Approach in Glomerular DiseasesApproach in Glomerular Diseases

์ผศ.นพ. เถลิงศักดิ์ กาญจนบุษย

สาขาวิชาโรคไต ภาควิชาอายุรศาสตร

ั ั โ ไ ป ึหัวหนาศูนยวิจัยโรคไตและความผิดปกติทางเมตาบอลิซึม

จุฬาลงกรณมหาวิทยาลัย

JCMS  2009

HematuriaHematuriaDysmorphic

AcanthocyteProteinuriaProteinuriaP i i       /dAcanthocyte

RBC castProteinuria > 2 gm/day

GFR ↓GFR ↓iAzotemia

Oliguria 

GLOMERULARGLOMERULARSaltSalt--water retentionwater retention

EdemaGLOMERULAR GLOMERULAR DISEASEDISEASE

Edema

HT 

Helen Liapis, 2002

Afferent arterioleEfferent arteriole

Bowman’s capsule

Endothelium

Podocyte

Pedicle

PCT

GFR = snGFR x Nephron

snGFR = (PGC-PT) x KUF

AzotemiaOliguria

PPGCGC

KKUFUF

PPTT

MechanismMechanismGFR

Reabsorption

ManifestationsEdemaHTHT

Glomerular hematuria

Acute self-limited inflammation

Proteinuria usually < 3 gm/day

Salt retentionAGN DPGNOliguria, Azotemia

Abrupt, usually self‐ limiting

DPGN

Glomerular hematuria

GBM ruptureGlomerular hematuria

Proteinuria usually < 3 gm/day

Less salt retentionRPGNIC mediatedAnti-GBMPauci-immune

RF over days/week; progessivePauci-immune

HT

Progressive disease: ongoing, sclerosis

Proteinuria > 2 gm/day

Renal insufficiencyCGNIC mediatedNon-IC mediatedN iFit in CRF criteria Non-immune

Podocyte injury GBM charge lossProteinuria ≥ 3.5 gm/day/1.73 m2 ; UPCR > 3 

gm/day + Lipiduria

Podocyte injury, GBM charge loss

g y p

Edema

HyperlipidemiaNSMCDFSGS IgM nephropathy

Hypercoagulationg p p yMPGNMN

H t i     /HPIgATBM/Al t’

Less severe injuryHematuria > 2/HP

Asymptomatic

TBM/Alport’sPostinfectiousPost-GN

Proteinuria 0.15‐3.0 

gm/day ±

y pFSGS IgM

Hematuria > 2/HP MPGNMNIgA Alport’sIgA, Alport s IC mediated

Gross hematuriaMacroscopic hematuria

IgAStoneAIN&CTIN

GBM gaps

hematuria AIN&CTINLoin painhematuria

Case 1

A 43 year old female presented with 1 weeks of progressive facial edema, orthopnea, and PND . A day before admit she developed sudden gross hematuria PE revealsadmit, she developed sudden gross hematuria. PE reveals afebrile, BP 140/92 mm.Hg, and generalized edema. Laboratory evaluation reveals BUN 49 mg/dL, Cr 1.5 mg/dL, hypoalbuminemia hyperkalemic wide-gap MAhypoalbuminemia, hyperkalemic wide-gap MAUrinalysis revealed sp.gr. 1.020, 2+ urinary protein, RBC 80-100/HP, WBC 5-7/HP.

1) Which glomerular syndrome is fit for the patient? 2) What additional laboratory tests should be performed in

this patient ? p

1. Acute GN

2. Rapidly progressive GN Nephritis

3. Chronic GNNephrosis

 A i   i i  / h i

4. Nephrotic syndromep

5. Asymptomatic proteinuria / hematuria

Etiologies of Acute Glomerulonephritis

Low Complement Normal ComplementPrimary

Acute PSGN (>90%)MPGN

PrimaryIgA nephropathyIdiopathic CGN

Type I (50‐80%)Type II (80‐90%)

Secondary

pAnti‐GBMPauci‐immune

SecondaryySLE

Focal (75%)Diffuse (90%)

yHypersensitivity vasculitisWGHSP9

Acute‐subacute IE (90%)Visceral abscess“Shunt” nephritis

HSPGoodpasture syndrome

pCryoglobulinemia (85%)

