New alternatives in the treatment of myeloma kidney
Nuevas alternativas en el tratamiento del riñón del mieloma
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Although renal involvement in MM is around 40%, only 12%-20% of the cases develop acute renal failure (ARF) and it is a poor prognostic factor for patient survival,<span class="elsevierStyleSup">1,2</span> probably because the disease is more aggressive.<span class="elsevierStyleSup">3-5</span> Approximately 10% of patients with ARF due to MM require haemodialysis (HD).<span class="elsevierStyleSup">3,6</span> The mean survival of patients with MM on HD is 12 to 24 months, with one year survival rates ranging between 30% and 84% according to different series.<span class="elsevierStyleSup">7</span></p><p class="elsevierStylePara">The most common cause of ARF is an excessive production of free light chains (FLC), which causes a cast nephropathy known as myeloma kidney. These casts are composed of cell fragments, FLC and Tamm-Horsfall protein. Factors such as a low glomerular filtration rate, the acidic environment of the distal nephron and the presence of electrolytes such as sodium chloride facilitate coaggregation of FLC with the Tamm-Horsfall protein and its precipitation causes tubular obstruction. Most of the casts produce lumen obstruction of the distal tubule on a microscopic level and often induce a local inflammatory reaction with the creation of giant multinuclear cells typical of myeloma kidney.<span class="elsevierStyleSup">8</span> Glomerular involvement, which is due to amyloidosis AL (10%-15% of the cases), FLC deposits at this level or type I cryoglobulinaemia, is less common. Other mechanisms of renal injury are hypercalcaemia, hyperuricaemia and hyperviscosity syndrome.<span class="elsevierStyleSup">9</span></p><p class="elsevierStylePara">The objective of myeloma kidney treatment is to reduce the production of, and therefore exposure of the kidney to FLC. Until the middle of this decade, when we began to have access to a specific laboratory test, it was not possible to determine FLC and consequently, the latter could not be routinely measured in the follow-up of these patients. Studies carried out since 2008 show for the first time the relationship between the reduction of plasma levels of FLC by different methods and renal function recovery.<span class="elsevierStyleSup">10-12</span> Furthermore, not only is the reduction in plasma FLC significant but the rate of reduction is also important, and as such, patients who achieve a sustained reduction in the first three weeks of treatment have a significantly higher likelihood of recovering renal function than those who do not.<span class="elsevierStyleSup">13</span> New chemotherapeutic agents and combinations of techniques that increase FLC clearance have improved the survival of patients with myeloma kidney and the recovery of renal function in many cases.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">NEW chemotherapeutic agents</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">In recent years, the chemotherapeutic treatment of MM has changed with the introduction of new drugs that have increased the mean survival of patients from 30 to 45 months.<span class="elsevierStyleSup">14</span> Current regimens include, in addition to dexamethasone, proteasome inhibitors such as bortezomib and immunomodulators such as thalidomide and lenalidomide. Bortezomib, through a series of mechanisms including blocking the activation of nuclear factor κB, promotes apoptosis of plasma cells and sensitises them to the chemotherapeutic action of other agents.<span class="elsevierStyleSup">15</span> Since no dose adjustment is required in renal failure, it has become a first-line treatment in patients with myeloma kidney in combination with dexamethasone and other agents. Approximately 20%-30% of patients on dialysis recover renal function during treatment with bortezomib<span class="elsevierStyleSup">10,16</span> and this usually occurs early, during the first two or three cycles.<span class="elsevierStyleSup">17-19</span></p><p class="elsevierStylePara">Immunomodulators such as thalidomide and lenalidomide are generally used with other chemotherapeutic agents, although there are studies that show that, in combination with high-dose dexamethasone, thalidomide is associated with improvement of renal function in patients with myeloma kidney.<span class="elsevierStyleSup">20,21</span> Thalidomide is not eliminated by the kidney and therefore no dose adjustment is required, although in patients on dialysis, there may be hyperkalaemia, and therefore, it should be used with caution.