Chris Venner

Myeloma Renal Disease

Dr. Christopher Venner MD

Honorary Clinical Research Fellow

National Amyloidosis Center, UCL

Outline

Light chains in health

Light chains in disease

Cast nephropathy pathophysiology

Treatment

Production

Removal

Outcomes

Protein must be small enough to pass through glomerulus (~60kDa)

Also needs relative positive charge

Escape efficientscavenging mechanism in proximal convoluted tubule (PCT) Megalin

Cubulin

The PCT can absorb up to 10-30g total protein

Normal Renal Protein Metabolism Normal Renal Protein Metabolism

Kappa and lambda pass

freely through the

glomerulus due size and

charge.

In the serum free kappa

light chain exist as a

monomer(22.5 kD) and

lambda as a dimer(45 kD)

http://www.biology.arizona.edu/immunology/tutorials/antibody/structure.html

Normal Light Chain Metabolism

Free light chains are metabolized primarily in the kidney (size and charge dependent)

Secondarily, they are broken down by the reticuloendothelial system (production rate dependent)

Kappa is smaller (exists as a monomer) but produced at about twice the rate than lambda (exists as a dimer)

In renal failure metabolism is more dependent on rate of production and thus kappa is often higher

Epithelial

cell

Epithelial

cell

Interstitium

Proximal tubular

lumen

Cubulin

Megalin

Endosome

Light chain

H202 Bound in PCT by

binding to megalin and cubulin and then endocytosed

Proteins are degraded and smaller peptides for safe handling

Requires activation of endosome and marked increase in intracellular H2O2

The PCT can absorb up to 100-600mg light chain per day

Light chains and disease

Plasma cell dyscrasia defined by1. Clonal plasma cell population

2. End-organ damage (C) alcium, (R)enal, (A)nemia, (B)one lesions

Light/Heavy chain amyloid organ deposition

Light chain deposition disease (LCDD)

Hyperviscosity

Paraneoplastic (POEMS)

End-organ damage due, in part, to overproduction of toxic monoclonal-protein Intact Immunoglobulin (paraprotein)

Monoclonal light chain

Renal Disease

Kidney dysfunction is seen in approximately 50% of myeloma cases (10% ESRD)

Many causes:

Hypercalcemia

Dehydration

Sepsis

Cast nephropathy

Amyloid

LCDD/HCDD

Light chains and disease

Light chain production can increase

dramatically

May overwhelm the PCT absorptive capacity

allowing LC to find its way to the distal

nephron

This monoclonal LC is eventually secreted in

the urine = Bence Jones Protein

Bence Jones Protein

Initially described by Dr. Henry Bence Jones in 1847

(published 1848)

First to attribute the proteinaceous material in the urine to

underlying process giving rise to myeloma

Bence Jones Protein

Interpretating proteinuria

What is/are the protein(s) present?

Is it all light chain?

Is it all albumin?

Is there intact Ig molecule (major leakage)?

Is it a problem??

How are monoclonal proteins detected?

UPEP

SPEP

sFLC assay

http://pro2services.com/Lectures/Winter/Proteins/protein.htm

http://www.wikilite.com/

Cast Formation

Tamm-Horsfall protein (uromodulin)

Produced by the endothelial cells in the thick ascending loop of Henle (TALH)

Normal function not really known

? Antibacterial

? Clearance of other toxins/metabolites/protein

? Clearance of Calcium

Binds light chain precipitates forming thick waxy material which plugs the tubule leading to tubular rupture Hutchison, C. A. et al. Nat. Rev. Nephrol. 8, 4351 (2012);

Cast Formation

Depends on:

Polymerization potential in serum (large polymers

do not cross the glomerulus)

Isoelectric point (pI) for precipitation of given

monoclonal light chain (Determines if and where

it will ppt)

pH of urine (changes at different points in the

nephron)

Tubular flow rate

Other molecules/electrolytes (Ca+ and Cl-

impact of diuresis)

Cast Nephropathy

Nephropathy refers to the damage which

induces renal dysfunction

Casts themselves are not bad but the

sequlae leading to inflammation, functional

tissue destruction and fibrosis is!

