Diabetic nephropathy (DKD) is one of the most common complications that develop as type 2 diabetes progresses. It is a disease in which the blood vessels and tissues of the kidneys are damaged by chronic high blood sugar, leading to a gradual decline in kidney function. In advanced stages, it can lead to chronic kidney disease (CKD) or require dialysis treatment, and it remains a global medical challenge
In recent years, new treatment approaches from the field of regenerative medicine have attracted attention for cases where the progression of the disease cannot be adequately controlled by conventional blood glucose management and antihypertensive therapy alone. Among these, cell therapy using mesenchymal stem cells (MSCs) is being researched for its application to diabetic nephropathy due to its potential anti-inflammatory, immunomodulatory, and tissue repair effects
This article explains the NEPHSTROM trial, published in the Journal of the American Society of Nephrology in 2023, including its content and clinical significance
table of contents
What is diabetic nephropathy?
Diabetic nephropathy is a disease that develops when diabetes causes chronic damage to the glomeruli and blood vessels of the kidneys. In its early stages, there are few noticeable symptoms, but as it progresses, proteinuria and decreased kidney function appear, and in some cases, dialysis treatment may eventually be necessary
In particular, in patients with type 2 diabetes, it is believed that prolonged hyperglycemia, chronic inflammation, and oxidative stress are complexly involved, leading to the progression of renal tissue fibrosis and dysfunction
Why does kidney function decline?
In diabetic nephropathy, chronic inflammatory responses and immune abnormalities persist within the kidneys, gradually destroying normal tissue structure. Furthermore, vascular damage reduces blood flow to the kidneys, leading to progressive glomerular dysfunction
Current standard treatment aims to slow disease progression by managing blood sugar and blood pressure, but in some patients, it is difficult to adequately prevent kidney function decline. Therefore, new treatment strategies that target inflammation and tissue repair itself are needed
What is MSC therapy?
Mesenchymal stem cells (MSCs) are stem cells collected from bone marrow, adipose tissue, umbilical cord, etc., and are known to have immunomodulatory and anti-inflammatory effects
In recent years, the potential of cytokines and growth factors secreted by MSCs to improve the inflammatory environment and promote tissue repair has attracted attention, and research is progressing in a wide range of fields, including autoimmune diseases, neurological diseases, and cardiovascular diseases
In diabetic nephropathy, systemic administration of mesenchymal stem cells (MSCs) is expected to potentially address chronic inflammation and immune abnormalities within the kidneys
Overview of the NEPHSTROM trial
The NEPHSTROM trial was a randomized, double-blind, placebo-controlled phase 1b/2a trial conducted in patients with type 2 diabetes and progressive diabetic nephropathy
In this study, allogeneic bone marrow-derived measles stem cells (MSCs) "ORBCEL-M," selected using anti-CD362 antibodies, were used. The 16 participants were randomized in a 3:1 ratio, with 12 assigned to the ORBCEL-M group and 4 to the placebo group
The administered cell count was 80 × 10⁶cells, and follow-up evaluations were conducted for 18 months after intravenous administration.
| item | Content |
|---|---|
| exam name | NEPHSTROM |
| subject | 16 patients with type 2 diabetes + progressive diabetic nephropathy |
| cell type | Allogeneic bone marrow-derived MSCs (ORBCEL-M) |
| Method of administration | Intravenous administration |
| Tracking period | 18 months |
| Test design | Randomized, double-blind, placebo-controlled trial |
What results were obtained?
This study reported that the annual rate of decline in eGFR (estimated glomerular filtration rate) was significantly lower in the ORBCEL-M treatment group than in the placebo group
On the other hand, no significant differences were observed between groups in mGFR (measured glomerular filtration rate), and the authors mention the possibility of discrepancies between the estimation formula and the measured values, as well as pharmacodynamic time differences
Furthermore, immunological analysis revealed the following changes in the MSC-treated group:
- Maintenance of regulatory T cells
- Decrease in NK-T cells
- Stabilization of the inflammatory monocyte subset
These results suggest that MSC therapy may not be merely a symptomatic treatment, but rather acts on the chronic inflammatory environment itself
Regarding safety
In this study, ORBCEL-M was well-tolerated, and no serious safety signals were observed
One patient in the placebo group experienced a transient infusion reaction (bronchospasm), but no serious adverse events were reported in the MSC-treated group
In addition, two deaths were reported in the ORBCEL-M treatment group during the follow-up period, but no causal relationship with the study intervention was found in either case
While the overall safety profile of MSC therapy currently appears relatively favorable, further investigation is needed to assess its long-term safety
Future challenges and prospects
The NEPHSTROM trial was a relatively small, early-stage trial, and the results alone cannot definitively determine the efficacy of this drug against diabetic nephropathy
In particular, the discrepancy observed between mGFR and eGFR results requires further verification through larger-scale, longer-term clinical trials
On the other hand, this study is attracting attention as important initial data demonstrating the potential of MSC therapy as a new treatment option for diabetic nephropathy
In the future, further research including the number of cells administered, the timing of administration, patient selection criteria, and long-term safety evaluations is expected to accumulate more knowledge toward the practical application of regenerative medicine
summary
The NEPHSTROM trial showed that intravenous administration of allogeneic bone marrow-derived MSCs "ORBCEL-M" demonstrated good safety in patients with progressive diabetic nephropathy and suggested the possibility of suppressing the rate of eGFR decline
Diabetic nephropathy is a disease for which effective and fundamental treatments are still limited, and MSC therapy is expected to be a new regenerative medicine strategy that addresses chronic inflammation and immune abnormalities
On the other hand, this is still in the research stage, and further large-scale clinical trials and long-term safety evaluations are needed. Future research progress in the field of regenerative medicine is attracting attention
Paper information
Paper title:
Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM)
Authors:
WireMB, TomsJA, FletcherAG et al. (NEPHSTROM Consortium)
Publication:
Journal of the American Society of Nephrology (October 1, 2023)
DOI:
10.1681/ASN.2023
PMC full text:
https://pmc.ncbi.nlm.nih.gov/articles/PMC10561817/