Kidney in sickle cell disease

THE KIDNEY IN THE KIDNEY IN SICKLE CELL DISEASESICKLE CELL DISEASE

SICKLE CELL ANEMIASICKLE CELL ANEMIA Genetic defect of Hb polymerization resulting in RBC Genetic defect of Hb polymerization resulting in RBC deformation when deoxygenateddeformation when deoxygenated

ROBERT HERRICK (1910) – first description of clinical ROBERT HERRICK (1910) – first description of clinical findings and red cell morphology (including urinary findings 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 autopsy SYDENSTRICKER 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 hemoglobin LINUS PAULING (1949)– SCD due to abnormal hemoglobin moleculemolecule

INGRAM (1956) - b-chain of the sickle cell globin molecule INGRAM (1956) - b-chain of the sickle cell globin molecule differed by substitution of valine for glutamic acid at the differed by substitution of valine for glutamic acid at the sixth residuesixth residue

Hb S gene Hb S gene – Homozygous – sickle cell anemiaHomozygous – sickle cell anemia– Heterozygous – sickle cell traitHeterozygous – sickle cell trait

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, andArab–Indian ( It is the most common haplotype of the tribal peoples of India)

EpidemiologyEpidemiology

25% babies in the West Africa carry 25% babies in the West Africa carry the gene, compared to 8 % of Afro-the gene, compared to 8 % of Afro-AmericansAmericans1 in 600 Afro-Americans are 1 in 600 Afro-Americans are homozygous homozygous Clinical manifestations in African Clinical manifestations in African homozygotes are more severe than homozygotes are more severe than those in Asian or New World those in Asian or New World populations. populations. The Bantu haplotype is most The Bantu haplotype is most associated with severe organ failure associated with severe organ failure syndromes, including chronic renal syndromes, including chronic renal failurefailure

SCD – NATURAL HISTORYSCD – NATURAL HISTORYchildhood – 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

SCD – NATURAL HISTORYSCD – NATURAL HISTORYChildhood - crisesChildhood - crises

Hemolytic crisis – hemolysis > replenishmentAplastic crisis – Retics lag behind – Parvovirus B19Sequestration crisis – large scale splenic trapping of RBCs – pain, splenomegaly, circulatory collapsePainful infarctive crises – microinfarctions, vaso-occlusive disease

SCD – NATURAL HISTORYSCD – NATURAL HISTORYChildhood- Immune defectsChildhood- Immune defectsSplenic infarction – functional asplenia – predisposition to severe pneumococcal infection and sepsisOther 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

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 otherGram-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

SCD – NATURAL HISTORYSCD – NATURAL HISTORYChildhood – vaso-occlusive Childhood – vaso-occlusive

complicationscomplicationsCommonly affect bone, muscle, brain, lungs, spleen, kidneys, and bone marrowCommon 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

SCD – NATURAL HISTORY – SCD – NATURAL HISTORY – The adult patientThe adult patient

Painful and hemolytic crisis continueThrombotic cerebral infarctions less commonBone - Progressive osteonecrosisRecurrent acute chest syndrome- cor pulmonaleRenal - haematuria, papillary necrosis, nephrotic syndrome, and chronic renal failureLiver - 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

The frequency of major organ failure in The frequency of major organ failure in sickle cell anaemia patientssickle cell anaemia patients. (Reprinted from . (Reprinted from

Powars (1994)Powars (1994)

Epidemiology of Renal Epidemiology of Renal involvement in SCDinvolvement in SCD

26% of SCD patients have proteinuria 26% of SCD patients have proteinuria while 5-18% have renal failurewhile 5-18% have renal failureRenal failure is the major risk factor Renal failure is the major risk factor for early mortality in adult SCD for early mortality in adult SCD patientspatients30% of patients who die early of SCD 30% of patients who die early of SCD have chronic renal failurehave chronic renal failureProteinuria, hypertension, severe Proteinuria, hypertension, severe anemia and hematuria are predictors anemia and hematuria are predictors of renal failureof renal failure

Renal Manifestations in Renal Manifestations in Sickle Cell DiseaseSickle Cell Disease

