This study investigates the safety and efficacy of ACE Reno, an oral transmucosal solution containing standardized bioactive peptides and amino acids, in patients with nephropathy of various etiologies and stages. The trial evaluates whether 12 weeks of ACE Reno (1 mL sublingually four times daily) reduces albuminuria/proteinuria and stabilizes kidney function in participants with nephropathy due to diabetes, hypertension, autoimmune disease, reflux/UTI, chronic glomerulonephritis, unknown etiology, pre-dialysis CKD, or post-transplant proteinuria.

Nephropathy remains a global health burden, with ~9-10% of the population affected by chronic kidney disease (CKD), equating to >750 million individuals worldwide. The socioeconomic costs are substantial: in England CKD costs ~£7 billion annually, projected to rise to ~£14 billion by 2033; in Malaysia, prevalence rose from 9% to 15.5% within 7 years; in Egypt, CKD imposes heavy familial and financial burdens, especially for pediatric patients; in Turkey, CKD is among the top causes of disability, linked to the rising tide of diabetes, obesity, and hypertension.

ACE Reno is designed to address multiple drivers of CKD progression - glomerulosclerosis, fibrosis, endothelial dysfunction, and maladaptive RAAS/aldosterone signaling - through its peptide components that mimic antifibrotic (BMP-7, HGF, Klotho-like) and vasodilatory/cGMP-mediated (natriuretic peptide-like) pathways.

Study Objectives

Primary Objective:

To evaluate the effect of ACE Reno on urinary albumin-to-creatinine ratio (ACR) after 12 weeks of treatment in patients with nephropathy of diverse etiologies.

Secondary Objectives:

To assess the effect of ACE Reno on estimated glomerular filtration rate (eGFR) slope.

To evaluate changes in proteinuria, blood pressure, and patient-reported outcomes.

To assess safety and tolerability.

Exploratory Objectives:

To explore biomarker changes (e.g., TGF-β, cGMP, NGAL, KIM-1). To assess durability of response up to 6 months in responders. Investigational Product (IP) ACE Reno is a sublingual solution (1 mL four times daily for 12 weeks) containing a standardized panel of low-molecular-weight bioactive peptides and amino acids.

Key peptide domains include:

BMP-7-like sequences countering TGF-β-driven fibrosis. HGF-like fragments supporting epithelial repair. Klotho-like motifs antagonizing profibrotic pathways and RAAS/Wnt activity. Natriuretic-peptide-like domains enhancing cGMP signaling, with anti-fibrotic, vasodilatory, and endothelial-protective effects.

No genetic material is present; formulation is peptide-based only. Study Design Type: Prospective, multicenter, interventional, open-label. Model: Single-arm with within-patient comparisons. Duration: 12 weeks treatment + 4 weeks post-treatment safety follow-up. Visits: Screening, Baseline (Day 0), Week 4, Week 8, Week 12, and Week 16 safety call.

Participants

Inclusion:

Adults (≥18 years) with nephropathy of any degree (microalbuminuria, overt proteinuria, CKD stages 1-5 not on dialysis, or post-transplant with proteinuria). Stable background therapy with ACEi/ARB, SGLT2i, or MRA allowed.

Exclusion:

Dialysis at baseline. Recent kidney transplant (<12 months). Uncontrolled acute infection or unstable autoimmune disease. Pregnancy or lactation. Known hypersensitivity to study components. Categories (Strata: 17 Subgroups) Diabetic nephropathy - microalbuminuria Diabetic nephropathy - macroalbuminuria Diabetic nephropathy - CKD Stage 3 Diabetic nephropathy - CKD Stage 4-5 (non-dialysis) Hypertensive nephropathy - microalbuminuria Hypertensive nephropathy - proteinuric CKD Hypertensive nephropathy - advanced CKD (3-5) Autoimmune nephropathy - Class II-III Autoimmune nephropathy - Class IV-V Reflux nephropathy - mild/moderate scarring Reflux nephropathy - severe scarring Chronic glomerulonephritis - nephrotic range proteinuria Chronic glomerulonephritis - CKD <60 mL/min/1.73m² CKD of unknown etiology - Stage 1-2 CKD of unknown etiology - Stage 3-4 ESRD pre-dialysis (eGFR <15) Post-transplant CKD with proteinuria Sample Size and Rationale

Primary endpoint powering (paired design):

Detect 30% reduction in ACR (δ = ln(0.70) = -0.357), assuming σ = 0.8, r = 0.6 → ~32 analyzable patients needed.

Planned enrollment (pooled cohort, with 17 categories):

~182 analyzable patients (~214 enrolled allowing for 15% attrition). Each category will include a minimum of 8-12 patients (more for common etiologies such as diabetic proteinuria).

Total enrollment stratified by prevalence across categories. Endpoints

Primary Endpoint:

Change in urinary ACR from baseline to Week 12 (log-transformed).

Secondary Endpoints:

Change in eGFR slope. Change in 24-h proteinuria (selected patients). Blood pressure change. Patient-reported outcomes (KDQOL-36, EQ-5D). Safety (hyperkalemia, creatinine rise, liver tests, hematology).

Exploratory Endpoints:

Biomarker profiles (TGF-β, cGMP, NGAL, KIM-1). Hospitalization rate. Extended follow-up outcomes at 6 months. Follow-Up Plan

Monthly Visits (Week 4, 8, 12):

Clinical: BP, vitals, weight, adherence. Labs: creatinine/eGFR, electrolytes, liver panel, CBC, urine ACR. Safety: hyperkalemia, creatinine rise. PROs brief (fatigue, QoL).

Final (Week 12):

Primary endpoint assessment (duplicate ACR). PROs full set. Investigator global assessment.

Safety Call (Week 16):

AE/SAE resolution, concomitant therapy updates. Statistical Analysis Primary analysis: Paired t-test and mixed model for repeated measures (MMRM) on log(ACR).

Secondary: eGFR slope via linear mixed model, BP change via ANCOVA, responder rate (≥30% reduction in ACR).

Subgroups: Category-by-time interaction analysis; forest plots for effect estimates.

Multiplicity: Subgroup effects exploratory; overall primary endpoint tested at α=0.05.

Inclusion Criteria:

• Adults (≥18 years) with nephropathy of any degree (microalbuminuria, overt proteinuria, CKD stages 1-5 not on dialysis, or post-transplant with proteinuria). Stable background therapy with ACEi/ARB, SGLT2i, or MRA allowed.

Exclusion Criteria:

• Recent kidney transplant (<12 months). Uncontrolled acute infection or unstable autoimmune disease. Pregnancy or lactation. Known hypersensitivity to study components.