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      Current Trends of Renal Impairment in Multiple Myeloma

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          Background: Renal impairment (RI) is a common complication of multiple myeloma (MM). Around 50% of patients with MM have RI at presentation, and up to 5% require dialysis treatment. Severe acute kidney injury (AKI) as a cause of RI is a particular challenge as historically the survival of patients who sustain this complication and require dialysis is very poor. However, in this current period, survival is improving and the focus is on optimum use of novel chemotherapies and the evaluation of extra-corporeal therapies for removal of serum immunoglobulin light chains. Summary: RI in patients with MM is commonly associated with excess monoclonal free light chain (FLC) production; myeloma cast nephropathy is the predominant renal pathology in patients presenting with severe RI secondary to AKI. The majority of patients have mild to moderate RI and recover renal function. However, patients with more severe RI, in particular those with a requirement for dialysis, are less likely to recover renal function. Rapid diagnosis and prompt institution of anti-myeloma therapy is an important determinant of renal function recovery, through targeting early and sustained reduction of involved monoclonal FLC. Novel agents are associated with excellent disease response, and bortezomib is now widely used as a first-line agent in the management of MM in patients with severe RI. Extended haemodialysis using high cut-off dialysers is more effective for extracorporeal removal of FLC than plasma exchange, and clinical trials are in process. High-dose chemotherapy with autologous stem cell transplantation does have a role in patients with severe RI but requires careful patient selection. Key Messages: RI is very common in patients with MM, and renal function recovery is associated with improved clinical outcomes. We summarise the epidemiology of MM in the UK, present the impact of RI and renal function recovery on patient outcome, and describe the current management of MM in western countries. Facts from East and West: (1) A serum creatinine level >2 mg/dl has been reported in 16, 21, 24, and 33% of patients with MM in cohort studies from Japan, Europe, China, and Korea, respectively. A creatinine clearance rate <30 ml/min was observed in 30 and 15% of patients in Chinese and Western MM cohorts, respectively. The commonest cause of severe RI in patients with MM is myeloma cast nephropathy. (2) The efficacy of novel treatments (bortezomib, carfilzomib, thalidomide, and lenalidomide) has predominantly been assessed in Western patients. Bortezomib and dexamethasone are the current standard of care for MM and severe RI in the West. Severe RI is not a contraindication to autologous stem cell transplantation (ASCT). Most of the data are from the West; there are case reports from China describing good outcomes with ASCT. The removal of FLC by high-cut-off hemodialysis is under evaluation in randomized controlled trials (RCTs) in the West. Studies in this area are not yet conducted in China. In China, new treatments, such as bortezomib, are more widely used than before, and favorable results are being reported; however, RCT studies are still needed in this area to confirm the efficacy and safety of this and other novel treatments.

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          Most cited references 108

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          Using serum creatinine to estimate glomerular filtration rate: accuracy in good health and in chronic kidney disease.

          The National Kidney Foundation has advocated the use of the abbreviated Modification of Diet in Renal Disease (MDRD) equation to estimate glomerular filtration rate (GFR) from serum creatinine measurements in clinical laboratories. However, healthy persons were not included in the development of the MDRD equation. To assess the accuracy of the MDRD equation in patients with chronic kidney disease compared with healthy persons and to develop a new equation that uses both patients with chronic kidney disease and healthy persons. Cross-sectional study. The Mayo Clinic, a tertiary-care medical center. Consecutive patients (n = 320) who had an iothalamate clearance test specifically for chronic kidney disease evaluation and consecutive healthy persons (n = 580) who had an iothalamate clearance test specifically for kidney donor evaluation. Serum creatinine levels, GFR, demographic characteristics, and clinical characteristics were abstracted from the medical record. The MDRD equation underestimated GFR by 6.2% in patients with chronic kidney disease and by 29% in healthy persons. Re-estimated coefficients for serum creatinine and sex were similar to the original MDRD equation in the chronic kidney disease series but not in the healthy series. At the same serum creatinine level, age, and sex, GFR was on average 26% higher in healthy persons than in patients with chronic kidney disease (P < 0.001). A quadratic GFR equation was developed to estimate logarithmic GFR from the following covariates: 1/SCr, 1/SCr2, age, and sex (where SCr = serum creatinine). The new equation was not developed in a general population sample. Elderly and African-American persons were underrepresented. The MDRD equation systematically underestimates GFR in healthy persons. A new equation developed with patients who have chronic kidney disease and healthy persons may be a step toward accurately estimating GFR when the diagnosis of chronic kidney disease is unknown.
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            Limitations of creatinine as a filtration marker in glomerulopathic patients.

