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Kidney in sickle cell disease
This document discusses the kidney involvement in sickle cell disease. It begins by providing background on the discovery of sickle cell disease and the genetic basis involving a mutation in the hemoglobin gene. It then covers the epidemiology and natural history of sickle cell disease, including clinical manifestations involving the kidneys. It discusses various renal pathologies seen in sickle cell disease like hematuria, proteinuria, renal papillary necrosis and chronic renal failure. Finally, it explores the pathophysiology of renal involvement, with sickling of red blood cells in the kidney vasculature and medulla playing a key role in reduced perfusion and infarction leading to chronic kidney damage.
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Kidney in sickle cell disease
- 1. THE KIDNEY INSICKLETHE KIDNEY IN SICKLE CELL DISEASECELL DISEASE
- 2. SICKLE CELL ANEMIASICKLECELL 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
- 4. Worldwide distribution ofthe 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 inthe 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
- 7. SCD – NATURALHISTORYSCD – 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
- 8. SCD – NATURALHISTORYSCD – NATURAL HISTORY Childhood - crisesChildhood - crises Hemolytic crisis – hemolysis > replenishment Aplastic crisis – Retics lag behind – Parvovirus B19 Sequestration crisis – large scale splenic trapping of RBCs – pain, splenomegaly, circulatory collapse Painful infarctive crises – microinfarctions, vaso-occlusive disease
- 9. SCD – NATURALHISTORYSCD – 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 ofinfection 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 – NATURALHISTORYSCD – 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 – NATURALHISTORY –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 ofmajor 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 RenalEpidemiologyof 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
- 15. Renal Manifestations inSickleRenal Manifestations in Sickle Cell DiseaseCell Disease Asymptomatic hematuriaAsymptomatic hematuria HyposthenuriaHyposthenuria Renal acidification and potassiumRenal acidification and potassium excretion defectsexcretion defects Glomerular dysfunctionGlomerular dysfunction Proteinuria and Nephrotic syndromeProteinuria and Nephrotic syndrome Renal papillary necrosisRenal papillary necrosis Urinary Tract InfectionsUrinary Tract Infections HypertensionHypertension Acute renal failureAcute renal failure Chronic renal failureChronic renal failure Renal medullary carcinomaRenal medullary carcinoma
- 16. Epidemiology contd…Epidemiology contd… Clinicalheterogenity 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
- 17. SCD - PATHOPHYSIOLOGYSCD- PATHOPHYSIOLOGY
- 18. Pathophysiology contd…Pathophysiology contd… Basicdefect 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
- 23. Pathophysiology contdPathophysiology contd…… SCDRBC 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 underliesseveralChronic 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 involvementcontd..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
- 28. Injection micrograph ofkidneys 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 crisisresults 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 fillingup 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 invasa 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).
- 33. Pathophysiology –RenalPathophysiology –Renal involvementcontd..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 involvementcontd..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 involvementcontd..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 INSCDRENAL 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.. Glomerularhypertrophy 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 withsickle 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 ina 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 samefromthe 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 increasein 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 areno 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 cellnephropathy,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 abundanthemoglobin 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 Unlikein 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 onsetof renal features of sickle cell diseaseAge at onset of renal features of sickle cell disease
- 51. CLINICAL FEATURESCLINICAL FEATURES FIRSTDECADEFIRST DECADE – Decreased medullary blood flowDecreased medullary blood flow – NocturiaNocturia – EnuresisEnuresis – HyposthenuriaHyposthenuria – HyperfiltrationHyperfiltration
- 52. CLINICAL FEATURESCLINICAL FEATURES SECONDDECADESECOND 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 THIRDDECADETHIRD 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 renalmanifestationMost 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 evidenceof 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 andRenalAcidification 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 GFRinitially 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 NephroticProteinuriaand 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)
- 59. PrevalencePrevalence rates ofrates of proteinuriproteinuri aanda and renalrenal failure perfailure per decade ofdecade of lifelife
- 60. Renal Papillary NecrosisRenalPapillary 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 ofrenal 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 InfectionsUrinaryTract 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 FailureAcuteRenal 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 FailureChronicRenal 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 ofsurvival (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 Distinctiverenal 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 CARCINOMAcontd..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 serioussickle 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 likealpha –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 selflimiting – 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 - RenaltransplantationTREATMENT - 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 nephropathyis 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.
- 76.