Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal failure is a common accompaniment of multiple myeloma and is usually due to cast nephropathy, or "myeloma kidney." To understand this lesion, four human Bence Jones proteins (BJP) were purified from the urine of volunteers who had either no evidence of renal dysfunction (BJP1) or renal failure from cast nephropathy (BJP2, BJP3, BJP4). When infused directly into the rat nephron in vivo, BJP2, BJP3, and BJP4 produced intraluminal obstruction by precipitating in the distal nephron; protein casts were never identified before the tip of the loop of Henle. Obstruction was related to the concentration of BJP in the perfusate. Addition of furosemide to the perfusate augmented obstruction in a concentration-dependent fashion. Pretreatment of rats with colchicine completely prevented obstruction and cast formation of perfused nephrons; beta-lumicolchicine did not prevent obstruction. Tamm-Horsfall glycoprotein purified from beta-lumicolchicine-treated and untreated rats coaggregated with BJP3 in vitro. Tamm-Horsfall glycoprotein from colchicine-treated rats did not contain sialic acid and did not aggregate with BJP3 in vitro. Thus, cast-forming human BJP coaggregated with Tamm-Horsfall glycoprotein and obstructed the rat distal nephron. Intranephronal obstruction was aggravated by decreasing extracellular fluid volume or adding furosemide. Finally, by decreasing secretion and altering the carbohydrate moiety of Tamm-Horsfall glycoprotein, colchicine prevented intraluminal cast formation and obstruction of the rat nephron.
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PMID:Pathobiology of cast nephropathy from human Bence Jones proteins. 173 51

Monoclonal antibodies (Mo-Abs) were prepared by fusing mouse myeloma cells (PAI) with spleen cells of mice immunized with Tamm-Horsfall glycoprotein (THGP). Six Mo-Abs screened for the presence of anti-THGP antibodies by enzyme linked immunosorbent assay and by immunoblotting assay have been produced. The specificity studies clearly indicated that the Mo-Ab individualized four distinct epitopes. The immunofluorescent reaction by the Mo-Abs have been analyzed in the human kidney section with normal or a minimal change. The No. 1, 2, 3 and 5 of Mo-Abs reacted with the cytoplasm of distal convoluted renal tubules, while the No. 4 and 6 of Mo-Abs reacted with a substance in the capsular space as well as with the cytoplasm of distal convoluted tubules. The sites of synthesis of this substance, detected in the capsular space by No. 4 and 6 of Mo-Abs and held the immunological cross-reactivity with tubular THGP, is presently uncertain. The specificity of the Mo-Ab may be of considerable value for further studies.
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PMID:[A study of antigenic characterization of Tamm-Horsfall glycoprotein using monoclonal antibodies]. 768 37

The focus of therapy of cast nephropathy, or "myeloma kidney," has been chemotherapy to decrease production of the abnormal monoclonal immunoglobulin and immunoglobulin light chain, known as Bence Jones protein. Little attention has been given to understanding and disrupting the pathophysiologic mechanisms involved in production of intraluminal casts that obstruct and ultimately destroy renal function. Myeloma casts develop in the distal nephron when cast-forming light chains bind to a specific portion of Tamm-Horsfall glycoprotein, secreted by cells of the thick ascending limb of the loop of Henle, to form an insoluble protein complex. A variety of factors including tubule fluid flow rate and concentrations of calcium and sodium chloride in the distal nephron modify the interactions between these proteins and thus influence subsequent clinical renal failure. This review summarizes the latest developments in the pathogenesis and management of cast nephropathy.
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PMID:Pathogenesis and treatment of myeloma kidney. 793 Aug 73

Bence Jones proteins (BJPs) are the major pathogenic factor causing cast nephropathy ("myeloma kidney") by coaggregation with Tamm-Horsfall glycoprotein (THP). Understanding the interaction between these proteins is therefore important in developing treatment strategies to prevent renal failure from cast formation in multiple myeloma. We developed an enzyme-linked immunoassay to examine this phenomenon. Five different human BJPs (four kappa and one lambda immunoglobulin light chains) were used in this assay that demonstrated these proteins bound THP with different affinity. BJPs competed among themselves for binding to THP. The binding site was a peptide portion of THP since these proteins also bound deglycosylated THP. Also, one monoclonal antibody directed against a peptide segment of human THP prevented binding of THP to BJPs. By altering the conformation of THP, reducing agents decreased binding between these two proteins in concentration-dependent fashion. In turbidity studies, the monoclonal antibody that prevented binding and a reducing agent, dithiothreitol, decreased coaggregation. Deglycosylated THP did not coaggregate with BJPs. We concluded that ionic interaction between BJPs and a specific peptide binding site on THP promoted heterotypic coaggregation. The carbohydrate moiety of THP was also essential for coaggregation, perhaps by facilitating homotypic aggregation of THP.
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PMID:Bence Jones proteins bind to a common peptide segment of Tamm-Horsfall glycoprotein to promote heterotypic aggregation. 825 51