            To determine the reliability of creatinine as a measure of the glomerular filtration rate (GFR), we compared the simultaneous clearance of creatinine to that of three true filtration markers of graded size in 171 patients with various glomerular diseases. Using inulin (radius [rs] = 15 A) as a reference marker, we found that the fractional clearance of 99mTc-DTPA (rs = 4 A) was 1.02 +/- 0.14, while that of a 19 A rs dextran was 0.98 +/- 0.13, with neither value differing from unity. In contrast, the fractional clearance (relative to inulin) of creatinine (rs = 3 A) exceeded unity, averaging 1.64 +/- 0.05 (P less than 0.001), but could be lowered towards unity by acute blockade of tubular creatinine secretion by IV cimetidine. Cross-sectional analysis of all 171 patients revealed fractional creatinine secretion to vary inversely with GFR. This inverse relationship was confirmed also among individual patients with either deteriorating (N = 28) or remitting (N = 26) glomerular disease, who were studied longitudinally. As a result, changes in creatinine relative to inulin clearance were blunted considerably or even imperceptible. We conclude that true filtration markers with rs less than 20 A, including inulin, are unrestricted in glomerular disease, and that creatinine is hypersecreted progressively by remnant renal tubules as the disease worsens. Accordingly, attempts to use creatinine as a marker with which to evaluate or monitor glomerulopathic patients will result in gross and unpredictable overestimates of the GFR.
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              Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma.

              The antiangiogenic activity of thalidomide (Thal), coupled with an increase in bone marrow angiogenesis in multiple myeloma (MM), provided the rationale for the use of Thal in MM. Previously, the direct anti-MM activity of Thal and its analogues (immunomodulatory drugs, IMiDs) on MM cells was demonstrated, suggesting multiple mechanisms of action. In this study, the potential immunomodulatory effects of Thal/IMiDs in MM were examined. It was demonstrated that Thal/IMiDs do not induce T-cell proliferation alone but act as costimulators to trigger proliferation of anti-CD3-stimulated T cells from patients with MM, accompanied by an increase in interferon-gamma and IL-2 secretion. However, an increase in autologous T-cell killing of patient MM cells could not be demonstrated. A role for natural killer (NK)- and LAK-cell-mediated killing is suggested because IL-2-primed peripheral blood mononuclear cells (PBMCs) treated with Thal/IMiDs demonstrated significantly increased lysis of MM cell lines. Cold target inhibition assays suggested NK- rather than LAK-cell-mediated killing. Furthermore, this killing was not major histocompatibility complex-class restricted, and the depletion of CD56(+) cells blocked the drug-induced MM cell lysis. It was significant that increased killing of patient MM cells by autologous PBMCs treated with Thal/IMiDs was also observed. Although the in vivo relevance of NK-cell-mediated MM cell killing is unknown, phenotypic analysis performed in MM patients receiving Thal therapy demonstrated an increase in CD3(-)CD56(+) cells in patients responding to therapy. Thus in vitro and in vivo data support the hypothesis that Thal may mediate its anti-MM effect, at least in part, by modulating NK cell number and function.

                Author and article information

                Kidney Diseases
                S. Karger AG
                March 2016
                03 February 2016
                : 1
                : 4
                : 241-257
                aDepartment of Renal Medicine, Queen Elizabeth Hospital, bSchool of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, cBirmingham Institute of Translational Medicine, and dDepartment of Haematology, Queen Elizabeth Hospital, Birmingham, UK
                Author notes
                *Prof. Paul Cockwell, Department of Renal Medicine, Queen Elizabeth Hospital, Mindelsohn Way, Edgbaston, Birmingham B15 2GW (UK), E-Mail paul.cockwell@uhb.nhs.uk
                442511 PMC4934811 Kidney Dis 2015;1:241-257
                © 2016 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Tables: 3, References: 141, Pages: 17
                Myeloma-Related Kidney Disease: Review


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