H202

H202

H202

H202

H202Cytokines

Cytokines Cytokines

Cytokines

Cytokines

Hutchison, C. A. et al. Nat. Rev. Nephrol. 8, 4351 (2012);

Vicious circle

1. Monoclonal light chains activate PTEC cells

? activation of the endosome/lysosome

? direct activation through receptor mediated pathways at cell surface

End result is interstitial inflammation (AIN)

2. Distal obstruction due to LC casts causes obstructive uropathy Direct damage

By standarad inflammation worsens AIN

3. As nephrons die the light chain load placed on surviving nephrons increases

Larger load on PCT (more AIN) thus larger LC load in TALH (more casts)

Acceleration of damage at multiple levels of the nephron with exponential loss of renal function

Impact of Renal Failure on Survival in

MM

Renal failure is a poor prognostic marker

Component of Durie-Salmon staging system

Indirectly measured in International Staging

System as renal failure can lead to marked

increase in 2-microglobulin

May trump other traditional poor prognostic

factors Knudsen et al. Eur J Haematol. 2000Hutchison et al J Am Soc Nephrol 22: 11291136, 2011.

Knudsen et al. Eur J Haematol. 2000

P = 0.05

Management

Reduce light chain production Chemo (bortezomib)

Remove light chains Plasma exchange

High cut-off dialysis membranes (porous to molecules up to 60kD)

Supportive care Hydration, hydration, hydration

Remove offending agents (NSAIDS, diuretics, ACEI)

Treat exacerbating problems (hypercalcemia, sepsis etc)

Key to success is a deep and sustained response

Management








Management








Reduce

Proteosome inhibition

Capitalize on pro-apoptotic protein stress

Plasma cells have high protein stress which is increased in malignant state (overproduction of immunoglobulin components)

http://renalfellow.blogspot.co.uk/2010/01/bortezomib-in-myeloma-

cast-nephropathy.html

Reduce

Limited prospective experience in patients

with renal failure

Small case series suggest approximately 60%

renal response rates including 40-50%

normalizaion of renal function in patients with

dialysis dependent cast nephropathy

VISTA and APEX

Specifically

examined renal

failure

All treated with

bortezomib

based

regimens

Roussou et al, Leukemia & Lymphoma, May 2008; 49(5): 890895

Bort

Dex

VMP

MP

APEX (Bort vs Dex in

relapsed myeloma)

VISTA (MP vs VMP in

upfront myeloma)

Time to reversal of renal failure

(VISTA)Remove

Plasma exchange:

Removal of all plasma (extracellular) protein component of blood

Addresses intravascular light chains

3 RCTs with conflicting results

High cut-off dialysis

More efficient removal

Limits size (

High Cut-Off Dialysis

plasma

membrane

HCO dialysis

In 8 patients tested there was a

35-70% drop in sFLC within 2hr of

HCOD

3/5 became dialysis independent

HCO Dialysis and Chemotherapy

Rebound effect due to:

Ongoing production by plasma cells

Intravascular seepage of interstitial light chains as

vascular pool is depleted

Therefore, must address the ongoing

production with cytotoxic agents

HCO Dialysis and Chemotherapy

67 pt with dialysis dependent renal failure due to MM

61 % and 63% had marked reduction in sFLC by 12d and 21d respectively

71% became dialysis independent

Depth of light chain removal

Hutchison et al Nephrol Dial

Transplant (2012) 0: 16

19 pt with dialysis

dependent renal failure

due to MM

73.7% became dialysis

independent

Emphasized importance

of rapid initiation of

therapy

HCO Dialysis and Chemotherapy Eulite

The EUropean trial of free LIght chain removal

by exTEnded haemodialysis in cast

nephropathy

Unanswered questions:

1. Is bortezomib-based chemo enough?

2. Is survival impacted in the era of novel agents by

the use of HCO dialysis

Summary

The kidney is an important organ in the metabolism of light chains both in health and in disease

Cast nephropathy is a medical emergency that can have significant impact on renal morbidity and overall survival longterm

Cast formation is due to factors intrinsic to the light chain and external factors promoting polymerization

Longterm damage depends on degree of fibrosis present

In addition to supportive care treatment strategies are geared toward reducing light chain production and improving light chain removal

Documents

Chris Venner