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)

Interleukin-6 (IL-6) is a pleiotropic cytokine that has been postulated as playing a role in the pathogenesis of multiple myeloma, chronic autoimmune diseases, and alcoholic liver cirrhosis. We generated transgenic mice carrying a fusion between the mouse metallothionein-I (MT-I) gene promoter and the human IL-6 cDNA. MT-I/IL-6 transgenics express IL-6 constitutively in the liver and secrete the cytokine in the blood. They show initially activation of acute-phase response genes and accumulation of alpha 2- and beta-globulins in the plasma, which is followed by polyclonal hypergammaglobulinemia. MT-I/IL-6 transgenics die between 12 to 20 weeks of age. Histologic examination of transgenic animals at different ages and after necropsy showed, as expected from previous studies of IL-6 disregulation in vivo, an increase in the number of megakaryocytes in the spleen and bone marrow and, at later stages, IgG plasmacytosis in the spleen, lymph nodes, and thymus. However, no plasma cell infiltration was detected in other organs. The distinguishing feature of MT-I/IL-6 transgenics is the development of a progressive kidney pathology, in which the initial membranous glomerulonephritis is followed by focal glomerulosclerosis and finally by extensive tubular damage that reproduces the damage observed in patients at terminal stages of multiple myeloma (myeloma kidney). The pathogenetic role of IL-6 overproduction and of the resulting serum protein overload in the kidney damage is discussed.
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PMID:Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. 751 4

Renal biopsies and autopsy specimens of 23 patients with light chain deposition disease (LCDD) and one with only heavy chain deposits, were studied by light (LM) and electron microscopy (EM) as well as immunohistology (IH). Thirteen patients had multiple myeloma; 1 had lymphoma, and 1 chronic myeloid leukaemia with polycythaemia vera. In nine patients, no lymphoproliferative disease was identified. The LM lesions most suggestive of LCDD, nodular glomerulosclerosis (NS) and thickening and wrinkling of the tubular basement membranes (TBM), were present in only ten and 13 patients, respectively. In five of seven specimens without NS or TBM thickening by LM, EM was negative, indicating a limited value of EM in confirming the diagnosis. Renal amyloidosis was not identified, but in one patient amyloid in the heart and tongue was seen at autopsy. One patient had both granular and extensive glomerular non-amyloid fibrillary deposits. In two patients myeloma casts were identified. Twenty-one patients showed renal LC immune reactivity, 1 had both alpha heavy and lambda LC, 1 had only detectable gamma heavy chain. One biopsy was negative by IH, but had characteristic electron dense deposits. In six patients with immune reactivity to LC, no electron dense deposits could be identified by EM. This study emphasizes the spectrum of renal changes by LM and EM in LCDD, the frequent lack of consistency between deposits detected by IH and EM and the difficulty in coming to a definite diagnosis without LM, EM and IH. The results of this study and examination of the literature indicates that extensive morphological changes are more often present in kappa than in lambda LCDD.
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PMID:Light chain deposition disease of the kidney. Morphological aspects in 24 patients. 781 13

Renal biopsy of a 70-year-old woman with clinical features of rapidly progressive glomerulonephritis revealed nodular glomerulosclerosis with conspicuous crescent formation. Other peculiar findings were the presence of many mesangiolytic cystic lesions and multinucleated giant cells in the cystic lesions. By immunofluorescent microscopic study, lambda light and gamma heavy chains were found in mesangial nodules, Bowman's capsule and the tubular basement membrane. Multiple myeloma was diagnosed by bone marrow examination. Autopsy performed two months later revealed systemic deposition of lambda light and gamma heavy chains, and fairly advanced nodular glomerulosclerosis. Most of the glomerular nodular lesions had a lamellar structure. Amyloid was not found. The high incidence of both mesangiolytic lesions in the biopsy specimen and laminated glomerular nodules in the autopsy material supports the previously proposed pathogenetic relationship of these two findings.
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PMID:Glomerular nodular lesions in non-amyloid immunoglobulin deposition disease: their pathogenetic relationship to mesangiolysis. 802 13

We report a case of a 40-year-old woman with benign monoclonal gammopathy who developed focal segmental glomerulosclerosis associated with widespread deposition of large crystalline inclusions in the glomerular podocytes. Electron microscopy showed that the crystalline structures were electron dense and needle shaped or polygonal. At a higher magnification, they were seen to be surrounded by unit membranes and to feature a longitudinal filamentous substructure. These inclusions showed positive immunohistochemical staining for kappa light chain. Clinically, the patient had shown nephrotic syndrome on the first medical examination, and later revealed chronic renal failure and monoclonal gammopathy of the immunoglobulin G kappa type, but no evidence of multiple myeloma or other lymphoproliferative diseases. This patient seems to have had a rare form of glomerular involvement associated with benign monoclonal gammopathy.
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PMID:Crystalline inclusions in the glomerular podocytes in a patient with benign monoclonal gammopathy and focal segmental glomerulosclerosis. 820 69

