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Plasma exchange for myeloma kidney: cast(s) away?

2008; Elsevier BV; Volume: 73; Issue: 11 Linguagem: Inglês

10.1038/ki.2008.117

1523-1755

William F. Clark, Amit X. Garg,

Myeloproliferative Neoplasms: Diagnosis and Treatment

Leung et al. (this issue) present a retrospective study of 40 patients. Observations in 14/40 led to the suggestion of restitution of plasma exchange for light-chain responsive, biopsy-proven myeloma kidney until a better randomized control trial (RCT) is constructed. A careful analysis of their study and a recent RCT suggest little difference in outcome between plasma exchange and control groups. The analysis supports restitution of a better RCT of plasma exchange for myeloma kidney rather than off-label use. Leung et al. (this issue) present a retrospective study of 40 patients. Observations in 14/40 led to the suggestion of restitution of plasma exchange for light-chain responsive, biopsy-proven myeloma kidney until a better randomized control trial (RCT) is constructed. A careful analysis of their study and a recent RCT suggest little difference in outcome between plasma exchange and control groups. The analysis supports restitution of a better RCT of plasma exchange for myeloma kidney rather than off-label use. Acute kidney injury in the setting of multiple myeloma has a strong impact on patient morbidity, mortality, health-care utilization, and cost.1.Torra R. Blade J. Cases A. et al.Patients with multiple myeloma requiring long-term dialysis: presenting features, response to therapy, and outcome in a series of 20 cases.Br J Haematol. 1995; 91: 854-859Crossref PubMed Scopus (127) Google Scholar, 2.Winearls C.G. Acute myeloma kidney.Kidney Int. 1995; 48: 1347-1361Abstract Full Text PDF PubMed Scopus (113) Google Scholar, 3.Chandna S.M. Schulz J. Lawrence C. et al.Is there a rationale for rationing chronic dialysis? A hospital based study of factors affecting survival and morbidity.BMJ. 1999; 318: 217-223Crossref PubMed Scopus (205) Google Scholar, 4.Blade J. Fernandez-Llama P. Bosch F. et al.Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution.Arch Intern Med. 1998; 158: 1889-1893Crossref PubMed Scopus (339) Google Scholar A unique and important cause of acute kidney injury in multiple myeloma is cast nephropathy, in which renal inflammation results from an excess of filtered monoclonal light chains that are transported to the interstitium of the kidney via specific receptors in the proximal tubule. The receptors become overloaded by the light chains, which then combine with Tamm-Horsfall protein, forming obstructive casts in the renal tubules.5.Clark A.D. Shetty A. Soutar R. Renal failure and multiple myeloma: pathogenesis and treatment of renal failure and management of underlying myeloma.Blood Rev. 1999; 13: 79-90Abstract Full Text PDF PubMed Scopus (104) Google Scholar Plasma exchange has been shown to remove light chains transiently and may have an adjunctive effect when combined with effective chemotherapy in the treatment of cast nephropathy.3.Chandna S.M. Schulz J. Lawrence C. et al.Is there a rationale for rationing chronic dialysis? A hospital based study of factors affecting survival and morbidity.BMJ. 1999; 318: 217-223Crossref PubMed Scopus (205) Google Scholar, 6.Cserti C. Haspel R. Stowell C. Dzik W. Light-chain removal by plasmapheresis in myeloma-associated renal failure.Transfusion. 2007; 47: 511-514Crossref PubMed Scopus (56) Google Scholar, 7.Hutchison C.A. Cockwell P. Reid S. et al.Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies.J Am Soc Nephrol. 2007; 18: 886-895Crossref PubMed Scopus (234) Google Scholar Two small randomized controlled trials (RCTs) of 29 and 21 patients provided conflicting results regarding the benefit of plasma exchange.8.Johnson W.J. Kyle R.A. Pineda A.A. et al.Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis and chemotherapy.Arch Intern Med. 1990; 150: 863-869Crossref PubMed Google Scholar,9.Zuchelli P. Pasquali S. Cagnoli L. Ferrari G. Controlled plasma exchange trial in acute renal failure due to multiple myeloma.Kidney Int. 1988; 33: 1175-1180Abstract Full Text PDF PubMed Scopus (187) Google Scholar Recently, in a larger RCT, 97 patients presenting with myeloma and acute renal failure were randomized to receive standard chemotherapy with or without plasma exchange. This study failed to demonstrate a benefit of the addition of plasma exchange therapy.10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar (this issue) now reconsider the role of plasma exchange in myeloma cast nephropathy in a retrospective case series. The series suffers from the usual shortcomings of a small retrospective analysis of a heterogeneous mixture of acute, subacute, and chronic renal failure patients with the diagnosis of myeloma (incident and recurrent cases) who receive a range of 1–19 plasma exchanges and 12 different chemotherapy protocols. In this report, 40 cases are initially reported; 28 of these patients agreed to undergo renal biopsy, of whom 18 had cast nephropathy as a diagnosis. Of the 18, 14 had serum free-light chain measurement, and of these, 50% demonstrated a renal response to their plasma exchange therapy plus or minus other types of chemotherapy. In an exploratory uncorrected sub-sub-sub-subgroup analysis, nine patients had a greater than 50% reduction in serum free-light chains with a diagnosis of cast nephropathy, and seven demonstrated a renal response. A renal response was a composite outcome, which required the patient to be alive at 6 months and to have had a reduction in his or her baseline serum creatinine of 50% and to be independent of dialysis. Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar contend that their results are dependent on identification of patients with myeloma and renal failure who have cast nephropathy confirmed by renal biopsy and have serum free-light chain measurement. Unfortunately, only 14 of their 40 subjects met these requirements. This retrospective analysis noted no correlation between the number of plasma exchanges that patients received and their serum free-light chain response or their renal response. Although the subjects did receive 12 different types of chemotherapy, renal response did show a weak correlation with high-dose dexamethasone therapy. The renal response rates in the 18 patients with biopsy-proven cast nephropathy and the 14 patients with biopsy-proven cast nephropathy and serum free-light chain measurement are similar to the response rates noted for both control and plasma exchange subjects in the previous RCT (Table 1). The subjects in the previous RCT had incident myeloma, were followed prospectively, and had well-defined acute renal failure.10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar The expected incidence of cast nephropathy for this well-defined group would be anywhere between 77% and 100%.1.Torra R. Blade J. Cases A. et al.Patients with multiple myeloma requiring long-term dialysis: presenting features, response to therapy, and outcome in a series of 20 cases.Br J Haematol. 1995; 91: 854-859Crossref PubMed Scopus (127) Google Scholar, 2.Winearls C.G. Acute myeloma kidney.Kidney Int. 1995; 48: 1347-1361Abstract Full Text PDF PubMed Scopus (113) Google Scholar, 4.Blade J. Fernandez-Llama P. Bosch F. et al.Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution.Arch Intern Med. 1998; 158: 1889-1893Crossref PubMed Scopus (339) Google Scholar Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar used a composite outcome that required that the patient be alive, have a 50% reduction in baseline serum creatinine, and dialysis independence at 6 months. The Clark et al.10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar outcome was death, dialysis dependence, or creatinine clearance less than 30 ml/min/1.73 m2, and the inverse would be similar to the Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar outcome: life, dialysis independence, and serum creatinine improvement of 50% at 6 months from the time of diagnosis of acute renal failure (Table 1).Table 1OutcomesOutcomes: 6 monthsComposite renal responseDialysis independenceLeung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar18/40=45% Myeloma, renal failure2/9=22% PE9/18=50% PE, CN7/14=50% PE, CN, sFLCClark et al.10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar13/26=50% Control7/19=37% Control21/38=55% PE10/24=42% PECN, cast nephropathy; PE, plasma exchange; sFLC, serum free light chains. Open table in a new tab CN, cast nephropathy; PE, plasma exchange; sFLC, serum free light chains. Table 1 demonstrates the comparative outcomes and shows that Leung et al.'s11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar plasma exchange group did not have a significantly different outcome from that of the control and plasma exchange arms of the Clark et al. RCT10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar (Table 1). However, the optimal outcomes noted for the sub-subgroup of cast nephropathy patients who responded with a 50% reduction in serum free-light chains after an unspecified number of plasma exchanges and differing chemotherapy appear superior to the RCT results. It is the outcome of this highly selected subgroup that has encouraged Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar to suggest restitution of plasma exchange therapy. The increased benefit for the optimized patient group with biopsy and serum free-light chain reduction of 50% is more likely to be due to the type of chemotherapy and the responsiveness of the myeloma, rather than the plasma exchange therapy.2.Winearls C.G. Acute myeloma kidney.Kidney Int. 1995; 48: 1347-1361Abstract Full Text PDF PubMed Scopus (113) Google Scholar, 6.Cserti C. Haspel R. Stowell C. Dzik W. Light-chain removal by plasmapheresis in myeloma-associated renal failure.Transfusion. 2007; 47: 511-514Crossref PubMed Scopus (56) Google Scholar, 7.Hutchison C.A. Cockwell P. Reid S. et al.Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies.J Am Soc Nephrol. 2007; 18: 886-895Crossref PubMed Scopus (234) Google Scholar This is why the mortality rate among patients who received standardized chemotherapy in the Clark et al. study10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar did not differ between the plasma exchange and control arms, in contrast to the major difference between the response and the non-response group in the Leung et al. study.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar The magnitude of survival advantage reported by Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar would be expected if a 50% reduction in serum free-light chain levels was merely a marker for patients whose myeloma was responsive to chemotherapy. Plasma exchange is not able to induce a lasting light chain response in the absence of chemotherapy in patients with myeloma.6.Cserti C. Haspel R. Stowell C. Dzik W. Light-chain removal by plasmapheresis in myeloma-associated renal failure.Transfusion. 