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J Am Soc Nephrol. 2012 Nov;23(11):1777-81. doi: 10.1681/ASN.2012040388. Epub 2012Sep 20.
Mechanisms of light chain injury along the tubular nephron.
Sanders PW(1).
Author information:
(1)Division of Nephrology, Department of Medicine, Nephrology Research and
Training Center, University of Alabama at Birmingham, Birmingham, Alabama
35294-0007, USA. psanders@uab.edu
The tubular nephron is responsible for reabsorption and catabolism of filtered
low molecular weight proteins that include Ig free light chains. In the setting
of a plasma cell dyscrasia, significant amounts of free light chains, now
monoclonal proteins, present to the tubular nephron for disposal. The result may
be clinical renal dysfunction in the form of AKI, progressive CKD, and end-stage
kidney disease. Here, I review the mechanisms involved in these processes that
result in tubular injury, including proximal tubulopathy and cast nephropathy.
PMID: 22997259 [PubMed - indexed for MEDLINE]
J Clin Invest. 2012 May;122(5):1777-85. doi: 10.1172/JCI46490. Epub 2012 Apr 9.
Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent
model.
Ying WZ(1), Allen CE, Curtis LM, Aaron KJ, Sanders PW.
Author information:
(1)Division of Nephrology, Department of Medicine, Nephrology Research and
Training Center, University of Alabama at Birmingham, Birmingham, Alabama
35294-0007, USA.
Comment in
Nat Rev Nephrol. 2012 Jun;8(6):316.
J Clin Invest. 2012 May;122(5):1605-8.
A common renal complication of multiple myeloma is "myeloma kidney," a condition
also known as cast nephropathy. The renal lesions (casts) are directly related to
the production of monoclonal immunoglobulin free light chains (FLCs), which
coprecipitate with Tamm-Horsfall glycoprotein (THP) in the lumen of the distal
nephron, obstructing tubular fluid flow. Here, we report that analysis of the
binding interaction between FLCs and THP demonstrates that the secondary
structure and key amino acid residues on the complementarity-determining region 3
(CDR3) of FLCs are critically important determinants of the molecular interaction
with THP. The findings permitted development of a cyclized competitor peptide
that demonstrated strong inhibitory capability in the binding of FLCs to THP in
vitro. When used in a rodent model of cast nephropathy, this cyclized peptide
construct served as an effective inhibitor of intraluminal cast formation and
prevented the functional manifestations of acute kidney injury in vivo. These
experiments provide proof of concept that intraluminal cast formation is
integrally involved in the pathogenesis of acute kidney injury from cast
nephropathy. Further, the data support a clinically relevant approach to the
management of renal failure in the setting of multiple myeloma.
PMCID: PMC3336971
PMID: 22484815 [PubMed - indexed for MEDLINE]
Arch Intern Med. 1990 Apr;150(4):863-9.
Treatment of renal failure associated with multiple myeloma. Plasmapheresis,
hemodialysis, and chemotherapy.
Johnson WJ(1), Kyle RA, Pineda AA, O'Brien PC, Holley KE.
Author information:
(1)Division of Nephrology, Mayo Clinic, Rochester, MN 55905.
The aims of this study were to examine in a prospective, randomized trial the
efficacy of plasmapheresis in preventing irreversible renal failure in patients
with multiple myeloma and to study the renal biopsy tissues from such patients.
Twenty-one patients with active myeloma and progressive renal failure were
randomized to one of two groups: group 1, forced diuresis and chemotherapy (10
patients), and group 2, forced diuresis, chemotherapy, and plasmapheresis (11
patients). Plasmapheresis and chemotherapy lowered the serum myeloma protein
value much more rapidly than chemotherapy alone. Of 5 patients who were oliguric
and undergoing dialysis at presentation, only 3 who were treated by
plasmapheresis recovered. Of 16 polyuric patients, 5 in group 1 and 7 in group 2
showed improvement in renal function. The main factor that determined
irreversibility of renal failure was the severity of myeloma cast formation.
PMID: 2183734 [PubMed - indexed for MEDLINE]
Ann Intern Med. 2005 Dec 6;143(11):777-84.
Plasma exchange when myeloma presents as acute renal failure: a randomized,
controlled trial.
Clark WF(1), Stewart AK, Rock GA, Sternbach M, Sutton DM, Barrett BJ, Heidenheim
AP, Garg AX, Churchill DN; Canadian Apheresis Group.
Author information:
(1)University of Western Ontario, London, Ontario, Canada.
Erratum in
Ann Intern Med. 2007 Mar 20;146(6):471.
Comment in
Ann Intern Med. 2005 Dec 6;143(11):835-7.
Ann Intern Med. 2006 Mar 21;144(6):455; author reply 455.
Summary for patients in
Ann Intern Med. 2005 Dec 6;143(11):I20.
BACKGROUND: Two small, randomized trials provide conflicting evidence about the
benefits of plasma exchange for patients with acute renal failure at the onset of
multiple myeloma.
OBJECTIVE: To assess the effect of 5 to 7 plasma exchanges on a composite outcome
in patients with acute renal failure at the onset of multiple myeloma.
DESIGN: Randomized, open, controlled trial, stratified by chemotherapy and
dialysis dependence, conducted from 1998 to 2004.
SETTING: Hospital plasma exchange units in 14 Canadian medical centers.
