Dataset Information

Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model.

ABSTRACT: 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.

SUBMITTER: Ying WZ

PROVIDER: S-EPMC3336971 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model.

Ying Wei-Zhong WZ Allen Christopher E CE Curtis Lisa M LM Aaron Kristal J KJ Sanders Paul W PW

The Journal of clinical investigation 20120409 5

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 re ...[more]

PMID: 22484815

Similar Datasets

Project description:BackgroundAcute kidney injury (AKI) caused by cast nephropathy is associated with increased morbidity and mortality among patients with multiple myeloma (MM). High cut-off haemodialysis (HCO-HD) has proven to be effective in the removal of serum light chains but the effect on clinical outcomes, especially renal recovery, remains uncertain.MethodsA systematic review and meta-analysis were performed examining all randomized controlled trials (RCTs) and observational studies (OBSs) assessing the effect of HCO-HD on clinical outcomes of patients with MM complicated by cast nephropathy-induced severe AKI. The primary outcome was all-cause mortality at the end of the study. The secondary outcomes included all-cause mortality at 12 months, HD independence and serum kappa and lambda light chain reduction. Pooled analysis was performed using random effects models.ResultsWe identified five studies, comprising two RCTs and three retrospective cohort studies, including 276 patients with a mean follow-up of 18.7 months. The majority of the studies were of suboptimal quality and underpowered. Compared with patients treated with conventional HD, HCO-HD was not associated with a survival benefit at 12 months {five studies, 276 patients, relative risk [RR] 1.02 [95% confidence interval (CI) 0.76-1.35], I 2 = 33.9%} or at the end of the studies at an average of 34 months [five studies, 276 patients, RR 1.32 (95% CI 0.71-2.45), I 2 = 62.0%]. There was no difference in HD independence at 90 days [two trials, 78 patients, RR 2.23 (95% CI 1.09-4.55)], 6 months [two studies, 188 patients, RR 1.19 (95% CI 0.68-2.06)] or 12 months [two studies, 188 patients, RR 1.14 (95% CI 0.58-2.26)]. Patients receiving HCO dialysis, however, had a greater reduction in serum kappa [two studies, 188 patients, weighted mean difference (WMD) 46.7 (95% CI 38.6-54.7), I 2 = 52.0%] and lambda [two studies, 188 patients, WMD 50.3 (95% CI 21.4-79.3), I 2 = 95.1%] light chain levels.ConclusionCurrent evidence from RCTs and OBSs suggests HCO dialysis is able to reduce serum free light chains but makes no significant improvement in all-cause mortality and renal outcomes compared with conventional HD for patients with myeloma cast nephropathy. However, there is a trend towards better renal outcomes with the use of HCO dialysis. The lack of long-term data and the small sample sizes of the included studies limit this analysis. Therefore further large-scale RCTs with longer follow-up are needed to assess the effect of HCO dialysis on clinical outcomes in patients with myeloma cast nephropathy.

Dataset Information

Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model.

Publications

Mechanism and prevention of acute kidney injury from cast nephropathy in a rodent model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets