Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins.

Sanders, Paul W.; Booker, B. B.; Bishop, James; Cheung, Herbert C.

doi:10.1172/jci114474

Cited by 118 publications

(86 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Hemodynamics and intravascular volume should be optimized in an effort to ensure adequate urine output. Oliguric patients may benefit from a trial of volume repletion but should not receive loop diuretics, because they may contribute to paraprotein cast formation (54). Alkalinization of the urine is of uncertain benefit and can theoretically raise the risk of abnormal calcification in the kidney or elsewhere, particularly if hypercalcemia is present.…”

Section: Management Of Aki From Paraprotein-mediated Diseasementioning

confidence: 99%

Kidney Disease and Multiple Myeloma

Heher

Rennke

Laubach

et al. 2013

Clinical Journal of the American Society of Nephrology

146

122

View full text Add to dashboard Cite

SummaryKidney injury is a common complication of multiple myeloma and other plasma cell dyscrasias, and it is associated with increased mortality. Multiple pathogenic mechanisms can contribute to kidney injury in the patient with myeloma, some of which are the result of nephrotoxic monoclonal Ig and some of which are independent of paraprotein deposition. The pathogenic mechanisms that underlie paraprotein-related kidney disease are increasingly well understood. A novel assay allowing the quantification of free light chains in the serum has aided the diagnosis of new onset disease and allowed for the earlier detection of relapse. Novel myeloma agents have shown considerable promise in reversing renal failure in some patients and improving outcomes. Stem cell transplantation remains a mainstay of management for younger patients with myeloma who are suitable candidates for intensive therapy, whereas the role of new drugs, plasma exchange, and kidney transplantation continues to evolve.

show abstract

Section: Management Of Aki From Paraprotein-mediated Diseasementioning

confidence: 99%

Kidney Disease and Multiple Myeloma

Heher

Rennke

Laubach

et al. 2013

Clinical Journal of the American Society of Nephrology

146

122

View full text Add to dashboard Cite

show abstract

“…[11][12][13] Factors such as dehydration, hypercalcemia, acidosis and furosemide promote light chain/Tamm-Horsfall protein aggregate formation. [13][14][15][16] Tubular obstruction increases intraluminal pressure, reduces glomerular filtration rate and reduces interstitial blood flow, thus further compromising the renal function. The reduced tubular clearance of light chains further increases their concentration in the tubules and contributes to the vicious circle that results in myeloma cast nephropathy.…”

Section: Pathogenesismentioning

confidence: 99%

“…In general, the variable region of the light chain determines nephrotoxicity of the specific light chain by determining, for example, the affinity with Tamm-Horsfall protein. 14,16 It has been suggested that Tamm-Horsfall protein interacts with the hypervariable regions of the light chains. This region contains the amino acids that give diversity, conformation flexibility and allow for interactions with various proteins to promote antigen binding by immunoglobulins.…”

Section: Pathogenesismentioning

confidence: 99%

Pathogenesis and treatment of renal failure in multiple myeloma

et al. 2008

View full text Add to dashboard Cite

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.

show abstract

“…14 This leads to a greatly increased burden of light chain on PTECs and saturation of the megalin-cubilin pathway, 6,8,9 allowing light chain to travel to the distal nephron where they may interact with Tamm-Horsfall protein and appear in the urine. [15][16][17] There is a mounting body of evidence pointing to exposure of PTECs to excess filtered proteins, resulting in cytokine release, recruitment of inflammatory cells, and the acceleration of interstitial fibrosis. 18 Light chains have been shown to cause nuclear translocation of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-B), resulting in the release of interleukin-6 (IL-6), IL-8, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-␤ (TGF-␤), and are much more potent inducers of these cytokines than other proteins, such as albumin, which may be filtered and enter the proximal tubule in significant amounts, especially in glomerular disease states.…”

mentioning

confidence: 99%

Immunoglobulin Light Chains Activate Tubular Epithelial Cells through Redox Signaling

Basnayake

Ying

Wang

et al. 2010

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

The renal proximal tubule metabolizes circulating low-molecular-weight proteins such as Ig free light chains. In the setting of plasma cell dyscrasias, the burden of filtered protein can be very high. Endocytosis of certain nephrotoxic light chains induces H 2 O 2 production and monocyte chemoattractant protein-1 (MCP-1) release, leading to recruitment of inflammatory cells and interstitial fibrosis, but how these processes are linked mechanistically is not well understood. This study investigated the relationship between H 2 O 2 generated after light chain endocytosis by human proximal tubular (HK-2) cells and activation of c-Src, a redox-sensitive tyrosine kinase. HK-2 cells exposed to two different light chains upregulated c-Src activity, which increased the production of MCP-1. In parallel, we observed a time-dependent oxidation of c-Src. Inhibition of c-Src activity and silencing c-Src expression abrogated the light chain-induced MCP-1 response, but had no effect on H 2 O 2 , indicating that production of H 2 O 2 is upstream of c-Src in the signaling cascade. Silencing megalin and cubilin expression inhibited the MCP-1 response, whereas extracellular catalase did not, indicating that endocytosis is required and that intracellular generation of reactive oxygen species activates c-Src. These data show that intracellular H 2 O 2 induced by endocytosis of monoclonal free light chains oxidizes and activates c-Src, which promotes release of MCP-1.

show abstract

Mechanisms of intranephronal proteinaceous cast formation by low molecular weight proteins.

Cited by 118 publications

References 34 publications

Kidney Disease and Multiple Myeloma

Kidney Disease and Multiple Myeloma

Pathogenesis and treatment of renal failure in multiple myeloma

Immunoglobulin Light Chains Activate Tubular Epithelial Cells through Redox Signaling

Contact Info

Product

Resources

About