[PPT] - Amyloidosis Nelson Leung Mayo Clinic (Rochester MN USA) PowerPoint Presentation

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Nelson Leung Mayo Clinic (Rochester MN USA) Discussant: Sonia Pasquali (Reggio Emilia Italy)

Amyloidosis

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EFFECTIVE THERAPY Amyloidosis

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Amyloidoses are treatable (curable?)

Palladini G, Merlini G Haematologica, 94: 1004 - 2009

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Early diagnosis
Accurate clinical approach
Accurate follow-up

Keys to effective treatment:

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DIAGNOSING AMYLOIDOSIS

Key points:

Diagnosis relies on demonstration on tissue biopsy
f fibrillar deposits

which are congophilic and birefringent under polarized light, or typical, rigid, nonbranching, 7.5-10 nm wide fibrils by electron microscopy

Unequivocal identification of amyloid protein is

essential for:

appropriate treatment
assess prognosis
genetic counseling (when appropriate)

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DIAGNOSIS AND TYPING OF SYSTEMIC AMYLOIDOSES

Abdominal fat biopsy Renal biopsy

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Diagnosis of Systemic Amyloidoses

Biopsy site: fine needle abdominal fat aspirate (sensitivity 80-85%, specificity 98-100%) biopsy of the labial minor salivary glands (sensitivity 85-90%, specificity 98-100%) rectal biopsy (sensitivity 70-80%, specificity 98-100%)

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Diagnosis of Systemic Amyloidoses

Biopsy site: fine needle abdominal fat aspirate (sensitivity 80-85%, specificity 98-100%) biopsy of the labial minor salivary glands (sensitivity 85-90%, specificity 98-100%) rectal biopsy (sensitivity 70-80%, specificity 98-100%) biopsy of the organ involved

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Early diagnosis

Question: the role of renal biopsy ?

Keys to effective treatment:

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D.M.: AA AMYLOIDOSIS

IGS

DONINI 2002

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Heart: Mean wall thickness >12 mm on echocardiogram, no other cardiac disease responsible for the increase in wall thickness Liver: Total liver span >15 cm in the absence

f heart failure, oralkaline phosphatase level

>1.5 times upper limit of normal Nerve: Symmetric sensorimotor peripheral neuropathy in the legs, gastric-emptying disorder, pseudo-obstruction, voiding dysfunction notrelated to direct organ infiltration Gastrointestinal tract: Symptoms and verification by means of biopsy Soft tissue: Tongue enlargement, arthropathy, skin purpura, Lymph node involvement, carpal tunnel syndrome

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Kidney 24-h urinary protein >0.5 g/day, predominantly albumin with or without renal insufficiency

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Kidney (patients with renal insufficiency)

reduction in proteinuria by at least 50% in the absence of 25 % or greater

reduction in renal function

Heart: Mean interventricular septal thickness decreased by 2 mm, 20% improvement in ejectionf raction,improvement by two New York Heart Association classes without an increase in diuretic use, and no increase in wall thickness. Liver: 50% decrease in abnormal alkaline phosphatase value, at least 2-cm decrease in liver size on radiographic imaging Nerve: Improvement in nerve conduction velocity on electromyogram

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Complete response: Serum and urine negative for a monoclonal protein by means of immunofixation, normal kappa:lambda free light-chain ratio Partial response: Serum M component >0.5 g/dl and 50% reduction; light chain in the urine with a visible peak >100 mg/day and 50% reduction; or free light chain>10 mg/dl and 50% reduction

IF anti λ

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Early diagnosis
Accurate clinical approach

Question: The differential diagnosis

f AL Amyloidosis and MM

with Amyloidosis ?

Keys to effective treatment:

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MULTIPLE MYELOMA

+

AL AMYLOIDOSIS AL AMYLOIDOSIS

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PROGNOSTIC FACTORS IN AL AMYLOIDOSIS

Cox multivariate analysis (705 patients): hematologic response to therapy p=9.2x10-24 heart involvement p=1.7x10-14

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Other; 7,5 Hemorrage; 2 Liver failure; 3 Renal failure; 3,5 Cachexia; 4 Infection; 5 Myocardial infarction/stroke; 7,5 Sudden death; 21,5 CHF; 46

Cause of death (%) in 258/600 patients with AL AMYLOIDOSIS Cardiac 75%

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AL patients developing end-stage renal failure requiring dialysis: 18 % (Gertz et al, Arch Intern Med 1992;152:2245-50) AL patients with renal involvement developing end-

stage

renal failure requiring dialysis: 23% (IASG, Budapest Amyloid Symposium, 2001) The most important predictors of renal failure requiring

dialysis are:

24-h u.protein > 2 g
s. creatinine (> 1.7 mg/dL)

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Hypertens Res 2001; 24: 691-97

Nephron 2001; 187: 333-39

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Responders (6 pts) Non responders (6 pts) p

GFR

(15-29 ml/min) 0% 50% 0.09

Proteinuria

(> 5g/24h) 67% 17% ns

Serum uric acid (>8 mg/dl)

0% 50% 0.09

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Responders (6 pts) Non responders (6 pts) p

Duration disease (>12 months)

33% 100% 0.03

Heart involvement

0% 33% ns

Hematologic response

100% 50% 0.09

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Early diagnosis
Accurate clinical approach
Accurate follow-up

Question: the prognostic role of serum uric acid ?

Keys to effective treatment:

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Plasma Exchange is effective at reversing

Plasma Exchange is effective at reversing renal failure if it is due to cast renal failure if it is due to cast nephropathy and if sFLC levels can be nephropathy and if sFLC levels can be reduced by at least 50% (improvement in reduced by at least 50% (improvement in 78% of cases) 78% of cases)

The diagnosis is a key factor in the

The diagnosis is a key factor in the success of therapy success of therapy

(Leung N. et al. Kidney Int 2008;73:1282-1288)

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in vitro pure resins screen

Toyopearl CM-650C Toyopearl HW40C Toyopearl Megacap SP-550EC Toyopearl SP-550C BEL-0406-RAM-1 BEL-0406-RAM-2 Toyopearl Super SP CG71 CG161 MDR3 (CG300) Toyopearl CM-650C Toyopearl HW40C Toyopearl Megacap SP-550EC Toyopearl SP-550C BEL-0406-RAM-1 BEL-0406-RAM-2 Toyopearl Super SP CG71 CG161 MDR3 (CG300)

50 100 150 200 250 300 350

30 120 Lambda

in vitro mixed resins screen

M D R 3 + T

y
p

e a r l C M

6

5 C M D R 3 + T

y
p

e a r l H W

4

C M D R 3 + T

y
p

e a r l M e g a c a p S P

5

5 E C M D R 3 + T

y
p

e a r l S P

5

5 C M D R 3 + B E L

4

6

R

A M

1

M D R 3 + B E L

4

6

R

A M

2

M D R 3 + T

y
p

e a r l S u p e r S P M D R 3 + C G 7 1 M D R 3 + C G 1 6 1 M D R 3 + C G 7 1 M D R 3 + T

y
p

e a r l C M

6

5 C M D R 3 + T

y
p

e a r l H W

4

C M D R 3 + T

y
p

e a r l M e g a c a p S P

5

5 E C M D R 3 + T

y
p

e a r l S P

5

5 C M D R 3 + B E L

4

6

R

A M

1

M D R 3 + B E L

4

6

R

A M

2

M D R 3 + T

y
p

e a r l S u p e r S P M D R 3 + C G 7 1 M D R 3 + C G 1 6 1 M D R 3 + C G 7 1

50 100 150 200 250 300 350

30 120

Lambda

CG71 35 micron 250 angstrom 500 m2/g Bead diameter Pore diameter Area MDR3 75 micron 300 angstrom 700 m2/g CG161 75 micron 150 angstrom 900 m2/g

bead

Best results

Programma di ricerca Regione-Università 2007-2010

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Pore Sizes of High Cut-Off (HCO) Membranes in comparisson to HighFlux and plasmafiltration membranes

HighFlux HCO Plasmafilter

p

r

e s i z e [ µ m ]

0,001 0,01 0,1 1

n / n

[
]

0,0 0,2 0,4 0,6 0,8 1,0

HighFlux High Cut-Off Plasmafilter

p

r

e s i z e [ µ m ]

0,001 0,01 0,1 1

n / n

[
]

0,0 0,2 0,4 0,6 0,8 1,0

HighFlux High Cut-Off

p

r

e s i z e [ µ m ]

0,001 0,01 0,1 1

n / n

[
]

0,0 0,2 0,4 0,6 0,8 1,0

HighFlux

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Aim: Evaluate the removal of FLCs by extended HD in patients with biopsy proven cast nephropathy + dialysis dependent acute renal failure Outcomes: Reduction in serum FLC concentrations Recovery of renal function + patient survival Study population compared with a case matched historical control population Of 27 multiple myeloma patients with dialysis dependent renal failure assessed, 19 meet inclusion criteria

Hutchison et al. cJASN 2009

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mg/L

1562 899 1111 450,6 848 655 570,6 353 500 1000 1500 2000 4 h 8 h Rebound Lambda Kappa

Kappa: - 68% Lambda: - 58%

1562 899 1111 450,6 848 655 570,6 353 500 1000 1500 2000 4 h 8 h Rebound Lambda Kappa

Kappa: - 68% Lambda: - 58%

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Removal of circulating light chains Removal of circulating light chains The role in amyloidosis treatment? The role in amyloidosis treatment?

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Early diagnosis
Accurate clinical approach
Accurate follow-up

Highy individualized treatment

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