Asymptomatic hematuriaAsymptomatic hematuriaHyposthenuriaHyposthenuriaRenal acidification and potassium Renal acidification and potassium excretion defectsexcretion defectsGlomerular dysfunctionGlomerular dysfunctionProteinuria and Nephrotic syndromeProteinuria and Nephrotic syndromeRenal papillary necrosisRenal papillary necrosisUrinary Tract InfectionsUrinary Tract InfectionsHypertensionHypertensionAcute renal failureAcute renal failureChronic renal failureChronic renal failureRenal medullary carcinomaRenal medullary carcinoma

Epidemiology contd…Epidemiology contd…

Clinical heterogenity in Clinical 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

s-haplotypess-haplotypes

Coexistence of Coexistence of -Thalassemia-Thalassemia

Environmental factorsEnvironmental factors

SCD - SCD - PATHOPHYSIOLOGYPATHOPHYSIOLOGY

Pathophysiology contd…Pathophysiology contd…Basic defect is the polymerization of Basic defect is the polymerization of deoxygenated Hb S deoxygenated Hb S HbS undergo a spatial molecular HbS undergo a spatial molecular rearrangement leading to chain-like rearrangement leading to chain-like formations. formations. This process changes the shape of the This process changes the shape of the normally biconcave RBCs to sickle shape normally biconcave RBCs to sickle shape This imparts rigidity to the distorted red This imparts rigidity to the distorted red blood cell, making it likely to occlude blood cell, making it likely to occlude small vesselssmall vesselsSlowing of passage of RBCs potentiates Slowing of passage of RBCs potentiates this processthis process

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 peroxidationReactive species will divert vasoactive nitric oxide from mechanisms of vascular relaxation to agents of inflammation and constrictionSuperoxide combines with NO to form Superoxide combines with NO to form peroxynitritesperoxynitrites induces the enzyme NO synthase induces the enzyme NO synthase in the tubular epithelial cells in the tubular epithelial cells induce apoptosis induce apoptosis

PathophysiologyPathophysiology

Chronic sickling underlies several Chronic sickling underlies several mechanisms for kidney injurymechanisms for kidney injurySickling promoted in vasa rectae by:Sickling promoted in vasa rectae by:– Postglomerular arteriolar vasculature has low Postglomerular 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 viscosityVenous engorgementVenous engorgementInterstitial edemaInterstitial edemaPredispostion of renal microcirculation to Predispostion of renal microcirculation to edema and infarction edema and infarction

Pathophysiology –Renal involvementPathophysiology –Renal involvementRenal hypertrophy in the setting of prominent Renal hypertrophy in the setting of prominent hemodynamic and vascular alterationshemodynamic and vascular alterations

Hematuria may be due to sickling in the vasa recta Hematuria may be due to sickling in the vasa recta stasis and ischemia stasis and ischemia extravasation of blood into extravasation of blood into the renal parenchyma and collecting system, or in the renal parenchyma and collecting system, or in some cases to micropapillary or macropapillary some cases to micropapillary or macropapillary necrosisnecrosis

Cortical circulation – increased GFR and RPF ; Cortical circulation – increased GFR and RPF ; Medullary perfusion diminished by vaso-occlusive Medullary perfusion diminished by vaso-occlusive disease disease increases the vasoactive PGs which increases the vasoactive PGs which further increase the RPF and GFRfurther increase the RPF and GFR

Due to distal vaso-occlusion and efferent arteriolar Due to distal vaso-occlusion and efferent arteriolar vaso-constriction, the intraglomerular pressure goes vaso-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 the Increased NO synthase induction accentuates the GFR elevationGFR elevation

Pathophysiology –Renal Pathophysiology –Renal involvement contd..involvement contd..

