Kidney Failure and Its Treatment - Why Are Current Treatments Alone Insufficient?
Chronic Kidney Disease (CKD) is a silently progressing condition, also known as the "silent disease," and is estimated to affect over 13 million people. When kidney function significantly declines to End-Stage Renal Disease (ESRD), renal replacement therapy (RRT) becomes necessary, including options such as hemodialysis, peritoneal dialysis, or kidney transplantation.
However, in actual clinical practice, the number of patients undergoing dialysis continues to increase annually, with over 330,000 individuals receiving chronic dialysis therapy by 2017. Conversely, the number of kidney transplants, a curative treatment, has remained below 1,700 cases per year, leaving many patients desiring transplantation unable to achieve it.
Underlying this situation is a critical donor shortage. Furthermore, while dialysis therapy is a vital means of life support, the following burdens on daily life are unavoidable:
- Routine visits three times per week with treatment time (4-5 hours per session)
- Sustained food and fluid restriction
- Risk of complications such as infection and cardiovascular disease.
Renal transplantation also presents challenges, including donor acquisition issues, rejection, the adverse effects of immunosuppressants, and the substantial financial burden of medical costs.
Conservative management (comprising dietary and pharmacological therapies) can decelerate progression, but is incapable of restoring the diminished renal function itself. In essence, under the current medical paradigm, "we can halt the deterioration but cannot restore the kidneys to their original state."
Against this backdrop, there is a strong demand for novel treatment strategies that can replace or complement dialysis and transplantation.
Key Point
- CKD is considered a "new national disease" affecting approximately 1 in 8 adults.
- Dialysis and transplantation are important treatments but cannot meet the needs of all patients.
- Given current therapeutic approaches, it is highly challenging to restore intrinsic renal function.
- New treatment methods are required to expand quality of life and treatment options.
Kidney-restoring options for renal failure are beginning to emerge.
The treatment of renal failure has historically been dominated by replacement therapies such as dialysis and kidney transplantation. However, with recent advancements in regenerative medicine, the concept of repairing the kidney itself has become a reality.
Particular attention is paid to therapies utilizing stem cells.
Stem cells are unique cells that possess the self-renewal capability to produce identical copies of themselves, and pluripotency to differentiate into other cell types as needed. Leveraging these capabilities, the rationale behind Stem Cell Therapy is to regenerate damaged organs and tissues.
In the field of nephrology, mesenchymal stem cells (MSCs) have garnered significant attention. MSCs can be obtained from sources such as bone marrow, adipose tissue, and umbilical cord, among others, and possess various therapeutic actions including anti-inflammatory effects, immune modulation, and tissue repair.
Preclinical (animal) studies and early clinical trials have demonstrated that MSCs can modulate immunity, mitigate inflammation-induced renal damage, and contribute to the preservation and enhancement of renal function.
Characteristics of MSCs Derived from Wharton's Jelly (WJ-MSC)
Among the various MSCs, umbilical cord-derived stem cells (WJ-MSC) are considered the most promising.
WJ-MSCs are cells extracted from the gelatinous tissue known as Wharton's Jelly, found within the umbilical cord that is discarded after birth, and possess the following characteristics:
-
Young and active cells
Because they are derived from newborns, these cells are young, with a higher proliferation capacity than those derived from bone marrow or fat, and greater secretion of growth factors. -
Partially rejected
The antigen expression involved has low immunogenicity, so that when administered to others, it does not easily elicit a rejection reaction. -
Minor Ethical Issue
There is no burden for the donor during collection, and since it is obtained from the umbilical cord, which is naturally discarded after birth, it is a relatively ethically acceptable material. -
Consistent supply is achievable.
Culture and proliferation outside the body are easily performed, and large quantities can be guaranteed, making them suitable for clinical applications.
WJ-MSC, as "readily obtainable, high-quality, and allogeneic cells," emerges as a leading candidate for Stem Cell Therapy for renal failure.
In Japan, several medical facilities have also begun implementing Stem Cell Therapy using WJ-MSC as private treatments, garnering attention as an approach distinct from traditional kidney transplantation.
Key Point
- Stem cell therapy is a form of regenerative medicine that aims to "heal the kidney itself."
- MSC excels in immune modulation, anti-inflammatory properties, and tissue repair, with the potential to improve renal function.
- WJ-MSC are nascent, active, exhibit low immunogenicity, and offer a stable supply.
- As a novel treatment strategy that eliminates the need for donor organs, it can serve as an alternative to renal transplantation.
How Do Stem Cells Work in the Kidneys?
Underlying the effectiveness of Stem Cell Therapy in treating renal failure are the various biological actions demonstrated by MSCs injected into the kidney.
Specifically, Wharton's Jelly-derived Mesenchymal Stem Cells (WJ-MSCs) are reported to possess actions that "suppress inflammation, protect cells, and initiate repair," thereby addressing the root cause of renal damage.
Below, its main actions are explained from three perspectives.
Resolving Inflammation: Immune Modulation and Anti-inflammatory Actions
The progression of chronic kidney disease and kidney failure is closely related to excessive inflammatory reactions and immune abnormalities.
MSC acts as a brake for this "runaway immunity" and makes the following adjustments:
- Suppressing the activity of pro-inflammatory immune cells such as T cells and macrophages.
- Reducing the release of inflammatory cytokines (e.g., IL-6, TNF-α)
- Preventing apoptosis (programmed cell death) and suppressing tissue destruction.
In this way, MSCs contribute to halting the damage caused by renal inflammation and establishing a quiescent environment conducive to repair.
Protecting Renal Tissue: Repair Support and Anti-Fibrosis
When the kidney is damaged, over time, the area is replaced by hard scar tissue (fibrotic tissue). This means an irreversible decline in kidney function.
MSC takes the following actions regarding this development:
- Releasing growth factors (e.g., VEGF, HGF, IGF-1) and promoting blood vessel regeneration (angiogenesis).
- Promoting the survival and proliferation of damaged cells.
- Secreting anti-fibrotic cytokines (inhibiting TGF-β, among others).
This enables an approach to "prevent fibrosis and preserve native functional renal tissue."
Protection from Oxidative Stress: Antioxidant Activity
In chronic kidney disease, oxidative stress due to reactive oxygen species (ROS) is also a cause of cellular damage. MSCs promote the production of antioxidant substances and bolster cellular defenses.
Specifically, the exosomes (extracellular vesicles) released by umbilical cord-derived WJ-MSCs contain numerous molecules that suppress the production of reactive oxygen species, and it has been confirmed in animal experiments that oxidative stress is suppressed and renal cells are protected.
What is the Secretome? - The Identity of Stem Cell-Derived Bioactive Factors
The majority of the effects of Stem Cell Therapy on the kidneys are not due to the MSCs themselves differentiating into kidney cells. Rather, various factors secreted by MSCs act on kidney cells, functioning through paracrine mechanisms that promote self-repair.
This collection of secreted factors is referred to as the secretome.
The secretome comprises the following components:
- Cytokines and growth factors (HGF, VEGF, IL-10, etc.)
- Anti-inflammatory and anti-fibrotic molecules
- Small extracellular vesicles (such as exosomes)
In essence, MSCs serve as a biological manufacturing unit, delivering the necessary therapeutic agents for regeneration to the compromised renal environment.
Key Point
- MSC suppresses dysregulated immune responses and alleviates renal inflammation.
- Promotes the repair of damaged cells and protects tissues by preventing fibrosis.
- Combat oxidative stress and reduce renal cell death.
- The primary action is based on the paracrine effect by the secretome.
Is Kidney Failure Reversible? Prospects Revealed Through Stem Cell Therapy
Confirmed renoprotective effects in animal models
In animal model studies where nephritis or renal failure was induced, numerous instances have been reported where MSC administration suppressed inflammation and fibrosis, and both renal structure and function improved.
Visible Signs of Improvement in Clinical Trials
In a randomized controlled trial targeting diabetic nephropathy, allogeneic MSCs were administered once intravenously to patients with moderate to severe CKD. Compared to the placebo group, the following trends were observed:
- At 12 weeks post-administration, eGFR demonstrated an average improvement of +4 mL/min/1.73㎡.
- The placebo group demonstrated a decrease in eGFR.
- Potential cessation of functional decline
- No serious side effects have been reported in association with the administration.
Examples of Clinical Improvement in Patients with End-Stage Kidney Disease
In the case of a 70-year-old male (CKD Stage V) who received an intravenous infusion of Wharton's Jelly-derived stem cells (WJ-MSC), the following improvements were observed within 4 months of treatment:
- eGFR: 12.5 → 16.4 mL/min (Stage V → Stage IV)
- Creatinine decreased from 4.7 to 3.9 mg/dL.