PARTICIPANTS: 104 patients between 18 and 81 years of age with acute renal
failure at the onset of myeloma.
INTERVENTION: Study participants were randomly assigned to conventional therapy
plus 5 to 7 plasma exchanges of 50 mL per kg of body weight of 5% human serum
albumin for 10 days or conventional therapy alone. Ninety-seven participants
completed the 6-month follow-up.
MEASUREMENTS: The primary outcome was a composite measure of death, dialysis
dependence, or glomerular filtration rate less than 0.29 mL x s(-2) x m(-2) (<30 br="">mL/min per 1.73 m2).
RESULTS: At enrollment, the plasma exchange and control groups were similar for
dialysis dependence, chemotherapy, sex, age, hypercalcemia, serum albumin level,
24-hour urine protein level, serum creatinine level, and Durie-Salmon staging.
The primary composite end point occurred in 33 of 57 (57.9%) patients in the
plasma exchange group and in 27 of 39 (69.2%) patients in the control group
(difference between groups, 11.3% [95% CI, -8.3% to 29.1%]; P = 0.36). One third
of patients in each group died.
LIMITATIONS: The study was small, used a composite outcome, and did not use renal
biopsy as an inclusion criterion. Recruiting physicians were blinded to treatment
allocation but not to treatment thereafter.
CONCLUSIONS: In patients with acute renal failure at the onset of multiple
myeloma, there is no conclusive evidence that 5 to 7 plasma exchanges
substantially reduce a composite outcome of death, dialysis dependence, or
glomerular filtration rate less than 0.29 mL.s(-2).m(-2) (<30 1.73="" br="" m2="" min="" ml="" per="">at 6 months.
PMID: 16330788 [PubMed - indexed for MEDLINE]
N Engl J Med. 2011 Jun 16;364(24):2365-6. doi: 10.1056/NEJMc1101834.
Renal improvement in myeloma with bortezomib plus plasma exchange.
Burnette BL, Leung N, Rajkumar SV.
Comment in
N Engl J Med. 2011 Sep 15;365(11):1061-2; author reply 1062.
N Engl J Med. 2011 Sep 15;365(11):1061; author reply 1062.
PMID: 21675906 [PubMed - indexed for MEDLINE]
J Am Soc Nephrol. 2007 Mar;18(3):886-95. Epub 2007 Jan 17.
Efficient removal of immunoglobulin free light chains by hemodialysis for
multiple myeloma: in vitro and in vivo studies.
Hutchison CA(1), Cockwell P, Reid S, Chandler K, Mead GP, Harrison J, Hattersley
J, Evans ND, Chappell MJ, Cook M, Goehl H, Storr M, Bradwell AR.
Author information:
(1)Department of Renal medicine, Queen Elizabeth Hospital, QEMC, Birmingham, B15
2TH UK. me@colinhutchison.com
Of patients with newly diagnosed multiple myeloma, approximately 10% have
dialysis-dependent acute renal failure, with cast nephropathy, caused by
monoclonal free light chains (FLC). Of these, 80 to 90% require long-term renal
replacement therapy. Early treatment by plasma exchange reduces serum FLC
concentrations, but randomized, controlled trials have shown no evidence of renal
recovery. This outcome can be explained by the low efficiency of the procedure. A
model of FLC production, distribution, and metabolism in patients with myeloma
indicated that plasma exchange might remove only 25% of the total amount during a
3-wk period. For increasing FLC removal, extended hemodialysis with a
protein-leaking dialyzer was used. In vitro studies indicated that the Gambro HCO
1100 dialyzer was the most efficient of seven tested. Model calculations
suggested that it might remove 90% of FLC during 3 wk. This dialyzer then was
evaluated in eight patients with myeloma and renal failure. Serum FLC reduced by
35 to 70% within 2 hr, but reduction rates slowed as extravascular
re-equilibration occurred. FLC concentrations rebounded on successive days unless
chemotherapy was effective. Five additional patients with acute renal failure
that was caused by cast nephropathy then were treated aggressively, and three
became dialysis independent. A total of 1.7 kg of FLC was removed from one
patient during 6 wk. Extended hemodialysis with the Gambro HCO 1100 dialyzer
allowed continuous, safe removal of FLC in large amounts. Proof of clinical value
now will require larger studies.
PMID: 17229909 [PubMed - indexed for MEDLINE]
Study List:
Study 1:
Title: European Trial of Free Light Chain Removal by Extended Haemodialysis in Cast Nephropathy
Recruitment: Recruiting
Study Results: No Results Available
Conditions: Multiple Myeloma|Cast Nephropathy|Kidney Failure
Interventions: Device: FLC removal HD (Gambro HCO 1100)|Procedure: Standard dialysis on a high flux ployflux dialyser
URL: http://ClinicalTrials.gov/show/NCT00700531
Study 2:
Title: Studies in Patients With Multiple Myeloma and Renal Failure Due to Myeloma Cast Nephropathy
Recruitment: Recruiting
Study Results: No Results Available
Conditions: Chronic Renal Failure With Uremic Nephropathy
Interventions: Drug: Cyclophosphamide + Bortezomib + Dexamethasone regimen|Drug: Bortezomib +Dexamethasone regimen|Device: HCO group|Device: conventional high-flux dialyzer
URL: http://ClinicalTrials.gov/show/NCT01208818
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