2007; 47: 511-514Crossref PubMed Scopus (56) Google Scholar,7.Hutchison C.A. Cockwell P. Reid S. et al.Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies.J Am Soc Nephrol. 2007; 18: 886-895Crossref PubMed Scopus (234) Google Scholar The weak correlation noted by Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar for renal response to chemotherapy, coupled with the lack of association of the number of plasma exchanges with serum free-light chain response, is consistent with this interpretation. Plasma exchange without chemotherapy is unlikely to exhibit clinical benefit in cast nephropathy because of free-light chain removal. Free-light chains are relatively small molecules (25–50 kilodaltons) and are present in similar concentration in the intravascular and extravascular compartments.6.Cserti C. Haspel R. Stowell C. Dzik W. Light-chain removal by plasmapheresis in myeloma-associated renal failure.Transfusion. 2007; 47: 511-514Crossref PubMed Scopus (56) Google Scholar Thus about 15%–20% of free-light chains are available for removal, of which one volume plasma exchange would remove about 10%–15%. This would have little impact if chemotherapy did not reduce production. This has been clearly demonstrated in two recent publications that deal with the kinetics of free-light chain removal with the use of chemotherapy and plasma exchange.6.Cserti C. Haspel R. Stowell C. Dzik W. Light-chain removal by plasmapheresis in myeloma-associated renal failure.Transfusion. 2007; 47: 511-514Crossref PubMed Scopus (56) Google Scholar,7.Hutchison C.A. Cockwell P. Reid S. et al.Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies.J Am Soc Nephrol. 2007; 18: 886-895Crossref PubMed Scopus (234) Google Scholar We would contend that the 50% reduction in free-light chains noted by Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar marks those who responded to chemotherapy, as is suggested by the two recent publications and the recent RCT.6.Cserti C. Haspel R. Stowell C. Dzik W. Light-chain removal by plasmapheresis in myeloma-associated renal failure.Transfusion. 2007; 47: 511-514Crossref PubMed Scopus (56) Google Scholar, 7.Hutchison C.A. Cockwell P. Reid S. et al.Efficient removal of immunoglobulin free light chains by hemodialysis for multiple myeloma: in vitro and in vivo studies.J Am Soc Nephrol. 2007; 18: 886-895Crossref PubMed Scopus (234) Google Scholar, 10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar Is it time to cast away plasma exchange forever as an ineffective method of improving renal and broader outcomes in patients with multiple myeloma? The answer is clearly no. As Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar highlight, the jury is still out, and there is no debate that better RCTs are needed to clarify the role of this therapy in multiple myeloma. However, is the American Society for Apheresis correct to describe plasma exchange as ‘having suggestion of benefit for which existing evidence is insufficient to establish the efficacy of benefit’? Our position is that the answer at this time is a clear yes. Our emphasis as a community should be to encourage patients to participate in future trials. There is a current RCT in the United Kingdom led by Dr Gill Gaskin that commenced in 2004 and intends to enroll 280 patients with newly diagnosed multiple myeloma and acute kidney failure. Free-light chain measurement will be included, but renal biopsy is not an inclusion criterion in this well-constructed trial. We await this larger study with anticipation, but in view of the concerns of Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar about the need for renal biopsy, we would strongly encourage Leung et al. and those of similar interests to use both renal biopsy and serum free-light chain measurements in constructing the randomized control study that will test their hypothesis that plasma exchange improves renal outcomes in myeloma cast nephropathy. In the present environment it may be easier to recruit the numbers needed to carry out an RCT, as there will be less of the off-label use of plasma exchange that was noted in the previous RCT.10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar The RCT by Clark et al.10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar did suffer from the absence of renal biopsy and the measurement of serum free-light chain levels. However, we should not forget that the response rate with biopsy-proven cast nephropathy and measurement of free-light chains resulted in a similar 50% improvement in renal outcome for the cast nephropathy group of Leung et al.11.Leung N. Gertz M.A. Zeldenrust S.R. et al.Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.Kidney Int. 2008; 73: 1282-1288Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar and the control and plasma exchange arms of the Clark et al. RCT.10.Clark W.F. Stewart A.K. Rock G.A. et al.Plasma exchange when myeloma presents as acute renal failure: a randomized controlled trial.Ann Intern Med. 2005; 143: 776-784Google Scholar WF Clark is a professor of medicine at the University of Western Ontario. AX Garg is supported by a Clinician Scientist Award from the Canadian Institutes of Health Research.