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Renal vascular diseases Renal vascular diseases CPCCPC

G.A. Appel MDG.A. Appel MDM.B. Stokes MDM.B. Stokes MD

Case 1Case 1

A 36 year old previously healthy A 36 year old previously healthy female develops fever and bruisingfemale develops fever and bruisingfemale develops fever and bruising . female develops fever and bruising . She goes to her LMD and CBC shows She goes to her LMD and CBC shows plats 15 K, Hct 28%, normal PT and plats 15 K, Hct 28%, normal PT and PTT. PTT.

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Case 1Case 1

Smear shows Smear shows microangiopathicmicroangiopathicmicroangiopathic microangiopathic hemolytic anemia.hemolytic anemia.

Schistocytes

Over next few days her urine output Over next few days her urine output d li d h d l ddd li d h d l dddeclines and she develops sudden declines and she develops sudden blindness followed by decreased blindness followed by decreased mental status. mental status. A renal biopsy is performed.A renal biopsy is performed.

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Glomerulus with thrombus

Platelets and RBCs

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Arteriole with thrombus

Entrapped RBCs in arteriole wall

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Case 1Case 1

Pathologic findings: Thrombotic Pathologic findings: Thrombotic microangiopathymicroangiopathymicroangiopathy microangiopathy Diagnosis: Thrombotic Diagnosis: Thrombotic Thrombocytopenic Purpura (TTP)Thrombocytopenic Purpura (TTP)

Case 1Case 1

Followup:Followup:Sh i t t d ith lSh i t t d ith lShe is treated with plasma She is treated with plasma exchange. exchange. An assay for metalloprotease An assay for metalloprotease shows marked reduction ( ADAMTS shows marked reduction ( ADAMTS 13 ).13 ).13 ).13 ).Over the ensuing weeks her mental Over the ensuing weeks her mental status improves, vision returns, and status improves, vision returns, and renal function improves.renal function improves.

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Thrombotic thrombocytopenic Thrombotic thrombocytopenic purpura (TTP)purpura (TTP)

Familial or acquiredFamilial or acquiredSingle episode or relapsingSingle episode or relapsingSingle episode, or relapsingSingle episode, or relapsingF:M 3: 2F:M 3: 2Peak in 3Peak in 3rdrd decadedecadeCNS, other extrarenal signs often predominate CNS, other extrarenal signs often predominate (e.g. fever; purpura; heart failure; lung edema; (e.g. fever; purpura; heart failure; lung edema; elevated LDH)elevated LDH)elevated LDH)elevated LDH)Acute renal failure; microangiopathic hemolytic Acute renal failure; microangiopathic hemolytic anemia; thrombocytopeniaanemia; thrombocytopenia

ADAMTS 13

A disintegrin and metalloprotease, with TSP-1-like domains

( aka vWF-clearing protease)Protease, normally degrades vWF multimersDeficiency →

platelets GPIbα ↔ vWF multimersMutations or autoAb

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ADAMTS and TTP

Levy et al, Nature 2002

Criteria for Inclusion of TTP CasesCriteria for Inclusion of TTP Cases

Presence of thrombocytopenia & microangiopathic Presence of thrombocytopenia & microangiopathic hemolysishemolysisyy

No plausible causesNo plausible causesNo features suggestive of typical or atypical HUSNo features suggestive of typical or atypical HUSAge > 10 yrAge > 10 yr

127 Cases in 4 yrs 127 Cases in 4 yrs –– All severe ADAMTS 13 All severe ADAMTS 13 deficientdeficientdeficientdeficient

Tsai HTsai H--M. JASN 14: 1072M. JASN 14: 1072--1081, 2003.1081, 2003.

