Cast Nephropathy &
Plasmapheresis
Alicia Notkin
February 6, 2008
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
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
Pathogenesis of cast nephropathy
(Sanders 1990)
• Bence Jones proteins  loop segment dysfunction 
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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)
% change in turbidity (from co-precipitation) v.
NaCl concentration for in vitro solutions of THP
w/ various low molecular weight proteins
(Sanders 1990)
Pathogenesis of cast nephropathy:
in vivo rat data (Sanders 1992)
• Obstruction occurred in the distal nephron only
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& 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
Change in turbidity of in vitro solutions of rat
THP +/- colchicine w/ increasing concentrations
of furosemide (Sanders 1992)
Compounding factors…
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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
Treatment of cast nephropathy
• Volume repletion: decrease tubular light chain
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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 TammHorsfall proteins (controversial)
Chemotherapy to decrease immunoglobulin
production
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
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
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
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
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
References
• Clark, WF et al. Plasma exchange when myeloma presents as acute renal failure: a
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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.