Renal failure (RF) is a common accompaniment of multiple myeloma and is identified in over half of patients at presentation. RF is usually related to the presence of Bence-Jones protein (immunoglobulin light chain) which damages all the compartments of the kidney: glomerule, tubulo-interstitium and vasculature. The most common renal lesion is cast nephropathy, named "myeloma kidney": Cast are produced by two mechanisms: proximal tubule damage and intratubular cast formation. The predominant pathophysiologic mechanism of tubule damage appears to be a precipitation of Bence-Jones protein and Tamm-Horsfall glycoprotein produced by cells of ascending limb of Henle's loop in the tubule lumen. The therapeutic maneuvers to reduce renal damage and preserve renal function are reduction of plasma concentration of light chain with chemotherapy, elimination of factors which favour coprecipitation of Tamm-Horsfall protein with light chain (hypercalcemia, acid urine, radiocontrast material, furosemide, oliguria). At last, colchicine (1.2 mg/day) will also be efficacious in the acute management of patients with cast nephropathy.
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PMID:[Renal involvement in multiple myeloma. Physiopathology and therapy]. 881 49

Cast nephropathy is a severe complication of multiple myeloma. Binding of filtered monoclonal light chains (LC) with Tamm-Horsfall glycoprotein (THP) triggers heterotypic aggregation of these two proteins to form casts in the distal nephron of the kidney. To localize the LC binding site on THP, human THP was deglycosylated and underwent limited trypsin digestion in the presence or absence of a nephrotoxic LC known to bind THP. A 29.6-kD band was protected from trypsin digestion by the addition of LC. NH2-terminal amino acid sequence and amino acid analyses revealed this band was located between the 6th and 287th amino acid residues of THP. Six peptides located within this 29.6-kD fragment were synthesized and used as potential inhibitors of binding or aggregation of five different nephrotoxic LCs with THP. Peptide AHWSGHCCL (from amino acid 225 to 233) completely inhibited binding and aggregation of these proteins. Optimal inhibition required a cystine residue in this peptide. Truncation experiments demonstrated the entire sequence was necessary for ideal inhibition and the histidine residue explained the effects of pH on binding. These studies provided a basis for further study of LC-THP interaction and a potential approach toward the prevention of cast nephropathy.
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PMID:Localization of a single binding site for immunoglobulin light chains on human Tamm-Horsfall glycoprotein. 904 77

Renal failure is a common complication in the course of multiple myeloma (MM). It is being observed in 20-40% of patients at the moment of disease diagnosis and in 10-36% of the cases dialysis treatment is required. Kidney damage is mainly caused by the toxic effect of monoclonal light chains, also known as Bence-Jones proteins produced by the pathological plasma cells. Light chains coaggregate with Tamm-Horsfall glycoprotein leading to casts formation in the distal nephron (cast nephropathy). Additional factors causing renal damage in MM may be dehydration, hypercalcemia, hyperuricemia as well as drug nephrotoxicity. We have described a 49 year-old woman diagnosed with IgA multiple myeloma at IIIB advance stage according to Durie and Salmona classification. The disease course was complicated by renal failure. Myeloma treatment (cyclophosphamide + talidomid + dexamethasone) was initiated simultaneously with hemodialysis therapy. Treatment with this was successful even though disease course was very severe and required longer-term hemodialysotherapy. Complete hematological remission was obtained and after 17 months of renal replacement therapy--hemodialysis treatment was ceased due to improvement of renal function. The presented case confirms the necessity of dialysis therapy initiation in every case of acute renal failure in the course of multiple myeloma--even when symptoms indicates an advanced stage of the disease. Initiation of dialysis therapy allows to initiate and continue the effective multiple myeloma treatment. This is the chance for recovery of renal function to such a level that dialysis treatment could be ceased, even after many months of dialysis therapy.
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PMID:[Withdrawal of maintenance dialysis in a patient with diagnosed multiple myeloma and renal failure as a consequence of effective anti-tumor treatment]. 2138 73

Cast nephropathy is the result of coprecipitation of immunoglobulin free light chains (FLCs) with Tamm-Horsfall glycoprotein (THP). It is a hallmark of multiple myeloma that has significant consequences. Treatment strategies in the past focused on reduction of serum FLC by control of the myeloma. In this issue, Ying et al. report on their successful synthesis of a cyclized competitor peptide that blocks the binding of FLC to THP. In animal studies, this cyclized peptide was capable of reducing cast formation and kidney injury, representing a novel treatment strategy for cast nephropathy that does not depend on the responsiveness of the myeloma to chemotherapy.
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PMID:Treating myeloma cast nephropathy without treating myeloma. 2248 15

A common renal complication of multiple myeloma is "myeloma kidney," a condition also known as cast nephropathy. The renal lesions (casts) are directly related to the production of monoclonal immunoglobulin free light chains (FLCs), which coprecipitate with Tamm-Horsfall glycoprotein (THP) in the lumen of the distal nephron, obstructing tubular fluid flow. Here, we report that analysis of the binding interaction between FLCs and THP demonstrates that the secondary structure and key amino acid residues on the complementarity-determining region 3 (CDR3) of FLCs are critically important determinants of the molecular interaction with THP. The findings permitted development of a cyclized competitor peptide that demonstrated strong inhibitory capability in the binding of FLCs to THP in vitro. When used in a rodent model of cast nephropathy, this cyclized peptide construct served as an effective inhibitor of intraluminal cast formation and prevented the functional manifestations of acute kidney injury in vivo. These experiments provide proof of concept that intraluminal cast formation is integrally involved in the pathogenesis of acute kidney injury from cast nephropathy. Further, the data support a clinically relevant approach to the management of renal failure in the setting of multiple myeloma.
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PMID:Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model. 2254 31