
90% success and 4% perioperative90% success and 4% perioperative
mortalitymortality
72. TREATMENTTREATMENT
Hematuria is self limiting – treat the cause; correctHematuria is self limiting – treat the cause; correct
anemia, dehydration; can use EACA (2-8 gm/day);anemia, dehydration; can use EACA (2-8 gm/day);
radiological localization and embolization; avoidradiological localization and embolization; avoid
nephrectomy unless exsanguinating hemorrhagenephrectomy unless exsanguinating hemorrhage
presentspresents
ACE inhibitors known to definitely reduce theACE inhibitors known to definitely reduce the
proteinuria associated with SCDproteinuria associated with SCD
Whether long tern ACE inhibitor use has a salutaryWhether long tern ACE inhibitor use has a salutary
effect in preventing renal failure is unknowneffect in preventing renal failure is unknown
ACE inhibitors should be used cautiously in SCDACE inhibitors should be used cautiously in SCD
patients due to the potassium excretion defectspatients due to the potassium excretion defects
Specific treatment of renal failure in SCD patients isSpecific treatment of renal failure in SCD patients is
poorly exploredpoorly explored
Even mild renal failure patients may have severelyEven mild renal failure patients may have severely
symptomatic anemia requiring transfusionssymptomatic anemia requiring transfusions
73. TABLE 1 -- Diagnostic and therapeutic approach to patients with SCNa
Renal Finding Evaluation Possible Treatment
Proteinuria (>1 g) Non-nephrotic consider
biopsy: R/O immune
glomerulopathy
Nephrotic range consider
biopsy: R/O renal vein
thrombosis, MCNS, and
immune glomerulopathy
Angiotensin inhibitors -
cautious use
Gross hematuria R/O other coagulopathies
R/O other nephropathies,
calculi and UTI
Localize source of bleeding
Detect papillary necrosis
Detect medullary carcinoma
Mild: Correct anemia and
maintain good hydration
Severe: EACA, local
embolization, nephrectomy
(rarely)
ESRD Detect renal osteodystrophy,
electrolyte disturbances
Low-protein diet
PO4
binders, vitamin D;
dialysis and transplantation
74. TREATMENT - Renal transplantationTREATMENT - Renal transplantation
Transplantation is a better option for SCD patients withTransplantation is a better option for SCD patients with
renal failure.renal failure.
However, results may be less satisfactory than for otherHowever, results may be less satisfactory than for other
non SCD patients with renal failure – due to sickling eventsnon SCD patients with renal failure – due to sickling events
and recurrence of SC Nephropathyand recurrence of SC Nephropathy
Post transplant rise in erythropoietin and hence hematocritPost transplant rise in erythropoietin and hence hematocrit
levels predispose to more sickling eventslevels predispose to more sickling events
Transplanted SS patients have 56% ten yr survivalTransplanted SS patients have 56% ten yr survival
compared to 14% in non-transplanted SS patientscompared to 14% in non-transplanted SS patients
75. SUMMARYSUMMARY
Sickle cell nephropathy is an importantSickle cell nephropathy is an important
cause of mortality in SCD patients, withcause of mortality in SCD patients, with
specific clinical markers that can indicatespecific clinical markers that can indicate
further progression to ESRD.further progression to ESRD.
Chronic sickling promotes differentChronic sickling promotes different
mechanisms of kidney injury: structuralmechanisms of kidney injury: structural
papillectomy, urine concentration defects,papillectomy, urine concentration defects,
hyperfiltration, and glomerular enlargementhyperfiltration, and glomerular enlargement
and sclerosis.and sclerosis.
Clinical detection of the manifestations ofClinical detection of the manifestations of
these processes, as well as detection of riskthese processes, as well as detection of risk
factors for medullary carcinoma, can permitfactors for medullary carcinoma, can permit
the clinician to offer a rational treatment tothe clinician to offer a rational treatment to
the SCD patient.the SCD patient.
Chronic dialysis and transplantationChronic dialysis and transplantation
represent reasonable options for thoserepresent reasonable options for those
patients who reach ESRD.patients who reach ESRD.