Direct endothelial damage + hyperfiltration Direct endothelial damage + hyperfiltration endothelial hyperplasia and Interstitial fibrosis endothelial hyperplasia and Interstitial fibrosis efferent glomerular capillary obstruction efferent glomerular capillary obstruction intraglomerular pressure further goes up intraglomerular pressure further goes up progressive reactive sclerosisprogressive reactive sclerosis

Medullary fibrosis >> cortical fibrosis Medullary fibrosis >> cortical fibrosis juxtamedullary nephrons are most affected by juxtamedullary nephrons are most affected by FSGSFSGS

Collapsing pattern of FSGS due to capillary Collapsing pattern of FSGS due to capillary collapse secondary to sickling and ischemia collapse secondary to sickling and ischemia whereas expansive form is due to mesangial whereas expansive form is due to mesangial reaction to capillary collapsereaction to capillary collapse

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 rectaeB- Sickle cell traitB- Sickle cell trait – cortical vasculature decreased and vasa – cortical vasculature decreased and vasa rectae attenuated and distortedrectae attenuated and distortedC- Sickle cell diseaseC- Sickle cell disease – cortical vasculature markedly – cortical vasculature markedly decreased and vasa rectae virtually abent.decreased and vasa rectae virtually abent.

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).

Marked congestion filling up capillary loopsMarked congestion filling up capillary loops is evident is evident in this case of sickle cell crisis, with occasional sickled in this case of sickle cell crisis, with occasional sickled RBCs discernible (right) (Hematoxylin and eosin, X400). RBCs discernible (right) (Hematoxylin and eosin, X400).

Marked sickling in vasa rectaMarked sickling in vasa recta is illustrated in this patient is illustrated in this patient who died in acute sickle cell crisis (Hematoxylin and who died in acute sickle cell crisis (Hematoxylin and

eosin, X400). eosin, X400).


Anemia potentiates glomerulomegalyAnemia potentiates glomerulomegaly

Iron deposition in tubular cells due to iron Iron deposition in tubular cells due to iron overload may have additional role in the overload may have additional role in the chronic nephropathy of SCDchronic nephropathy of SCD

Parvovirus infection in SCD patients not Parvovirus infection in SCD patients not only causes aplastic crises but also only causes aplastic crises but also accelerate renal diseaseaccelerate renal disease

Uric acid nephropathy also can contribute to Uric acid nephropathy also can contribute to some renal damagesome renal damage


Tubular damage results in mild acidification and Tubular damage results in mild acidification and potassium secreting defectpotassium secreting defect

H+ and K+ ion secretion is by intercalated duct cells H+ 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 area since 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 response Titrable acid and ammonium generation in response to an ammonium chloride challenge in SCD patients to an ammonium chloride challenge in SCD patients is slightly decreased, but maximal stimulus produces is slightly decreased, but maximal stimulus produces normal acidificationnormal acidification

Potassium excretion is impaired but hyperkalemia is Potassium excretion is impaired but hyperkalemia is rare without renal failurerare without renal failure


Even though there is defective acidification Even though there is defective acidification and potassium excretion it is not due to and potassium excretion it is not due to aldosterone deficiency as evidenced by aldosterone deficiency as evidenced by their normal levels and normal response to their normal levels and normal response to volume depletionvolume depletion

Electrolyte abnormalities may resemble Electrolyte abnormalities may resemble type IV RTA but are actually a consequence type IV RTA but are actually a consequence of medullary fibrosisof medullary fibrosis

ACE inhibitors and potassium sparing ACE inhibitors and potassium sparing diuretics should be used cautiously in SCD diuretics should be used cautiously in SCD patientspatients

RENAL PATHOLOGY IN RENAL PATHOLOGY IN SCDSCDDistinctive findings– Distinctive findings–

– medullary / papillary fibrosis with inflammation and scarring medullary / papillary fibrosis with inflammation and scarring – FSGS with glomerular hypertrophyFSGS with glomerular hypertrophy– MPGNMPGN– Tubular hemosiderin depositsTubular hemosiderin deposits

Obliteration of medullary vasculature Obliteration of medullary vasculature segmental scarring segmental scarring and interstitial fibrosis and interstitial fibrosis dilated renal pelvic capillaries and dilated renal pelvic capillaries and veinsveins

RPN – initial dilatation of vasa rectae RPN – initial dilatation of vasa rectae engorgement engorgement destruction of vasa rectae with medullary fibrosis destruction of vasa rectae with medullary fibrosis small small focal infarctions of the papilla.focal infarctions of the papilla.

