Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease

University of Michigan7 enrolled

Overview

Adalimumab, a treatment which blocks tumor necrosis factor (TNF), was tested to see if it changed levels of urine biomarker levels, tissue inhibitor of metalloprotease-1 (TIMP1), and monocyte chemoattractant protein-1 (MCP1). Results may help develop individualized treatment options for future patients with TNF-driven focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD).

Study Type

INTERVENTIONAL

Allocation

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

FSGS MCD Focal Segmental Glomerulosclerosis Minimal Change Disease

Interventions

Eligibility

Sex: ALLMin age: 6 YearsMax age: 80 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Kidney biopsy confirmed Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD) * For Minimal Change Disease patients only, history of resistance to corticosteroid therapy * Increased urinary excretion of biomarkers of Tumor Necrosis Factor (TNF) activation (MCP1/Cr and/ or TIMP1/Cr) at study screening * eGFR\>30 ml/min/1.73 m2 at screening * Urine protein:creatinine ratio ≥1.5 g/g at screening * Weight \>15 kg * Stable therapy with angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and oral immunosuppression agents for at least 30 days prior to enrollment * Birth control use in females of child bearing potential * Informed consent and assent if applicable Exclusion Criteria: * Kidney or other solid organ or bone marrow transplant recipient * Allergy or intolerance to investigational agent * Secondary Focal Segmental Glomerulosclerosis (FSGS) * Severe obesity * Live virus vaccine in the past 3 months * Malignancy, current or in the past 5 years * Active local or systemic bacterial, fungal or viral infection * Active or latent Hepatitis B, Hepatitis C, HIV, or tuberculosis * History of demyelinating disease, e.g. Multiple Sclerosis or Guillain-Barre * History of heart failure * Active liver disease * Systemic lupus erythematosus or ANA \> 1:80 * History of inflammatory bowel disease, e.g. ulcerative colitis or Crohns disease * Cyclophosphamide in past 90 days, Rituximab in the past 180 days * Pregnancy or nursing * Blood white blood cell count \<4,500/mm3; Hg \<9 g/dL; Platelet count \<150,000/mm3 at enrollment. - Use of an erythropoiesis stimulating agent will not be an exclusion criterion. * Concurrent use of interleukin-1 antagonist (Anakinra), other TNF blocking agent, methotrexate or abatacept * Diabetes Mellitus

Outcomes

Primary Outcomes

Change in Urine MCP1/Cr Levels

MCP1 is an established marker of intra-renal TNF pathway activation. A reduction in MCP1 reflects a reduction in the activation of the TNF pathway in the kidney. Values were measured by enzyme-linked immunosorbent assay (ELISA) testing and standardized over serum creatinine.

Time frame: 10 Weeks

Change in Urine TIMP1/Cr Levels

TIMP1 is an established marker of intra-renal TNF pathway activation. A reduction in TIMP1 reflects a reduction in the activation of the TNF pathway in the kidney. Values were measured by enzyme-linked immunosorbent assay (ELISA) testing and standardized over serum creatinine.

Time frame: 10 Weeks

Secondary Outcomes

Incidence of Adverse Events (AEs)

AEs for this outcome measure were classified using the following definitions: * Mild: no or mild symptoms, and not requiring intervention * Moderate: with minimal or local intervention, and limiting age-appropriate activities * Severe: intervention necessary and limiting age-appropriate activities but not immediately life-threatening, and requiring hospitalization or prolongation of hospitalization * Serious AE: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, pregnancy or congenital anomaly/birth defect. Some participants experienced multiple types of AE during the course of the trial.

Time frame: 14 weeks

Change in Estimated Glomerular Filtration Rate (eGFR)

eGFR is a measure of kidney functioning based on a blood sample and clinical information to calculate it. Normal kidney function is greater than 90 ml/min/1.73 m2. Result data is the percent change in eGFR following the intervention. The lower the number shows the greater decline in kidney function.

Time frame: 10 Weeks

Change in Urine Protein Creatinine Ratio (UPCR)

UPCR is a measure of protein spillage from the kidney based on a urine specimen. Normal reference range is less than 0.03 mg/mg. Result is the percent change in UPCR following the intervention, with lower number showing less protein spilling from the kidney, reflecting better disease control.

Time frame: 10 Weeks

Proportion of Participants Who Achieved Both a Nadir Urine Protein Creatinine Ratio (UPCR) of Less Than 1.5 g/g and at Least a 40% Reduction From Baseline

UPCR is a measure of protein spillage from the kidney based on a urine specimen. Normal reference range is less than 0.03 mg/mg. Result is the count of participants who simultaneously met the criteria of having both a raw UPCR value of less than 1.5 g/g and at least a 40% reduction from baseline.

Time frame: 10 Weeks

Tumor Necrosis Factor Inhibition in Focal Segmental Glomerulosclerosis and Treatment Resistant Minimal Change Disease

Overview

Conditions

Interventions

Eligibility

Locations (4)

Outcomes

Primary Outcomes

Secondary Outcomes