Quickly identify patients at risk from kidney damage

Free light chains are nephrotoxic

Figure 1

 

Figure 1. Myeloma Kidney.

The kidney is often affected in plasma cell dyscrasias, usually due to the effects of nephrotoxic monoclonal free light chains. Monoclonal light chains produced by different individuals have different nephrotoxic properties. For example, some monoclonal light chains may form fibrils (AL amyloidosis), whilst others may form deposits localised to the renal basement membranes (light chain deposition disease) or the tubulo-interstitium (cast nephropathy).
At presentation, approximately 50% of Multiple Myeloma (MM) patients have renal impairment, varying from mild (asymptomatic) to severe renal insufficiency. 12 - 20% of MM patients present with acute renal failure. The majority of cases are caused by cast nephropathy, also known as "myeloma kidney". In cast nephropathy free light chains, in association with Tamm-Horsfall protein, form waxy deposits that block the distal tubules, Figure 1.

10% of all MM patients will remain on long-term haemodialysis and for these individuals there is a high mortality rate and treatment options are limited.

Improve screening protocols for monoclonal gammopathy

Freelite can be used in conjunction with serum protein electrophoresis, to rapidly screen for monoclonal gammopathy in those patients presenting with unexplained renal impairment.

Figure 2

 

Figure 2. Adapted from figure originally published in "Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure"
BMC Nephrology 2008;9:11 doi: 10.1186/1471-2369-9-11

The highly sensitive Freelite assay quantifies kappa (κ) and lambda (λ) free light chain levels using a routine serum sample and can eliminate the need to perform urine Bence Jones Protein (BJP) analysis.
In monoclonal gammopathy associated with severe renal insufficiency, e.g. cast nephropathy, reductions in glomerular filtration rate (GFR) lead to reduced urine output. Therefore, the concentrations of urinary free light chains do not reflect serum concentrations and production. One major advantage of the Freelite assay in such cases is that the serum κ/λ ratio is little affected by renal function. With renal insufficiency, kappa and lambda concentrations rise but the κ/λ ratio will usually remain within normal limits1.

A recent study proposes using an extended reference range for the κ/λ ratio in patients with renal impairment2. Using this extended range, diagnostic specificity of the Freelite assays increased whilst maintaining it's high sensitivity3,4.

Improve monitoring of monoclonal gammopathy

Figure 3

 

Figure 3. Increase in serum FLC before an increase in serum creatinine. After treatment serum creatinine levels fell but to a higher level than baseline indicating some residual damage to the kidney. Courtesy of S. Abdalla, St. Mary's Hospital, London, UK.

Monitoring serum FLC levels in monoclonal gammopathy patients may identify those individuals at risk of light chain mediated renal damage. The case study in Figure 3 demonstrates increasing FLC concentrations that precede renal impairment (measured by serum creatinine). It can be speculated that the rising concentrations of FLC contributed to the increasing renal impairment. This case highlights the benefit of the Freelite assay to identify patients at risk of renal impairment.

Improve monitoring of haemodialysis
Extended haemodialysis on the Gambro protein-leaking HCO 1100 dialyzer has been shown to efficiently and safely remove large amounts of free light chains from the serum5. In this initial study three out of five patients with acute renal failure caused by cast nephropathy treated with the HCO 1100 in combination with chemotherapy became dialysis independent.

A further prospective pilot study6 assessed the combination of standard chemotherapy with extended haemodialysis, using a high cut-off dialyser (HCO-HD), on serum free light chain (FLC) concentrations and renal recovery in patients with biopsy-proven cast nephropathy and dialysis-dependent acute renal failure.
Out of 19 patients who met the study entry criteria, 13 received uninterrupted chemotherapy and extended HCO-HD and demonstrated sustained reductions in serum FLC concentrations and recovered renal function. Of the 6 patients who had chemotherapy temporarily withheld or discontinued, early reductions in serum FLC concentrations were not sustained and only one subsequently became independent of dialysis. A multi-centre, randomised control trial has commenced to address the hypothesis that extended HCO-HD increases the percentage of patients with cast nephropathy who become independent of dialysis.