<span class="elsevierStyleSup">22</span> Lenalidomide, a second generation derivative, is eliminated by the kidney, and as such, it is necessary to adjust the dose in patients with renal failure. Most studies with lenalidomide exclude patients with renal failure, although one trial with small numbers of patients showed an improvement in renal function.<span class="elsevierStyleSup">23</span> Compared with immunomodulator-based regimens, it seems that bortezomib is more effective recovering renal function and furthermore, the latter occurs earlier.<span class="elsevierStyleSup">24</span> In addition to its chemotherapeutic effect, its anti-inflammatory effect through the inhibition of nuclear factor κB could help prevent inflammation and renal fibrosis.<span class="elsevierStyleSup">5</span> The International Myeloma Working Group recommends using bortezomib-based regimens as the first choice in patients with myeloma kidney. Adding thalidomide to these regimens seems to improve response, but there have not yet been any conclusive studies.<span class="elsevierStyleSup">25</span></p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">ELIMINATION OF FREE LIGHT CHAINS IN PLASMA</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Kappa and lambda FLC are normally found in serum as monomers or dimers with a molecular weight of 22.5kDa and 45kDa respectively, with a half-life of 3 to 6 hours. In MM, in addition to the great overproduction of FLC, the latter form high molecular weight multimers. If there is renal failure, the half-life of these multimers increases to 2-3 days, which prolongs exposure of the kidney to FLC and increases renal toxicity, even if the response to chemotherapy is good. In patients presenting with severe renal failure and requiring dialysis, there is minimal renal clearance of FLC and the possibility of non-recovery of renal function is very high.<span class="elsevierStyleSup">26</span> For this reason, it is necessary to use additional therapies to eliminate FLC from plasma in these patients.</p><p class="elsevierStylePara">The first attempts at FLC elimination were made with plasmapheresis. Although initial studies seemed promising, in 2005 Clark published a randomised controlled study with 104 patients with MM and ARF that does not show substantial clinical benefits (substantial reduction in mortality, dependence from dialysis or an improved glomerular filtration rate) after plasmapheresis treatment associated with chemotherapy.<span class="elsevierStyleSup">27</span> By contrast, another study in 2008 demonstrated that plasmapheresis is effective for recovery of renal function if the FLC level is reduced by 50%<span class="elsevierStyleSup">12</span> and a more recent observational study on a small number of patients demonstrated that when bortezomib is used and plasmapheresis is performed daily, high renal recovery rates can be achieved.<span class="elsevierStyleSup">28</span> Although the idea of eliminating FLC by plasmapheresis is attractive, body distribution of FLC, balanced between intra-and extravascular compartments, with 80% in the latter compartment, results in poor elimination with a regular exchange of plasma volume (1.5 times in about 2-3 hours). Given the very high cut-off of plasma filters, higher rates of plasma exchange have the disadvantage that they are associated with loss of other higher molecular weight proteins that are essential for the body and, therefore, it is not advisable to use these aggressive therapies.</p><p class="elsevierStylePara">In recent years, several studies have been published on the efficacy of eliminating FLC from very high patency, high-cut-off (HCO) dialysis membranes designed for this purpose. HCO membranes have large pores with a cut-off of 45-60kD, therefore allowing both kappa and lambda FLC filtration. Hutchison et al. have shown that when used in patients with dialysis-dependent ARF due to MM in combination with bortezomib-based chemotherapy regimens, renal function recovery rates of 60%-74% are achieved.<span class="elsevierStyleSup">11,29-31</span> Dialysis with HCO membranes is more effective the earlier the diagnosis and treatment of MM.<span class="elsevierStyleSup">3,32</span> Furthermore, a linear relationship exists between the early treatment and the rate of renal function recovery, which is associated with survival,<span class="elsevierStyleSup">13</span> and this is probably due to reduced renal exposure to FLC. In subsequent studies, on a smaller number of patients, similar results were obtained, although a higher rate of FLC reduction has not been directly associated with renal recovery.