The calyces are affected separately and sequentially and The 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 of RPN – focal – few surviving collecting ducts within area of diffuse fibrosis, destroyed vasa rectae diffuse fibrosis, destroyed vasa rectae (as against in analgesic (as against in analgesic RPN where the vasa rectae are spared but most lesions occur in RPN where the vasa rectae are spared but most lesions occur in peritubular capillaries)peritubular capillaries)

PATHOLOGY contd..PATHOLOGY contd..Glomerular hypertrophy associated with Glomerular hypertrophy associated with FSGS –glomerulomegaly is very commonFSGS –glomerulomegaly is very commonEarliest distinctive lesion in SCD Earliest distinctive lesion in SCD glomerulopathy - sub endothelial zone glomerulopathy - sub endothelial zone lucency in the glomerular capillary loop lucency in the glomerular capillary loop followed by capillary collapse or followed by capillary collapse or mesangial proliferative process mesangial proliferative process FSGS – expansive or collapsing patternFSGS – expansive or collapsing patternProteinuria with no immune complex Proteinuria with no immune complex deposition – non immune MPGN deposition – non immune MPGN Focal tubulointerstitial fibrosis is present Focal tubulointerstitial fibrosis is present adjacent to the sclerotic glomeruliadjacent to the sclerotic glomeruliHemosiderin granules in cytoplasmHemosiderin granules in cytoplasm

In patients with sickle cell disease, who present with chronic renal disease and In patients with sickle cell disease, who present with chronic renal disease and proteinuria, proteinuria, marked glomerular enlargementmarked glomerular enlargement is present, often with is present, often with mesangial expansion mesangial expansion

and segmental sclerosisand segmental sclerosis. This glomerulus shows . This glomerulus shows glomerulomegaly and mesangial glomerulomegaly and mesangial expansionexpansion. There is . There is abundant brown pigmentabundant brown pigment, representing broken down hemoglobin, in , representing broken down hemoglobin, in

surrounding tubules, and surrounding tubules, and interstitial fibrosis and vascular sclerosisinterstitial fibrosis and vascular sclerosis (Hematoxylin and (Hematoxylin and

eosin, X100).eosin, X100).

Large Large glomerulus in a glomerulus in a patient with patient with sickle cell sickle cell anemia showing anemia showing distended, distended, congested congested capillary loops capillary loops (silver (silver methenamine; methenamine; magnification magnification ×465).×465).

Sickle cell anemia. Subendothelial Sickle cell anemia. Subendothelial zone of lucency in the glomerular zone of lucency in the glomerular capillary loop (Jones silver stain).capillary loop (Jones silver stain).

Glomerulus Glomerulus from the from the same patient same patient exhibiting a exhibiting a segmental segmental sclerosing sclerosing lesion lesion (arrowheads) (arrowheads) (silver (silver methenaminmethenamineoriginal eoriginal magnificatiomagnification ×385)n ×385)

Sickle cell anemia. Focal segmental Sickle cell anemia. Focal segmental glomerulosclerosis (Jones silver glomerulosclerosis (Jones silver stain with hematoxylin and eosin stain with hematoxylin and eosin

counter stain).counter stain).

Sickle cell anemia. Sickle cell anemia. Membranoproliferative lesion Membranoproliferative lesion

(hematoxylin and eosin).(hematoxylin and eosin).

Moderate diffuse increase in mesangial matrixModerate diffuse increase in mesangial matrix is evident in this case of sickle cell is evident in this case of sickle cell nephropathy, with nephropathy, 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 to This 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 may may also be present in addition to this glomerular basement membrane injury (Jones' silver also be present in addition to this glomerular basement membrane injury (Jones' silver

stain, X400).stain, X400).

There are There are no depositsno deposits in the injury related to sickle cell nephropathy, but in the injury related to sickle cell nephropathy, but evidence of evidence of endothelial injury with mild to moderate expansion of the endothelial 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 also are also seen in the lumen, and there is seen in the lumen, and there is expanded mesangial matrix without expanded mesangial matrix without

depositsdeposits (Transmission electron microscopy, X8000). (Transmission electron microscopy, X8000).

