Monoclonal gammopathies of renal significance

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"autores" => array:4 [ 0 => array:4 [ "nombre" => "Fernando" "apellidos" => "Caravaca-Fontán" "email" => array:1 [ 0 => "fcaravacaf@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Eduardo" "apellidos" => "Gutiérrez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Ramón" "apellidos" => "Delgado Lillo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Manuel" "apellidos" => "Praga" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Ruber Juan Bravo, Madrid, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Gammapatías monoclonales de significado renal" ] ] "textoCompleto" => "IntroductionSeveral clinical entities are grouped under the name monoclonal gammopathies (MGs). They share a clonal proliferation of B-cells or plasma cells with the capacity to produce and secrete large amounts of a unique type of immunoglobulin or a constituent part of it (monoclonal component). The monoclonal component may be constituted of a heavy chain (normally γ chain and, less frequently, α, μ, δ, ¿ chains) along with a light chain (κ or λ), isolated light chains and, in exceptional circumstances, only heavy chains.<a class="elsevierStyleCrossRef" href="#bib0670">1</a>The range of diseases, clinical manifestations and adverse health effects and persistence of entities is not only related to neoplastic cell proliferation, but also to the damage produced by the deposit of these monoclonal proteins in different organs, or through more complex pathogenic mechanisms, including autoimmunity, inflammation and fibrogenesis.<a class="elsevierStyleCrossRefs" href="#bib0675">2–4</a>In 2003, the International Myeloma Working Group<a class="elsevierStyleCrossRef" href="#bib0675">2</a> revised the criteria for the diagnosis and classification of the clinical entities that are grouped under the term MG. In accordance with these criteria, there are four different entities:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">1.MG of undetermined significance (MGUS): monoclonal component <30g/l, with proliferation of plasma cells in bone marrow (<10%) and lack of clinical evidence of myeloma, lymphoma or amyloidosis.</li><li class="elsevierStyleListItem" id="lsti0010">2.Asymptomatic or quiescent myeloma: monoclonal component ≥30g/l, with proliferation of bone marrow plasma cells ≥10%, but without evidence of organs or tissues involvement and, absence of the typical tetrad of hypercalcaemia, renal involvement, anaemia and bone lesions.</li><li class="elsevierStyleListItem" id="lsti0015">3.Symptomatic myeloma which requires involvement of organs or tissues and which can also present as non-secretory (with no secretory component of monoclonal proteins). In 2014, the following additional criteria were incorporated: the presence of ≥60% plasma cells in bone marrow, a involved/uninvolved serum free light chain ratio ≥100, or the existence of more than one focal lesion using advanced imaging techniques (computed tomography [CT], magnetic resonance imaging [MRI] or positron emission tomography with 18F-fluorodeoxyglucose [PET-CT]).<a class="elsevierStyleCrossRef" href="#bib0690">5</a></li><li class="elsevierStyleListItem" id="lsti0020">4.Solitary bone plasmacytoma, extramedullary plasmacytoma and multiple solitary plasmacytomas.</li></ul>Approximately 60% of all MGs are MGUS.<a class="elsevierStyleCrossRef" href="#bib0695">6</a> In MGUS, a clone of B-cells or plasma cells, which are generally not neoplastic, produces and secretes small quantities of a monoclonal immunoglobulin or its components (light or heavy chains).<a class="elsevierStyleCrossRefs" href="#bib0700">7,8</a>This entity is a relatively common finding in the adult population (prevalence of 0.7% in the general population, increasing to 3% in those over the age of 50 and to 5% in those above the age of 70),<a class="elsevierStyleCrossRef" href="#bib0705">8</a> with an annual standardised incidence of 4–15 cases per 100,000 according to different studies,<a class="elsevierStyleCrossRefs" href="#bib0710">9,10</a> but which may peak at 169 cases per 100,000 in individuals older than 80.<a class="elsevierStyleCrossRef" href="#bib0715">10</a>It is estimated that in MGUSs there is neoplastic transformation (myeloma or lymphoma) in 1% annually.<a class="elsevierStyleCrossRefs" href="#bib0720">11–13</a> The factors which have proven to be determinant risk factors for neoplastic transformation are the following<a class="elsevierStyleCrossRefs" href="#bib0720">11–13</a>: abnormal kappa (κ) to lambda (λ) free light chains ratio, different monoclonal immunoglobulin component (light or heavy chains) or of IgA type, and monoclonal protein concentration ≥15g/l. If these three factors are present, the risk of neoplastic progression reaches 58% in 20 years, while it is only 5% if none of these characteristics is present.<a class="elsevierStyleCrossRef" href="#bib0730">13</a>In addition to the risk of neoplastic transformation, it has been demonstrated that these patients are also three to five times more likely to suffer from kidney diseases,<a class="elsevierStyleCrossRef" href="#bib0735">14</a> and it has been observed in some studies that 23% of patients with light-chain MGUS have kidney disease.<a class="elsevierStyleCrossRef" href="#bib0740">15</a>In the 1980s, there were already reports that the pathological scope of an MGUS was not only limited to neoplastic transformation, but that the synthesis and secretion of monoclonal (M) proteins could also cause other pathological processes with systemic effects which may develop by different pathogenic mechanisms.<a class="elsevierStyleCrossRefs" href="#bib0745">16–18</a> The kidney is one of the most commonly involved organs in the clinical course of an MGUS.Renal involvement is very common in symptomatic myeloma, while the main pathogenic mechanism of myeloma-associated nephropathy is intratubular precipitation of monoclonal proteins produced by neoplastic cells (“cylinder nephropathy”).<a class="elsevierStyleCrossRefs" href="#bib0760">19–22</a> In this case, the secretion of large quantities of the M-protein are required to produce a massive precipitation, and the pathogenic key in this nephropathy is conditioned by the high burden and aggressiveness of the tumour.<a class="elsevierStyleCrossRefs" href="#bib0770">21,22</a>Descriptions of different pathological renal processes related to MGs have been increasingly reported. This led to the term MG of renal significance (MGRS)<a class="elsevierStyleCrossRefs" href="#bib0670">1,23–28</a> being adopted in order to distinguish and remove the uncertainty that exists on the benign progression of other MGs.The importance of differentiating the term MGRS lies mainly in indicating targeted diagnostic and therapeutic procedures to control the synthesis and secretion of M-proteins — if it is confirmed that these are pathogenically linked to the nephropathy — irrespective of the classic haematological criteria which are more closely linked to the spread of the malignant tumour.<a class="elsevierStyleCrossRefs" href="#bib0680">3,4,22,26</a>In this review, the main clinical–pathological characteristics of MGRSs are described, the most appropriate diagnostic approach is detailed and the therapeutic advances and future perspectives are also discussed.Kidney disease associated with monoclonal gammopathiesKidney disease associated with MGRSs is highly heterogeneous, which means that the renal biopsy is considered a key diagnostic test.<a class="elsevierStyleCrossRefs" href="#bib0670">1,22,25–28</a> However, the concomitant presence of kidney disease of another aetiology may make the correct histological interpretation difficult in some cases and be a confounding factor.<a class="elsevierStyleCrossRef" href="#bib0790">25</a>For a correct investigation and interpretation of the findings, the optical microscopy must be accompanied of immunofluorescence with a panel of antibodies against light chains and immunoglobulin isotypes, electron microscopy (EM), must also be performed as well.<a class="elsevierStyleCrossRefs" href="#bib0685">4,22,25,29</a> In some cases, more sensitive but complex techniques should also be used, such as immunoelectron microscopy (IEM),<a class="elsevierStyleCrossRef" href="#bib0815">30</a> or laser microdissection followed by proteomic mass spectrometry,<a class="elsevierStyleCrossRefs" href="#bib0820">31–34</a> to confirm the composition of the deposits and where they are located.Immunofluorescence is crucial in the diagnosis to establish the pathogenic link to blood dyscrasia and, therefore, the use of anti- (κ and λ) light-chain antibodies should be compulsory practice in the histological study of any renal biopsy.<a class="elsevierStyleCrossRef" href="#bib0790">25</a>In cases in which there is no usable kidney tissue in the frozen sample for immunofluorescence, it is possible to carry out “rescue” techniques of the sample in paraffin (Pronase treatment) with a high likelihood of success for the immunohistochemical detection of light chains.<a class="elsevierStyleCrossRef" href="#bib0840">35</a>Different methods to classify the MGRSs have been proposed.<a class="elsevierStyleCrossRefs" href="#bib0670">1,4</a> One method considers the predominant location of the kidney damage (glomerular, tubular or mixed),<a class="elsevierStyleCrossRef" href="#bib0670">1</a> although in practice it is not uncommon for more than one entity to overlap in the same biopsy.<a class="elsevierStyleCrossRefs" href="#bib0845">36–39</a> In <a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1–3</a>, the main clinical entities and their histological findings are summarised according to the extent of the damage.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia>The most accepted classification of lesions associated with MGRS is based on the distinction of the structure of deposits or inclusions according to whether these show an “organised” or “non-organised” configuration<a class="elsevierStyleCrossRefs" href="#bib0685">4,25</a> (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>).<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>“Organised” deposits are subdivided into: fibrils, microtubules and crystals or inclusions.The pathological processes associated with fibrils are: immunoglobulin-related amyloidosis (of light chains, heavy chains or mixtures of light and heavy chains)<a class="elsevierStyleCrossRefs" href="#bib0685">4,25,40–43</a> and fibrillary glomerulonephritis.<a class="elsevierStyleCrossRefs" href="#bib0685">4,33,44,45</a>When the microstructure of the deposits adopts a microtubular structure, two entities can be distinguished<a class="elsevierStyleCrossRefs" href="#bib0685">4,25</a>: immunotactoid glomerulonephritis, also known as glomerulonephritis with organised microtubules and monoclonal immunoglobulin deposits,<a class="elsevierStyleCrossRefs" href="#bib0830">33,44,46</a> and type 1 cryoglobulinaemia-associated glomerulonephritis.<a class="elsevierStyleCrossRefs" href="#bib0830">33,47–51</a>The crystal and inclusion deposits<a class="elsevierStyleCrossRefs" href="#bib0685">4,25</a> produce a predominantly tubular and interstitial disease, and two subtypes can be distinguished: proximal tubulopathy (with or without Fanconi syndrome)<a class="elsevierStyleCrossRefs" href="#bib0925">52–54</a> and histiocytosis with crystals stores,<a class="elsevierStyleCrossRefs" href="#bib0920">51,55–59</a> in which the crystal deposits are not found in the tubular epithelial cells, but instead inside the histiocytes.<a class="elsevierStyleCrossRef" href="#bib0670">1</a> Cases of acute interstitial nephritis unrelated to the crystal deposits or intratubular precipitation of cylinders have also been reported, but with light chain deposits shown in the tubular basement membranes.<a class="elsevierStyleCrossRef" href="#bib0965">60</a>Disease entities with “non-organised” deposits include: Randall-type monoclonal immunoglobulin deposit disease (disease caused by deposits of light chains, heavy chains or a combination of both)<a class="elsevierStyleCrossRefs" href="#bib0790">25,61–63</a>; proliferative glomerulonephritis with monoclonal immunoglobulin deposits<a class="elsevierStyleCrossRefs" href="#bib0750">17,25,64–68</a> and monoclonal gammapathy-associated C3 glomerulopathy (C3G).<a class="elsevierStyleCrossRefs" href="#bib1010">69–74</a> In the case of proliferative glomerulonephritis with monoclonal immunoglobulin deposits, involvement is limited to the glomerulus, while in monoclonal immunoglobulin deposit disease there is extraglomerular and, frequently, extrarenal involvement.<a class="elsevierStyleCrossRef" href="#bib0685">4</a>In addition to these processes, there are reports suggesting a possible pathogenic involvement of MG in other glomerulopathies, such as membranous GN,<a class="elsevierStyleCrossRefs" href="#bib1040">75,76</a> focal segmental glomerulosclerosis,<a class="elsevierStyleCrossRef" href="#bib1050">77</a> pauci-immune extracapillary glomerulonephritis,<a class="elsevierStyleCrossRef" href="#bib1055">78</a> C4 proliferative glomerulonephritis<a class="elsevierStyleCrossRef" href="#bib1060">79</a> and in thrombotic microangiopathies.<a class="elsevierStyleCrossRefs" href="#bib1060">79–83</a>Clinical presentationMGRSs may show a wide range of manifestations, depending on the underlying pathogenic mechanism and the primary site of involvement.<a class="elsevierStyleCrossRefs" href="#bib0670">1,3,4</a> In the majority of cases, the deposit of M-proteins is responsible for the kidney disease, while in other cases it is caused indirectly through a deregulation of the complement system's alternative pathway, resulting in C3G,<a class="elsevierStyleCrossRefs" href="#bib0670">1,3,4,71</a> or, more rarely, in atypical haemolytic uraemic syndrome.<a class="elsevierStyleCrossRef" href="#bib1070">81</a> Thus, the monoclonal component would be able to interfere with the regulatory proteins of the complement system, acting as miniautoantibodies against factor H,<a class="elsevierStyleCrossRefs" href="#bib1030">73,74</a> or as a C3 nephritic factor, which stabilises the C3 convertase of the alternative pathway and maintains its hyperactivation.<a class="elsevierStyleCrossRefs" href="#bib0670">1,70,71</a>The structural and chemical characteristics of each specifc M-protein, and the inflammatory response of each individual, seem to be key to determine the type of kidney damage being produced.<a class="elsevierStyleCrossRefs" href="#bib0755">18,84</a> High-molecular-weight proteins, such as immunoglobulins (formed by heavy and light chains), do not cross the filtration barrier and are deposited in the glomerulus which triggers an inflammatory processes. In contrast, light chains are able to cross the filtration barrier and generate a variety of tubular damage.Renal involvement is often the first manifestation of blood dyscrasia.<a class="elsevierStyleCrossRef" href="#bib0795">26</a> According to the different series, the age of diagnosis tends to be over 50. The disease of monoclonal immunoglobulin deposits is more common in males and proliferative glomerulonephritis with monoclonal immunoglobulin deposits is more common in women.<a class="elsevierStyleCrossRefs" href="#bib0980">63,66,85</a>Within the clinical manifestations of MGRSs, it is common to find different degrees of proteinuria, which may reach the nephrotic range, together with microhaematuria and hypertension in certain cases. Renal failure is detected in a high percentage of patients at the time of diagnosis, which may progress to end-stage kidney disease.<a class="elsevierStyleCrossRefs" href="#bib0685">4,63,66,86</a> This is of particular importance given that the recurrence of some of these diseases in transplanted kidneys is very common.<a class="elsevierStyleCrossRefs" href="#bib1100">87–92</a> This fact illustrate the need for a correct diagnosis, even when it is unlikely to preserve the function of the native kidneys.Extrarenal manifestations may also be presented, especially in cases of amyloidosis, monoclonal immunoglobulin deposition disease and type 1 cryoglobulinaemia, with involvement predominantly of the heart, liver, skin and joints.<a class="elsevierStyleCrossRefs" href="#bib0670">1,4,93</a> The possibility of the disease spreading to other organs and tissues in patients diagnosed with amyloidosis should be investigated,<a class="elsevierStyleCrossRef" href="#bib0880">43</a> due to the common nature of cardiac involvement, which tends to be the main determinant of mortality.<a class="elsevierStyleCrossRef" href="#bib0880">43</a>Cases of osteomalacia secondary to Fanconi syndrome have also been reported.<a class="elsevierStyleCrossRef" href="#bib0925">52</a>Other systemic manifestations of an MG may be related to endothelial damage and systemic thrombotic microangiopathy associated with the secretion of vascular endothelial growth factor (VEGF), as occurs in POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, MG and skin lesions)<a class="elsevierStyleCrossRef" href="#bib1135">94</a> and scleromyxoedema.<a class="elsevierStyleCrossRef" href="#bib1140">95</a>Diagnosis of monoclonal gammopathies of renal significanceThe appropriate diagnostic procedure of an MGRS should include, in addition to a renal biopsy, the demonstration and identification of MG in plasma or urine, a haematological study which determines the nature and extent of the cell clone causing the MG and, in some processes (e.g. amyloidosis), extension of the study to determine the spreading of the disease to other organs.<a class="elsevierStyleCrossRefs" href="#bib0685">4,25,26</a> The main techniques for the haematological and histological diagnosis are summarised in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>.<elsevierMultimedia ident="tbl0025"></elsevierMultimedia>The diagnosis of a suspected MGRS is almost always established by associating renal involvement (deterioration of function, proteinuria, Fanconi syndrome or other metabolic abnormalities associated with tubulointerstitial dysfunction) together with the presence of a monoclonal peak in the electrophoretic spectrum.<a class="elsevierStyleCrossRefs" href="#bib0685">4,96,97</a>In most cases, the diagnosis of MG is performed using conventional electrophoresis on plasma or urine.<a class="elsevierStyleCrossRefs" href="#bib0685">4,96</a> The presence of monoclonal immunoglobulins is usually identified by a tall narrow peak in the beta or gamma region, unlike polyclonal increase, which tends to create a wide band in the gamma region.<a class="elsevierStyleCrossRef" href="#bib1145">96</a>However, in some cases the concentration of monoclonal protein in plasma or urine is so small that electrophoresis is unable to detect it. In fact, some cases of renal involvement in MG are diagnosed mainly by the findings in the renal biopsy (immunohistochemistry), without being suspected when the biopsy was indicated.In addition to conventional electrophoresis, plasma and urine immunofixation must be performed in all cases to identify the type of M-protein, as this is more sensitive than electrophoresis in detecting the M-protein.<a class="elsevierStyleCrossRefs" href="#bib0685">4,96,98</a>Another diagnostic method is the determination of free light chains (FLCs) in blood and urine.<a class="elsevierStyleCrossRefs" href="#bib1145">96,98–102</a> The concentration of these proteins can be measured by a nephelometric immunoassay using polyclonal antibodies targeting light chain epitopes, which are exposed when the chain is in its free form but hidden when the chain is bound, creating the structure of the Ig.<a class="elsevierStyleCrossRef" href="#bib1160">99</a>These measurements of FLCs are very sensitive, but the drawback is that they are not able to demonstrate the monoclonality of FLCs. This possibility is suggested indirectly by the ratio between the concentrations of the κ and λ chains.<a class="elsevierStyleCrossRefs" href="#bib1155">98,100</a>An abnormal ratio of κ and λ concentrations should be interpreted more carefully in patients with deterioration of kidney function.<a class="elsevierStyleCrossRefs" href="#bib0685">4,102</a> There is a strong correlation between the FLC concentration and kidney function; as the glomerular filtration rate decreases, the polyclonal FLC concentrations, of both κ and λ increase. Furthermore, in patients with normal kidney function, the greater physiological production of polyclonal κ FLC is masked by the more rapid clearance of monomeric forms of κ FLC, compared to the larger dimeric λ forms. This is how a change is produced in the ratio of κ and λ FLC concentrations in the case of renal failure.<a class="elsevierStyleCrossRefs" href="#bib0685">4,102</a> When kidney function is normal, the range of this ratio ranges from 0.26 to 1.65, while when kidney failure is present, the ratio accepted as normal ranges between 0.37 and 3.17, however a range for each stage of kidney failure has not been established.<a class="elsevierStyleCrossRef" href="#bib1175">102</a>The difference in concentrations between FLCs is very useful not only for diagnosis, but also for follow-up and as a measure of the response to treatment. It is therefore recommended that it is monitored frequently.<a class="elsevierStyleCrossRef" href="#bib1180">103</a>FLCs are also currently included in the treatment response criteria for AL amyloidosis.<a class="elsevierStyleCrossRef" href="#bib1185">104</a> Therefore, a normalisation of the ratio of κ and λ concentrations, together with a negative result in the blood and urine immunofixation, is needed to be certain of a complete remission.Using the FLCs measurement as an isolated test for detecting an MG is subject to debate<a class="elsevierStyleCrossRef" href="#bib1190">105</a> and, although it may be useful to support the diagnosis of MG in myeloma, macroglobulinaemia and amyloidosis, the current recommendations state that electrophoresis (EP) and blood and urine immunofixation should be used for the diagnosis of MG.More complex tests (western blot or electrotransfer) on blood and urine are required for the detection of some subclasses of immunoglobulins (IgG) or circulating monoclonal incomplete heavy chains. These tests are able to detect very small concentrations of monoclonal proteins with a high sensitivity,<a class="elsevierStyleCrossRef" href="#bib1195">106</a> unfortunately these techniques are not routinely available.In order to confirm the diagnosis of MGRS, it is not only necessary to prove the pathogenic involvement of MG in the kidney, but, in addition, myeloma must be ruled out and the cell clone producing the M-protein must be characterised because its relevance in the design of the therapeutic strategy. The support of a Haematology Department is needed for this.<a class="elsevierStyleCrossRefs" href="#bib0680">3,4,107</a>In cases of MGRS in which the renal biopsy shows IgG, IgA or LC, the bone marrow aspiration and biopsy use to be sufficient to demonstrate the clone using flow cytometry and immunohistochemical techniques.<a class="elsevierStyleCrossRef" href="#bib0685">4</a> In addition, the spread of the bone tumour or the presence of solitary plasmacytoma should be ruled out with imaging techniques (CT, MRI or PET-CT).<a class="elsevierStyleCrossRefs" href="#bib0685">4,5</a> MRI is the technique with the greatest sensitivity in the detection of bone marrow infiltration, although it is laborious.<a class="elsevierStyleCrossRef" href="#bib0690">5</a> PET-CT, on the other hand, is able to identify changes in the lesions throughout the follow up and avoids the use of intravenous contrast. However, it exposes patients to high levels of radiation and is more expensive.<a class="elsevierStyleCrossRef" href="#bib0690">5</a>The possibility that a clone is from B-cells instead of from plasma cells should be suspected in patients with IgM MGRS. Then, the imaging study include areas suspected of hosting lymphadenopathies for biopsy.<a class="elsevierStyleCrossRef" href="#bib0680">3</a>TreatmentThe treatment strategies for MGRSs are based on chemotherapy that must be adapted to the nature of the cell clone, both for lymphocytes and plasma cells, to the kidney function and to the presence or non-presence of extrarenal involvement.<a class="elsevierStyleCrossRefs" href="#bib0775">22,107</a>The rapid suppression of nephrotoxic monoclonal immunoglobulin has proven to be a treatment with satisfactory results on kidney function and patient survival in several forms of MGRS.<a class="elsevierStyleCrossRef" href="#bib1200">107</a> However, as will be emphasised later, more studies and clinical experience are required to obtain therapeutic protocols based on solid evidence.The fundamental objective of treatment, except for the case of light chain amyloidosis, must be aimed at preserving kidney function.<a class="elsevierStyleCrossRefs" href="#bib0795">26,91,107,108</a> This means that patients with irreversible kidney damage would not be candidates to receive chemotherapy treatment, unless there is a desire to obtain complete haematological remission to prevent recurrence in a kidney transplant.<a class="elsevierStyleCrossRef" href="#bib1200">107</a>In 2013, the International Kidney and Monoclonal Gammopathy Working Group published a consensus document on the treatment regimens recommended for MGRSs, based on the clinical experience of the treatment of malignant blood dyscrasias.<a class="elsevierStyleCrossRef" href="#bib1200">107</a><a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a> summarises the group's main recommendations. However, given the heterogeneity of MGRS-associated diseases, there is uncertainty regarding the optimal treatment for some more complex presentations with a clinical experience that is limited to isolated case reports or small series of cases.<a class="elsevierStyleCrossRefs" href="#bib0980">63,64,70,71,77,109</a> Thus, different regimens have been used for fibrillary glomerulonephritis, including cyclophosphamide, mycophenolate mofetil, cyclosporine, melphalan, lenalidomide and rituximab, with limited results.<a class="elsevierStyleCrossRefs" href="#bib0885">44,45,110</a> Furthermore, treatment regimens similar to those used for proliferative glomerulonephritis with monoclonal immunoglobulin deposits have been used for monoclonal gammopathy-associated C3 glomerulopathy.<a class="elsevierStyleCrossRefs" href="#bib1015">70,71,107</a> However, the information available on the long-term prognosis of these processes using the current therapies is insufficient.<a class="elsevierStyleCrossRef" href="#bib0795">26</a><elsevierMultimedia ident="tbl0030"></elsevierMultimedia>Due to the growing importance of MGRSs in clinical nephrology, it is essential to be aware of the main therapeutic agents which are currently used, their tolerance and the most common side effects. Many of these treatments are administered in a combined form due to the synergistic effect on the B-cells and plasma cells.<a class="elsevierStyleCrossRef" href="#bib1220">111</a> The main combinations include<a class="elsevierStyleCrossRefs" href="#bib1200">107,111,112</a>: bortezomib, cyclophosphamide and dexamethasone; bendamustine and rituximab, and immunomodulatory agents, such as thalidomide and lenalidomide.Bortezomib has a pivotal role within the therapeutic arsenal because of its safety profile and the possibility of being administered in full doses to patients with advanced kidney disease.<a class="elsevierStyleCrossRefs" href="#bib1225">112–114</a> The mechanism of action is based on the inhibition of proteasome activity, which produces apoptosis of the plasma cell and also inhibits the NF-κB pathway by reducing the release of proinflammatory cytokines and inducing anti-apoptotic pathways at the tubular level.<a class="elsevierStyleCrossRefs" href="#bib1240">115–117</a> Usually the side effects are not serious; it causes development or worsening of peripheral neuropathy, although this is less common when the route of administration is subcutaneous.<a class="elsevierStyleCrossRef" href="#bib1255">118</a> Prophylaxis against herpes zoster is also recommended due to the risk of reactivation.<a class="elsevierStyleCrossRef" href="#bib1220">111</a>Among the cytotoxic agents, both melphalan and cyclophosphamide have an effect on B-cells and plasma cells, however cyclophosphamide is used more frequently because it is less toxic.<a class="elsevierStyleCrossRefs" href="#bib1200">107,111</a> Another alternative is bendamustine, approved for the treatment of some lymphomas and suitable for patients with renal failure since it is predominantly metabolised in the liver.<a class="elsevierStyleCrossRefs" href="#bib1260">119–121</a>Melphalan is used in myeloablative doses as a conditioning therapy for autologous haematopoietic stem cell transplantation in selected cases with no significant extrarenal disease.<a class="elsevierStyleCrossRefs" href="#bib1200">107,111</a> This autologous transplant has been proven to improve survival of patients with multiple myeloma and light chain amyloidosis. However, in practice less than 20% of patients are suitable candidates for this treatment, which is associated with high morbidity and mortality.<a class="elsevierStyleCrossRefs" href="#bib1095">86,122–124</a>Monoclonal antibodies such as rituximab (targeting the CD20 antigen) are a suitable therapeutic option in the different forms of B-cell mediated MGRS, because of their good tolerance and limited number of side effects.<a class="elsevierStyleCrossRefs" href="#bib1200">107,111,112</a> The use of daratumumab (targeting CD38) for relapsed or refractory myeloma has been approved.<a class="elsevierStyleCrossRef" href="#bib1290">125</a> However, experience on its use in cases of MGRS is currently lacking.Within the family of immunomodulatory drugs, thalidomide would be more suitable than lenalidomide, due to the fact that the latter is excreted by the kidneys and can also cause kidney function deterioration in some cases.<a class="elsevierStyleCrossRefs" href="#bib1295">126–128</a> However, side effects have also been reported with thalidomide, such as the development of hyperkalaemia.<a class="elsevierStyleCrossRef" href="#bib1310">129</a>ConclusionsMGRSs are associated with a wide range of kidney diseases resulting from the depositions of immunoglobulin or of its components in the kidneys, or through the deregulation of the complement system. Although the mortality of patients with MGRS is lower than that of myeloma or other related neoplastic forms, the likelihood of developing advanced chronic kidney disease is very high. For this reason, when evaluating patients with suspected MGRS it is necessary to conduct complete anatomopathological, haematological and biochemical studies. These studies allow to determine the type of entity and the extension of the disese. Advances in the understanding of these entities have made it possible to improve the clinical course and survival in several forms of MGRS. However, more studies and clinical experience are necessary to design more effective therapeutic protocols. It is a priority the close collaboration between nephrologists and haematologists to individualise the treatment to the clinical characteristics and comorbidity of patients, in an attempt to improve the overall prognosis of these diseases.The incidence and prevalence of this group of diseases in the Spanish population is not currently known. There are few cases published.<a class="elsevierStyleCrossRef" href="#bib1315">130</a> According to the clinical experience, these diseases are not frequent, but so far no epidemiological studies have been conducted which confirm these assessments. Furthermore, as they are rare diseases, but requiring a complex study, the diagnosis might end up being less appropriate or incomplete in patients attended to in many hospitals which do not have the necessary non-conventional diagnostic tools. Nevertheless the implementation of these tools in all hospitals does not seem to be an efficient measure. Therefore, the creation of centres of excellence and diagnostic–therapeutic reference for these types of diseases could be an appropriate investment to benefit from the health care, academic and economic value.GLOSEN study proposalIn 2009, an international group for research into MGRSs was created. Nephrology, haematology and anatomical pathology departments from several countries participate in the group.<a class="elsevierStyleCrossRefs" href="#bib0685">4,26,107</a> The studies and publications by the members of this research group are currently recognised as the forefront of research into these diseases, with very significant diagnostic and therapeutic advances. The incorporation of Spanish groups into this international group could result in mutual benefits, such as training and transfer of experience to Spanish members, as well as the incorporation of Spanish centres and patients into international clinical trials.All of these reasons could justify the creation of a national MGRS register which would help to research the clinical–pathological characteristics of these entities, and to identify evolutionary and response determinants to current treatments.We believe that the ‘Grupo de Estudio de la Patología Glomerular de la Sociedad Española de Nefrología’ [Glomerular Disease Study Group of the Spanish Society of Nephrology] (GLOSEN) may be the ideal framework to lead a study of these characteristics, given its ample experience in conducting collaborative projects.<a class="elsevierStyleCrossRefs" href="#bib1320">131–133</a>As an initial project, it is proposed to collect retrospectively all diagnosed cases of MGRS with renal biopsy during recent years from the different centres taking part in the study. Although a work proposal will be sent to all members of the group soon, we are hereby launching a message to attract the interest of all nephrologists and pathologists interested in glomerular diseases, and requesting their collaboration in the study.Conflicts of interestThe authors declare that they have no conflicts of interest related to the publication of this article.<elsevierMultimedia ident="tb0005"></elsevierMultimedia>" "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres912440" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec892035" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres912439" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec892034" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Kidney disease associated with monoclonal gammopathies" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Clinical presentation" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Diagnosis of monoclonal gammopathies of renal significance" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Treatment" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conclusions" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "GLOSEN study proposal" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 12 => array:2 [ "identificador" => "xack304748" "titulo" => "Acknowledgements" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-12-16" "fechaAceptado" => "2017-03-14" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec892035" "palabras" => array:4 [ 0 => "Chronic kidney disease" 1 => "Glomerulonephritis" 2 => "Monoclonal gammopathy of renal significance" 3 => "Monoclonal protein" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec892034" "palabras" => array:4 [ 0 => "Enfermedad renal crónica" 1 => "Gammapatía monoclonal de significado renal" 2 => "Glomerulonefritis" 3 => "Proteína monoclonal" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The term monoclonal gammopathy of renal significance (MGRS) comprises a group of diseases pathogenetically characterised by proliferation of a B-cell or plasma cell clone that synthesises and secretes a monoclonal immunoglobulin or its components (light and/or heavy chains), that may deposit and cause glomerular, tubular, interstitial and/or vascular damage. The importance of differentiating the term MGRS from other monoclonal gammopathies lies in the fact that diagnostic and therapeutic procedures aimed at controlling monoclonal protein synthesis and secretion can be indicated, irrespective of the classic criteria based on malignant tumour expansion. Renal pathology associated with MGRS is highly heterogeneous, and therefore renal biopsy should be considered a key diagnostic tool. A precise diagnostic approach, however, must also identify the monoclonal protein in plasma and/or in urine, together with a complete haematological study in order to determine the nature and extension of cell clones. Recent advances in the understanding of these entities have resulted in significant improvements in clinical course and survival in several forms of MGRS, although more studies and clinical experience are needed in order to delineate more effective therapeutic strategies. In this review, we summarise the main clinical and pathological features of MGRS, highlighting the most appropriate diagnostic approach and current therapeutic options." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "Bajo el término gammapatías monoclonales de significado renal (GMSR) se engloban un conjunto de enfermedades que se caracterizan patogénicamente por la proliferación de un clon de linfocitos B o células plasmáticas que sintetizan y segregan una inmunoglobulina monoclonal o uno de sus componentes (cadenas ligeras o pesadas), con capacidad para depositarse y producir daño a nivel glomerular, tubular, intersticial o vascular. La importancia de discriminar el término GMSR radica en poder indicar procedimientos diagnósticos y terapéuticos dirigidos al control de la síntesis y secreción de las proteínas monoclonales independientemente de los criterios clásicos vinculados con la expansión tumoral maligna. La patología renal asociada a las GMSR es muy heterogénea, lo que confiere a la biopsia renal una consideración de prueba diagnóstica clave. La correcta investigación diagnóstica de una GMSR debe incluir, además, la identificación en plasma u orina de la proteína monoclonal y un estudio hematológico completo que determine la naturaleza y extensión del clon celular. Los avances en el conocimiento de estas entidades han permitido mejorar el curso evolutivo y la supervivencia en varias formas de GMSR, aunque son necesarios más estudios y experiencia clínica para delinear protocolos terapéuticos más efectivos. En la presente revisión se resumen las principales características clínico-patológicas de las GMSR, se detalla la aproximación diagnóstica más adecuada, así como las opciones terapéuticas disponibles en el momento actual." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Caravaca-Fontán F, Gutiérrez E, Delgado Lillo R, Praga M. Gammapatías monoclonales de significado renal. Nefrologia. 2017;37:465–477." ] ] "multimedia" => array:7 [ 0 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "C3GN: C3 glomerulonephritis; DDD: dense deposit disease; Ig: immunoglobulin; MPGN: membranoproliferative glomerulonephritis; PAS: periodic acid–Schiff.Adapted from: Sethi et al.<a class="elsevierStyleCrossRef" href="#bib0670">1</a> and Bridoux et al.<a class="elsevierStyleCrossRef" href="#bib0685">4</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Glomerular disease \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical manifestations \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Optical microscopy \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Immunofluorescence \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Electron microscopy \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Proliferative glomerulonephritis with monoclonal Ig deposits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Proteinuria, variable microhaematuria, hypertension. Kidney disease. Frequent C3 hypocomplementaemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MPGN. Less common: mesangial proliferative, crescentic, sclerosing or diffuse proliferative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG (G3>G1>G2) with restriction of κ or λ light chains in mesangium and capillary wall. Less common: IgM or IgA. C3 or C1q deposits. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Double image of glomerular capillaries’ profile. Mesangial and subendothelial electron-dense deposits. Less common: subepithelial or intramembranous \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Type 1 cryoglobulinaemia-associated glomerulonephritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Arthralgia, arthritis, purpura, neuropathy. Proteinuria, microhaematuria, kidney disease. Frequent hypertension. Frequent C3 and C4 hypocomplementaemia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MPGN or endocapillary proliferative glomerulonephritis. PAS+ intraluminal deposits \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Granular deposits in mesangium and capillaries. Monoclonal IgG, IgM or IgA deposits (more common with κ chains). C3, C4 or C1q deposits. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Subendothelial and intracapillary deposits. Frequently organised in fibrils, microtubules or “in fingerprint”. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fibrillary glomerulonephritis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nephrotic proteinuria, microhaematuria and kidney disease. Rarely a rapidly progressive course \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mesangial proliferation or MPGN. Sometimes presence of crescents. Congo red negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG (G4 and G1) most commonly polyclonal \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–30nm fibrils with random orientation in mesangium and capillaries \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Immunotactoid glomerulopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Nephrotic proteinuria, microhaematuria and kidney disease. Often associated with chronic lymphocytic leukaemia or lymphocytic lymphoma \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MPGN or membranous glomerulonephritis. Less common: proliferative endocapillary \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">IgG (most common IgG1) with restriction of κ or λ light chains. C3 deposits. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">30–90nm microtubules with subendothelial or subepithelial deposits \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">C3 glomerulopathy/atypical haemolytic uraemic syndrome associated with monoclonal gammopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">By indirect deregulation of the complement system's alternative pathway. Proteinuria, nephrotic syndrome, microhaematuria, kidney disease, thrombotic microangiopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MPGN, proliferative endocapillary, mesangial or crescentic glomerulonephritis. Arterial thrombosis or glomerular capillaries \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intense deposits of C3 in mesangium and capillaries. Absence or lack of other reactants. Pronase treatment may be required to detect monoclonal Ig. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Mesangial, intramembranous and subendothelial deposits in C3GN, and mesangial and intramembranous in DDD \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1535958.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Histological patterns of glomerular damage." ] ] 1 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "H&E: haematoxylin and eosin; Ig: immunoglobulin; MM: multiple myeloma; MPGN: membranoproliferative glomerulonephritis; PAS: periodic acid–Schiff.Adapted from: Sethi et al.<a class="elsevierStyleCrossRef" href="#bib0670">1</a> and Bridoux et al.<a class="elsevierStyleCrossRef" href="#bib0685">4</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Tubular disease \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical manifestations \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Optical microscopy \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Immunofluorescence \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Electron microscopy \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cylinder nephropathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Associated with MM in 90% of cases. Acute deterioration of kidney function or progressive course. Presence of light chains in blood or urine \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Presence of eosinophilic cylinders in H&E stain, negative in PAS, with intense surrounding inflammatory reaction (neutrophils, lymphocytes). More common in distal tubule \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intense staining for a light chain (κ or λ) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Intratubular electron-dense material \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Light chain proximal tubulopathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Proteinuria and deterioration of kidney function. Fanconi syndrome sometimes associated with glycosuria, aminoaciduria and phosphaturia \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Cytoplasmic inclusions in proximal tubular epithelium (crystalline or non-crystalline). Normal glomeruli. May be associated with tubular atrophy and interstitial fibrosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Restriction for κ light chain in crystalline forms. Pronase treatment is sometimes required to detect light chains \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Rectangular or rhomboidal crystals in lysosomes or free in the cytoplasm. In the non-crystalline forms, increased lysosomes with mottled appearance \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Crystal-storing histiocytosis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Non-nephrotic proteinuria or complete nephrotic syndrome. Kidney disease. There may also be medullary, pulmonary or corneal deposits. Associated most frequently with MM and lymphoproliferative processes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Predominantly interstitial infiltration of histiocytes with eosinophilic inclusions. Sometimes also in tubular epithelium and podocytes \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Monoclonal Ig with restriction of κ light chain. Pronase treatment is sometimes required to detect light chains \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Interstitial histiocytes filled with crystals. Less common in tubular epithelium and podocytes \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1535955.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Histological patterns of tubular damage." ] ] 2 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AH: heavy-chain amyloidosis; AHL: heavy- and light-chain amyloidosis; AL: light-chain amyloidosis; Ig: immunoglobulin; MPGN: membranoproliferative glomerulonephritis; PAS: periodic acid–Schiff.Adapted from: Sethi et al.<a class="elsevierStyleCrossRef" href="#bib0670">1</a> and Bridoux et al.<a class="elsevierStyleCrossRef" href="#bib0685">4</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Glomerular and tubular disease \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical manifestations \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Optical microscopy \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Immunofluorescence \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Electron microscopy \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ig-related amyloidosis (AL, AH, AHL) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Proteinuria and nephrotic syndrome, with varying degrees of renal failure. Rare microhaematuria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">PAS and silver-negative deposits in glomeruli, vessels and interstitium. Congo red positive \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">AL more common with λ or κ light chains. Heavy chains (γ), or heavy and light chains less common \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">10–30nm fibrils with random orientation in glomeruli, vessels and interstitium \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monoclonal Ig deposition disease (disease from deposits of light or heavy chains or a mixture of both) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Proteinuria, nephrotic syndrome and kidney disease. Presence of light chains and albumin in urine. Variable extrarenal manifestations due to Ig deposits in other organs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">MPGN pattern, mesangial proliferative or nodular sclerosis. Thickened glomerular and tubular basement membranes. Congo red negative \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Diffuse linear staining for light chain, heavy chain or both in glomerular and tubular basement membrane. Most common light chain: κ; Most common heavy chain: γ \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">Granular deposits in mesangium and glomerular and tubular basement membranes \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1535953.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Histological patterns of mixed glomerular and tubular damage." ] ] 3 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AH: heavy-chain amyloidosis; AHL: heavy- and light-chain amyloidosis; AL: light-chain amyloidosis; Ig: immunoglobulin.Source: A modified version of the original scheme by Bridoux et al.<a class="elsevierStyleCrossRef" href="#bib0685">4</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="6" align="left" valign="top">Organised deposits</td><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Fibrils</td><td class="td" title="table-entry " align="left" valign="top">Ig-related amyloidosis (AL, AH, AHL) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fibrillary glomerulonephritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Microtubules</td><td class="td" title="table-entry " align="left" valign="top">Immunotactoid glomerulonephritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Type 1 cryoglobulinaemic glomerulonephritis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Crystals or inclusions</td><td class="td" title="table-entry " align="left" valign="top">Proximal tubulopathy (with or without Fanconi syndrome) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Crystal-storing histiocytosis \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="3" align="left" valign="top">Non-organised deposits</td><td class="td" title="table-entry " colspan="2" align="left" valign="top">Monoclonal Ig deposition disease (light or heavy chains or a mixture of both)</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Proliferative glomerulonephritis with monoclonal Ig deposits</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="2" align="left" valign="top">Monoclonal Ig-associated C3 glomerulonephritis</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1535957.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Classification scheme of MGRS-associated disease according to the presence of organised or non-organised deposits." ] ] 4 => array:8 [ "identificador" => "tbl0025" "etiqueta" => "Table 5" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at5" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:3 [ "leyenda" => "CT: computed tomography; IgG: immunoglobulin G; MRI: magnetic resonance imaging; PET-CT: positron emission tomography with 18F-fluorodeoxyglucose." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Haematological \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Renal histology \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommended procedures \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">-Electrophoresis on plasma or urine -Immunofixation on plasma or urine -Free light chains in blood and urine -Bone marrow aspiration/biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">-Optical microscopy -Immunofluorescence with staining of light chains (κ and λ) and Pronase treatment in selected cases -Electron microscopy \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Additional diagnostic procedures<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">-Western blot technique for detection of IgG subclasses -Imaging test: CT, MRI or PET-CT -Lymph node biopsy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">-Immunoelectron microscopy -Laser microdissection and mass spectrometry \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1535956.png" ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "Depending on the diagnostic suspicion and clinical course, as well as availability in the centre." ] ] ] "descripcion" => array:1 [ "en" => "Techniques for the haematological and renal histology diagnosis of MGRSs." ] ] 5 => array:8 [ "identificador" => "tbl0030" "etiqueta" => "Table 6" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at6" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "AH: heavy-chain amyloidosis; AHL: heavy- and light-chain amyloidosis; AL: light-chain amyloidosis; CKD: chronic kidney disease; HSCT: haematopoietic stem cell transplantation; Ig: immunoglobulin; NT-proBNP: N-terminal pro-brain natriuretic peptide.Source: Adapted from original by Fermand et al.<a class="elsevierStyleCrossRef" href="#bib1200">107</a>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disease \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " rowspan="6" align="left" valign="top">Proliferative glomerulonephritis with monoclonal Ig deposits</td><td class="td" title="table-entry " align="left" valign="top">•Stage 1–2 CKD, proteinuria <1g/day: observation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">•Stage 1–2 CKD with proteinuria >1g/day, progressive CKD or stage 3–4 CKD: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">-Cyclophosphamide+bortezomib+dexamethasone if IgG or IgA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">-Rituximab±cyclophosphamide+dexamethasone if IgM \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">-If <65 years: high-dose melphalan following an HSCT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">•Stage 5 CKD candidate for kidney transplant: high-dose melphalan+HSCT \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="5" align="left" valign="top">Type 1 cryoglobulinaemia-associated glomerulonephritis</td><td class="td" title="table-entry " align="left" valign="top">•Paucisymptomatic or low-grade B-cell proliferation: observation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">•Symptomatic: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">-Plasmacytic clone: bortezomib+cyclophosphamide±thalidomide \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">-Lymphoplasmacytic clone: rituximab \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">-Alternative: bendamustine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Immunotactoid glomerulopathy</td><td class="td" title="table-entry " align="left" valign="top">•Treatment regimens similar to those employed in CLL, based on cyclophosphamide or bendamustine±rituximab \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">•For isolated gammopathy, treatment regimen based on bortezomib \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="4" align="left" valign="top">Ig-related amyloidosis (AL, AH, AHL)</td><td class="td" title="table-entry " align="left" valign="top">•Classification in three stages according to the increase in levels of NT-proBNP and troponin \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">•Stage 1–2: melphalan or cyclophosphamide+dexamethasone+bortezomib \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">•Stage 3: cyclophosphamide+dexamethasone+bortezomib \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">•Heart transplant if cardiac involvement; HSCT in selected cases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Monoclonal Ig deposition disease</td><td class="td" title="table-entry " align="left" valign="top">•Stage 1–3 CKD: cyclophosphamide+bortezomib+dexamethasone, with subsequent HSCT in selected cases. Alternative: bendamustine \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">•Stages 4–5 CKD: cyclophosphamide+bortezomib+dexamethasone+HSCT if candidate for kidney transplant \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " rowspan="2" align="left" valign="top">Light chain proximal tubulopathy</td><td class="td" title="table-entry " align="left" valign="top">•Stage 1–3 CKD: cyclophosphamide, bortezomib or thalidomide+HSCT in selected cases \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">•Stage 4–5 CKD: HSCT if they are candidates for a kidney transplant. If not, conservative management \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1535954.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Therapeutic regimens proposed for MGRSs." ] ] 6 => array:5 [ "identificador" => "tb0005" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "Key concepts<ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025">1.MGRSs are characterised by the proliferation of a clone of B-cells or plasma cells which synthesise and secrete a monoclonal immunoglobulin or one of its components (light or heavy chains), with the capacity to be deposited and be the cause glomerular, tubular, interstitial or vascular damage.</li><li class="elsevierStyleListItem" id="lsti0030">2.Given the heterogeneity of MGRS-associated kidney disease, the renal biopsy is fundamental, and its proper histological analysis must include optical microscopy, immunofluorescence and electron microscopy.</li><li class="elsevierStyleListItem" id="lsti0035">3.There are different ways of classifying MGRS-associated kidney disease, although the most accepted method is in accordance with the organisation of the deposits: “organised” (fibrils, microtubules and crystals) or “non-organised” (monoclonal immunoglobulin deposition disease, proliferative glomerulonephritis with monoclonal immunoglobulin deposits and monoclonal immunoglobulin-associated C3 glomerulonephritis).</li><li class="elsevierStyleListItem" id="lsti0040">4.The diagnostic study should also include electrophoresis and plasma and urine immunofixation to identify the monoclonal protein and the determination of free light chains.</li><li class="elsevierStyleListItem" id="lsti0045">5.In addition, myeloma should be ruled out and the cell clone producing the monoclonal protein should be characterised by a bone marrow aspiration and biopsy.</li><li class="elsevierStyleListItem" id="lsti0050">6.Current treatment is based on clinical experience of the treatment of malignant blood dyscrasias. 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Gammapatías monoclonales de significado renal

Fernando Caravaca-Fontána,

Corresponding author

fcaravacaf@gmail.com

Corresponding author.

, Eduardo Gutiérreza, Ramón Delgado Lillob, Manuel Pragaa

a Servicio de Nefrología, Hospital Universitario 12 de Octubre, Madrid, Spain

b Servicio de Nefrología, Hospital Ruber Juan Bravo, Madrid, Spain

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      "es" => array:1 [
        "titulo" => "Gammapat&#237;as monoclonales de significado renal"
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Several clinical entities are grouped under the name monoclonal gammopathies &#40;MGs&#41;&#46; They share a clonal proliferation of B-cells or plasma cells with the capacity to produce and secrete large amounts of a unique type of immunoglobulin or a constituent part of it &#40;monoclonal component&#41;&#46; The monoclonal component may be constituted of a heavy chain &#40;normally <span class="elsevierStyleItalic">&#947;</span> chain and&#44; less frequently&#44; <span class="elsevierStyleItalic">&#945;&#44; &#956;&#44; &#948;&#44; ¿</span> chains&#41; along with a light chain &#40;<span class="elsevierStyleItalic">&#954;</span> or <span class="elsevierStyleItalic">&#955;</span>&#41;&#44; isolated light chains and&#44; in exceptional circumstances&#44; only heavy chains&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The range of diseases&#44; clinical manifestations and adverse health effects and persistence of entities is not only related to neoplastic cell proliferation&#44; but also to the damage produced by the deposit of these monoclonal proteins in different organs&#44; or through more complex pathogenic mechanisms&#44; including autoimmunity&#44; inflammation and fibrogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0675"><span class="elsevierStyleSup">2&#8211;4</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In 2003&#44; the International Myeloma Working Group<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">2</span></a> revised the criteria for the diagnosis and classification of the clinical entities that are grouped under the term MG&#46; In accordance with these criteria&#44; there are four different entities&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0020" class="elsevierStylePara elsevierViewall">MG of undetermined significance &#40;MGUS&#41;&#58; monoclonal component &#60;30<span class="elsevierStyleHsp" style=""></span>g&#47;l&#44; with proliferation of plasma cells in bone marrow &#40;&#60;10&#37;&#41; and lack of clinical evidence of myeloma&#44; lymphoma or amyloidosis&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Asymptomatic or quiescent myeloma&#58; monoclonal component &#8805;30<span class="elsevierStyleHsp" style=""></span>g&#47;l&#44; with proliferation of bone marrow plasma cells &#8805;10&#37;&#44; but without evidence of organs or tissues involvement and&#44; absence of the typical tetrad of hypercalcaemia&#44; renal involvement&#44; anaemia and bone lesions&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Symptomatic myeloma which requires involvement of organs or tissues and which can also present as non-secretory &#40;with no secretory component of monoclonal proteins&#41;&#46; In 2014&#44; the following additional criteria were incorporated&#58; the presence of &#8805;60&#37; plasma cells in bone marrow&#44; a involved&#47;uninvolved serum free light chain ratio &#8805;100&#44; or the existence of more than one focal lesion using advanced imaging techniques &#40;computed tomography &#91;CT&#93;&#44; magnetic resonance imaging &#91;MRI&#93; or positron emission tomography with 18F-fluorodeoxyglucose &#91;PET-CT&#93;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">5</span></a></p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4&#46;</span><p id="par0035" class="elsevierStylePara elsevierViewall">Solitary bone plasmacytoma&#44; extramedullary plasmacytoma and multiple solitary plasmacytomas&#46;</p></li></ul></p><p id="par0040" class="elsevierStylePara elsevierViewall">Approximately 60&#37; of all MGs are MGUS&#46;<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">6</span></a> In MGUS&#44; a clone of B-cells or plasma cells&#44; which are generally not neoplastic&#44; produces and secretes small quantities of a monoclonal immunoglobulin or its components &#40;light or heavy chains&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">7&#44;8</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">This entity is a relatively common finding in the adult population &#40;prevalence of 0&#46;7&#37; in the general population&#44; increasing to 3&#37; in those over the age of 50 and to 5&#37; in those above the age of 70&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">8</span></a> with an annual standardised incidence of 4&#8211;15 cases per 100&#44;000 according to different studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0710"><span class="elsevierStyleSup">9&#44;10</span></a> but which may peak at 169 cases per 100&#44;000 in individuals older than 80&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">10</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">It is estimated that in MGUSs there is neoplastic transformation &#40;myeloma or lymphoma&#41; in 1&#37; annually&#46;<a class="elsevierStyleCrossRefs" href="#bib0720"><span class="elsevierStyleSup">11&#8211;13</span></a> The factors which have proven to be determinant risk factors for neoplastic transformation are the following<a class="elsevierStyleCrossRefs" href="#bib0720"><span class="elsevierStyleSup">11&#8211;13</span></a>&#58; abnormal kappa &#40;<span class="elsevierStyleItalic">&#954;</span>&#41; to lambda &#40;<span class="elsevierStyleItalic">&#955;</span>&#41; free light chains ratio&#44; different monoclonal immunoglobulin component &#40;light or heavy chains&#41; or of IgA type&#44; and monoclonal protein concentration &#8805;15<span class="elsevierStyleHsp" style=""></span>g&#47;l&#46; If these three factors are present&#44; the risk of neoplastic progression reaches 58&#37; in 20 years&#44; while it is only 5&#37; if none of these characteristics is present&#46;<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">13</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In addition to the risk of neoplastic transformation&#44; it has been demonstrated that these patients are also three to five times more likely to suffer from kidney diseases&#44;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">14</span></a> and it has been observed in some studies that 23&#37; of patients with light-chain MGUS have kidney disease&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">15</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">In the 1980s&#44; there were already reports that the pathological scope of an MGUS was not only limited to neoplastic transformation&#44; but that the synthesis and secretion of monoclonal &#40;M&#41; proteins could also cause other pathological processes with systemic effects which may develop by different pathogenic mechanisms&#46;<a class="elsevierStyleCrossRefs" href="#bib0745"><span class="elsevierStyleSup">16&#8211;18</span></a> The kidney is one of the most commonly involved organs in the clinical course of an MGUS&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">Renal involvement is very common in symptomatic myeloma&#44; while the main pathogenic mechanism of myeloma-associated nephropathy is intratubular precipitation of monoclonal proteins produced by neoplastic cells &#40;&#8220;cylinder nephropathy&#8221;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">19&#8211;22</span></a> In this case&#44; the secretion of large quantities of the M-protein are required to produce a massive precipitation&#44; and the pathogenic key in this nephropathy is conditioned by the high burden and aggressiveness of the tumour&#46;<a class="elsevierStyleCrossRefs" href="#bib0770"><span class="elsevierStyleSup">21&#44;22</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Descriptions of different pathological renal processes related to MGs have been increasingly reported&#46; This led to the term MG of renal significance &#40;MGRS&#41;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">1&#44;23&#8211;28</span></a> being adopted in order to distinguish and remove the uncertainty that exists on the benign progression of other MGs&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">The importance of differentiating the term MGRS lies mainly in indicating targeted diagnostic and therapeutic procedures to control the synthesis and secretion of M-proteins &#8212; if it is confirmed that these are pathogenically linked to the nephropathy &#8212; irrespective of the classic haematological criteria which are more closely linked to the spread of the malignant tumour&#46;<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">3&#44;4&#44;22&#44;26</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">In this review&#44; the main clinical&#8211;pathological characteristics of MGRSs are described&#44; the most appropriate diagnostic approach is detailed and the therapeutic advances and future perspectives are also discussed&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Kidney disease associated with monoclonal gammopathies</span><p id="par0085" class="elsevierStylePara elsevierViewall">Kidney disease associated with MGRSs is highly heterogeneous&#44; which means that the renal biopsy is considered a key diagnostic test&#46;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">1&#44;22&#44;25&#8211;28</span></a> However&#44; the concomitant presence of kidney disease of another aetiology may make the correct histological interpretation difficult in some cases and be a confounding factor&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">25</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">For a correct investigation and interpretation of the findings&#44; the optical microscopy must be accompanied of immunofluorescence with a panel of antibodies against light chains and immunoglobulin isotypes&#44; electron microscopy &#40;EM&#41;&#44; must also be performed as well&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;22&#44;25&#44;29</span></a> In some cases&#44; more sensitive but complex techniques should also be used&#44; such as immunoelectron microscopy &#40;IEM&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">30</span></a> or laser microdissection followed by proteomic mass spectrometry&#44;<a class="elsevierStyleCrossRefs" href="#bib0820"><span class="elsevierStyleSup">31&#8211;34</span></a> to confirm the composition of the deposits and where they are located&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Immunofluorescence is crucial in the diagnosis to establish the pathogenic link to blood dyscrasia and&#44; therefore&#44; the use of anti- &#40;<span class="elsevierStyleItalic">&#954;</span> and <span class="elsevierStyleItalic">&#955;</span>&#41; light-chain antibodies should be compulsory practice in the histological study of any renal biopsy&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">25</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">In cases in which there is no usable kidney tissue in the frozen sample for immunofluorescence&#44; it is possible to carry out &#8220;rescue&#8221; techniques of the sample in paraffin &#40;Pronase treatment&#41; with a high likelihood of success for the immunohistochemical detection of light chains&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">35</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Different methods to classify the MGRSs have been proposed&#46;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">1&#44;4</span></a> One method considers the predominant location of the kidney damage &#40;glomerular&#44; tubular or mixed&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">1</span></a> although in practice it is not uncommon for more than one entity to overlap in the same biopsy&#46;<a class="elsevierStyleCrossRefs" href="#bib0845"><span class="elsevierStyleSup">36&#8211;39</span></a> In <a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1&#8211;3</a>&#44; the main clinical entities and their histological findings are summarised according to the extent of the damage&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">The most accepted classification of lesions associated with MGRS is based on the distinction of the structure of deposits or inclusions according to whether these show an &#8220;organised&#8221; or &#8220;non-organised&#8221; configuration<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;25</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">&#8220;Organised&#8221; deposits are subdivided into&#58; fibrils&#44; microtubules and crystals or inclusions&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The pathological processes associated with fibrils are&#58; immunoglobulin-related amyloidosis &#40;of light chains&#44; heavy chains or mixtures of light and heavy chains&#41;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;25&#44;40&#8211;43</span></a> and fibrillary glomerulonephritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;33&#44;44&#44;45</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">When the microstructure of the deposits adopts a microtubular structure&#44; two entities can be distinguished<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;25</span></a>&#58; immunotactoid glomerulonephritis&#44; also known as glomerulonephritis with organised microtubules and monoclonal immunoglobulin deposits&#44;<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">33&#44;44&#44;46</span></a> and type 1 cryoglobulinaemia-associated glomerulonephritis&#46;<a class="elsevierStyleCrossRefs" href="#bib0830"><span class="elsevierStyleSup">33&#44;47&#8211;51</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The crystal and inclusion deposits<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;25</span></a> produce a predominantly tubular and interstitial disease&#44; and two subtypes can be distinguished&#58; proximal tubulopathy &#40;with or without Fanconi syndrome&#41;<a class="elsevierStyleCrossRefs" href="#bib0925"><span class="elsevierStyleSup">52&#8211;54</span></a> and histiocytosis with crystals stores&#44;<a class="elsevierStyleCrossRefs" href="#bib0920"><span class="elsevierStyleSup">51&#44;55&#8211;59</span></a> in which the crystal deposits are not found in the tubular epithelial cells&#44; but instead inside the histiocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">1</span></a> Cases of acute interstitial nephritis unrelated to the crystal deposits or intratubular precipitation of cylinders have also been reported&#44; but with light chain deposits shown in the tubular basement membranes&#46;<a class="elsevierStyleCrossRef" href="#bib0965"><span class="elsevierStyleSup">60</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Disease entities with &#8220;non-organised&#8221; deposits include&#58; Randall-type monoclonal immunoglobulin deposit disease &#40;disease caused by deposits of light chains&#44; heavy chains or a combination of both&#41;<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">25&#44;61&#8211;63</span></a>&#59; proliferative glomerulonephritis with monoclonal immunoglobulin deposits<a class="elsevierStyleCrossRefs" href="#bib0750"><span class="elsevierStyleSup">17&#44;25&#44;64&#8211;68</span></a> and monoclonal gammapathy-associated C3 glomerulopathy &#40;C3G&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib1010"><span class="elsevierStyleSup">69&#8211;74</span></a> In the case of proliferative glomerulonephritis with monoclonal immunoglobulin deposits&#44; involvement is limited to the glomerulus&#44; while in monoclonal immunoglobulin deposit disease there is extraglomerular and&#44; frequently&#44; extrarenal involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">4</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">In addition to these processes&#44; there are reports suggesting a possible pathogenic involvement of MG in other glomerulopathies&#44; such as membranous GN&#44;<a class="elsevierStyleCrossRefs" href="#bib1040"><span class="elsevierStyleSup">75&#44;76</span></a> focal segmental glomerulosclerosis&#44;<a class="elsevierStyleCrossRef" href="#bib1050"><span class="elsevierStyleSup">77</span></a> pauci-immune extracapillary glomerulonephritis&#44;<a class="elsevierStyleCrossRef" href="#bib1055"><span class="elsevierStyleSup">78</span></a> C4 proliferative glomerulonephritis<a class="elsevierStyleCrossRef" href="#bib1060"><span class="elsevierStyleSup">79</span></a> and in thrombotic microangiopathies&#46;<a class="elsevierStyleCrossRefs" href="#bib1060"><span class="elsevierStyleSup">79&#8211;83</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Clinical presentation</span><p id="par0145" class="elsevierStylePara elsevierViewall">MGRSs may show a wide range of manifestations&#44; depending on the underlying pathogenic mechanism and the primary site of involvement&#46;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">1&#44;3&#44;4</span></a> In the majority of cases&#44; the deposit of M-proteins is responsible for the kidney disease&#44; while in other cases it is caused indirectly through a deregulation of the complement system&#39;s alternative pathway&#44; resulting in C3G&#44;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">1&#44;3&#44;4&#44;71</span></a> or&#44; more rarely&#44; in atypical haemolytic uraemic syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib1070"><span class="elsevierStyleSup">81</span></a> Thus&#44; the monoclonal component would be able to interfere with the regulatory proteins of the complement system&#44; acting as miniautoantibodies against factor H&#44;<a class="elsevierStyleCrossRefs" href="#bib1030"><span class="elsevierStyleSup">73&#44;74</span></a> or as a C3 nephritic factor&#44; which stabilises the C3 convertase of the alternative pathway and maintains its hyperactivation&#46;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">1&#44;70&#44;71</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The structural and chemical characteristics of each specifc M-protein&#44; and the inflammatory response of each individual&#44; seem to be key to determine the type of kidney damage being produced&#46;<a class="elsevierStyleCrossRefs" href="#bib0755"><span class="elsevierStyleSup">18&#44;84</span></a> High-molecular-weight proteins&#44; such as immunoglobulins &#40;formed by heavy and light chains&#41;&#44; do not cross the filtration barrier and are deposited in the glomerulus which triggers an inflammatory processes&#46; In contrast&#44; light chains are able to cross the filtration barrier and generate a variety of tubular damage&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Renal involvement is often the first manifestation of blood dyscrasia&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">26</span></a> According to the different series&#44; the age of diagnosis tends to be over 50&#46; The disease of monoclonal immunoglobulin deposits is more common in males and proliferative glomerulonephritis with monoclonal immunoglobulin deposits is more common in women&#46;<a class="elsevierStyleCrossRefs" href="#bib0980"><span class="elsevierStyleSup">63&#44;66&#44;85</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Within the clinical manifestations of MGRSs&#44; it is common to find different degrees of proteinuria&#44; which may reach the nephrotic range&#44; together with microhaematuria and hypertension in certain cases&#46; Renal failure is detected in a high percentage of patients at the time of diagnosis&#44; which may progress to end-stage kidney disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;63&#44;66&#44;86</span></a> This is of particular importance given that the recurrence of some of these diseases in transplanted kidneys is very common&#46;<a class="elsevierStyleCrossRefs" href="#bib1100"><span class="elsevierStyleSup">87&#8211;92</span></a> This fact illustrate the need for a correct diagnosis&#44; even when it is unlikely to preserve the function of the native kidneys&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Extrarenal manifestations may also be presented&#44; especially in cases of amyloidosis&#44; monoclonal immunoglobulin deposition disease and type 1 cryoglobulinaemia&#44; with involvement predominantly of the heart&#44; liver&#44; skin and joints&#46;<a class="elsevierStyleCrossRefs" href="#bib0670"><span class="elsevierStyleSup">1&#44;4&#44;93</span></a> The possibility of the disease spreading to other organs and tissues in patients diagnosed with amyloidosis should be investigated&#44;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">43</span></a> due to the common nature of cardiac involvement&#44; which tends to be the main determinant of mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">43</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Cases of osteomalacia secondary to Fanconi syndrome have also been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">52</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Other systemic manifestations of an MG may be related to endothelial damage and systemic thrombotic microangiopathy associated with the secretion of vascular endothelial growth factor &#40;VEGF&#41;&#44; as occurs in POEMS syndrome &#40;polyneuropathy&#44; organomegaly&#44; endocrinopathy&#44; MG and skin lesions&#41;<a class="elsevierStyleCrossRef" href="#bib1135"><span class="elsevierStyleSup">94</span></a> and scleromyxoedema&#46;<a class="elsevierStyleCrossRef" href="#bib1140"><span class="elsevierStyleSup">95</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagnosis of monoclonal gammopathies of renal significance</span><p id="par0180" class="elsevierStylePara elsevierViewall">The appropriate diagnostic procedure of an MGRS should include&#44; in addition to a renal biopsy&#44; the demonstration and identification of MG in plasma or urine&#44; a haematological study which determines the nature and extent of the cell clone causing the MG and&#44; in some processes &#40;e&#46;g&#46; amyloidosis&#41;&#44; extension of the study to determine the spreading of the disease to other organs&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;25&#44;26</span></a> The main techniques for the haematological and histological diagnosis are summarised in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#46;</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0185" class="elsevierStylePara elsevierViewall">The diagnosis of a suspected MGRS is almost always established by associating renal involvement &#40;deterioration of function&#44; proteinuria&#44; Fanconi syndrome or other metabolic abnormalities associated with tubulointerstitial dysfunction&#41; together with the presence of a monoclonal peak in the electrophoretic spectrum&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;96&#44;97</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">In most cases&#44; the diagnosis of MG is performed using conventional electrophoresis on plasma or urine&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;96</span></a> The presence of monoclonal immunoglobulins is usually identified by a tall narrow peak in the beta or gamma region&#44; unlike polyclonal increase&#44; which tends to create a wide band in the gamma region&#46;<a class="elsevierStyleCrossRef" href="#bib1145"><span class="elsevierStyleSup">96</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">However&#44; in some cases the concentration of monoclonal protein in plasma or urine is so small that electrophoresis is unable to detect it&#46; In fact&#44; some cases of renal involvement in MG are diagnosed mainly by the findings in the renal biopsy &#40;immunohistochemistry&#41;&#44; without being suspected when the biopsy was indicated&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">In addition to conventional electrophoresis&#44; plasma and urine immunofixation must be performed in all cases to identify the type of M-protein&#44; as this is more sensitive than electrophoresis in detecting the M-protein&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;96&#44;98</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Another diagnostic method is the determination of free light chains &#40;FLCs&#41; in blood and urine&#46;<a class="elsevierStyleCrossRefs" href="#bib1145"><span class="elsevierStyleSup">96&#44;98&#8211;102</span></a> The concentration of these proteins can be measured by a nephelometric immunoassay using polyclonal antibodies targeting light chain epitopes&#44; which are exposed when the chain is in its free form but hidden when the chain is bound&#44; creating the structure of the Ig&#46;<a class="elsevierStyleCrossRef" href="#bib1160"><span class="elsevierStyleSup">99</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">These measurements of FLCs are very sensitive&#44; but the drawback is that they are not able to demonstrate the monoclonality of FLCs&#46; This possibility is suggested indirectly by the ratio between the concentrations of the <span class="elsevierStyleItalic">&#954;</span> and <span class="elsevierStyleItalic">&#955;</span> chains&#46;<a class="elsevierStyleCrossRefs" href="#bib1155"><span class="elsevierStyleSup">98&#44;100</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">An abnormal ratio of <span class="elsevierStyleItalic">&#954;</span> and <span class="elsevierStyleItalic">&#955;</span> concentrations should be interpreted more carefully in patients with deterioration of kidney function&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;102</span></a> There is a strong correlation between the FLC concentration and kidney function&#59; as the glomerular filtration rate decreases&#44; the polyclonal FLC concentrations&#44; of both <span class="elsevierStyleItalic">&#954;</span> and <span class="elsevierStyleItalic">&#955;</span> increase&#46; Furthermore&#44; in patients with normal kidney function&#44; the greater physiological production of polyclonal <span class="elsevierStyleItalic">&#954;</span> FLC is masked by the more rapid clearance of monomeric forms of <span class="elsevierStyleItalic">&#954;</span> FLC&#44; compared to the larger dimeric <span class="elsevierStyleItalic">&#955;</span> forms&#46; This is how a change is produced in the ratio of <span class="elsevierStyleItalic">&#954;</span> and <span class="elsevierStyleItalic">&#955;</span> FLC concentrations in the case of renal failure&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;102</span></a> When kidney function is normal&#44; the range of this ratio ranges from 0&#46;26 to 1&#46;65&#44; while when kidney failure is present&#44; the ratio accepted as normal ranges between 0&#46;37 and 3&#46;17&#44; however a range for each stage of kidney failure has not been established&#46;<a class="elsevierStyleCrossRef" href="#bib1175"><span class="elsevierStyleSup">102</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">The difference in concentrations between FLCs is very useful not only for diagnosis&#44; but also for follow-up and as a measure of the response to treatment&#46; It is therefore recommended that it is monitored frequently&#46;<a class="elsevierStyleCrossRef" href="#bib1180"><span class="elsevierStyleSup">103</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">FLCs are also currently included in the treatment response criteria for AL amyloidosis&#46;<a class="elsevierStyleCrossRef" href="#bib1185"><span class="elsevierStyleSup">104</span></a> Therefore&#44; a normalisation of the ratio of <span class="elsevierStyleItalic">&#954;</span> and <span class="elsevierStyleItalic">&#955;</span> concentrations&#44; together with a negative result in the blood and urine immunofixation&#44; is needed to be certain of a complete remission&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Using the FLCs measurement as an isolated test for detecting an MG is subject to debate<a class="elsevierStyleCrossRef" href="#bib1190"><span class="elsevierStyleSup">105</span></a> and&#44; although it may be useful to support the diagnosis of MG in myeloma&#44; macroglobulinaemia and amyloidosis&#44; the current recommendations state that electrophoresis &#40;EP&#41; and blood and urine immunofixation should be used for the diagnosis of MG&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">More complex tests &#40;western blot or electrotransfer&#41; on blood and urine are required for the detection of some subclasses of immunoglobulins &#40;IgG&#41; or circulating monoclonal incomplete heavy chains&#46; These tests are able to detect very small concentrations of monoclonal proteins with a high sensitivity&#44;<a class="elsevierStyleCrossRef" href="#bib1195"><span class="elsevierStyleSup">106</span></a> unfortunately these techniques are not routinely available&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">In order to confirm the diagnosis of MGRS&#44; it is not only necessary to prove the pathogenic involvement of MG in the kidney&#44; but&#44; in addition&#44; myeloma must be ruled out and the cell clone producing the M-protein must be characterised because its relevance in the design of the therapeutic strategy&#46; The support of a Haematology Department is needed for this&#46;<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">3&#44;4&#44;107</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">In cases of MGRS in which the renal biopsy shows IgG&#44; IgA or LC&#44; the bone marrow aspiration and biopsy use to be sufficient to demonstrate the clone using flow cytometry and immunohistochemical techniques&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">4</span></a> In addition&#44; the spread of the bone tumour or the presence of solitary plasmacytoma should be ruled out with imaging techniques &#40;CT&#44; MRI or PET-CT&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;5</span></a> MRI is the technique with the greatest sensitivity in the detection of bone marrow infiltration&#44; although it is laborious&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">5</span></a> PET-CT&#44; on the other hand&#44; is able to identify changes in the lesions throughout the follow up and avoids the use of intravenous contrast&#46; However&#44; it exposes patients to high levels of radiation and is more expensive&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">5</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">The possibility that a clone is from B-cells instead of from plasma cells should be suspected in patients with IgM MGRS&#46; Then&#44; the imaging study include areas suspected of hosting lymphadenopathies for biopsy&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Treatment</span><p id="par0255" class="elsevierStylePara elsevierViewall">The treatment strategies for MGRSs are based on chemotherapy that must be adapted to the nature of the cell clone&#44; both for lymphocytes and plasma cells&#44; to the kidney function and to the presence or non-presence of extrarenal involvement&#46;<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">22&#44;107</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">The rapid suppression of nephrotoxic monoclonal immunoglobulin has proven to be a treatment with satisfactory results on kidney function and patient survival in several forms of MGRS&#46;<a class="elsevierStyleCrossRef" href="#bib1200"><span class="elsevierStyleSup">107</span></a> However&#44; as will be emphasised later&#44; more studies and clinical experience are required to obtain therapeutic protocols based on solid evidence&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">The fundamental objective of treatment&#44; except for the case of light chain amyloidosis&#44; must be aimed at preserving kidney function&#46;<a class="elsevierStyleCrossRefs" href="#bib0795"><span class="elsevierStyleSup">26&#44;91&#44;107&#44;108</span></a> This means that patients with irreversible kidney damage would not be candidates to receive chemotherapy treatment&#44; unless there is a desire to obtain complete haematological remission to prevent recurrence in a kidney transplant&#46;<a class="elsevierStyleCrossRef" href="#bib1200"><span class="elsevierStyleSup">107</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">In 2013&#44; the International Kidney and Monoclonal Gammopathy Working Group published a consensus document on the treatment regimens recommended for MGRSs&#44; based on the clinical experience of the treatment of malignant blood dyscrasias&#46;<a class="elsevierStyleCrossRef" href="#bib1200"><span class="elsevierStyleSup">107</span></a><a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a> summarises the group&#39;s main recommendations&#46; However&#44; given the heterogeneity of MGRS-associated diseases&#44; there is uncertainty regarding the optimal treatment for some more complex presentations with a clinical experience that is limited to isolated case reports or small series of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0980"><span class="elsevierStyleSup">63&#44;64&#44;70&#44;71&#44;77&#44;109</span></a> Thus&#44; different regimens have been used for fibrillary glomerulonephritis&#44; including cyclophosphamide&#44; mycophenolate mofetil&#44; cyclosporine&#44; melphalan&#44; lenalidomide and rituximab&#44; with limited results&#46;<a class="elsevierStyleCrossRefs" href="#bib0885"><span class="elsevierStyleSup">44&#44;45&#44;110</span></a> Furthermore&#44; treatment regimens similar to those used for proliferative glomerulonephritis with monoclonal immunoglobulin deposits have been used for monoclonal gammopathy-associated C3 glomerulopathy&#46;<a class="elsevierStyleCrossRefs" href="#bib1015"><span class="elsevierStyleSup">70&#44;71&#44;107</span></a> However&#44; the information available on the long-term prognosis of these processes using the current therapies is insufficient&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">26</span></a></p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0275" class="elsevierStylePara elsevierViewall">Due to the growing importance of MGRSs in clinical nephrology&#44; it is essential to be aware of the main therapeutic agents which are currently used&#44; their tolerance and the most common side effects&#46; Many of these treatments are administered in a combined form due to the synergistic effect on the B-cells and plasma cells&#46;<a class="elsevierStyleCrossRef" href="#bib1220"><span class="elsevierStyleSup">111</span></a> The main combinations include<a class="elsevierStyleCrossRefs" href="#bib1200"><span class="elsevierStyleSup">107&#44;111&#44;112</span></a>&#58; bortezomib&#44; cyclophosphamide and dexamethasone&#59; bendamustine and rituximab&#44; and immunomodulatory agents&#44; such as thalidomide and lenalidomide&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">Bortezomib has a pivotal role within the therapeutic arsenal because of its safety profile and the possibility of being administered in full doses to patients with advanced kidney disease&#46;<a class="elsevierStyleCrossRefs" href="#bib1225"><span class="elsevierStyleSup">112&#8211;114</span></a> The mechanism of action is based on the inhibition of proteasome activity&#44; which produces apoptosis of the plasma cell and also inhibits the NF-<span class="elsevierStyleItalic">&#954;</span>B pathway by reducing the release of proinflammatory cytokines and inducing anti-apoptotic pathways at the tubular level&#46;<a class="elsevierStyleCrossRefs" href="#bib1240"><span class="elsevierStyleSup">115&#8211;117</span></a> Usually the side effects are not serious&#59; it causes development or worsening of peripheral neuropathy&#44; although this is less common when the route of administration is subcutaneous&#46;<a class="elsevierStyleCrossRef" href="#bib1255"><span class="elsevierStyleSup">118</span></a> Prophylaxis against herpes zoster is also recommended due to the risk of reactivation&#46;<a class="elsevierStyleCrossRef" href="#bib1220"><span class="elsevierStyleSup">111</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">Among the cytotoxic agents&#44; both melphalan and cyclophosphamide have an effect on B-cells and plasma cells&#44; however cyclophosphamide is used more frequently because it is less toxic&#46;<a class="elsevierStyleCrossRefs" href="#bib1200"><span class="elsevierStyleSup">107&#44;111</span></a> Another alternative is bendamustine&#44; approved for the treatment of some lymphomas and suitable for patients with renal failure since it is predominantly metabolised in the liver&#46;<a class="elsevierStyleCrossRefs" href="#bib1260"><span class="elsevierStyleSup">119&#8211;121</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">Melphalan is used in myeloablative doses as a conditioning therapy for autologous haematopoietic stem cell transplantation in selected cases with no significant extrarenal disease&#46;<a class="elsevierStyleCrossRefs" href="#bib1200"><span class="elsevierStyleSup">107&#44;111</span></a> This autologous transplant has been proven to improve survival of patients with multiple myeloma and light chain amyloidosis&#46; However&#44; in practice less than 20&#37; of patients are suitable candidates for this treatment&#44; which is associated with high morbidity and mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib1095"><span class="elsevierStyleSup">86&#44;122&#8211;124</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">Monoclonal antibodies such as rituximab &#40;targeting the CD20 antigen&#41; are a suitable therapeutic option in the different forms of B-cell mediated MGRS&#44; because of their good tolerance and limited number of side effects&#46;<a class="elsevierStyleCrossRefs" href="#bib1200"><span class="elsevierStyleSup">107&#44;111&#44;112</span></a> The use of daratumumab &#40;targeting CD38&#41; for relapsed or refractory myeloma has been approved&#46;<a class="elsevierStyleCrossRef" href="#bib1290"><span class="elsevierStyleSup">125</span></a> However&#44; experience on its use in cases of MGRS is currently lacking&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">Within the family of immunomodulatory drugs&#44; thalidomide would be more suitable than lenalidomide&#44; due to the fact that the latter is excreted by the kidneys and can also cause kidney function deterioration in some cases&#46;<a class="elsevierStyleCrossRefs" href="#bib1295"><span class="elsevierStyleSup">126&#8211;128</span></a> However&#44; side effects have also been reported with thalidomide&#44; such as the development of hyperkalaemia&#46;<a class="elsevierStyleCrossRef" href="#bib1310"><span class="elsevierStyleSup">129</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="par0305" class="elsevierStylePara elsevierViewall">MGRSs are associated with a wide range of kidney diseases resulting from the depositions of immunoglobulin or of its components in the kidneys&#44; or through the deregulation of the complement system&#46; Although the mortality of patients with MGRS is lower than that of myeloma or other related neoplastic forms&#44; the likelihood of developing advanced chronic kidney disease is very high&#46; For this reason&#44; when evaluating patients with suspected MGRS it is necessary to conduct complete anatomopathological&#44; haematological and biochemical studies&#46; These studies allow to determine the type of entity and the extension of the disese&#46; Advances in the understanding of these entities have made it possible to improve the clinical course and survival in several forms of MGRS&#46; However&#44; more studies and clinical experience are necessary to design more effective therapeutic protocols&#46; It is a priority the close collaboration between nephrologists and haematologists to individualise the treatment to the clinical characteristics and comorbidity of patients&#44; in an attempt to improve the overall prognosis of these diseases&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">The incidence and prevalence of this group of diseases in the Spanish population is not currently known&#46; There are few cases published&#46;<a class="elsevierStyleCrossRef" href="#bib1315"><span class="elsevierStyleSup">130</span></a> According to the clinical experience&#44; these diseases are not frequent&#44; but so far no epidemiological studies have been conducted which confirm these assessments&#46; Furthermore&#44; as they are rare diseases&#44; but requiring a complex study&#44; the diagnosis might end up being less appropriate or incomplete in patients attended to in many hospitals which do not have the necessary non-conventional diagnostic tools&#46; Nevertheless the implementation of these tools in all hospitals does not seem to be an efficient measure&#46; Therefore&#44; the creation of centres of excellence and diagnostic&#8211;therapeutic reference for these types of diseases could be an appropriate investment to benefit from the health care&#44; academic and economic value&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">GLOSEN study proposal</span><p id="par0315" class="elsevierStylePara elsevierViewall">In 2009&#44; an international group for research into MGRSs was created&#46; Nephrology&#44; haematology and anatomical pathology departments from several countries participate in the group&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">4&#44;26&#44;107</span></a> The studies and publications by the members of this research group are currently recognised as the forefront of research into these diseases&#44; with very significant diagnostic and therapeutic advances&#46; The incorporation of Spanish groups into this international group could result in mutual benefits&#44; such as training and transfer of experience to Spanish members&#44; as well as the incorporation of Spanish centres and patients into international clinical trials&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">All of these reasons could justify the creation of a national MGRS register which would help to research the clinical&#8211;pathological characteristics of these entities&#44; and to identify evolutionary and response determinants to current treatments&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">We believe that the &#8216;Grupo de Estudio de la Patolog&#237;a Glomerular de la Sociedad Espa&#241;ola de Nefrolog&#237;a&#8217; &#91;Glomerular Disease Study Group of the Spanish Society of Nephrology&#93; &#40;GLOSEN&#41; may be the ideal framework to lead a study of these characteristics&#44; given its ample experience in conducting collaborative projects&#46;<a class="elsevierStyleCrossRefs" href="#bib1320"><span class="elsevierStyleSup">131&#8211;133</span></a></p><p id="par0330" class="elsevierStylePara elsevierViewall">As an initial project&#44; it is proposed to collect retrospectively all diagnosed cases of MGRS with renal biopsy during recent years from the different centres taking part in the study&#46; Although a work proposal will be sent to all members of the group soon&#44; we are hereby launching a message to attract the interest of all nephrologists and pathologists interested in glomerular diseases&#44; and requesting their collaboration in the study&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conflicts of interest</span><p id="par0335" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest related to the publication of this article&#46;<elsevierMultimedia ident="tb0005"></elsevierMultimedia></p></span></span>"
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          "titulo" => "Introduction"
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          "titulo" => "Kidney disease associated with monoclonal gammopathies"
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          "titulo" => "Clinical presentation"
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          "titulo" => "Diagnosis of monoclonal gammopathies of renal significance"
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    "fechaRecibido" => "2016-12-16"
    "fechaAceptado" => "2017-03-14"
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          "palabras" => array:4 [
            0 => "Chronic kidney disease"
            1 => "Glomerulonephritis"
            2 => "Monoclonal gammopathy of renal significance"
            3 => "Monoclonal protein"
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          "palabras" => array:4 [
            0 => "Enfermedad renal cr&#243;nica"
            1 => "Gammapat&#237;a monoclonal de significado renal"
            2 => "Glomerulonefritis"
            3 => "Prote&#237;na monoclonal"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The term monoclonal gammopathy of renal significance &#40;MGRS&#41; comprises a group of diseases pathogenetically characterised by proliferation of a B-cell or plasma cell clone that synthesises and secretes a monoclonal immunoglobulin or its components &#40;light and&#47;or heavy chains&#41;&#44; that may deposit and cause glomerular&#44; tubular&#44; interstitial and&#47;or vascular damage&#46; The importance of differentiating the term MGRS from other monoclonal gammopathies lies in the fact that diagnostic and therapeutic procedures aimed at controlling monoclonal protein synthesis and secretion can be indicated&#44; irrespective of the classic criteria based on malignant tumour expansion&#46; Renal pathology associated with MGRS is highly heterogeneous&#44; and therefore renal biopsy should be considered a key diagnostic tool&#46; A precise diagnostic approach&#44; however&#44; must also identify the monoclonal protein in plasma and&#47;or in urine&#44; together with a complete haematological study in order to determine the nature and extension of cell clones&#46; Recent advances in the understanding of these entities have resulted in significant improvements in clinical course and survival in several forms of MGRS&#44; although more studies and clinical experience are needed in order to delineate more effective therapeutic strategies&#46; In this review&#44; we summarise the main clinical and pathological features of MGRS&#44; highlighting the most appropriate diagnostic approach and current therapeutic options&#46;</p></span>"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Bajo el t&#233;rmino gammapat&#237;as monoclonales de significado renal &#40;GMSR&#41; se engloban un conjunto de enfermedades que se caracterizan patog&#233;nicamente por la proliferaci&#243;n de un clon de linfocitos B o c&#233;lulas plasm&#225;ticas que sintetizan y segregan una inmunoglobulina monoclonal o uno de sus componentes &#40;cadenas ligeras o pesadas&#41;&#44; con capacidad para depositarse y producir da&#241;o a nivel glomerular&#44; tubular&#44; intersticial o vascular&#46; La importancia de discriminar el t&#233;rmino GMSR radica en poder indicar procedimientos diagn&#243;sticos y terap&#233;uticos dirigidos al control de la s&#237;ntesis y secreci&#243;n de las prote&#237;nas monoclonales independientemente de los criterios cl&#225;sicos vinculados con la expansi&#243;n tumoral maligna&#46; La patolog&#237;a renal asociada a las GMSR es muy heterog&#233;nea&#44; lo que confiere a la biopsia renal una consideraci&#243;n de prueba diagn&#243;stica clave&#46; La correcta investigaci&#243;n diagn&#243;stica de una GMSR debe incluir&#44; adem&#225;s&#44; la identificaci&#243;n en plasma u orina de la prote&#237;na monoclonal y un estudio hematol&#243;gico completo que determine la naturaleza y extensi&#243;n del clon celular&#46; Los avances en el conocimiento de estas entidades han permitido mejorar el curso evolutivo y la supervivencia en varias formas de GMSR&#44; aunque son necesarios m&#225;s estudios y experiencia cl&#237;nica para delinear protocolos terap&#233;uticos m&#225;s efectivos&#46; En la presente revisi&#243;n se resumen las principales caracter&#237;sticas cl&#237;nico-patol&#243;gicas de las GMSR&#44; se detalla la aproximaci&#243;n diagn&#243;stica m&#225;s adecuada&#44; as&#237; como las opciones terap&#233;uticas disponibles en el momento actual&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Please cite this article as&#58; Caravaca-Font&#225;n F&#44; Guti&#233;rrez E&#44; Delgado Lillo R&#44; Praga M&#46; Gammapat&#237;as monoclonales de significado renal&#46; Nefrologia&#46; 2017&#59;37&#58;465&#8211;477&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">C3GN&#58; C3 glomerulonephritis&#59; DDD&#58; dense deposit disease&#59; Ig&#58; immunoglobulin&#59; MPGN&#58; membranoproliferative glomerulonephritis&#59; PAS&#58; periodic acid&#8211;Schiff&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Adapted from&#58; Sethi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">1</span></a> and Bridoux et al&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">4</span></a></p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Glomerular disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical manifestations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Optical microscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Immunofluorescence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Electron microscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Proliferative glomerulonephritis with monoclonal Ig deposits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Proteinuria&#44; variable microhaematuria&#44; hypertension&#46; Kidney disease&#46;<br>Frequent C3 hypocomplementaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPGN&#46;<br>Less common&#58; mesangial proliferative&#44; crescentic&#44; sclerosing or diffuse proliferative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IgG &#40;G3<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G1<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>G2&#41; with restriction of <span class="elsevierStyleItalic">&#954;</span> or <span class="elsevierStyleItalic">&#955;</span> light chains in mesangium and capillary wall&#46;<br>Less common&#58; IgM or IgA&#46;<br>C3 or C1q deposits&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Double image of glomerular capillaries&#8217; profile&#46;<br>Mesangial and subendothelial electron-dense deposits&#46; Less common&#58; subepithelial or intramembranous&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Type 1 cryoglobulinaemia-associated glomerulonephritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Arthralgia&#44; arthritis&#44; purpura&#44; neuropathy&#46;<br>Proteinuria&#44; microhaematuria&#44; kidney disease&#46; Frequent hypertension&#46; Frequent C3 and C4 hypocomplementaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPGN or endocapillary proliferative glomerulonephritis&#46;<br>PAS&#43; intraluminal deposits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Granular deposits in mesangium and capillaries&#46;<br>Monoclonal IgG&#44; IgM or IgA deposits &#40;more common with <span class="elsevierStyleItalic">&#954;</span> chains&#41;&#46; C3&#44; C4 or C1q deposits&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Subendothelial and intracapillary deposits&#46; Frequently organised in fibrils&#44; microtubules or &#8220;in fingerprint&#8221;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fibrillary glomerulonephritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nephrotic proteinuria&#44; microhaematuria and kidney disease&#46; Rarely a rapidly progressive course&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mesangial proliferation or MPGN&#46; Sometimes presence of crescents&#46; Congo red negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IgG &#40;G4 and G1&#41; most commonly polyclonal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;30<span class="elsevierStyleHsp" style=""></span>nm fibrils with random orientation in mesangium and capillaries&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Immunotactoid glomerulopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Nephrotic proteinuria&#44; microhaematuria and kidney disease&#46; Often associated with chronic lymphocytic leukaemia or lymphocytic lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPGN or membranous glomerulonephritis&#46; Less common&#58; proliferative endocapillary&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">IgG &#40;most common IgG1&#41; with restriction of <span class="elsevierStyleItalic">&#954;</span> or <span class="elsevierStyleItalic">&#955;</span> light chains&#46; C3 deposits&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30&#8211;90<span class="elsevierStyleHsp" style=""></span>nm microtubules with subendothelial or subepithelial deposits&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">C3 glomerulopathy&#47;atypical haemolytic uraemic syndrome associated with monoclonal gammopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">By indirect deregulation of the complement system&#39;s alternative pathway&#46;<br>Proteinuria&#44; nephrotic syndrome&#44; microhaematuria&#44; kidney disease&#44; thrombotic microangiopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPGN&#44; proliferative endocapillary&#44; mesangial or crescentic glomerulonephritis&#46;<br>Arterial thrombosis or glomerular capillaries&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intense deposits of C3 in mesangium and capillaries&#46; Absence or lack of other reactants&#46;<br>Pronase treatment may be required to detect monoclonal Ig&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Mesangial&#44; intramembranous and subendothelial deposits in C3GN&#44; and mesangial and intramembranous in DDD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Histological patterns of glomerular damage&#46;</p>"
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      1 => array:8 [
        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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            "identificador" => "at2"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">H&#38;E&#58; haematoxylin and eosin&#59; Ig&#58; immunoglobulin&#59; MM&#58; multiple myeloma&#59; MPGN&#58; membranoproliferative glomerulonephritis&#59; PAS&#58; periodic acid&#8211;Schiff&#46;</p><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Adapted from&#58; Sethi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">1</span></a> and Bridoux et al&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">4</span></a></p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Tubular disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical manifestations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Optical microscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Immunofluorescence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Electron microscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Cylinder nephropathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Associated with MM in 90&#37; of cases&#46;<br>Acute deterioration of kidney function or progressive course&#46; Presence of light chains in blood or urine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Presence of eosinophilic cylinders in H&#38;E stain&#44; negative in PAS&#44; with intense surrounding inflammatory reaction &#40;neutrophils&#44; lymphocytes&#41;&#46;<br>More common in distal tubule&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intense staining for a light chain &#40;<span class="elsevierStyleItalic">&#954;</span> or <span class="elsevierStyleItalic">&#955;</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Intratubular electron-dense material&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Light chain proximal tubulopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Proteinuria and deterioration of kidney function&#46; Fanconi syndrome sometimes associated with glycosuria&#44; aminoaciduria and phosphaturia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Cytoplasmic inclusions in proximal tubular epithelium &#40;crystalline or non-crystalline&#41;&#46; Normal glomeruli&#46; May be associated with tubular atrophy and interstitial fibrosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Restriction for &#954; light chain in crystalline forms&#46; Pronase treatment is sometimes required to detect light chains&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Rectangular or rhomboidal crystals in lysosomes or free in the cytoplasm&#46; In the non-crystalline forms&#44; increased lysosomes with mottled appearance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Crystal-storing histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Non-nephrotic proteinuria or complete nephrotic syndrome&#46; Kidney disease&#46; There may also be medullary&#44; pulmonary or corneal deposits&#46; Associated most frequently with MM and lymphoproliferative processes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Predominantly interstitial infiltration of histiocytes with eosinophilic inclusions&#46; Sometimes also in tubular epithelium and podocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Monoclonal Ig with restriction of <span class="elsevierStyleItalic">&#954;</span> light chain&#46;<br>Pronase treatment is sometimes required to detect light chains&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Interstitial histiocytes filled with crystals&#46; Less common in tubular epithelium and podocytes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Histological patterns of tubular damage&#46;</p>"
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      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">AH&#58; heavy-chain amyloidosis&#59; AHL&#58; heavy- and light-chain amyloidosis&#59; AL&#58; light-chain amyloidosis&#59; Ig&#58; immunoglobulin&#59; MPGN&#58; membranoproliferative glomerulonephritis&#59; PAS&#58; periodic acid&#8211;Schiff&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Adapted from&#58; Sethi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">1</span></a> and Bridoux et al&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">4</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Glomerular and tubular disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Clinical manifestations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Optical microscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Immunofluorescence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Electron microscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ig-related amyloidosis &#40;AL&#44; AH&#44; AHL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Proteinuria and nephrotic syndrome&#44; with varying degrees of renal failure&#46; Rare microhaematuria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">PAS and silver-negative deposits in glomeruli&#44; vessels and interstitium&#46; Congo red positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">AL more common with <span class="elsevierStyleItalic">&#955;</span> or <span class="elsevierStyleItalic">&#954;</span> light chains&#46;<br>Heavy chains &#40;<span class="elsevierStyleItalic">&#947;</span>&#41;&#44; or heavy and light chains less common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">10&#8211;30<span class="elsevierStyleHsp" style=""></span>nm fibrils with random orientation in glomeruli&#44; vessels and interstitium&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Monoclonal Ig deposition disease &#40;disease from deposits of light or heavy chains or a mixture of both&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Proteinuria&#44; nephrotic syndrome and kidney disease&#46; Presence of light chains and albumin in urine&#46; Variable extrarenal manifestations due to Ig deposits in other organs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">MPGN pattern&#44; mesangial proliferative or nodular sclerosis&#46; Thickened glomerular and tubular basement membranes&#46; Congo red negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Diffuse linear staining for light chain&#44; heavy chain or both in glomerular and tubular basement membrane&#46; Most common light chain&#58; <span class="elsevierStyleItalic">&#954;</span>&#59; Most common heavy chain&#58; <span class="elsevierStyleItalic">&#947;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Granular deposits in mesangium and glomerular and tubular basement membranes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Histological patterns of mixed glomerular and tubular damage&#46;</p>"
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      3 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
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          "leyenda" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">AH&#58; heavy-chain amyloidosis&#59; AHL&#58; heavy- and light-chain amyloidosis&#59; AL&#58; light-chain amyloidosis&#59; Ig&#58; immunoglobulin&#46;</p><p id="spar0070" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; A modified version of the original scheme by Bridoux et al&#46;<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">4</span></a></p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="6" align="left" valign="top">Organised deposits</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Fibrils</td><td class="td" title="table-entry  " align="left" valign="top">Ig-related amyloidosis &#40;AL&#44; AH&#44; AHL&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Fibrillary glomerulonephritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Microtubules</td><td class="td" title="table-entry  " align="left" valign="top">Immunotactoid glomerulonephritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Type 1 cryoglobulinaemic glomerulonephritis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Crystals or inclusions</td><td class="td" title="table-entry  " align="left" valign="top">Proximal tubulopathy &#40;with or without Fanconi syndrome&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Crystal-storing histiocytosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="3" align="left" valign="top">Non-organised deposits</td><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Monoclonal Ig deposition disease &#40;light or heavy chains or a mixture of both&#41;</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Proliferative glomerulonephritis with monoclonal Ig deposits</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="2" align="left" valign="top">Monoclonal Ig-associated C3 glomerulonephritis</td></tr></tbody></table>
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Classification scheme of MGRS-associated disease according to the presence of organised or non-organised deposits&#46;</p>"
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        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">CT&#58; computed tomography&#59; IgG&#58; immunoglobulin G&#59; MRI&#58; magnetic resonance imaging&#59; PET-CT&#58; positron emission tomography with 18F-fluorodeoxyglucose&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Diagnosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Haematological&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Renal histology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Recommended procedures&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-<span class="elsevierStyleHsp" style=""></span>Electrophoresis on plasma or urine<br>-<span class="elsevierStyleHsp" style=""></span>Immunofixation on plasma or urine<br>-<span class="elsevierStyleHsp" style=""></span>Free light chains in blood and urine<br>-<span class="elsevierStyleHsp" style=""></span>Bone marrow aspiration&#47;biopsy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-<span class="elsevierStyleHsp" style=""></span>Optical microscopy<br>-<span class="elsevierStyleHsp" style=""></span>Immunofluorescence with staining of light chains &#40;<span class="elsevierStyleItalic">&#954;</span> and <span class="elsevierStyleItalic">&#955;</span>&#41; and Pronase treatment in selected cases<br>-<span class="elsevierStyleHsp" style=""></span>Electron microscopy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Additional diagnostic procedures<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-<span class="elsevierStyleHsp" style=""></span>Western blot technique for detection of IgG subclasses<br>-<span class="elsevierStyleHsp" style=""></span>Imaging test&#58; CT&#44; MRI or PET-CT<br>-<span class="elsevierStyleHsp" style=""></span>Lymph node biopsy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">-<span class="elsevierStyleHsp" style=""></span>Immunoelectron microscopy<br>-<span class="elsevierStyleHsp" style=""></span>Laser microdissection and mass spectrometry&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Techniques for the haematological and renal histology diagnosis of MGRSs&#46;</p>"
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          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">AH&#58; heavy-chain amyloidosis&#59; AHL&#58; heavy- and light-chain amyloidosis&#59; AL&#58; light-chain amyloidosis&#59; CKD&#58; chronic kidney disease&#59; HSCT&#58; haematopoietic stem cell transplantation&#59; Ig&#58; immunoglobulin&#59; NT-proBNP&#58; N-terminal pro-brain natriuretic peptide&#46;</p><p id="spar0095" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">Source</span>&#58; Adapted from original by Fermand et al&#46;<a class="elsevierStyleCrossRef" href="#bib1200"><span class="elsevierStyleSup">107</span></a></p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry  " rowspan="6" align="left" valign="top">Proliferative glomerulonephritis with monoclonal Ig deposits</td><td class="td" title="table-entry  " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Stage 1&#8211;2 CKD&#44; proteinuria &#60;1<span class="elsevierStyleHsp" style=""></span>g&#47;day&#58; observation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Stage 1&#8211;2 CKD with proteinuria &#62;1<span class="elsevierStyleHsp" style=""></span>g&#47;day&#44; progressive CKD or stage 3&#8211;4 CKD&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>Cyclophosphamide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>bortezomib<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>dexamethasone if IgG or IgA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>Rituximab<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>cyclophosphamide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>dexamethasone if IgM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>If &#60;65 years&#58; high-dose melphalan following an HSCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Stage 5 CKD candidate for kidney transplant&#58; high-dose melphalan<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HSCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="5" align="left" valign="top">Type 1 cryoglobulinaemia-associated glomerulonephritis</td><td class="td" title="table-entry  " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Paucisymptomatic or low-grade B-cell proliferation&#58; observation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Symptomatic&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>Plasmacytic clone&#58; bortezomib<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>cyclophosphamide<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>thalidomide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>Lymphoplasmacytic clone&#58; rituximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>-<span class="elsevierStyleHsp" style=""></span>Alternative&#58; bendamustine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Immunotactoid glomerulopathy</td><td class="td" title="table-entry  " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Treatment regimens similar to those employed in CLL&#44; based on cyclophosphamide or bendamustine<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>rituximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>For isolated gammopathy&#44; treatment regimen based on bortezomib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="4" align="left" valign="top">Ig-related amyloidosis &#40;AL&#44; AH&#44; AHL&#41;</td><td class="td" title="table-entry  " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Classification in three stages according to the increase in levels of NT-proBNP and troponin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Stage 1&#8211;2&#58; melphalan or cyclophosphamide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>dexamethasone<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>bortezomib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Stage 3&#58; cyclophosphamide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>dexamethasone<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>bortezomib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Heart transplant if cardiac involvement&#59; HSCT in selected cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Monoclonal Ig deposition disease</td><td class="td" title="table-entry  " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Stage 1&#8211;3 CKD&#58; cyclophosphamide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>bortezomib<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>dexamethasone&#44; with subsequent HSCT in selected cases&#46; Alternative&#58; bendamustine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Stages 4&#8211;5 CKD&#58; cyclophosphamide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>bortezomib<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>dexamethasone<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HSCT if candidate for kidney transplant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">Light chain proximal tubulopathy</td><td class="td" title="table-entry  " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Stage 1&#8211;3 CKD&#58; cyclophosphamide&#44; bortezomib or thalidomide<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>HSCT in selected cases&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">&#8226;<span class="elsevierStyleHsp" style=""></span>Stage 4&#8211;5 CKD&#58; HSCT if they are candidates for a kidney transplant&#46; If not&#44; conservative management&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Therapeutic regimens proposed for MGRSs&#46;</p>"
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        "identificador" => "tb0005"
        "tipo" => "MULTIMEDIATEXTO"
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          "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Key concepts</span><p id="par0340" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0010"><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">1&#46;</span><p id="par0345" class="elsevierStylePara elsevierViewall">MGRSs are characterised by the proliferation of a clone of B-cells or plasma cells which synthesise and secrete a monoclonal immunoglobulin or one of its components &#40;light or heavy chains&#41;&#44; with the capacity to be deposited and be the cause glomerular&#44; tubular&#44; interstitial or vascular damage&#46;</p></li><li class="elsevierStyleListItem" id="lsti0030"><span class="elsevierStyleLabel">2&#46;</span><p id="par0350" class="elsevierStylePara elsevierViewall">Given the heterogeneity of MGRS-associated kidney disease&#44; the renal biopsy is fundamental&#44; and its proper histological analysis must include optical microscopy&#44; immunofluorescence and electron microscopy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0035"><span class="elsevierStyleLabel">3&#46;</span><p id="par0355" class="elsevierStylePara elsevierViewall">There are different ways of classifying MGRS-associated kidney disease&#44; although the most accepted method is in accordance with the organisation of the deposits&#58; &#8220;organised&#8221; &#40;fibrils&#44; microtubules and crystals&#41; or &#8220;non-organised&#8221; &#40;monoclonal immunoglobulin deposition disease&#44; proliferative glomerulonephritis with monoclonal immunoglobulin deposits and monoclonal immunoglobulin-associated C3 glomerulonephritis&#41;&#46;</p></li><li class="elsevierStyleListItem" id="lsti0040"><span class="elsevierStyleLabel">4&#46;</span><p id="par0360" class="elsevierStylePara elsevierViewall">The diagnostic study should also include electrophoresis and plasma and urine immunofixation to identify the monoclonal protein and the determination of free light chains&#46;</p></li><li class="elsevierStyleListItem" id="lsti0045"><span class="elsevierStyleLabel">5&#46;</span><p id="par0365" class="elsevierStylePara elsevierViewall">In addition&#44; myeloma should be ruled out and the cell clone producing the monoclonal protein should be characterised by a bone marrow aspiration and biopsy&#46;</p></li><li class="elsevierStyleListItem" id="lsti0050"><span class="elsevierStyleLabel">6&#46;</span><p id="par0370" class="elsevierStylePara elsevierViewall">Current treatment is based on clinical experience of the treatment of malignant blood dyscrasias&#46; Close collaboration between nephrologists and haematologists to personalise the treatment to the clinical characteristics and comorbidity of patients is therefore a priority&#46;</p></li></ul></p></span></span>"
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      "titulo" => "References"
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                      ]
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              "identificador" => "bib0675"
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Criteria for the classification of monoclonal gammopathies&#44; multiple myeloma and related disorders&#58; a report of the International Myeloma Working Group"
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                      "titulo" => "Monoclonal gammopathy&#58; the good&#44; the bad and the ugly"
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                  "contribucion" => array:1 [
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                        "tituloSerie" => "Kidney Int"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Monoclonal gammopathy of undetermined significance &#40;MGUS&#41;"
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Article information

ISSN: 20132514
Original language: English

DOI:10.1016/j.nefroe.2017.09.002

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Year/Month	Html	Pdf	Total

2024 November	14	7	21
2024 October	83	51	134
2024 September	128	31	159
2024 August	115	67	182
2024 July	88	24	112
2024 June	102	33	135
2024 May	115	52	167
2024 April	110	40	150
2024 March	93	51	144
2024 February	62	40	102
2024 January	50	36	86
2023 December	55	25	80
2023 November	57	44	101
2023 October	68	31	99
2023 September	59	30	89
2023 August	51	26	77
2023 July	49	26	75
2023 June	54	27	81
2023 May	74	30	104
2023 April	61	22	83
2023 March	71	25	96
2023 February	54	34	88
2023 January	37	44	81
2022 December	83	50	133
2022 November	85	64	149
2022 October	73	51	124
2022 September	70	53	123
2022 August	71	57	128
2022 July	49	61	110
2022 June	60	45	105
2022 May	87	49	136
2022 April	55	67	122
2022 March	72	50	122
2022 February	138	63	201
2022 January	102	71	173
2021 December	72	62	134
2021 November	76	48	124
2021 October	142	72	214
2021 September	262	68	330
2021 August	273	61	334
2021 July	121	54	175
2021 June	113	55	168
2021 May	130	67	197
2021 April	292	119	411
2021 March	209	93	302
2021 February	176	74	250
2021 January	110	35	145
2020 December	66	31	97
2020 November	92	34	126
2020 October	90	48	138
2020 September	100	26	126
2020 August	98	35	133
2020 July	95	43	138
2020 June	81	32	113
2020 May	107	20	127
2020 April	86	55	141
2020 March	79	19	98
2020 February	70	47	117
2020 January	93	41	134
2019 December	190	41	231
2019 November	160	75	235
2019 October	183	70	253
2019 September	275	99	374
2019 August	161	75	236
2019 July	86	45	131
2019 June	109	62	171
2019 May	140	58	198
2019 April	149	79	228
2019 March	191	78	269
2019 February	224	45	269
2019 January	122	56	178
2018 December	411	69	480
2018 November	813	28	841
2018 October	660	18	678
2018 September	159	14	173
2018 August	154	14	168
2018 July	74	15	89
2018 June	83	15	98
2018 May	159	22	181
2018 April	165	15	180
2018 March	202	17	219
2018 February	139	4	143
2018 January	205	16	221
2017 December	231	11	242
2017 November	141	13	154
2017 October	66	24	90
2017 September	2	0	2

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