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Case 2Case 2

A 4 yo female child goes to a petting zoo with A 4 yo female child goes to a petting zoo with her parents . She cuddles the sheep, calves, her parents . She cuddles the sheep, calves, p p, ,p p, ,and other baby animals. She does not wash and other baby animals. She does not wash her hands immediately afterwards.her hands immediately afterwards.3 d later she develops abdominal cramps, 3 d later she develops abdominal cramps, diarrhea, and bloody stools. N/V, fever. Given diarrhea, and bloody stools. N/V, fever. Given antibiotics by pediatrician.antibiotics by pediatrician.Day 6 echymoses of extremities and lips, Day 6 echymoses of extremities and lips, th b t i li i d ith b t i li i d ithrombocytopenia, oliguria, and seizures.thrombocytopenia, oliguria, and seizures.Stool is + for E.coli O157:H7.Stool is + for E.coli O157:H7.

Case 4: E.coliCase 4: E.coli--associated HUSassociated HUS

Pathologic findingsPathologic findings

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Colon: hemorrhagic necrosis

Fibrin/RBC thrombi

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Thrombus (trichrome stain)

Cortical necrosis

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Case 2Case 2

Diagnosis: Shiga toxinDiagnosis: Shiga toxin--related (Stx+) related (Stx+) h l ti i d ( D+HUS )h l ti i d ( D+HUS )hemolytic uremic syndrome ( D+HUS )hemolytic uremic syndrome ( D+HUS )

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Childhood HUSChildhood HUS

STx Associated STx Associated 2 1 100 000 / k < 52 1 100 000 / k < 52.1per 100,000 /yr peak < 5 yo2.1per 100,000 /yr peak < 5 yoWarm summer monthsWarm summer monthsOnset GI sx, cramps, diarrhea, n/v, feverOnset GI sx, cramps, diarrhea, n/v, fever70% bloody diarrhea w/i 2 days70% bloody diarrhea w/i 2 daysE.coli 0157 3E.coli 0157 3--7%sporadic, 20%epidemic7%sporadic, 20%epidemicp , pp , pSTx STx –– E coli in stool for wksE coli in stool for wks

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Role of Shiga ToxinRole of Shiga Toxin

Epidemics with hemorrhagic colitis +/Epidemics with hemorrhagic colitis +/-- HUSHUSEpidemics in fast food outletsEpidemics in fast food outletsEpidemics in fast food outletsEpidemics in fast food outletsE. coli 0157:H7E. coli 0157:H7

Sporadic HUS sameSporadic HUS sameA filterable agent in stool causes Hem. A filterable agent in stool causes Hem. Colitis & cytopathic to green monkey kidney Colitis & cytopathic to green monkey kidney cells (verotoxin)cells (verotoxin)cells (verotoxin)cells (verotoxin)E. Coli 0157:H7 produce both STX1 and STX2E. Coli 0157:H7 produce both STX1 and STX2

Transmission of E. Coli Transmission of E. Coli -- STXSTX

E. coli in cattle (& other animals) E. coli in cattle (& other animals) ––manure water troughs farmsmanure water troughs farmsmanure, water troughs, farmsmanure, water troughs, farmsTransmit by food or waterTransmit by food or waterUsually beef contaminated at slaughterUsually beef contaminated at slaughterAlso raw milk, fruit & veg, apple cider, Also raw milk, fruit & veg, apple cider, apple juiceapple juicePerson to person Person to person –– day care centersday care centers

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ShigatoxinShigatoxin--1 and Endothelium1 and Endothelium

Binds to Gb3 on glomerular endotheliumBinds to Gb3 on glomerular endotheliumgg

Gb3 expression equal in children vs. adultsGb3 expression equal in children vs. adults

Mechanism for childhood susceptibility Mechanism for childhood susceptibility remains undeterminedremains undetermined

Ergonul, Clayton, Fogo, Kohan, 2003

Verotoxin

•A subunit binds 60S•A subunit binds 60SRibosomes, inhibit proteinsynthesis

•5 B subunits binds glycolipidreceptors (gb3) onsurface of colonic epithelium,su ace o co o c ep t e u ,endothelium, and WBCs

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Shiga Toxin and Cell Injury

Moake, NEJM 2002

Higher Risk HUSHigher Risk HUS

AntibioticsAntibioticsBloody diarrheaBloody diarrheaFever, vomitingFever, vomitingLeukocytosisLeukocytosis< 5 yo< 5 yofemalesfemales

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Course ARF Childhood HUSCourse ARF Childhood HUS

50% dialysis50% dialysis75% transfusions75% transfusions25% Neuro sx ( CVA, sz, coma )25% Neuro sx ( CVA, sz, coma )33--5% die in acute phase5% die in acute phaseLong term renal dysfunction commonLong term renal dysfunction common

Residual Renal Disease in Childhood Residual Renal Disease in Childhood HUSHUS

33--18% ESRD18% ESRD1010--40% low GFR, proteinuria, CRF, HBP40% low GFR, proteinuria, CRF, HBPDuration anuria predicts dysfunctionDuration anuria predicts dysfunction

7.5 % anuria < 10 days low GFR7.5 % anuria < 10 days low GFR42.5% anuria > 16 days low GFR42.5% anuria > 16 days low GFR

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Case 3Case 3

An 28 year old male has a hx of TTPAn 28 year old male has a hx of TTP--HUS HUS at age 12 yo. He progressed to ESRD at age 12 yo. He progressed to ESRD slowly over a few years and has a Hx of aslowly over a few years and has a Hx of aslowly over a few years, and has a Hx of a slowly over a few years, and has a Hx of a renal txp from his mother at 20 yo renal txp from his mother at 20 yo elsewhere that failed 3 months post Txp. elsewhere that failed 3 months post Txp. His brother is a dialysis patient as well.His brother is a dialysis patient as well.The bx report from the failed Txp reads The bx report from the failed Txp reads “thrombotic microangiopathy”.“thrombotic microangiopathy”.Th ti t l t l lTh ti t l t l lThe patients complement values are low The patients complement values are low especially his C3 level.especially his C3 level.His father is offering him a kidney. Should His father is offering him a kidney. Should he take it?he take it?

Case 3Case 3

Diagnosis: Atypical Hemolytic Uremic Diagnosis: Atypical Hemolytic Uremic Syndrome (D Syndrome (D ––HUS)HUS)

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Atypical Hemolytic Uremic SyndromeAtypical Hemolytic Uremic SyndromeAtypical hemolytic uremic syndrome= Shiga Atypical hemolytic uremic syndrome= Shiga

Toxin Negative HUS.Toxin Negative HUS.

Most cases due to continuous activation of the Most cases due to continuous activation of the alternate complement system due to genetic alternate complement system due to genetic

defects in regulatory proteins Factor H, Factor I defects in regulatory proteins Factor H, Factor I or MCP.or MCP.

Some cases due to antibodies that alter the Some cases due to antibodies that alter the action of these complement regulatory proteins.action of these complement regulatory proteins.

In some patients liver transplant along with In some patients liver transplant along with kidney transplant is the therapy of choice ( tokidney transplant is the therapy of choice ( tokidney transplant is the therapy of choice ( to kidney transplant is the therapy of choice ( to

replace the missing complement inhibitor)replace the missing complement inhibitor)Registry of nonRegistry of non--STx HUS/TTP includes 164 STx HUS/TTP includes 164

centers worldcenters world--wide; Total pts wide; Total pts –– 412 ( familial 85, 412 ( familial 85, sporadic 327)sporadic 327)

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Thrombotic thrombocytopenic Thrombotic thrombocytopenic purpura (TTP)purpura (TTP)

CNS signs predominateCNS signs predominateDeficiencies of vWF cleaving Deficiencies of vWF cleaving metalloproteinase (ADAMTS13), eithermetalloproteinase (ADAMTS13), either

Hereditary (rare)Hereditary (rare)Acquired (autoantibodies)Acquired (autoantibodies)

