1. Myeloma and the Kidney Ryan Sanford 2.22.2010

2. How Often is the Kidney Involved Symptomatic MM: CRAB – hyperCalcemia – Renal dysfunction – Anemia – Bone lesions 1/5 to 2/5 patients with MM have renal involvement

3. What Does it Signify? At presentation – SCr < 1.5  80% alive at 1 year – SCr > 2.3  50% alive at 1 year Renal Improvement to MM Treatment also favorable

4. The Immunoglobulin Light Chains come in lambda and kappa

5. A Few General Points First The Proteins of MM – Light chains (LC) almost always the problem – Various potential proteins to be produced Intact immunoglobulins +/- Light Chains and Heavy Chains The SPEP: – Not a good test to identify LCs – Increased sensitivity if coupled with serum immunofixation – Can only quantify LCs with direct assessment The UPEP – Prior to serum free light chain assessment, the UPEP was the test of choice to find LCs

6. The Light Chain (LC) aka Bence Jones proteins – Monoclonal – A ratio of κ:λ Freely filtered, absorbed in PCT The LC biochemical properties determines the type, if any, of renal disease

7. The Serum Free Light Chain Assessment Polyclonal ABs directed at hidden LC epitopes (when a full Ig) used for sensitive quantification of κ and λ light chains Coupled with SPEP more Sn/Sp than SPEP/UPEP Could be replacing UPEP as test of choice

8. What Types of Involvement Light chain cast nephropathy – Myeloma Kidney [>40% of cases] Light chain deposition disease [<10%] Primary AL Amyloidosis [<10%] Also: Hypercalcemia, interstitial nephritis, acquired Fanconi’s syndrome, GN

9. Proteinuria in MM Albuminuria [a grossly positive U/a for protein] – If positive: Nonspecfic glomerular leak, nephrosis LCDD or Amyloidosis – If negative: other proteins or no protein in urine; cast nephropathy Addition of Sulfosalicylic Acid to Supernatant – If bland sediment and minimal protein on U/a – Precipitates all urinary protein – If positive suggestive of light chains in urine

10. Cast Nephropathy / Myeloma Kidney Acute or Chronic Worsened by volume depletion Two mechanisms – Intratubular casts and obstruction LC has affinity for Tamm-Horsfall protein (secreted in thick AL) See casts in distal nephron – Direct tubular toxicity U/a: trace/no protein; bland sediment

11. With the Microscope LC Cast with Obstruction

12. Treatment of Cast Nephropathy Chemotherapy to reduce LC production Aggressive hydration Plasmapheresis? – Rapid removal of toxic LC – Contentious – If beneficial – best for those with high levels of LCs, severe renal failure, and firm diagnosis of cast nephropathy

13. AL Amyloidosis LC uptake, processing, and secretion by macrophages Secretion product precipitates into β-pleated fibrils, becoming Congophilic Nephrosis and progressive loss of GFR

14. Light Chain Deposition Disease Similar to AL Amyloidosis, except no fibril formation of Congophilic staining Nephrosis and progressive loss of GFR

15. Tubular Malfunction LCs reabsorbed in PCT and accumulate – Fanconi Syndrome Phosphate wasting Proximal RTA [type 2] Hypouricemia Glycosuria Proteinuria Hypokalemia and hypochloremia

16. References UpToDate.com Hutchison, C.A. et al. Nat Rev Nephrol. Serum free light chain assessment in monoclonal gammopathy and kidney disease. 5, 621-627 (2009)