Pathway  Complement  Glomerular diseasePathway affected

Complement changes

Glomerular disease

Classical ‐C3, C4, CH50 MPGN I

LN III, IV

Alternative ‐C3, CH50 PSAGN, HUS

Infection related+ C3 nephritic factor MPGN II

Disease C’ levels Comment

Atheroembolism ↓C3, ± ↓C4 Usually transient, mainly during acute t e oe bo s ↓C3, ↓C4 Usua y t a s e t, a y du g acuteembolism

Severe sepsis ↓C3, ↓C4 Esp. with shock

HUS/TTP ↓C3, ± ↓C4 ~50% of cases

Acute pancreatitis ↓C3  ↓C4 Subsides in a few daysAcute pancreatitis ↓C3, ↓C4 Subsides in a few days

Severe malnutrition ↓C3, ± N C4 C1q is also low

Severe liver disease ↓C3, ↓C4 C1q levels are normal

Inherited C4 deficiency N C3, ±↓C4 20‐40% of normals have one or two C4 null genes; higher incidence found in SLE

Case 1

A 43 year old female presented with 1 weeks of progressive facial edema, orthopnea, and PND . A day before admit she developed sudden gross hematuria PE revealsadmit, she developed sudden gross hematuria. PE reveals afebrile, BP 140/92 mm.Hg, and generalized edema. Laboratory evaluation reveals BUN 49 mg/dL, Cr 1.5 mg/dL, hypoalbuminemia hyperkalemic wide-gap MAhypoalbuminemia, hyperkalemic wide-gap MAUrinalysis revealed sp.gr. 1.020, 2+ urinary protein, RBC 80-100/HP, WBC 5-7/HP.Further investigations found low C3 but normal C4, negativeFurther investigations found low C3 but normal C4, negative viral serologies, and UPCI 2.2

1) What is your final conclusion?2) How to confirm the diagnosis?3) How to manage the patient?

Nephrotic Features Nephritic Features

MCD  ++++ ‐MN ++++ +FSGS +++ ++Fibrillary GN +++ ++Mesangioproliferative  GN ++ ++g p ++ ++MPGN ++ +++Diffuse proliferative GN ++ +++Diffuse proliferative GN ++ +++Acute PSGN + ++++

iCrescentic GN + ++++

Children (%) Elderly (%)

Hematuria 100 100

Proteinuria 80 92

Edema 90 75

Hypertension 60-80 83

Oliguria 10-50 58

Dyspnea/heart failure <5 43

Nephrotic proteinuria 4 20

Azotemia 25-40 83

Early mortality <1 25

Case 1

A 43 year old female presented with 1 weeks of progressive facial edema, orthopnea, and PND . A day before admit she developed sudden gross hematuria PE revealsadmit, she developed sudden gross hematuria. PE reveals afebrile, BP 140/92 mm.Hg, and generalized edema. Laboratory evaluation reveals BUN 49 mg/dL, Cr 1.5 mg/dL, hypoalbuminemia hyperkalemic wide-gap MAhypoalbuminemia, hyperkalemic wide-gap MAUrinalysis revealed sp.gr. 1.020, 2+ urinary protein, RBC 80-100/HP, WBC 5-7/HP.Further investigations found low C3 but normal C4, negativeFurther investigations found low C3 but normal C4, negative viral serologies, and UPCI 2.2

1) What is your final conclusion?2) How to confirm the diagnosis?3) How to manage the patient?