In sickle cell nephropathy, In sickle cell nephropathy, iron deposits may be demonstrated iron deposits may be demonstrated in glomerular cells, as shown by Prussian blue positivity in in glomerular cells, as shown by Prussian blue positivity in

glomerular visceral epithelial cells and also in tubular epithelial glomerular 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).

The abundant The abundant hemoglobin accumulation in tubuleshemoglobin accumulation in tubules with surrounding with surrounding tubulointerstitial fibrosis and atrophic tubulestubulointerstitial fibrosis and atrophic tubules is illustrated in this case of is illustrated in this case of sickle cell nephropathy, with sickle cell nephropathy, with segmental sclerosis of the glomerulus on the segmental sclerosis of the glomerulus on the

rightright (Hematoxylin and eosin, X200). (Hematoxylin and eosin, X200).

CLINICAL FEATURESCLINICAL FEATURES

Unlike in other organs, vaso-Unlike in other organs, vaso-occlusive events in kidney are occlusive events in kidney are surprisingly asymptomatic surprisingly asymptomatic except for episodes of gross except for episodes of gross hematuriahematuria

Clinical renal involvement is age Clinical renal involvement is age dependentdependent

Age at onset of renal features of sickle Age at onset of renal features of sickle cell diseasecell disease


FIRST DECADEFIRST DECADE– Decreased medullary blood flowDecreased medullary blood flow– NocturiaNocturia– EnuresisEnuresis– HyposthenuriaHyposthenuria– HyperfiltrationHyperfiltration


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


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

HematuriaHematuria

Most prevalent renal manifestationMost prevalent renal manifestationD/D -papillary necrosis, glomerulonephritis, D/D -papillary necrosis, glomerulonephritis, tuberculosis, tumor, stones, and urinary tuberculosis, tumor, stones, and urinary tract infection tract 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- increased Left (80%) >>right (20%) (long LRV- increased

venous pr.)venous pr.)– Dramatic / prolonged Dramatic / prolonged – Mostly self limitingMostly self limiting

HyposthenuriaHyposthenuria

1st clinical evidence of defective medullary 1st clinical evidence of defective medullary tonicitytonicityOutput >=2000ml/day, nocturia and Output >=2000ml/day, nocturia and enuresisenuresisMax concentrating ability falls to Max 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 >15yrsNo change in ADH production or diluting No change in ADH production or diluting capacity of kidneycapacity of kidneyIncreases risk of dehydration –consequent Increases risk of dehydration –consequent sicklingsickling

Renal Acidification and Renal Acidification and Potassium excretion defectsPotassium excretion defects

Renal acidification normal in SCTRenal acidification normal in SCTSCD – greater acidic stimulus is SCD – greater acidic stimulus is necessary to achieve max. Urine to necessary to achieve max. Urine to Blood HBlood H+ + ion gradiention gradientNo proximal bicarbonaturia and No proximal bicarbonaturia and systemic acidosis is raresystemic acidosis is rareImpaired KImpaired K+ + excretion – but no excretion – but no hyperkalemia without renal failure or hyperkalemia without renal failure or hemolysishemolysisHyperuricemia observed in 15% Hyperuricemia observed in 15% children and 40% adults with SCD – children and 40% adults with SCD – due to increase in production and due to increase in production and decreased renal clearance decreased renal clearance

Glomerular DysfunctionGlomerular Dysfunction

GFR initially rises, then GFR initially rises, then normalizes and finally reduces normalizes and finally reduces with agewith ageRenal plasma flow is elevated in Renal plasma flow is elevated in excess of GFR indicating a excess of GFR indicating a reduced filtration fractionreduced filtration fractionGFR maintained in SCD patients GFR maintained in SCD patients with prostaglandin mechanisms – with prostaglandin mechanisms – careful use of NSAIDs for paincareful use of NSAIDs for pain