Thrombotic microangiopathy: diverse etiologies

Antiphospholipid antibody (+/- SLE)

Wolf G. NDT 2004

Malignant HTN

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27 yo F stock analyst has a hx of three 27 yo F stock analyst has a hx of three spontaneous abortions, and Raynaud’s spontaneous abortions, and Raynaud’s phenomenon. Two years ago she deleoped a DVT phenomenon. Two years ago she deleoped a DVT of the right calf after a long auto trip. She of the right calf after a long auto trip. She develops arthralgias, low temps, and malaise.develops arthralgias, low temps, and malaise.

Case 4

Px BP 152/92, P 84, malar flush, 2/6 SEM, swollen Px BP 152/92, P 84, malar flush, 2/6 SEM, swollen MCP and PIP joints, livedo reticularis of legs and MCP and PIP joints, livedo reticularis of legs and arms , 2+ ankle edema. arms , 2+ ankle edema.

WBC 3.6 K, Hct 24%, plts 89KWBC 3.6 K, Hct 24%, plts 89KU/A 4+ prot, 3+ heme, 8U/A 4+ prot, 3+ heme, 8--15 rbc, + rbc casts15 rbc, + rbc castsBUN 43 mg/dl, Pcreat 2.6 mg/dl, 24 hr UV prot BUN 43 mg/dl, Pcreat 2.6 mg/dl, 24 hr UV prot

1.8g/d, PT 14.6 , PTT 85.1.8g/d, PT 14.6 , PTT 85.ANA + 1:160, antiANA + 1:160, anti--dsDNA negative, complement dsDNA negative, complement

borderline, + VDRL.borderline, + VDRL.

Diagnosis: Antiphospholipid antibody Syndrome (anticardiolipin syndrome)

Case 4

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Case 4:Antiphospholipid antibody Case 4:Antiphospholipid antibody syndromesyndrome

Pathologic findingsPathologic findings

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Ischemic wrinkling

Glomeruli show ischemic changes (global wrinkling of glomerular basement membranes, tuft retraction, and cystic dilation of Bowman's space)

Glomeruli show segmental intracapillary fibrin

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Arteries show widespread luminal narrowing with extensive subendothelial hyalinosis, endothelial swelling, focal myocyte dropout, focal mucoid intimal fibroplasia, and focal intramural fibrin with entrapped red blood cells.

Artery shows intimal expansion and luminal obliteration

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Artery shows fibrin thrombus and entrapped RBCs

Artery with fibrin thrombus

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Recanalized artery (healed thrombus))

Fibrin

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Subendothelial Fibrin

Endothelial cell

GBM

Case 5Case 5

70WM with longstanding HTN70WM with longstanding HTNMild CKDMild CKDMild CKD Mild CKD BP becomes increasing difficult to controlBP becomes increasing difficult to control

Renal MR angiogram performedRenal MR angiogram performed

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Renal artery stenosisRenal artery stenosis

Renal artery atherosclerosisRenal artery atherosclerosis

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Case 5 (cont’d)Case 5 (cont’d)

Rx: AngioplastyRx: AngioplastyBP t bili b t th d l ARFBP t bili b t th d l ARFBP stabilizes but then develops ARF, BP stabilizes but then develops ARF, rash, eosinophiliarash, eosinophilia

Renal biopsy performedRenal biopsy performed

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Case 5Case 5

Renal biopsy findings:Renal biopsy findings:

Hypertensive nephrosclerosisFinely granular surface

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Hypertensive nephrosclerosis

Thin renal cortex

Hypertensive arteriolosclerosisHypertensive arteriolosclerosis

Arteriolar sclerosis and hyalinosis

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Cholesterol embolus

Case 5Case 5

Diagnoses: Diagnoses: 1. Renal atheroembolic disease1. Renal atheroembolic disease2. Hypertensive 2. Hypertensive arterionephrosclerosisarterionephrosclerosis