Cast Nephropathy & Plasmapheresis

1. Cast Nephropathy & Plasmapheresis Alicia Notkin February 6, 2008

2. Pathogenesis of cast nephropathy • Renal failure from immunoglobulin or κ or λ light chains: direct tubular toxicity & obstruction • Light chains (MW 22000) are freely filtered across the glomerulus & then reabsorbed by proximal tubular epithelial cells

3. Pathogenesis of cast nephropathy • Overproduction of light chains  tubular capacity for reabsorption is exceeded • Filtered light chains & immunoglobulins then bind Tamm-Horsfall glycoprotein (secreted in the medullary TAL of the loop of Henle) • Cast formation & obstruction in the distal nephron subsequently results

4. Pathogenesis of cast nephropathy(Sanders 1990) • Bence Jones proteins  loop segment dysfunction  decreased NaCl absorption  increased early distal tubule NaCl concentration which promotes aggregation/cast formation (shown in rats in vivo) • Proteins w/ isoelectric points > 5.1 aggregate w/ THP in vitro (increasing NaCl or CaCl2 concentration enhances aggregation); in vivo, not all cationic proteins  casts (partly b/c of differences in distal nephron NaCl concentration & b/c of variable affinity of the immunoglobulin light chains to the binding site on the THP)

5. % change in turbidity (from co-precipitation) v. NaCl concentration for in vitro solutions of THP w/ various low molecular weight proteins(Sanders 1990)

6. Pathogenesis of cast nephropathy:in vivo rat data (Sanders 1992) • Obstruction occurred in the distal nephron only & showed direct BJP-concentration dependence • Obstruction took significantly longer to develop in rats given volume infusion at high rates • Obstruction developed more rapidly with increasing furosemide concentrations • Colchicine prevented obstruction by decreasing tubular secretion & carbohydrate content of THP

7. Change in turbidity of in vitro solutions of rat THP +/- colchicine w/ increasing concentrations of furosemide (Sanders 1992)

8. Compounding factors… • Hypercalcemia • Hyperuricemia • Infection • Volume depletion or loop diuretics • Nephrotoxic drugs, IV contrast • Proximal tubular injury from light chain reabsorption & interference w/ lysosomal function; cycle whereby dysfunction  further decrease in light chain reabsorption

9. Treatment of cast nephropathy • Volume repletion: decrease tubular light chain concentration, decrease tubular NaCl concentration • Increase urine flow: decrease light chain precipitation • Alkalinize urine: raise urine pH above isoelectric point to decrease affinity toward anionic Tamm-Horsfall proteins (controversial) • Chemotherapy to decrease immunoglobulin production

10. Plasmapheresis to remove circulating free light chains? • Many studies are small, non-randomized, retrospective, are heterogeneous… • 3 prospective, randomized trials: 2 favor plasmapheresis, while most recent one casts doubt on its use

11. Plasmapheresis? • Zucchelli 1988: 29 patients (24/83% req dialysis), 59% biopsied, Cr > 5mg/dl not responsive to hydration, 80% treated previously w/ cytotoxic drugs, all given methylprednisolone & cyclophosphamide & randomized to plasmapheresis w/ prn HD vs. prn PD; 13/15 v. 2/14 w/ renal improvement; also survival benefit

12. Plasmapheresis? • Johnson 1990: 21 patients (57% req dialysis), 76% biopsied, all given melphalan, prednisone, & forced diuresis, 11 plasmapheresed, subgroup analysis of dialysis dependent patients – renal recovery in 47% pheresed v. 0% control

13. Plasmapheresis? • Clark 2005: 97 patients (26 v. 36% initially on dialysis in plasmapheresis v. control group), few biopsied, treated w/ vincristine, adriamycin, dexamethasone or melphalan & prednisone, +/- plasmapheresis, no statistically significant difference in composite endpoint of death, dialysis dependence, gfr < 30 ml/min @ 6 months

14. Plasmapheresis? • Leung 2007: retrospective study in 40 patients, cast nephropathy in 18/28 patients (64.3%) that were biopsied, w/ these patients having renal response associated w/ >/= 50% reduction in sFLC levels (77.8% v. 0%, p = 0.001), & w/ sFLC reduction not affecting renal recovery in the other 10 patients, post-treatment sFLC level predicted renal response (p = 0.01) & renal response predicted long-term survival (p = 0.04) – median survival 31.8 v. 11 months

15. References • Clark, WF et al. Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial. Ann Intern Med 2005; 143:777. • Huang, ZQ et al. Localization of a single binding site for immunoglobulin light chains on human Tamm-Horsfall glycoprotein. J Clin Invest 1997; 99:732. • Johnson, WJ et al. Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis, and chemotherapy. Arch Intern Med 1990; 150:863. • Leung, N et al. Plasma exchange is an important and useful adjuvant therapy in cast nephropathy. XIth International Myeloma Workshop and IVth International Workshop in Waldenstrom’s Macroglobulinemia 2007. • Sanders, PW et al. Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins. J Clin Invest 1990; 85:570. • Sanders, PW et al. Pathobiology of cast nephropathy from human Bence Jones proteins. J Clin Invest 1992; 89:630. • Zucchelli, P et al. Controlled plasma exchange trial in acute renal failure due to multiple myeloma. Kidney Int 1988; 33:1175.