Proteinuria and Nephrotic Proteinuria and Nephrotic syndromesyndrome

26% SCD patients have proteinuria; 26% SCD patients have proteinuria; increases with age; 13% are in the increases with age; 13% are in the nephrotic rangenephrotic rangeNephrotic syndrome is seen in 40% of Nephrotic syndrome is seen in 40% of patients with sickle cell nephropathypatients with sickle cell nephropathyNephrotic syndrome leads to renal Nephrotic syndrome leads to renal failure in 2/3 of patients and death in failure in 2/3 of patients and death in 2 years in 1/2 of these patients2 years in 1/2 of these patientsPatients with albuminuria and normal Patients with albuminuria and normal GFR have a decrease in ultrafiltration GFR have a decrease in ultrafiltration coefficient (selectivity for proteinuria)coefficient (selectivity for proteinuria)

PrevalencPrevalence rates of e rates of proteinurproteinuria and ia and renal renal failure failure per per decade of decade of lifelife

Renal Papillary NecrosisRenal Papillary Necrosis

Mostly asymptomaticMostly asymptomaticOften associated with infectionOften associated with infectionCalyceal clubbingCalyceal clubbingFornicial extension into medulla Fornicial extension into medulla (sinus tracts)(sinus tracts)Garland pattern of calcification of Garland pattern of calcification of renal pyramids around the renal renal pyramids around the renal pelvispelvisSonographic echogenicity without Sonographic echogenicity without calcification (SCT > SCD)calcification (SCT > SCD)IVP shows irregularities in the IVP shows irregularities in the calyceal anatomy - calyceal anatomy - pseudodiverticulae of the renal pseudodiverticulae of the renal paillary tipspaillary tips

Radiographic pattern of renal papillary Radiographic pattern of renal papillary necrosis:necrosis:Partial paillary necrosis – medullary typePartial paillary necrosis – medullary typeTotal papillary necrosis – papillary typeTotal papillary necrosis – papillary type

Normal calyx

Medullary ring

sinus

Ring shadow due to sequestered papilla

caliectasis

Renal papillary necrosis. Kidneys are normal Renal papillary necrosis. Kidneys are normal sized and smooth in contour. Central sized and smooth in contour. Central cavitation is present in many papillae, cavitation is present in many papillae, particularly in right interpolar areas particularly in right interpolar areas

(arrows).(arrows).

Urinary Tract InfectionsUrinary Tract Infections

Asymptomatic bacteruria and symptomatic Asymptomatic bacteruria and symptomatic urinary tract infections are commonurinary tract infections are commonfrequent urinalyses and periodic urine frequent urinalyses and periodic urine cultures with colony counts may be useful cultures with colony counts may be useful as a routine surveillance measureas a routine surveillance measureAssociated with renal papillary necrosis and Associated with renal papillary necrosis and acute renal failureacute renal failureCareful long term monitoring and evaluation Careful long term monitoring and evaluation for structural abnormalities should be donefor structural abnormalities should be donePatients with persistent or recurrent Patients with persistent or recurrent pyelonephritis should be considered for pyelonephritis should be considered for long-term antibiotic therapylong-term antibiotic therapy

HypertensionHypertension

Unusual in SCD (incidence varies from Unusual in SCD (incidence varies from 2-6% compared to 28% in non SCD 2-6% compared to 28% in non SCD patients)patients)Black > WhiteBlack > WhiteAssociated with renal failureAssociated with renal failureBP values that could be considered BP values that could be considered normal or that represent mild normal or that represent mild hypertension in healthy individuals hypertension in healthy individuals should be considered a risk for should be considered a risk for important cardiovascular important cardiovascular complications in patients with SCDcomplications in patients with SCDPositive association between Positive association between hypertension, stroke, heart failure hypertension, stroke, heart failure and increased mortalityand increased mortality

Acute Renal FailureAcute Renal Failure

Acute non-oliguric renal failure – Acute non-oliguric renal failure – in 10% of hospitalized patients in 10% of hospitalized patients with SCDwith SCD

Concomitant infection or Concomitant infection or rhabdomyolysis or NSAID userhabdomyolysis or NSAID use