 

A 2009 Nature Reviews publication7 entitled 'Serum free light chain assessment in monoclonal gammopathy and kidney disease' by Colin A. Hutchison, Kolitha Basnayake and Paul Cockwell is available to order below.

 

Interview

Read an interview with Guillermo Herrera, MD, Professor and Chairman, Dept. Pathology, St Louis University, USA for his view on the utility of serum free light chain assays in renal disease.

 

The Kidney in Plasma Cell Dyscrasias

The Kidney in Plasma Cell DyscrasiasEditor: G.A. Herrera, St. Louis, Mo.
Contributions to Nephrology, volume 153. Published by Karger.
"In recent years, the knowledge of how renal damage occurs in patients with plasma cell dyscrasias/myeloma has substantially increased. For the first time, this publication brings together issues relating to the diagnosis and pathogenesis of these disorders, as well as a summary of advances achieved in the treatment and management of patients."

Request your copy here.

References

  1. Mohammad R Nowrousian, Dieter Brandhorst, Christiane Sammet, Michaela Kellert, Rainer Daniels, Philipp Schuett, Miriam Poser, Siemke Mueller, Peter Ebeling, Anja Welt, Arthur R. Bradwell, Ulrike Buttkereit, Bertram Opalka, Michael Flasshove, Thomas Moritz and Siegfried Seeber.
    "Serum Free Light Chain Analysis and Urine Immunofixation Electrophoresis in Patients with Multiple Myeloma"
    Clin Cancer Res 2005;11 (24) 8706-8714

    Reference: MKG291 Quantity:

  2. C. Hutchison, S. Harding, P Hewins et al

    Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease

    Clin J Am Nephrology 3: 1684-1690, 2008

    Reference: MKG491 Quantity:

  3. Colin A Hutchison, Tim Plant, Mark Drayson, Paul Cockwell, Melpomeni Kountouri, Kolitha Basanayake, Stephen Harding, Arthur R Bradwell and Graham Mead.
    "Serum free light chain measurement aids the diagnosis of myeloma in patients with severe renal failure"
    BMC Nephrology 2008;9:11 doi: 10.1186/1471-2369-9-11

    Download the article here. This is a free access article, please review the copyright statement on the article front page http://www.biomedcentral.com/1471-2369/9/11

    Reference: MKG493 Quantity:

  4. Abadie, J.M., K.H. van Hoeven, and J.M. Wells
    "Are renal reference intervals required when screening for plasma cell disorders with serum free light chains and serum protein electrophoresis? "
    Am J Clin Pathol, 2009. 131(2): p. 166-71.

    Reference: MKG524 Quantity:

  5. Colin A. Hutchison, Paul Cockwell, Steven Reid, Katie Chandler, Graham P. Mead, John Harrison, John Hattersley, Neil D. Evans, Mike J. Chappell, Mark Cook, Hermann Goehl, Markus Storr, and Arthur R. Bradwell
    "Efficient Removal of Immunoglobulin Free Light Chains by Hemodialysis for Multiple Myeloma: In Vitro and In Vivo Studies"
    J Am Soc Nephrol 2007 18: 886-895

    Reference: MKG344 Quantity:

  6. Hutchison CA, et al
    "Treatment of acute renal failure secondary to multiple myeloma with chemotherapy and extended high cut-off hemodialysis. "
    Clin J Am Soc Nephrol 2009;4:745-54

    Reference: MKG516 Quantity:

  7. Hutchison CA, Kolitha Basnayake and Paul Cockwell

    Serum free light chain assessment in monoclonal gammopathy and kidney disease

    Nature Reviews November 2009; 5:621-627

    Reference: MKG549 Quantity: