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Bone marrow core biopsy with anaplastic multiple myeloma (hematoxylin and eosin, original magnification 400).
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Renal involvement is common in multiple myeloma and implies much worse prognosis. Most of the kidney disorders associated with myeloma are caused by the excess production of monoclonal light chains, and renal involvement is almost always accompanied by light chain proteinuria. Light chains have variable effects on the kidney; some are more toxic th...
Citations
... Most kidney disorders associated with myeloma are caused by the excess production of monoclonal light chains, and renal involvement is almost always accompanied by light chain proteinuria (Batuman, 2007;Heher et al., 2013). Regular light chains are filtered through the glomerulus, endocytosed by the proximal tubule cells through multiligand endocytic receptors megalin/cubilin, and degraded in lysosome (Sanders, 2011). ...
... When significant amounts of light chains are generated by multiple myeloma and filtered through the glomerulus, the proximal tubular endocytic process is overloaded. Cell stress responses that include lysosomal alterations, phosphorylation of MAPKs, nuclear transcription factors NF-kB, Toll-like receptors, and STAT1, leading to the production of proinflammatory cytokines including TNFα, MCP-1 and Il1 β, and profibrotic cytokines like TGF-β1 (Batuman, 2007;Luciani et al., 2016;Ying et al., 2019;Sirac et al., 2021). Intracellular H 2 O 2 induced by endocytosis of monoclonal free light chains oxidizes and activates c-Src, promoting the release of MCP-1 (Basnayake et al., 2010). ...
... Intracellular H 2 O 2 induced by endocytosis of monoclonal free light chains oxidizes and activates c-Src, promoting the release of MCP-1 (Basnayake et al., 2010). As a result, these proximal tubule alterations often progress to severe tubulointerstitial kidney disease, the most common type of kidney involvement responsible for end-stage renal failure seen in myeloma patients (Batuman, 2007). It has also been shown that silencing megalin and cubilin genes may inhibit the uptake of myeloma light chain, subsequently suppressing inflammation in PTECs, and ameliorating nephrotoxicity (Li et al., 2008). ...
Endocytosis is a crucial component of many pathological conditions. The proximal tubules are responsible for reabsorbing the majority of filtered water and glucose, as well as all the proteins filtered through the glomerular barrier via endocytosis, indicating an essential role in kidney diseases. Genetic mutations or acquired insults could affect the proximal tubule endocytosis processes, by disturbing or overstressing the endolysosomal system and subsequently activating different pathways, orchestrating renal fibrosis. This paper will review recent studies on proximal tubular endocytosis affected by other diseases and factors. Endocytosis plays a vital role in the development of renal fibrosis, and renal fibrosis could also, in turn, affect tubular endocytosis.
... It is also responsible for vitamin D metabolism [12,13]. The PT injury is the most common type of renal involvement, which has attracted extensive attention for exploring a wide variety of diseases [14,15]. Classically, the crystals were often formed in the distal tubule. ...
Background:
Urolithiasis with high prevalence and recurrence rate, has impacts on kidney injury in patients, becomes a socioeconomic and healthcare problem in worldwide. However, the biology of kidney with crystal formation and proximal tubular injury remains essentially unclear. The present study aims to evaluate the cell biology and immune-communications in urolithiasis mediated kidney injury, to provide new insights in the kidney stone treatment and prevention.
Results:
We identified 3 distinct injured-proximal tubular cell types based on the differentially expression injury markers (Havcr1 and lcn2) and functional solute carriers (slc34a3, slc22a8, slc38a3 and slc7a13), and characterized 4 main immune cell types in kidney and one undefined cell population, where F13a1+/high/CD163+/high monocyte & macrophage and Sirpa/Fcgr1a/Fcgr2a+/high granulocyte were the most enriched. We performed intercellular crosstalk analysis based on the snRNA-seq data and explored the potential immunomodulation of calculi stone formation, and founded that the interaction between ligand Gas6 and its receptors (Gas6-Axl, Gas6-Mertk) was specifically observed in the injured-PT1 cells, but not injured-PT2 and -PT3 cells. The interaction of Ptn-Plxnb2 was only observed between the injured-PT3 cells and its receptor enriched cells.
Conclusions:
Present study comprehensively characterized the gene expression profile in the calculi rat kidney at single nucleus level, identified novel marker genes for all cell types of rat kidney, and determined 3 distinct sub-population of injured-PT clusters, as well as intercellular communication between injured-PTs and immune cells. Our collection of data provides a reliable resource and reference for studies on renal cell biology and kidney disease.
... The physiological fate of free LC in the kidney includes free filtration in the glomerulus and receptormediated reabsorption by proximal tubules (15), a very efficient but saturable process (15). LC are then degraded within lysosomes (16). A quarter of the analyzed kidneys showed LC-R/C, making it a very frequent finding, as reported earlier for LCPT (9). ...
Monoclonal gammopathy (MG) causes various nephropathies, which may suffice for cytoreductive therapy even in the absence of diagnostic criteria for multiple myeloma or B-cell non-Hodgkin lymphoma. The aim of this study was to better understand the significance of light chain (LC) restriction or crystals (LC-R/C) in proximal tubules in the spectrum of LC-induced nephropathies. A consecutive cohort of 320 renal specimens with a history of B-cell dyscrasia was characterized. Special attention was paid to immunohistochemical LC restriction in proximal tubules, tubular crystals or constipation, and ultrastructural findings. Complementary cell culture experiments were performed to assess the role of LC concentrations in generating LC restriction. Light chain restriction or crystals in proximal tubules was found in a quarter of analyzed cases (81/316) and was associated with another LC-induced disease in 70.4% (57/81), especially LC cast-nephropathy (cast-NP) and interstitial myeloma infiltration. LC restriction without significant signs of acute tubular injury was observed in 11.1% (9/81). LC-R/C was not associated with inferior renal function compared to the remainder of cases, when cases with accompanying cast-NP were excluded. Besides crystals, cloudy lysosomes were significantly associated with LC-R/C on an ultrastructural level. In summary, LC-R/C is frequent and strongly associated with cast-NP, possibly indicating that a high load of clonal LC is responsible for this phenomenon, supported by the observation that LC restriction can artificially be generated in cell culture. This and the lack of significant tubular injury in a subgroup imply that in part LC-R/C is a tubular trafficking phenomenon rather than an independent disease process.
... Intense water reabsorption such as during high-dose diuretic therapy or dehydration for intercurrent disorders (gastroenteritis, colitis, water deprivation for any reason) enhances protein accumulation by reducing urine flow and increasing luminal protein concentration. This condition is not unique to MGRS or MM but occurs in massive nephrotic syndrome or crystal precipitation as well (e.g., urates or phosphates in the tumor lysis syndrome, polyethylene glycol intoxication, etc.) [45][46][47][48][49][50][51]. ...
... Diagnosis is based on immunofluorescence, which shows the selective κ or λ LC nature of the deposits, and by EM, showing the coarse aspect of deposits as opposed to the extracellular collagenous matrix of diabetic nephropathy [8,48]. Tubulo-interstitial LCDD is probably more common; although, renal biopsies are not performed in the majority of MGRS without renal failure or high-grade proteinuria [46][47][48]. Early clinical signs of tubular involvement can be grouped into the acquired "Fanconi syndrome", i.e., altered acidification mechanisms with tubular acidosis, tubular proteinuria (non-selective, mild, usually <1.5 g/day), glycosuria, aminoaciduria, low-serum phosphate, and uric acid due to impaired tubular reabsorption [49]. ...
... Cells undergo various processes of apoptosis, "blebbing", and vacuolization, with a decrease in viable cell numbers; loss of the brush-border can be noted in the proximal tubule. In advanced stages, detachment of the epithelial monolayer occurs, along with clumps of cellular debris amidst amorphous proteinaceous material, i.e., precipitated LC [46][47][48][49], within the tubular lumen. The resulting "cast nephropathy" shares features of acute tubular necrosis (ATN) [50,51]. ...
Monoclonal gammopathies (MG) encompass a variety of disorders related to clonal expansion and/or malignant transformation of B lymphocytes. Deposition of free immunoglobulin (Ig) components (light or heavy chains, LC/HC) within the kidney during MG may result over time in multiple types and degrees of injury, including acute kidney injury (AKI). AKI is generally a consequence of tubular obstruction by luminal aggregates of LC, a pattern known as “cast nephropathy”. Monoclonal Ig LC can also be found as intracellular crystals in glomerular podocytes or proximal tubular cells. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent form of kidney injury with a sizable impact on renal function. Hypercalcemia (in turn related to bone reabsorption triggered by proliferating plasmacytoid B cells) may lead to AKI via functional mechanisms. Pharmacologic treatment of MG may also result in additional renal injury due to local toxicity or the tumor lysis syndrome. The present review focuses on AKI complicating MG, evaluating predictors, risk factors, mechanisms of damage, prognosis, and options for treatment.
... [31][32][33] Other investigations with cell cultures in vitro and mice experiments in vivo demonstrated that FLCs activated nuclear transcription factor kappa-B and mitogen-activated protein kinases, leading to transcription and release into the medium of inflammatory cytokines, including interleukins 6 and 8, monocyte chemoattractant protein-1, and TGF-beta. 24,30,[34][35][36][37] Activation of toll-like receptors through the STAT1-HMGB1 axis led to oxidative stress and proinflammatory and profibrotic kidney injury. 10,11,30,37 Both in vitro studies with FLC-exposed kidney PTC and animal studies in vivo demonstrated FLCs can induce apoptosis, necrosis and epithelial-mesenchymal transformation of proximal tubule epithelial cells. ...
Plasma and B cells dyscrasias that overproduce monoclonal immunoglobulin free light chains (FLC) affect the kidney frequently in various ways. The hematologic dyscrasia responsible for the production of FLCs may or may not meet the criteria for cancer, such as multiple myeloma or lymphoma, or may remain subclinical. If there is overt malignancy, the accompanying kidney disorder is called myeloma- or lymphoma-associated. If the dyscrasia is subclinical, the associated kidney disorders are grouped as monoclonal gammopathy of renal significance. Both glomeruli and tubules may be involved. The proximal tubule disorders comprise a spectrum of interesting syndromes, which range in severity. This review focuses on the recent insights gained into the patterns and the mechanisms of proximal tubule toxicity of FLCs, including subtle transport disorders, such as proximal tubule acidosis, partial or complete Fanconi syndrome, or severe acute or chronic renal failure. Histologically, there may be crystal deposition in the proximal tubule cells, acute tubule injury, interstitial inflammation, fibrosis, and tubule atrophy. Specific structural alterations in the V domain of FLCs caused by somatic hypermutations are responsible for crystal formation as well as partial or complete Fanconi syndrome. Besides crystal formation, tubulointerstitial inflammation and proximal tubulopathy can be mediated by direct activation of inflammatory pathways through cytokines and toll-like receptors due to cell stress responses induced by excessive FLC endocytosis into the proximal tubule cells. Therapy directed against the clonal source of the toxic light chain can prevent progression to more severe lesions and may help preserve kidney function.
... Tubulointerstitial LCDD is even more common [52][53][54]. Early clinical signs of tubular involvement can be grouped into the acquired Fanconi syndrome, i.e., altered acidification mechanisms with tubular acidosis, tubular proteinuria (non-selective, mild, usually < 1.5 g/day), glycosuria, aminoaciduria, low serum phosphate, and uric acid due to impaired tubular reabsorption [55]. ...
Monoclonal Gammopathies of Renal Significance (MGRS) are a rather heterogeneous group of renal disorders caused by a circulating monoclonal (MC) immunoglobulin (Ig) component, often in the absence of multiple myeloma (MM) or another clinically relevant lymphoproliferative disorder. Nevertheless, substantial kidney damage could occur, despite the “benign” features of the bone-marrow biopsy. One example is renal amyloidosis, often linked to a small clone of plasma cells, without the invasive features of MM. However, patients with amyloidosis may present with a nephrotic syndrome and renal failure, eventually leading to end-stage kidney disease. At the same time, other organs, such as the heart and the liver, may be severely damaged by Ig light chains or amyloid deposits, occasionally resulting in fatal arrhythmias and/or organ failure. Acute kidney injury (AKI) may as well result from massive excretion of MC proteins, with deposition disease in glomeruli or renal tubules, not rarely obstructed by luminal aggregates, or “casts”. Proliferative glomerulonephritis with monoclonal Ig deposits is another, less frequent clinical presentation of an MGRS. The present review deals with the implications of MGRS for renal function and prognosis, and the potential of tools, such as the renal biopsy, for assessing clinical risk and guiding therapy of the underlying condition.
... In healthy state, plasma cells produce a slight excess of immunoglobulin free light chains (FLCs), both κ and λ, that are efficiently endocytosed and catabolized by the kidney proximal tubule cells (PTCs), and only minute amounts of FLC proteins normally appear in the urine (1). In MM, FLCs are produced in excessive quantities and overwhelm the endocytic capacity of PTCs (2). Overloading endocytic pathways elicits cell stress responses that result in activation of inflammatory pathways and cell injury, leading to a worse prognosis in patients with MM (2)(3)(4). ...
... In MM, FLCs are produced in excessive quantities and overwhelm the endocytic capacity of PTCs (2). Overloading endocytic pathways elicits cell stress responses that result in activation of inflammatory pathways and cell injury, leading to a worse prognosis in patients with MM (2)(3)(4). Nephrotoxic effects of FLCs include a cascade of inflammatory effects, such as generation of reactive oxygen species and activation of MAPK and NF-κB, followed by transcription and secretion of inflammatory and profibrotic cytokines, apoptosis, and epithelial-mesenchymal transition of PTCs (5)(6)(7)(8)(9)(10)(11). ...
Free light chains (FLCs) induce inflammatory pathways in proximal tubule cells (PTCs). The role of toll-like receptors (TLR) in these responses is unknown. Here we present findings on the role of TLRs in FLC-induced PTC injury. We exposed human kidney PTC cultures to κ and λ FLCs, and used cell supernatants and pellets for ELISA and gene expression studies. We also analyzed tissues from Stat1-/- and littermate control mice treated with daily intraperitoneal injections of a κ-FLC for 10 days. FLCs increased the expression of TLRs 2, 4, 6 via HMGB1, a damage-associated molecular pattern. Countering TLRs 2, 4, and 6 through GIT-27 or specific TLR-siRNAs reduced downstream cytokine responses. Blocking HMGB1 through siRNA or pharmacologic inhibition, or via STAT1 inhibition reduced FLC-induced TLRs 2, 4, and 6 expression. Blocking endocytosis of FLCs through silencing of megalin/cubilin, with bafilomycin-A1, or hypertonic sucrose attenuated FLC-induced cytokine responses in PTCs. Immunohistochemistry showed decreased TLR 4 and 6 expression in kidney sections from Stat1-/- mice compared to their littermate controls. PTCs exposed to FLCs released HMGB1, which induced TLRs 2, 4, 6 expression and downstream inflammation. Blocking FLCs' endocytosis, Stat1 knock-down, HMGB1 inhibition, and TLR knock-down each rescued PTCs from FLC-induced injury.
... In a previous work, our group showed that megalin knockdown in LLC-PK1 cells mimicked the effect of pathologic albumin concentration on different signaling pathways, which could be correlated with cell apoptosis and a pro-inflammatory response (Caruso-Neves et al., 2006;Peruchetti et al., 2014). In addition, changes in megalin expression have been correlated with TII in Fanconi syndrome as well as autoimmune renal diseases (Piwon et al., 2000;Christensen et al., 2003;Batuman, 2007;Nakhoul and Batuman, 2011;Vicinanza et al., 2011;Gaide Chevronnay et al., 2014;Eshbach and Weisz, 2017;Wang et al., 2017;Cez et al., 2018). ...
... Accordingly, with the view that megalin expression is associated with the development of TII, it has been shown that megalin is involved in the genesis of different renal diseases (Piwon et al., 2000;Christensen et al., 2003;Batuman, 2007;Nakhoul and Batuman, 2011;Vicinanza et al., 2011;Gaide Chevronnay et al., 2014;Eshbach and Weisz, 2017;Wang et al., 2017;Cez et al., 2018;Larsen et al., 2018;Peruchetti et al., 2018;Silva-Aguiar et al., 2018). Larsen et al. (2018) showed that megalin is the antigen target of human kidney anti-brush border antibody that causes a primary renal tubulointerstitial disease (ABBA disease). ...
... Larsen et al. (2018) showed that megalin is the antigen target of human kidney anti-brush border antibody that causes a primary renal tubulointerstitial disease (ABBA disease). Furthermore, megalin has been proposed to be involved in Fanconi's syndrome and Dent's syndrome, correlated with the increase in the pro-inflammatory response and TII (Piwon et al., 2000;Christensen et al., 2003;Batuman, 2007;Nakhoul and Batuman, 2011;Vicinanza et al., 2011; Gaide Chevronnay et al., 2014;Eshbach and Weisz, 2017;Wang et al., 2017;Cez et al., 2018). ...
Increasing evidence has highlighted the role of tubule-interstitial injury (TII) as a vital step in the pathogenesis of acute kidney injury (AKI). Incomplete repair of TII during AKI could lead to the development of chronic kidney disease. Changes in albumin endocytosis in proximal tubule epithelial cells (PTECs) is linked to the development of TII. In this context, interleukin (IL)-4 has been shown to be an important factor in modulating recovery of TII. We have studied the possible role of IL-4 in TII induced by albumin overload. A subclinical AKI model characterized by albumin overload in the proximal tubule was used, without changing glomerular function. Four groups were generated: (1) CONT, wild-type mice treated with saline; (2) BSA, wild-type mice treated with 10 g/kg/day bovine serum albumin (BSA); (3) KO, IL4Rα–/– mice treated with saline; and (4) KO + BSA, IL4Rα–/– mice treated with BSA. As reported previously, mice in the BSA group developed TII without changes in glomerular function. The following parameters were increased in the KO + BSA group compared with the BSA group: (1) tubular injury score; (2) urinary γ-glutamyltransferase; (3) CD4⁺ T cells, dendritic cells, macrophages, and neutrophils are associated with increases in renal IL-6, IL-17, and transforming growth factor β. A decrease in M2-subtype macrophages associated with a decrease in collagen deposition was observed. Using LLC-PK1 cells, a model of PTECs, we observed that (1) these cells express IL-4 receptor α chain associated with activation of the JAK3/STAT6 pathway; (2) IL-4 alone did not change albumin endocytosis but did reverse the inhibitory effect of higher albumin concentration. This effect was abolished by JAK3 inhibitor. A further increase in urinary protein and creatinine levels was observed in the KO + BSA group compared with the BSA group, but not compared with the CONT group. These observations indicate that IL-4 has a protective role in the development of TII induced by albumin overload that is correlated with modulation of the pro-inflammatory response. We propose that megalin-mediated albumin endocytosis in PTECs could work as a sensor, transducer, and target during the genesis of TII.
... Renal disease in patients with MM is usually present as proteinuria (excess serum proteins in the urine) 11,12 . In general, kidney diseases related to MM result from the kidneys' reduced ability to properly filter substances. ...
... Monoclonal myeloma plasma cells will overproduce one specific type of Ig light chains. The most common cause of severe renal failure in patients with MM is tubulointerstitial pathology resulting from high circulating concentrations of monoclonal Ig light chains 11 . ...
... It is important to note that not all monoclonal free light chains are toxic to the kidneys, and in fact, many patients with high amounts of serum free light chain have no renal impairment 7 . It appears that toxicity depends on the structure of a particular individual's free light chains' 3D structure or protein folding 11,14 . While high amounts of light chains can be a sign of MM, a more useful laboratory parameter is the serum kappa to lambda ratio. ...
Multiple myeloma (MM), a plasma cell cancer, is associated with many health challenges, including damage to the kidney by tubulointerstitial fibrosis. We develop a mathematical model which captures the qualitative behavior of the cell and protein populations involved. Specifically, we model the interaction between cells in the proximal tubule of the kidney, free light chains, renal fibroblasts, and myeloma cells. We analyze the model for steady-state solutions to find a mathematically and biologically relevant stable steady-state solution. This foundational model provides a representation of dynamics between key populations in tubulointerstitial fibrosis that demonstrates how these populations interact to affect patient prognosis in patients with MM and renal impairment.
... 2. Secondary to MCN, probable (albumin <30% of total urine protein, albuminuria <500 mg/24h and urine albumin/creatinine ratio <300 mg/g), or biopsy-proven. 3. Established diagnosis of multiple myeloma, with measurable serum monoclonal Ig by conventional electrophoresis, and/or Bence Jones proteinuria >0.5g/24h, and/or serum free LC level>2 x upper limit of normal (ULN), with abnormal kappa/lambda ratio. ...
... Renal failure in MCN results not only from tubular obstruction by LC casts, but also from severe tubulointerstitial inflammation, characterized by infiltrates of macrophages, mononuclear cells and giant cells around casts, resulting in major damage of the tubulo-interstitial compartment (Pirani 1987). Tubulointerstitial inflammation is enhanced by massive proximal tubular reabsorption of monoclonal LC, leading to phosphorylation of MAP kinases (p38 MAPK) and activation of transcription factors (NF-κB, AP-1) that generate local production of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin 6 and 8, and monocyte-chemoattractant protein (MCP)-1 (Batuman 2007). Cellular injury is accompanied by morphologic and functional alterations of proximal tubular cells, including epithelial-mesenchymal transition (Li 2008). ...
Importance
Cast nephropathy is the main cause of acute kidney injury in multiple myeloma and persistent reduction in kidney function strongly affects prognosis. Strategies to rapidly remove nephrotoxic serum-free light chains combined with novel antimyeloma agents have not been evaluated prospectively.
Objective
To compare the hemodialysis independence rate among patients newly diagnosed with myeloma cast nephropathy treated with hemodialysis using a high-cutoff dialyzer (with very large membrane pores and high permeability to immunoglobulin light chains) or a conventional high-flux dialyzer (with small pores and lower permeability).
Design, Setting, and Participants
Randomized clinical trial involving 98 patients with biopsy-proven myeloma cast nephropathy requiring hemodialysis treated at 48 French centers between July 2011 and June 2016; the final date of follow-up was June 29, 2016.
Interventions
Intensive hemodialysis (eight 5-hour sessions over 10 days) with either a high-cutoff dialyzer (46 patients) or a conventional high-flux dialyzer (48 patients). All patients received the same chemotherapy regimen of bortezomib and dexamethasone.
Main Outcomes and Measures
Primary end point was hemodialysis independence at 3 months; secondary end points: hemodialysis independence rates at 6 and 12 months, hemodialysis- and chemotherapy-related adverse events, and death.
Results
Among 98 randomized patients, 94 (96%) (median age, 68.8 years [interquartile range, 61.2-75.3 years]; 45% women) were included in the modified intent-to-treat analysis. The hemodialysis independence rate at 3 months was 41.3% (n = 19) in the high-cutoff hemodialysis group vs 33.3% (n = 16) in the conventional hemodialysis group (between-group difference, 8.0% [95% CI, −12.0% to 27.9%], P = .42); at 6 months, the rate was 56.5% (n = 26) vs 35.4% (n = 17), respectively (between-group difference, 21.1% [95% CI, 0.9% to 41.3%], P = .04); and at 12 months, the rate was 60.9% (n = 28) vs 37.5% (n = 18) (between-group difference, 23.4% [95% CI, 3.2% to 43.5%], P = .02). The incidence of hemodialysis-related adverse events was 43% in the high-cutoff hemodialysis group vs 39% in the conventional hemodialysis group; chemotherapy-related serious adverse events, 39% vs 37%, respectively; and at 12 months, 9 patients vs 10 patients died.
Conclusions and Relevance
Among patients with myeloma cast nephropathy treated with a bortezomib-based chemotherapy regimen, the use of high-cutoff hemodialysis compared with conventional hemodialysis did not result in a statistically significant difference in hemodialysis independence at 3 months. However, the study may have been underpowered to identify an early clinically important difference.
Trial Registration
clinicaltrials.gov Identifier: NCT01208818