83% survival with recovery 83% survival with recovery without progression to ESRDwithout progression to ESRD

Chronic Renal FailureChronic Renal FailureGFR initially rises in the 1GFR initially rises in the 1stst decade, begins decade, begins to fall by 2to fall by 2ndnd decade, normalises and falls decade, normalises and falls progressively with age in the 3progressively with age in the 3rdrd decade to decade to ESRD b/w 3ESRD b/w 3rdrd & 5 & 5thth decades decadesNephrotic syndrome progresses to CRF Nephrotic syndrome progresses to CRF faster in SCD patients compared to those faster in SCD patients compared to those with other causes of proteinuriawith other causes of proteinuria2/3 patients with SCD nephrotic syndrome 2/3 patients with SCD nephrotic syndrome developed renal failure within 2 yrsdeveloped renal failure within 2 yrsRenal failure is associated with inadequate Renal failure is associated with inadequate erythropoiesis and carries a mean survival erythropoiesis and carries a mean survival time of 4 years.time of 4 years.Biopsy most often reveals FSGS and Biopsy most often reveals FSGS and occasionally MPGNoccasionally MPGN

Cumulative probability of survival (beginning at age 10 years) Cumulative probability of survival (beginning at age 10 years) of patients with sickle cell anaemia. Patients with sickle renal of patients with sickle cell anaemia. Patients with sickle renal

failure were compared with a cohort comprising the Los failure were compared with a cohort comprising the Los Angeles population that had not developed renal failure. After Angeles population that had not developed renal failure. After 10 years of age, endstage renal disease is a significant cause 10 years of age, endstage renal disease is a significant cause

of death during young adult life (log-rank test, P = 0.02).of death during young adult life (log-rank test, P = 0.02).

RENAL MEDULLARY RENAL MEDULLARY CARCINOMACARCINOMA

Distinctive renal cell carcinoma in Distinctive renal cell carcinoma in SCD patientsSCD patientsVery aggressive tumourVery aggressive tumour<25 yrs M>F; >25 yrs M=F<25 yrs M>F; >25 yrs M=FGross hematuria , flank pain, weight Gross hematuria , flank pain, weight loss, palpable massloss, palpable massMean duration of symptoms ~ 8 Mean duration of symptoms ~ 8 weeksweeksMean survival after surgery ~15 Mean survival after surgery ~15 weeksweeks

RENAL MEDULLARY RENAL MEDULLARY CARCINOMA contd..CARCINOMA contd..

Right kidney >> left kidneyRight kidney >> left kidney

Satellite nodules in the cortex, perinephric and Satellite nodules in the cortex, perinephric and peripelvic soft tissue and Llbulated pattern in peripelvic soft tissue and Llbulated pattern in renal medullarenal medulla

Reticular or adenoid cystic pattern with Reticular or adenoid cystic pattern with regions of poor differentiation in a stroma with regions of poor differentiation in a stroma with a mucinoid, myxoid or edematous appearancea mucinoid, myxoid or edematous appearance

Chromosome 11 anomaly (monosomy or Chromosome 11 anomaly (monosomy or mutation)mutation)

Aggressive tumor – course unmodified by Aggressive tumor – course unmodified by treatmenttreatment

TREATMENTTREATMENTAlleviate frequent serious sickle cell crisesAlleviate frequent serious sickle cell crises

General Care – avoid hypoxia, immunise for General Care – avoid hypoxia, immunise for capsulated organisms, prophylactic antibiotics, capsulated organisms, prophylactic antibiotics, transfusional support during stress, increased fluid transfusional support during stress, increased fluid intake, iron chelation therapy, treatment of crises intake, iron chelation therapy, treatment of crises (pain relief, fluids, steroids, etc…) (pain relief, fluids, steroids, etc…)

Transfusion therapy - to prevent progression of Transfusion therapy - to prevent progression of complicationscomplications

NSAIDs carry untoward risk to renal function – since NSAIDs 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 with Care to be taken while treating pain crises with conventional analgesicsconventional analgesics