ASO ~ ASO ~ 7575% % AntiAnti--DNase B DNase B 9090%%AHA more sensitive for pyodermaAHA more sensitive for pyodermaAntiAnti--GAPDH (NPlr)GAPDH (NPlr)AntiAnti--SpeB/ ZymogenSpeB/ ZymogenDemonstrates streptococcal infection, but Demonstrates streptococcal infection, but does not predict development or severity does not predict development or severity

f GNf GNof GNof GN

Case 1

A 43 year old female presented with 1 weeks of progressive facial edema, orthopnea, and PND . A day before admit she developed sudden gross hematuria PE revealsadmit, she developed sudden gross hematuria. PE reveals afebrile, BP 140/92 mm.Hg, and generalized edema. Laboratory evaluation reveals BUN 49 mg/dL, Cr 1.5 mg/dL, hypoalbuminemia hyperkalemic wide-gap MAhypoalbuminemia, hyperkalemic wide-gap MAUrinalysis revealed sp.gr. 1.020, 2+ urinary protein, RBC 80-100/HP, WBC 5-7/HP.Further investigations found low C3 but normal C4, negativeFurther investigations found low C3 but normal C4, negative viral serologies, and UPCI 2.2

1) What is your final conclusion?2) How to confirm the diagnosis?3) How to manage the patient?

Atypical presentationCli i l Short latent period Clinical Short latent period 

Nephrotic syndrome or RPGN Anuria Multiorgan involvement

Lab Low antistreptococcal titerNormal C3Low C1q, C2 or C4 

Delayed resolution

Short term Renal failure: 2 weeksH i  h t i    kHypertension or gross hematuria: 3  weeksLow C3: 6  weeks

Long term Proteinuria:  6 monthsHematuria: 12 monthsHematuria: 12 months

Get rid source

Corticosteroid & immunosuppressive agentpp g

Some organisms still progress in spite of effective treatmentStaphylococcus aureus

ll iBrucellosisQuartan malariaSchistosomiasis

Case 2

A 43 year old year is found to have Scr of 1.6 mg/dland BUN of 32 mg/dl on her annual check up. Her urinalysis shows 3 4+ protein a few rbc’s with some dysmorphic but noshows 3-4+ protein, a few rbc’s with some dysmorphic but no rbc casts. She is found to have 3.8 g proteinuria daily. PE reveals a BP 160/92 mm.Hg, and no edema. Further laboratory evaluation reveals WBC 50 000 /mm3 a reducedlaboratory evaluation reveals WBC 50,000 /mm3, a reduced CH50, a borderline C3 level, and a reduced C4 level.

1) What is the differential diagnosis for renal diseases with1) What is the differential diagnosis for renal diseases with nephrito-NS?

2) What additional laboratory tests should be performed in this patient ?this patient ?

Classification of Glomerular Diseases

1o Glomerular Disease(idiopathic; renal‐limited)

MCD

2oGlomerular Disease(associated with multi‐system 

disease)MCDFSGSMesangial GN (IgA, IgM)

disease)Systemic diseasesSystemic Infections

MN MPGNCrescentic GN

Vascular diseasesMetabolic & Deposition diseasesHereditary nephropathiesCrescentic GN

Sclerosing GNUnclassified GN

Hereditary nephropathiesMiscellaneous

Mesangiocapillary GNDeposition diseases

Amyloidosis

Light‐chain deposition diseaseFibrillary GN and Immunotactoid GNFibrillary GN and Immunotactoid GN

Hereditary disease: Alport’s syndromeSome cases of mesangial  focal and diffused Some cases of mesangial, focal and diffused proliferative GN

IgA nephropathyg p p y

Post‐infectious GNLupus nephritis

Diabetic nephropathy

Case 2

A 43 year old year is found to have Scr of 1.6 mg/dland BUN of 32 mg/dl on her annual check up. Her urinalysis shows 3 4+ protein a few rbc’s with some dysmorphic but noshows 3-4+ protein, a few rbc’s with some dysmorphic but no rbc casts. She is found to have 3.8 g proteinuria daily. PE reveals a BP 160/92 mm.Hg, and no edema. Further laboratory evaluation reveals WBC 50 000 /mm3 a reducedlaboratory evaluation reveals WBC 50,000 /mm3, a reduced CH50, a borderline C3 level, and a reduced C4 level.

1) What is the differential diagnosis for renal diseases with1) What is the differential diagnosis for renal diseases with nephrito-NS?

2) What additional laboratory tests should be performed in this patient ?this patient ?

Classification of Cryoglobulinemia

Type I Type II Type III

Ig content Single mIg (IgMk, IgGk, pIgG pIgG

IgAk ) mIgM

(IgMk – IgG)

pIgM

(IgM – IgG)

RF Negative Positive Occ. positive

Associated

disease

Multiple myeloma

Dysproteinmias

HCV

HBV

Collagen vascular

Chronic infections

SBELymphoma Lymphoma •SBE

•Leprosy

•HBV

•HCV

Unknown genetic and environmental factor

HCV

Unknown genetic and environmental factor

HCV

E 2t (14,18 )t Bcl 2*

o ere pression

B B B

overexpressionCD 81

B cell NHLPolyclonal RF Oligoclonal RF

MC type III MC type II-III Cli E Rh t l 2003 21 (S l 31)MC type IIIOther autoimmune

disorder

MC type II-IIIMC type II

Clin Exp Rheumatol 2003; 21 (Suppl. 31)S78-S84.

Evidence for HCV Virus in EMC

Anti-HCV antibidies (by RIBA) pressent in 91% of 45 pts with EMC(Ferri et al. Infection 1991; 19:417)

HCV RNA detected in 86% of 45 patients with EMC (Ferri et al. Clin Exp Rheumatol 1991; 9:621)

HCV RNA and anti-HCV Ab are concentrated in the cryoglobulins (Agnello et al. NEJM 1992; 327:1490)

(Misiani et al. Ann Int Med 1992; 117:573)

Spectrum of HCV-Associated IC Disease

EMC EMC ĉ

MPGN

MPGN ĉ

Cryoglobulins

MPGN ŝ

Cryoglobulins

MN

IC Size

Case 3

A 66 year old, an accountant, develops cough, arthralgias, malaise, and weight loss. He is normotensive, and has no arthritis or edema. He is found to have a hazy LLLinfiltrate on his chest X-ray, a urinalysis with 3+ proteinuriaand 4+ heme, with many rbc’s and many dysmorphic acanthocytes, a BUN of 25 mg/dl and serum creatinine of 1.8

/dl d 24 h i h 5 6 lb i i d ilmg/dl, and 24 hour urine shows 5.6 grams albuminuria daily. ANA is positive 1:80, and complement is WNL.

1) What is the differential diagnosis of “renal pulmonary1) What is the differential diagnosis of renal-pulmonary syndromes” ? Which serologic tests are helpful in this case ?

2) A renal biopsy is performed but there is only a small piece2) A renal biopsy is performed, but there is only a small piece of tissue. Although there will be adequate amount for light microscopy, the pathologist asks you whether to put the remaining tissue for, IF, or EM. You advise ?g , ,

With pulmonary edemaARF with hypervolemiaSevere cardiac failureSevere cardiac failure

InfectiveSevere bacterial pneumonia (e.g. Legionella) with RFHantavirus infectionHantavirus infectionOpportunistic infections in the immunocompromised

OthersARDS with RF in multi‐organ failureARDS with RF in multi organ failureParaquat poisoningRenal vein/IVC thrombosis with pulmonary emboliDisease associated with Anti‐GBM (20‐40% of cases) ( 4 )Goodpasture’s disease (spontaneous anti‐GBM disease)

Anti-GBM Ab (20-40%)Goodpasture’s disease (spontaneous anti-GBM dis.)

Systemic vasculitis (60-80%)Wegener’s granulomatosis

Commong g

Microscopic polyangiitisSystemic lupus erythematosusChurg Strauss syndromeg yHenoch‐SchÖnlein purpuraBehçet’s diseaseEssential mixed cryoglobulinemiaEssential mixed cryoglobulinemiaRheumatoid vasculitisDrugs: penicillamine, hydralazine, propylthiouracil

Case 2

A 66 year old, an accountant, develops cough, arthralgias, malaise, and weight loss. He is normotensive, and has no arthritis or edema. He is found to have a hazy LLLinfiltrate on his chest X-ray, a urinalysis with 3+ proteinuriaand 4+ heme, with many rbc’s and many dysmorphic acanthocytes, a BUN of 25 mg/dl and serum creatinine of 1.8

/dl d 24 h i h 5 6 lb i i d ilmg/dl, and 24 hour urine shows 5.6 grams albuminuria daily. ANA is positive 1:80, and complement is WNL.

