ACE-inhibitors in Extracapillary Glomerulonephritis

Study Overview
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Brief Summary
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The natural course of extracapillary glomerulonephritis is severe leading to End-Stage Renal Disease (ESRD) or death in most cases. Despite immunosuppressive treatment, long-term renal outcome remains poor since active crescents usually progress to fibrotic scars with glomerular occlusion and disruption.In experimental models Angiotensin Converting Enzyme (ACE)-inhibitor therapy targeting the over-expression of angiotensin type 1 (AT1) receptors, that are responsible for dysregulated proliferation of parietal cell progenitors, blocks the formation of crescents and their fibrotic evolution. Should these drugs have similar effects in humans, ACE-inhibitor therapy on top of standard immunosuppression might be instrumental to prevent ESRD and promote renal function recovery in clinical practice.

Official Title
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A Pilot, Prospective, Randomized, Open-label, Blinded Endpoint (Probe) Histopathology Trial to Assess the Effects of ACE- Inhibition Therapy on Glomerular Proliferative Lesions in Patients With Extracapillary Glomerulonephritis

Conditions
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Extracapillary Glomerulonephritis

Intervention / Treatment
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* Drug: Lisinopril


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Rapidly progressive renal failure associated with acute nephritic syndrome and/or nephrotic syndrome; Histology evidence of extracapillary proliferation with less than 50% of sclerotic glomeruli and associated with: Type I: Anti-Glomerular Basement Membrane (GBM) antibody glomerulonephritis, Type II: Pauci-immune vasculitis or Anti Neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis; Type III: Immune-complex mediated glomerular diseases: Proliferative lupus nephritis (LN), IgA nephropathy (IgAN)/ Schönlein-Henoch purpura, Type I membranoproliferative glomerulonephropathy (MPGN), Primary or secondary membranous nephropathy (MN), Primary or idiopathic immune complex glomerulonephritis. Clinical indication to immunosuppressive therapy; No specific indication to treatment with Renin Angiotensin System (RAS) inhibitors such as heart failure or coronary ischemic disease; Written informed consent. Exclusion Criteria: Pre-existing advanced chronic renal failure (creatinine clearance less than 20 ml/min/1.73m2); Evidence of B or C virus active infection; HIV infection; Recent diagnosis of malignancy; Prolonged bleeding time and any other contraindication to kidney biopsy evaluation; Any specific contraindication to ACE inhibitor therapy (that is: history of angioedema or other treatment-related serious adverse events); Pregnancy or lactating; Women of childbearing potential without following a scientifically accepted form of contraception; Inability to understand the risks and benefit of the study or evidence of an uncooperative attitude; Legal incapacity.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lisinopril<br>Patients will receive, in addition to standard immunosuppressive therapy, lisinopril starting with 5 mg/day, then progressively up-titrated to reach the maximum tolerable dose (target dose) for 18 months. | Drug: Lisinopril<br> <br> |
| No Intervention: No intervention<br>Patients will receive only the standard immunosuppressive therapy. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The extent of extracapillary proliferation on light microscopy, measured as % of total glomeruli with proliferative lesions at post-treatment repeat biopsy. |  | Changes from baseline and 6 and 18 month. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression of parietal cell proliferation markers at glomerular level, graded on a scale of 0 to 3 (0: no staining, 1: mild, 2: moderate, 3: strong diffuse |  | Changes from baseline and 6 and 18 month. | 
| Number of fibrosclerotic crescents |  | Changes from baseline and 6 and 18 month. | 
| Glomerular Filtration Rate (GFR) measured by iohexol plasma clearance |  | Changes from baseline and 6, 12 and 18 month. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extracapillary glomerulonephritis, crescentic glomerulonephritis, rapidly progressive renal failure, chronic kidney disease, ACE-inhibitors, fibrosis