Hydroxyurea significantly decreases sickling by Hydroxyurea significantly decreases sickling by myelosuppression of Hb SS cell and thereby myelosuppression of Hb SS cell and thereby increasing Hb F – trials in adults and children show increasing Hb F – trials in adults and children show safe reduction in acute episodes and allowed normal safe reduction in acute episodes and allowed normal growth and developmentgrowth and development

TREATMENTTREATMENT

Adjuvant antioxidants like alpha – Adjuvant antioxidants like alpha – tocopherol and ascorbic acid may enhance tocopherol and ascorbic acid may enhance the safety of Hydroxyureathe safety of Hydroxyurea

Clotrimazole and magnesium have been Clotrimazole and magnesium have been studied and are proposed to reduce cellular studied and are proposed to reduce cellular dehydration that may precipitate sickling – dehydration that may precipitate sickling – but their clinical value is unknown but their clinical value is unknown

Bone marrow transplantation is curative – Bone marrow transplantation is curative – 90% success and 4% perioperative mortality90% success and 4% perioperative mortality

TREATMENTTREATMENTHematuria is self limiting – treat the cause; correct Hematuria 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; avoid radiological localization and embolization; avoid nephrectomy unless exsanguinating hemorrhage nephrectomy unless exsanguinating hemorrhage presentspresents

ACE inhibitors known to definitely reduce the ACE inhibitors known to definitely reduce the proteinuria associated with SCDproteinuria associated with SCD

Whether long tern ACE inhibitor use has a salutary Whether 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 SCD ACE 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 is Specific treatment of renal failure in SCD patients is poorly exploredpoorly explored

Even mild renal failure patients may have severely Even mild renal failure patients may have severely symptomatic anemia requiring transfusionssymptomatic anemia requiring transfusions

TABLE 1 -- Diagnostic and therapeutic approach to patients with SCN a

Renal Finding Evaluation Possible Treatment

Proteinuria (>1 g) Non-nephrotic consider biopsy: R/O immune glomerulopathyNephrotic range consider biopsy: R/O renal vein thrombosis, MCNS, and immune glomerulopathy

Angiotensin inhibitors - cautious use

Gross hematuria R/O other coagulopathiesR/O other nephropathies, calculi and UTILocalize source of bleedingDetect papillary necrosisDetect medullary carcinoma

Mild: Correct anemia and maintain good hydrationSevere: EACA, local embolization, nephrectomy (rarely)

ESRD Detect renal osteodystrophy, electrolyte disturbances

Low-protein dietPO4 binders, vitamin D; dialysis and transplantation

TREATMENT - Renal transplantationTREATMENT - Renal transplantationTransplantation is a better option for SCD patients with Transplantation is a better option for SCD patients with renal failure. renal failure.

However, results may be less satisfactory than for other However, results may be less satisfactory than for other non SCD patients with renal failure – due to sickling events non 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 hematocrit Post 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 survival Transplanted SS patients have 56% ten yr survival compared to 14% in non-transplanted SS patientscompared to 14% in non-transplanted SS patients

SUMMARYSUMMARYSickle cell nephropathy is an important Sickle cell nephropathy is an important cause of mortality in SCD patients, with cause of mortality in SCD patients, with specific clinical markers that can indicate specific clinical markers that can indicate further progression to ESRD. further progression to ESRD. Chronic sickling promotes different Chronic sickling promotes different mechanisms of kidney injury: structural mechanisms of kidney injury: structural papillectomy, urine concentration defects, papillectomy, urine concentration defects, hyperfiltration, and glomerular enlargement hyperfiltration, and glomerular enlargement and sclerosis. and sclerosis. Clinical detection of the manifestations of Clinical detection of the manifestations of these processes, as well as detection of risk these processes, as well as detection of risk factors for medullary carcinoma, can permit factors for medullary carcinoma, can permit the clinician to offer a rational treatment to the clinician to offer a rational treatment to the SCD patient.the SCD patient.Chronic dialysis and transplantation Chronic dialysis and transplantation represent reasonable options for those represent reasonable options for those patients who reach ESRD.patients who reach ESRD.

Kidney in sickle cell disease

Health & Medicine

Transcript of Kidney in sickle cell disease