<span class="elsevierStyleSup">33</span> In all published studies, long dialysis sessions of about 8-12 hours are carried out. At the beginning, the Theralite<span class="elsevierStyleSup">®</span> (Gambro) HCO 1100 dialyzer with a 1.1m<span class="elsevierStyleSup">2</span> area was used and, as the dialyzer clotted over time, two or more dialyzers were used per session. The 2.1m<span class="elsevierStyleSup">2</span> Theralite<span class="elsevierStyleSup">®</span> (Gambro) HCO 2100 dialyzer is currently used. Its clearance is more effective due to its larger area and only one filter is required. The main drawback of HCO membranes is that they cause a substantial loss of albumin, especially if associated with convective transport, and as such, replacement of the latter is required. Moreover, they can lead to decreased levels of chemotherapeutic agents that have a high rate of protein binding. Another drawback is their high price, to which albumin replacement must be added.</p><p class="elsevierStylePara">Recently, HFR (haemodiafiltration with ultrafiltrate regeneration by adsorption in resin) has been introduced as an extrarenal clearance technique that combines convection, adsorption and diffusion. It uses a dual chamber dialyzer: the first with a superflux polyphenylene membrane, with a cut-off of 42kD in which ultrafiltration is performed, and the second has the same membrane, but with low penetration, in which diffusion takes place. The ultrafiltrate obtained from the first chamber passes through a resin cartridge where adsorption occurs and it is reinfused before reaching the second chamber. This technique is employed in HD patients due to its high protein bound toxins adsorption capacity, with the great advantage that it does not adsorb albumin.<span class="elsevierStyleSup">34</span> Since the cut-off of 42kD theoretically allows the passage of FLC, especially kappa FLC, HFR may also be useful for eliminating FLC. A study has recently shown that HFR effectively removes kappa FLC in dialysis patients with both monoclonal and polyclonal gammopathies<span class="elsevierStyleSup">35</span> and our group is obtaining very promising preliminary results in patients with ARF due to MM who require HD.<span class="elsevierStyleSup">36</span></p><p class="elsevierStylePara">In this issue of the journal, Borrego et al. report five cases of ARF due to MM treated by HD with HCO, with excellent results.<span class="elsevierStyleSup">37</span> In association with a bortezomib-based chemotherapy regimen, all patients were treated with long dialysis sessions with a HCO membrane of 1.1m<span class="elsevierStyleSup">2</span> in one case and 2.1m<span class="elsevierStyleSup">2</span> in the others. Four of the five patients recovered renal function and became independent of dialysis and survival varied between 12 and 26 months at the end of the study. These results are comparable with those obtained by other authors<span class="elsevierStyleSup">26,33</span> and show that the elimination of circulating FLC is essential for the recovery of renal function in patients with myeloma kidney. It must be highlighted that this study also confirms that early treatment is fundamental for reducing FLC, as was already described,<span class="elsevierStyleSup">13</span> since the only patient who did not recover renal function was the patient in whom HCO dialysis was delayed. Another point that has been ruled out is the excessive loss of albumin, which requires it to be replaced, further increasing the cost of this therapy. The main limitations of the study by Borrego et al. are the small number of patients and the heterogeneity of the sample, as is the case in the majority of studies published, which furthermore, lack a control group. The multi-centre, randomised and controlled EuLITE (European Trial of Free Light Chain Removal by Extended Haemodialysis in Cast Nephropathy) study, is currently being carried out and is headed by Hutchison.<span class="elsevierStyleSup">38</span> It compares the effect of extended HD with HCO with that of high-flux HD in patients with ARF due to <span class="elsevierStyleItalic">de novo</span> diagnosed MM and treated with the same bortezomib-based chemotherapy regimen. The primary objective is independence from dialysis after three months and the secondary objectives are length of time on dialysis, reduction of FLC, myeloma response and survival. We impatiently await the results of this study that will surely shed much light on the hitherto gloomy outlook for myeloma kidney.