The Mesangium as a Target for Glomerulopathic Light and Heavy Chains: Pathogenic Considerations in Light and Heavy Chain-Mediated Glomerular Damage

Keeling, John; Herrera, Guillermo A.

doi:10.1159/000096764

Cited by 28 publications

(23 citation statements)

References 55 publications

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“…Recent studies demonstrated that monoclonal FLC promote proximal tubular injury by increasing intracellular oxidative stress with the subsequent production of monocyte chemoattractant protein 1 (28). Further work has shown that FLC induce epithelial-mesangial transition (29) and activate mesangial cells to proliferate and increase production of matrix proteins (30). The hypothesis that polyclonal FLC present in increasing concentrations in patients with CKD may be capable of inducing similar injuries is now being investigated.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Assessment of Serum and Urinary Polyclonal Free Light Chains in Patients with Chronic Kidney Disease

Hutchison¹,

Harding²,

Hewins³

et al. 2008

Clinical Journal of the American Society of Nephrology

311

233

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Results: Serum and FLC concentrations increased progressively with CKD stage (both P < 0.001) and strongly correlated with markers of renal function, including cystatin-C (: R ‫؍‬ 0.8, P < 0.01; and : R ‫؍‬ 0.79, P < 0.01). Urinary FLC concentrations varied significantly between disease groups (: P < 0.001; : P < 0.005) and also rose significantly with increasing CKD stage (both FLC P < 0.0001). Urinary FLC concentrations were positively correlated with their corresponding serum concentration (: R ‫؍‬ 0.63; : R ‫؍‬ 0.65; both P < 0.001) and urinary albumin creatinine ratio (: R ‫؍‬ 0.58; : R ‫؍‬ 0.65; both P < 0.001). The proportion of patients with abnormally high urinary FLC concentrations rose with both the CKD stage and the severity of albuminuria.Conclusions: This study demonstrates significant abnormalities of serum and urinary polyclonal FLC in patients with CKD. These data provide the basis for studies that assess the contribution of polyclonal FLC to progressive renal injury and systemic inflammation in patients with kidney disease.

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Section: Discussionmentioning

confidence: 99%

Quantitative Assessment of Serum and Urinary Polyclonal Free Light Chains in Patients with Chronic Kidney Disease

Hutchison¹,

Harding²,

Hewins³

et al. 2008

Clinical Journal of the American Society of Nephrology

311

233

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“…23,24 These proinflammatory cytokines promote infiltration by inflammatory cells that produce metalloproteinases and increase transforming growth factor-b production, resulting in matrix protein deposition and subsequent fibrosis and further compromising the ability of the nephron to restore function. 25 Light chains endocytosis may also cause tubular cell necrosis, leading to more severe renal dysfunction. 26 The exact mechanism has not been clarified, but it has been suggested that aggregation of light chains after endocytosis may initiate a cascade resulting in tubular cell death.…”

Section: Pathogenesismentioning

confidence: 99%

Pathogenesis and treatment of renal failure in multiple myeloma

et al. 2008

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Renal failure is a frequent complication in patients with multiple myeloma (MM) that causes significant morbidity. In the majority of cases, renal impairment is caused by the accumulation and precipitation of light chains, which form casts in the distal tubules, resulting in renal obstruction. In addition, myeloma light chains are also directly toxic on proximal renal tubules, further adding to renal dysfunction. Adequate hydration, correction of hypercalcemia and hyperuricemia and antimyeloma therapy should be initiated promptly. Recovery of renal function has been reported in a significant proportion of patients treated with conventional chemotherapy, especially when high-dose dexamethasone is also used. Severe renal impairment and large amount of proteinuria are associated with a lower probability of renal recovery. Novel agents, such as thalidomide, bortezomib and lenalidomide, have significant activity in pretreated and untreated MM patients. Although there is limited experience with thalidomide and lenalidomide in patients with renal failure, data suggest that bortezomib may be beneficial in this population. Clinical studies that have included newly diagnosed and refractory patients indicate that bortezomib-based regimens may result in rapid reversal of renal failure in up to 50% of patients and that full doses of bortezomib can be administered without additional toxicity.

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“…Our findings establish that a lower percentage of urine k FLC excretion associates with higher proteinuria, lower levels of eGFR, and higher histologic score in patients with IgAN. The design of the present study does not allow us to propose a mechanism responsible for the glomerular capture of k FLC or establish a role of k FLC renal deposition in the onset and progression of renal damage of IgAN, but the available literature suggests several possibilities, whereby k FLC deposition could promote renal injury (39,40).…”

Section: Discussionmentioning

confidence: 88%

Association of Urinary Laminin G-Like 3 and Free K Light Chains with Disease Activity and Histological Injury in IgA Nephropathy

Rocchetti

Papale

d'Apollo

et al. 2013

Clinical Journal of the American Society of Nephrology

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Summary Background and objectives IgA nephropathy has variable clinical presentation and progression. Its definitive diagnosis and prognosis require renal biopsy. The identification of new biomarkers allowing noninvasive diagnosis and monitoring of disease activity would be advantageous. This study analyzed the urine proteome of IgA nephropathy patients at an early stage of disease. Design, setting, participants, & measurements Urine from 49 IgA nephropathy patients, 42 CKD patients, and 40 healthy individuals was analyzed by surface-enhanced laser desorption/ionization time of flight/mass spectrometry. Differentially excreted proteins were identified by matrix-enhanced laser desorption/ionization time of flight/mass spectrometry, confirmed by immunologic methods, and validated in an independent set of patients (14 IgA nephropathy and 24 CKD). All patients were recruited at the Division of Nephrology of the University of Foggia from January of 2005 to March of 2007. Results Two proteins, with 21,598 and 23,458 m/z, were significantly decreased in IgA nephropathy and identified as Perlecan laminin G-like 3 peptide and Ig κ light chains, respectively. Western blot analysis confirmed the lower urinary excretion of laminin G-like 3 in IgA nephropathy patients compared with CKD patients and healthy individuals. Immunonephelometry analysis confirmed the lower urinary excretion of free κ light chains in IgA nephropathy patients compared with CKD patients and healthy individuals. Immunohistochemistry analysis justified the urinary excretion profile of such proteins in IgA nephropathy. Finally, urinary free κ light chains and laminin G-like 3 concentration inversely correlated with severity of clinical and histologic features of our IgA nephropathy cohort. Conclusions Laminin G-like 3 and free κ light chains can contribute to the noninvasive assessment of IgA nephropathy disease activity.

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The Mesangium as a Target for Glomerulopathic Light and Heavy Chains: Pathogenic Considerations in Light and Heavy Chain-Mediated Glomerular Damage

Cited by 28 publications

References 55 publications

Quantitative Assessment of Serum and Urinary Polyclonal Free Light Chains in Patients with Chronic Kidney Disease

Quantitative Assessment of Serum and Urinary Polyclonal Free Light Chains in Patients with Chronic Kidney Disease

Pathogenesis and treatment of renal failure in multiple myeloma

Association of Urinary Laminin G-Like 3 and Free K Light Chains with Disease Activity and Histological Injury in IgA Nephropathy

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