1) What is the differential diagnosis of “renal pulmonary1) What is the differential diagnosis of renal-pulmonary syndromes” ? Which serologic tests are helpful in this case ?

2) A renal biopsy is performed but there is only a small piece2) A renal biopsy is performed, but there is only a small piece of tissue. Although there will be adequate amount for light microscopy, the pathologist asks you whether to put the remaining tissue for, IF, or EM. You advise ?g , ,

DiagnosisFollow upp

Remission: 80% ANCA ‐Relapse: 75% ANCA +p 75No symptom: 1/4 ‐ 1/3 increasing titerLimitation:ANCA testing represents several testsANCA‐vasculitis represents several diseasesVary in criteria dx of relapseVary in criteria dx of relapse

Predict outcome

Age > 50 yrAge > 50 yr

Clinical presentationPrevalence of 

PI‐CGNPPV for PI‐

CGNNPV for PI‐

CGNClinical presentation PI‐CGN CGN CGN

RPGN 66% (82/124) 99% 65%

Hematuria, proteinuria, and Cr > 3 mg/dl

30% (147/497) 95% 89%Cr > 3 mg/dl

Hematuria, proteinuria, and Cr 1 5‐3 mg/dl

11% (36/311) 85% 97%Cr 1.5‐3 mg/dl

Hematuria, proteinuria, and Cr < 1 5 mg/dl

4% (7/195) 66% 99%Cr < 1.5 mg/dl

Case 3

A 66 year old, an accountant, develops cough, arthralgias, malaise, and weight loss. He is normotensive, and has no arthritis or edema. He is found to have a hazy LLLinfiltrate on his chest X-ray, a urinalysis with 3+ proteinuriaand 4+ heme, with many rbc’s and many dysmorphic acanthocytes, a BUN of 25 mg/dl and serum creatinine of 1.8

/dl d 24 h i h 5 6 lb i i d ilmg/dl, and 24 hour urine shows 5.6 grams albuminuria daily. ANA is positive 1:80, and complement is WNL.

1) What is the differential diagnosis of “renal pulmonary1) What is the differential diagnosis of renal-pulmonary syndromes” ? Which serologic tests are helpful in this case ?

2) A renal biopsy is performed but there is only a small piece2) A renal biopsy is performed, but there is only a small piece of tissue. Although there will be adequate amount for light microscopy, the pathologist asks you whether to put the remaining tissue for, IF, or EM. You advise ?g , ,

Case 4

A 48 year old female pharmacist has a history of DVT 4 yrs ago, and a PE 2 years ago. She is found to have an elevated Scr of 1.8 mg/dl, urinalysis 3+ protein 5-10 rbc’s 0 g , y pcasts. Physical exam shows BP 150/92 mm.Hg, 1+ pedal edema, prominent P2, and livedo reticularis of the legs. 24 hr urinary protein excretion is 1.9 g/day, ANA+ 1:160, anti DNA antibody negative, serum complement WNL; wbc 6,200, HCT 36%, platelets 100,000.

1) Wh t l i t t i ht fi th di i h ?1) What serologic tests might confirm the diagnosis here ?

2) What features in the history might help in the diagnosis ?

3) What other routine laboratory features are useful3) What other routine laboratory features are useful diagnostically while the definitive serologic tests are pending ?

Case 5A 29 year old. Female computer processor presents

with fever, lymphadenopathy, and diffuse arthritis of the small hand joints. She is found to have a WBC of 2,800, HCT 22%,platelets 168 000 Urinalysis shows 4+ protein 20 30 rbc andplatelets 168,000. Urinalysis shows 4+ protein, 20-30 rbc, and rbc casts; ANA 1:1280. A renal biopsy shows DPLN, WHO Class IV.

1) Which tests predict the best prognosis of this patient over the next decade ?

2) What serologic tests are the best guide to immediate therapy of this patient ?

3) If the patient had been taking minocycline for acne what3) If the patient had been taking minocycline for acne, what serologic tests might help in determining whether this is drug related disease ?

4) What medications can produce drug related SLE ? How is4) What medications can produce drug related SLE ? How is the diagnosis established ?

C4(mg/dL)(mg/dL)

C3 (mg/dL)

Case 5A 29 year old. Female computer processor presents

with fever, lymphadenopathy, and diffuse arthritis of the small hand joints. She is found to have a WBC of 2,800, HCT 22%,platelets 168 000 Urinalysis shows 4+ protein 20 30 rbc andplatelets 168,000. Urinalysis shows 4+ protein, 20-30 rbc, and rbc casts; ANA 1:1280. A renal biopsy shows DPLN, WHO Class IV.

1) Which tests predict the best prognosis of this patient over the next decade ?

2) What serologic tests are the best guide to immediate therapy of this patient ?

3) If the patient had been taking minocycline for acne what3) If the patient had been taking minocycline for acne, what serologic tests might help in determining whether this is drug related disease ?

4) What medications can produce drug related SLE ? How is4) What medications can produce drug related SLE ? How is the diagnosis established ?

Ag Specificity Clinical Association

dsDNA Marker for active disease; titers fluctuate with disease activityy

ssDNA Non-specific

Ro/SSA Cutaneous lupus (75%), photosensitivity, neonatal lupus

La/SSB With La, low prevalence of renal disease, neonatal lupus (75%)

Sm Marker for disease; 15-30 % sensitivity, may be asso. with CNS disease

RNP (U1-RNP) MCTD, required for diagnosis; in SLE-mild, non-renal

Phospholipids Hypercoaqulable state in some, no significance in others; thrombocytopenia, latertrimester abortionslatertrimester abortions

Histones >95% in drug-related lupus; present in RA> SLE, systemic sclerosis with pulmonary fibrosis

KU SLE, MCTD (Europeans/Americans): scleroderma/myositis overlap (Japanese)

Homogenous Peripheral

Speckle Nucleolar

D fi it P iblDefiniteProcainamideHydralazine

PossibleAnticonvulsants - phenytoinQuinidineHydralazine

DiltiazemMinocyclinePenicillamine

QuinidineAnti-thyroid drugsSulfonamidesLithiumPenicillamine

INHMethyldopaChlorpromazine

LithiumBeta-blockersNitofurantoinPASChlorpromazine

PractololPASCaptoprilInterferon alphaHCTZHCTZGlyburideCarbamazepineSulfasalazineSulfasalazineHydralazine

Fever, myalgias, rash, arthralgiasFever, myalgias, rash, arthralgias--arthritis, arthritis, serositis hemotologic abnomalitiesserositis hemotologic abnomalitiesserositis, hemotologic abnomalitiesserositis, hemotologic abnomalitiesKidney disease and CNS uncommonKidney disease and CNS uncommonAntiAnti DNA Ab and low C` uncommonDNA Ab and low C` uncommonAntiAnti--DNA Ab and low C uncommonDNA Ab and low C uncommonSome with renal disease are ANCA + (antiSome with renal disease are ANCA + (anti--MPO + lactoferin)MPO + lactoferin)MPO + lactoferin)MPO + lactoferin)

Clinical feature Spontaneous lupus Drug‐induced lupusUsual age 20‐40 50

Female to male ratio 9:1 1:1Female to male ratio 9:1 1:1

Race All “No blacks”

Acetylation type Slow = Fast Slow

O t  f  t G d l Ab tOnset of symptoms Gradual Abrupt

Constitutional symptoms 83 50

Arthralgia and arthritis 90 95

Pleuropericarditis (procainamide)

50 50

Hepatomegaly 25 25

Rash (all types) 74 10‐20

Discoid lesions 20 0

Malar erythema 42 2y 4

Renal diseases 53 5

CNS disease Common Unusual

Immunologic abnormalitiesANA 95 95

LE cells 90 90

Anti RNP 40 50 20Anti‐RNP 40‐50 20

Anti‐Sm 20‐30 Rare

Anti‐DNA 80 Rare

Antihistone 80 90

Complement Reduced Normal

Immune complexes Elevated NormalImmune complexes Elevated Normal

Present in > 95% drugPresent in > 95% drug--induced lupusinduced lupusPresent in > 95% drugPresent in > 95% drug induced lupusinduced lupusCommon with procainamide, hydralazine, Common with procainamide, hydralazine, chlorpromazine, quinidinechlorpromazine, quinidinep , qp , qCommon in native SLE ( but with AntiCommon in native SLE ( but with Anti--DNA DNA Abs, AntiAbs, Anti--Sm Ab, etc.)Sm Ab, etc.),, , ), )

Etiologies:Etiologies:H d l iH d l iHydralazine Hydralazine

High dose (>High dose (>200 200 mg/day mg/day ±± cumulative > cumulative > 100 100 gmgmFemaleFemaleFemaleFemaleSlow hepatic acetylationSlow hepatic acetylationHLAHLA--DR DR 44CC4 4 def.def.

MinocyclineMinocyclineANA ANA 9292%%pp--ANCA ANCA 8383%% Should not be used in SLE

ManifestationManifestationfrequent present with renalfrequent present with renalAntiAnti--dsDNA+dsDNA+AntiAnti histone: may negativehistone: may negativeAntiAnti--histone: may negativehistone: may negativeHigh titer MPOHigh titer MPOlupuslupus--like RPGN PANlike RPGN PANlupuslupus like, RPGN, PANlike, RPGN, PANMay need aggressive PX +drug withdrawalMay need aggressive PX +drug withdrawal

Case 6A 62 year old white female housewife develops y p

periorbital edema in the AM followed by pedal and ankle edema later in the day, and a 6 kg weight gain. PE shows BP 142/84 mm.Hg, CTS, and edema only. Lab shows Urinalysis 4+ protein, 2-3 rbc, few oval fat bodies, BUN 18 mg/dl, creatinine 0.9 mg/dl, glucose 118 mg/dl, plasma albumin 2.4g/dl, cholesterol 236 mg/dl, and 24 hour urinary protein 10

/dg/day.

1) What serologic tests are helpful in the nephrotic syndrome before biopsy ?p y

2) If the patient was 32 years old rather than 62 years old would the testing be different ?

3) Is biopsy useful here ?

Histopathologic diagnosis Age 15‐35 yrsN = 175 (%)

Age 36-60 yrsN = 180 (%)

Age > 60 yrsN = 46(%)

MCD 8MCD 22.4 7.8 13

FSGS 20 26.7 23.9

MN 12.1 17.8 10.9

MPGN 4.2 3.3 4.4

IgAN 23 11.7 4.4

Non‐IgA MesPGN  8.5 8.3 6.5

LNLN 1.2 1.1 4.4

DN 1 9.4 4.4

Post‐infectious GN 3 7.8 8.7

D iti  di 8Deposition diseases 0 1.1 8.7

Congenital glomerulopathies 1.2 0 0

Miscellaneous 5.1 4.4 2.1

U k 6 6Unknown 0.6 0.6 11

Clinical and lab. Features in AL amyloidosis 474 pts

Initial symptoms Laboratory findings

Fatigue 62%

Weight loss 52%

P i %

Increase plasma cell( BM> 6%) 56%

Anemia (Hb< 10 g/dL) 11%

Pain 5%

Purpura 15%

Gross bleeding 3%

Serum creatinine> 1.3 mg/dL 45%

Elevated alkaline phosphatase 26%

Physical finding

Palpable liver 24%

Hypercalcemia(>11 mg/dL) 2%

Proteinuria( > 1 g/24 hr) 55%

i li h h i %Palpable spleen 5%

Lymphadenopathy 3%

Macroglossia 9%

Urine light chain 73%

Ќ chain 23%

ג chain 50%Macroglossia 9%

Kyle, RA, Semin Hematol 1995; 32: 45.

Syndrome at diagnosis in 229 pts with AL l id iamyloidosis

Syndromes  Without myeloma 

(182 pts)

With myeloma 

(47 pts)Nephrotic syndrome % %Nephrotic syndrome 37% 13%

Carpal tunnel syndrome 21% 38%

h f lCongestive heart failure 23% 23%

Peripheral neuropathy 20% 6%

Orthostatic hypotension 16% 4%

Kyle, RA, Mayo Clin Proc 1983, 58:665

Echocardiography

LVH & RVH  ith  ki    LVH & RVH with sparking appearance, no restrictionEF 6 %EF 60%Mild TR & MR

Cardiac amyloidosisCardiac amyloidosis

ECG Decreased amplitude of the QRS complex in the limb lead,

Pseudoinfarct pattern across the anterior lead

Bone SurveyBone Survey

Case 6A 62 year old white female housewife develops y p

periorbital edema in the AM followed by pedal and ankle edema later in the day, and a 6 kg weight gain. PE shows BP 142/84 mm.Hg, CTS, and edema only. Lab shows Urinalysis 4+ protein, 2-3 rbc, few oval fat bodies, BUN 18 mg/dl, creatinine 0.9 mg/dl, glucose 118 mg/dl, plasma albumin 2.4g/dl, cholesterol 236 mg/dl, and 24 hour urinary protein 10

/dg/day.

1) What serologic tests are helpful in the nephrotic syndrome before biopsy ?p y

2) If the patient was 32 years old rather than 62 years old would the testing be different ?

3) Is biopsy useful here ?

Familial AmyloidosisFamilial Amyloidosis

ADADATTR  : most commonRenal disease : less common than ALRenal disease : less common than ALNeuropathy ( Sensori‐motor, ANS )GI : diarrhea, wt. lossNo macroglossiaCardiac involvement : Heart failure uncommon

Case 7A 38 year old. male drug addict is found to have 6g

proteinuria daily and a Scr of 1.4 mg/dl. He is found to be HIV+HIV+.

1) Is this likely to be HIV associated nephropathy (HIV AN) ? If this were HIV AN what laboratory tests would be? If this were HIV AN what laboratory tests would be useful to establish a diagnosis ?

2) What other possibilities could this patient have? What l i i h b h l f l i hi i iserologic tests might be helpful in this patient in

establishing a diagnosis ?

Renal cause

ATN

Nephrotoxic

Glomerular disease

IgA nephropathyATIN

IschemicPigment-relates

Immune complex GNOther glomerulopathy

Drug induced

Vascular disease

HUSCrystal asso. Nephropathy

TTPATIN

Drug-induceInfection

Uric acidSulfadiazine

AcyclovirIndinavirInfection

Plasmacytic interstitial nephritisIndinavirfoscanet

HIV asso. ATN

NephrotoxicIschemic

Pigmented induce

Rhabdomyolysis

Amphotericin BAminoglycoside

Pentamidine

Ischemic

ShockVasopresser Rx hemolysis

PentamidineRadiocontrast

NSAIDSRitonavir

Vasopresser Rxcocaine

Foscanetcidofovir

Am J Med Sci 2000:319;385-91

Glomerular Syndromes in HIVGlomerular Syndromes in HIV

1) HIV‐associated TMA

2) HIV‐associated IC renal disease

3) Classic HIV associated nephropathy3) Classic HIV‐associated nephropathy

Glomerular disease diag. by renal biopsy in 136 consecutive HIV pt.

Type of glomerular disease      N=127 Type of tubulointerstitial disease N=9

FSGS                                         88

MPGN                                        13

MCD                                           6

Interstitial nephritis                      5                      

ATN                                            3

Malignant lymphoma                    1MCD                                           6

MN                                             5

Lupus like nephritis                       4

Malignant lymphoma                    1

Amyloidosis                                  4

Acute postinfectious GN                2

F l  t l  ti i  GN     Focal segmental necrotizing GN     1

HUS                                            1

IgA nephropathy                          1

Immunolactoid glomerulopathy      1

End stage kidney disease              1Semin nephro;18;406-421:1998

AIDS-Associationed ESRD Incident in US

ESRD from AIDS Deaths in American

American with AIDS/Yr

1000

1200

25500

600

800

15500

20500

s/yr

s/yr

400 10500Cas

esC

ases

0

200

500

5500

(Bruggeman et al. JASN, 2001)

90 91 92 93 94 95 96 97 98 99 '00 '01 '02