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">KEY CONCEPTS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">1. The recovery of renal function in patients with myeloma kidney requires an energetic and early reduction of FLC in plasma.</p><p class="elsevierStylePara">2. Bortezomib, administered with high doses of dexamethasone, with or without immunomodulators, is the drug of choice in these patients and furthermore, it requires no dose adjustment.</p><p class="elsevierStylePara">3. In patients who require dialysis, the reduction of FLC in plasma, through clearance techniques with a high cut-off membrane, seems to improve prognosis. More studies are necessary to demonstrate this hypothesis and evaluate other techniques.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article.</p>" "pdfFichero" => "P1-E557-S4291-A12138-EN.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:38 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1027 patients with newly diagnosed multiple mieloma. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 3 | 7 | 10 |
| 2024 October | 48 | 32 | 80 |
| 2024 September | 53 | 22 | 75 |
| 2024 August | 65 | 72 | 137 |
| 2024 July | 48 | 34 | 82 |
| 2024 June | 65 | 35 | 100 |
| 2024 May | 62 | 31 | 93 |
| 2024 April | 51 | 31 | 82 |
| 2024 March | 44 | 30 | 74 |
| 2024 February | 45 | 33 | 78 |
| 2024 January | 40 | 33 | 73 |
| 2023 December | 35 | 21 | 56 |
| 2023 November | 41 | 40 | 81 |
| 2023 October | 34 | 36 | 70 |
| 2023 September | 31 | 183 | 214 |
| 2023 August | 35 | 27 | 62 |
| 2023 July | 58 | 32 | 90 |
| 2023 June | 32 | 35 | 67 |
| 2023 May | 71 | 28 | 99 |
| 2023 April | 40 | 28 | 68 |
| 2023 March | 34 | 23 | 57 |
| 2023 February | 21 | 20 | 41 |
| 2023 January | 45 | 27 | 72 |
| 2022 December | 46 | 24 | 70 |
| 2022 November | 50 | 33 | 83 |
| 2022 October | 43 | 36 | 79 |
| 2022 September | 45 | 33 | 78 |
| 2022 August | 39 | 41 | 80 |
| 2022 July | 37 | 47 | 84 |
| 2022 June | 35 | 44 | 79 |
| 2022 May | 39 | 35 | 74 |
| 2022 April | 41 | 43 | 84 |
| 2022 March | 67 | 53 | 120 |
| 2022 February | 58 | 45 | 103 |
| 2022 January | 71 | 36 | 107 |
| 2021 December | 71 | 50 | 121 |
| 2021 November | 41 | 36 | 77 |
| 2021 October | 66 | 56 | 122 |
| 2021 September | 58 | 39 | 97 |
| 2021 August | 46 | 48 | 94 |
| 2021 July | 48 | 37 | 85 |
| 2021 June | 40 | 21 | 61 |
| 2021 May | 65 | 32 | 97 |
| 2021 April | 212 | 59 | 271 |
| 2021 March | 106 | 30 | 136 |
| 2021 February | 84 | 26 | 110 |
| 2021 January | 87 | 33 | 120 |
| 2020 December | 69 | 18 | 87 |
| 2020 November | 76 | 30 | 106 |
| 2020 October | 55 | 7 | 62 |
| 2020 September | 65 | 16 | 81 |
| 2020 August | 73 | 22 | 95 |
| 2020 July | 66 | 19 | 85 |
| 2020 June | 68 | 14 | 82 |
| 2020 May | 90 | 19 | 109 |
| 2020 April | 46 | 11 | 57 |
| 2020 March | 60 | 11 | 71 |
| 2020 February | 64 | 21 | 85 |
| 2020 January | 69 | 21 | 90 |
| 2019 December | 78 | 41 | 119 |
| 2019 November | 105 | 20 | 125 |
| 2019 October | 88 | 15 | 103 |
| 2019 September | 102 | 20 | 122 |
| 2019 August | 93 | 14 | 107 |
| 2019 July | 75 | 26 | 101 |
| 2019 June | 57 | 24 | 81 |
| 2019 May | 88 | 19 | 107 |
| 2019 April | 148 | 46 | 194 |
| 2019 March | 109 | 24 | 133 |
| 2019 February | 53 | 20 | 73 |
| 2019 January | 75 | 29 | 104 |
| 2018 December | 94 | 36 | 130 |
| 2018 November | 89 | 19 | 108 |
| 2018 October | 61 | 13 | 74 |
| 2018 September | 75 | 13 | 88 |
| 2018 August | 59 | 22 | 81 |
| 2018 July | 51 | 12 | 63 |
| 2018 June | 53 | 21 | 74 |
| 2018 May | 50 | 15 | 65 |
| 2018 April | 65 | 14 | 79 |
| 2018 March | 61 | 12 | 73 |
| 2018 February | 49 | 9 | 58 |
| 2018 January | 37 | 11 | 48 |
| 2017 December | 46 | 13 | 59 |
| 2017 November | 41 | 14 | 55 |
| 2017 October | 31 | 10 | 41 |
| 2017 September | 47 | 12 | 59 |
| 2017 August | 36 | 20 | 56 |
| 2017 July | 45 | 22 | 67 |
| 2017 June | 35 | 24 | 59 |
| 2017 May | 42 | 22 | 64 |
| 2017 April | 37 | 27 | 64 |
| 2017 March | 39 | 14 | 53 |
| 2017 February | 28 | 38 | 66 |
| 2017 January | 23 | 17 | 40 |
| 2016 December | 66 | 11 | 77 |
| 2016 November | 84 | 20 | 104 |
| 2016 October | 90 | 13 | 103 |
| 2016 September | 138 | 9 | 147 |
| 2016 August | 228 | 7 | 235 |
| 2016 July | 222 | 7 | 229 |
| 2016 June | 129 | 0 | 129 |
| 2016 May | 160 | 0 | 160 |
| 2016 April | 126 | 0 | 126 |
| 2016 March | 93 | 0 | 93 |
| 2016 February | 113 | 0 | 113 |
| 2016 January | 119 | 0 | 119 |
| 2015 December | 123 | 0 | 123 |
| 2015 November | 107 | 0 | 107 |
| 2015 October | 89 | 0 | 89 |
| 2015 September | 73 | 0 | 73 |
| 2015 August | 81 | 0 | 81 |
| 2015 July | 66 | 0 | 66 |
| 2015 June | 38 | 0 | 38 |
| 2015 May | 55 | 0 | 55 |
| 2015 April | 5 | 0 | 5 |
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