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LDL-Apheresis for FSGS CardioRenal Outcomes

2019-09-18 03:27:36 | BioPortfolio

Summary

Focal segmental glomerulosclerosis (FSGS) is the most common cause of end-stage renal disease (ESRD) in adolescents. The refractory nature of FSGS and a more than 30% recurrence rate after kidney transplantation renders treatment of FSGS one of the most difficult challenges in pediatric nephrology. A significant knowledge gap in understanding the mechanism of FSGS treatment resistance and progression hampers development of successful treatment strategies. Beneficial effect of removal of low-density lipoproteins by LDL-apheresis indicates that lipids contribute to progression in FSGS.

The investigators will test the hypothesis that removal of Lp-PLA2 and lipid metabolites by LDL-apheresis ameliorates proteinuria and cardiovascular comorbidities. Patients with FSGS and FSGS recurrence after kidney transplantation receiving LDL-apheresis as part of standard of care will be enrolled to the study. Pre-and post serum and effluent concentrations of LPC, free FA, Lp-PLA2, oxidized LDL, fasting lipid profile, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-1β will be monitored in patients undergoing LDL-apheresis. Investigators will also study the impact of LDL-apheresis on cardiovascular and clinical comorbidities by monitoring degree of proteinuria, blood pressures and arterial stiffness index.

Description

Focal segmental glomerulosclerosis (FSGS) is the most common cause of end-stage renal disease (ESRD) in adolescents. The refractory nature of FSGS and a more than 30% recurrence rate after kidney transplantation renders treatment of FSGS one of the most difficult challenges in pediatric nephrology. A significant knowledge gap in understanding the mechanism of FSGS treatment resistance and progression hampers development of successful treatment strategies. Beneficial effect of removal of low-density lipoproteins by LDL-apheresis indicates that lipids contribute to progression in FSGS. We have previously reported increased urinary fatty acids (FA) and lysophosphatidylcholines (LPC) levels with non-targeted urinary lipidomic analysis in children with FSGS. Unregulated phospholipase A2(PLA2) activity causes an increase in intracellular concentrations of free FA and LPC altering plasma membrane and mitochondrial permeability.

Lipoprotein associated PLA2 is a biomarker involved in oxidative modification of LDL by hydrolyzing oxidative lysophosphatidylcholines (LPC) and oxidized free fatty acids (FFA) both of which are proinflammatory and atherogenic. Lp-PLA2 is efficiently removed by LDL-apheresis. The investigators hypothesize that LDL-apheresis ameliorates cellular injury and vascular changes by removing circulating Lp-PLA2, oxidized LDL, LPC, FA and cytokines in FSGS. In this proposal, the hypothesis that removal of Lp-PLA2 and lipid metabolites by LDL-apheresis ameliorates proteinuria and cardiovascular comorbidities will be tested. Patients with FSGS and FSGS recurrence after kidney transplantation receiving LDL-apheresis as part of standard of care will be enrolled to the study. Investigators will monitor pre-and post serum and effluent concentrations of LPC, free FA, Lp-PLA2, oxidized LDL, fasting lipid profile, IL-6, TNF-α, and IL-1β of patients undergoing LDL-apheresis. The impact of LDL-apheresis on cardiovascular and clinical comorbidities by monitoring degree of proteinuria, blood pressures and arterial stiffness index will also be investigated.

The investigators propose that LDL-apheresis as a conjunct therapy to standard treatment regimens is an efficient way to ameliorate progression prevent comorbidities such as systemic inflammation and lipid induced vascular changes thus progression in FSGS. Furthermore, removal of Lp-PLA2 and other lipids by LDL-apheresis can limit the direct toxicity caused by lipid metabolites to podocytes and proximal tubule epithelial cells. The investigators believe that this proposal will enhance understanding of lipid-mediated progression in FSGS and will delineate the role of LDL-apheresis as part of established treatment in treatment of FSGS.

Study Design

Conditions

Focal Segmental Glomerulosclerosis

Intervention

No intervention

Location

Cincinnati Children's Hospital Medical Center
Cincinnati
Ohio
United States
45229

Status

Enrolling by invitation

Source

Children's Hospital Medical Center, Cincinnati

Results (where available)

View Results

Links

Published on BioPortfolio: 2019-09-18T03:27:36-0400

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Medical and Biotech [MESH] Definitions

A clinicopathological syndrome or diagnostic term for a type of glomerular injury that has multiple causes, primary or secondary. Clinical features include PROTEINURIA, reduced GLOMERULAR FILTRATION RATE, and EDEMA. Kidney biopsy initially indicates focal segmental glomerular consolidation (hyalinosis) or scarring which can progress to globally sclerotic glomeruli leading to eventual KIDNEY FAILURE.

An ApoL protein highly expressed by the liver. It has anti-trypanosomal activity through its ability to permeabilize TRYPANOSOMA membranes. Mutations in the APOL1 gene are associated with type 4 FOCAL SEGMENTAL GLOMERULOSCLEROSIS .

A non-selective, calcium permeant TRPC cation channel that contains four ANKYRIN REPEATS and is activated by DIACYLGLYCEROL independently of PROTEIN KINASE C. It is expressed in placenta, lung, spleen, ovary and the small intestine, as well as by PODOCYTES in the kidney glomerulus. Mutations in the TRPC6 gene are associated with FOCAL SEGMENTAL GLOMERULOSCLEROSIS type 2.

Renal syndrome in human immunodeficiency virus-infected patients characterized by nephrotic syndrome, severe proteinuria, focal and segmental glomerulosclerosis with distinctive tubular and interstitial changes, enlarged kidneys, and peculiar tubuloreticular structures. The syndrome is distinct from heroin-associated nephropathy as well as other forms of kidney disease seen in HIV-infected patients.

INFLAMMATION of the PANCREAS that is characterized by recurring or persistent ABDOMINAL PAIN with or without STEATORRHEA or DIABETES MELLITUS. It is characterized by the irregular destruction of the pancreatic parenchyma which may be focal, segmental, or diffuse.

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Nephrology - kidney function
Nephrology is a specialty of medicine and pediatrics that concerns itself with the study of normal kidney function, kidney problems, the treatment of kidney problems and renal replacement therapy (dialysis and kidney transplantation). Systemic conditions...


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