Seven cases of nonamyloid heavy chain (gamma chain) deposition disease have been previously reported. We describe one case of a 79-year-old woman presenting with proteinuria and microscopic hematuria whose renal biopsy showed nodular glomerulosclerosis with deposition of gamma3 heavy chains and complement in the glomeruli and tubular basement membranes with no associated light chain deposition. The patient did not have multiple myeloma. This case is unique in that in all previously reported cases of heavy chain deposition disease the gamma chain subtype has been either gamma1 or gamma4.
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PMID:Monoclonal heavy chain (immunoglobulin G3) deposition disease: report of a case. 871 7

Data compiled during the 1970s and early 1980s indicated that during these periods, membranous nephropathy was the most common cause of unexplained nephrotic syndrome in adults, followed in order of frequency by minimal-change nephropathy and focal segmental glomerulosclerosis (FSGS). However, we and others recently reported an increase in the incidence of FSGS over the past two decades, and the number of cases of FSGS diagnosed by renal biopsies in these centers now exceeds the number of cases of membranous nephropathy. Nonetheless, as a substantial fraction of patients with FSGS do not have the nephrotic syndrome, it remained unclear as to what extent the relative frequencies of FSGS and other glomerulopathies as causes of the nephrotic syndrome have changed over this time. To address this concern, we reviewed data from 1,000 adult native kidney biopsies performed between January 1976 and April 1979 and from 1,000 biopsies performed between January 1995 and January 1997, identified all cases with a full-blown nephrotic syndrome of unknown etiology at the time of biopsy, and compared the relative frequencies with which specific diseases were diagnosed in these latter cases between the two time intervals. The main findings of this study were that, first, during the 1976 to 1979 period, the relative frequencies of membranous (36%) and minimal-change (23%) nephropathies and of FSGS (15%) as causes of unexplained nephrotic syndrome were similar to those observed in previous studies during the 1970s and early 1980s. In contrast, from 1995 to 1997, FSGS was the most common cause of this syndrome, accounting for 35% of cases compared with 33% for membranous nephropathy. Second, during the 1995 to 1997 period, FSGS accounted for more than 50% of cases of unexplained nephrotic syndrome in black adults and for 67% of such cases in black adults younger than 45 years. Third, although the relative frequency of nephrotic syndrome due to FSGS was two to three times higher in black than in white patients during both study periods, the frequency of FSGS increased similarly among both racial groups from the earlier to the later period. Fourth, the frequency of minimal-change nephrotic syndrome decreased from the earlier to the later study period in both black and white adults. Fifth, the relative frequency of membranoproliferative glomerulonephritis as a cause of the nephrotic syndrome declined from the 1976 to 1979 period to the 1995 to 1997 period, whereas that of immunoglobulin A nephropathy appeared to increase; the latter accounted for 14% of cases of unexplained nephrotic syndrome in white adults during the latter study period. Finally, 10% of nephrotic adults older than 44 years had AL amyloid nephropathy; none of these patients had multiple myeloma or a known paraprotein at the time of renal biopsy.
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PMID:Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. 937 Jan 76

IgA nephropathy (IgAN) is associated with increased serum IgA1 and IgA1-immune complexes (IC). As Fc alpha receptors (Fc alpha R) are candidate molecules to regulate IgA levels, increased receptor occupation by IgA1 prompted us to study the expression of Fc alpha R on blood cells of IgAN patients. Surface and cytoplasmic Fc alpha R expression were markedly decreased on monocytes, despite normal levels of transcripts. Fc alpha R expression on patients' neutrophils was slightly decreased, exclusively at the cell surface. However, when autologous plasma was removed from the cells Fc alpha R was up-regulated. This observation led us to search for circulating regulatory factors. In vitro experiments revealed that Fc alpha R was down-regulated on normal monocytes following long-term culture with control or patient purified serum IgA at high concentrations (5 mg/ml). Moreover, polymeric myeloma IgA1 induced stronger down-regulation than monomeric IgA1. These results point to a negative regulatory role of serum IgA on surface Fc alpha R expression. This is also supported by a negative correlation between levels of Fc alpha F on blood cells and serum IgA. On the other hand, endogenous IgA bound to IgAN cells was significantly higher than IgA bound to control cells pre-incubated with patients' plasma, suggesting abnormalities in the receptor-ligand interaction. Patient Fc alpha R had a higher Mr (60 to 85 kDa) than those of controls (55 to 75 kDa) and a decreased binding to a sialic acid-specific lectin on blots, indicating post-translational modifications with impaired sialylation of surface Fc alpha R molecules that might be involved in enhanced IgA binding. Continuous Fc alpha R occupation by IgA, associated with receptor down-regulation, might contribute to the enhancement of circulating IgA1 and IgA1-IC by impairing their binding and degradation. Finally, increased receptor occupation by IgA on monocytes was linked to mesangial proliferation and glomerular sclerosis, suggesting a role for IgA-bound cells in the pathogenesis of mesangial damage.
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PMID:Down-regulation of Fc alpha receptors on blood cells of IgA nephropathy patients: evidence for a negative regulatory role of serum IgA. 957 48

We herein report on the first two primary sequences (BOU and RAC) of monoclonal light chains of the lambda type responsible for nonamyloid lambda light chain deposition disease. Both patients were affected with severe forms of myeloma complicated with renal failure. The pathological presentation typically featured Congo red-negative deposits along tubular basement membranes but differed somewhat from the typical "Randall-type" kappa light chain deposition disease: they lacked the prominent glomerulosclerosis pattern often featuring nonamyloid kappa deposits and were associated with cylinders or myeloma casts. Both protein sequences were deduced from those of the corresponding complementary DNAs in the bone marrow plasma cells. For each chain, products of three independent amplifications by polymerase chain reaction were sequenced and found to be identical. BOU and RAC lambda mRNAs had a normal overall structure consisting of Vlambda2 segments rearranged to Jlambda2Clambda2 but displayed a number of unusual features within their primary sequences. These substitutions are likely responsible for changes in light chain conformation that promote their aggregation and deposition along renal tubule basement membranes.
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PMID:Complete primary sequences of two lambda immunoglobulin light chains in myelomas with nonamyloid (Randall-type) light chain deposition disease. 966 93

A 64-year-old man developed multiple myeloma (kappa light chain type), nephrotic syndrome, and renal insufficiency in 1993. A renal biopsy showed typical histological findings of light chain nephropathy: nodular glomerulosclerosis with deposition of kappa light chains in the mesangial area and subendothelial space of the glomerular capillary walls. Long-term intermittent MEVP chemotherapy (melphalan, 4 mg/d for 4 days; cyclophosphamide, 100 mg/d for 4 days; vincristine, 1 mg/d; prednisolone, 40 mg/d for 4 days) diminished proteinuria and improved renal function. In April 1999, a follow-up biopsy showed remarkable diminution of nodular lesions and disappearance of kappa light chain deposits. Although the prognosis of light chain nephropathy has been considered poor, long-term successful chemotherapy can clear light chain deposits and restore renal function.
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PMID:Disappearance of nodular mesangial lesions in a patient with light chain nephropathy after long-term chemotherapy. 1069 94

Renal involvement in 204 cases with multiple myeloma admitted over a 10-year period to this tertiary care center in north India was retrospectively examined. Renal involvement occurred in 55 cases (27%); the vast majority of whom (94.5%) had presented with renal failure and 7.3% had nephrotic syndrome. The diagnosis of multiple myeloma was made after admission in 51 of the 55 (92.7%) cases. Oliguria was seen in 23.6% and two-third patients required dialysis. Factors precipitating renal failure were identified in 53% and included dehydration (33%), hypercalcemia (24%), nephrotoxic drugs (16%), sepsis (9%), recent surgery (5%) and contrast media (2%), Severe anemia, hypercalcemia, Bence Jones proteinuria and skeletal abnormalities were more frequent in those with renal involvement. Patients with renal involvement were more likely to have a high tumor burden. The myeloma was of light chain type in 68% of those with renal involvement whereas IgG myeloma was commonest (57%) in those without evidence of renal disease. Renal histology was studied in 27 cases with myeloma cast nephropathy seen in over 60%. Tubulointerstitial nephritis was seen in 14% cases, 11% had amyloidosis, 7% had acute tubular necrosis and 3.6% each had nodular glomerulosclerosis and plasma cell infiltration. In 8 cases (14.6%), renal biopsy provided the first clue to the diagnosis of myeloma. Renal function improved in 33% cases. Only 22% of patients on dialysis survived over 6 months. Median survival in those with renal involvement was only 4 months. Development of unexplained renal failure in an elderly individual with normal sized kidneys, in association with disproportionate anemia even in the absence of skeletal lesions should alert the physician to the diagnosis of multiple myeloma.
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PMID:Renal involvement in multiple myeloma: a 10-year study. 1090 Nov 84


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