- BUN: Improving trend
- QOL Score (patient-reported symptoms and quality of life): Significant improvement
Consequently, Stem Cell Therapy not only mitigates disease progression but also demonstrates tangible potential for restoring renal function.
Key Point
- MSC demonstrates inhibition of renal inflammation, reduction of fibrosis, and restoration of function in animal experiments.
- Preliminary clinical trials also confirmed an improving trend in eGFR and safety.
- Cases of end-stage renal disease (ESRD) have also demonstrated sufficient improvement to delay dialysis.
- Stem cell therapy is receiving attention as a novel approach that could restore renal function.
Is Stem Cell Therapy Safe? Verification of Side Effects and Their Potential
Due to the novelty of the therapy, its safety was a frequent subject of inquiry. However, across the conducted research and clinical trials, no significant adverse events were reported in a substantial number of patients.
Negligible side effects upon administration.
For instance, in a clinical trial targeting diabetic nephropathy, allogeneic MSCs were administered once intravenously, and no serious treatment-related adverse events were observed. Notably, anti-HLA antibodies (a marker of transplant rejection) were not detected in patients receiving the treatment. This suggests the potential that even allogeneic cells may not elicit a rejection reaction and can function safely within the body.
Similarly, in cases of end-stage renal failure utilizing Wharton's Jelly-derived WJ-MSCs, an excellent safety profile was observed. Following intravenous infusion, no fever or allergic reactions were noted, and the treatment course was completed without complications.
Mild side effects may occur temporarily.
Generally, the reported side effects are the following mild ones:
- Mild fever
- Transient blood pressure fluctuations
- Discomfort or pain at the injection site
These are transient and typically resolve naturally within a few days. Furthermore, due to MSCs' inherent immunomodulatory properties, severe hypersensitivity reactions, such as anaphylaxis, are rare.
Area Requiring Further Verification
Conversely, given its relatively brief history as a therapy, the following points warrant careful future scrutiny:
- The impact of repeated and sustained administration.
- Safety during application for elderly or bariatric patients.
- Risk identification of side effects through long-term monitoring
Currently, the primary evaluation focuses on safe treatment methods with minimal serious side effects; however, further data accumulation is anticipated in the future.
Key Point
- In MSC therapy, virtually no serious adverse events have been reported post-administration.
- Even when derived from another individual, rejection reactions are not readily induced, and immunological safety is high.
- Should side effects occur, they are typically mild, such as a low-grade fever and injection site discomfort.
- Moving forward, it will be necessary to further verify the safety of ongoing administration, particularly in severe cases.
Conclusion: The Future Ushered In by Stem Cells
For patients confronting the reality of renal failure, the prospect of avoiding dialysis holds the utmost significance.
Regenerative medicine, utilizing mesenchymal stem cells, particularly Wharton's Jelly-derived MSCs (WJ-MSCs), is progressively transforming that hope into a reality.
It is currently offered by several medical facilities as part of private treatment. However, both domestic and international studies consistently report positive outcomes, including improvements in renal function, symptom relief, and a high safety profile.
Previously, when renal function had significantly deteriorated, the only options were dialysis or transplantation. However, with the advent of Stem Cell Therapy, the option to "cure the kidney" has finally become viable.
With the advancement of stem cell research, the phraseDon't give in to kidney failureno longer empty theory, but a real practical guide for living in the future.
- Utsunomiya Memorial Hospital "Chronic Kidney Disease" (2024) Information about CKD patient trends in Japan.
Chronic Kidney Disease, Utsunomiya Hospital - Tokyo Prefecture Okumura Hospital "Regarding Kidney Transplantation" (2020) Statistical source on the number of kidney transplant and dialysis patients.
About Renal Transplantation | Okumura Hospital - Eirin A.E. (2014) "Treatment of Chronic Kidney Failure with MSC" A review on the renal protective actions of MSC.
Stem Cell Research and Therapy - Zhang G. (2014) "Antioxidant Action of MSC Microvesicles" Research in a rat renal ischemia model.
PLOS One - Eleuteri S. (2019) "Possible Applications of MSC Secretome" Describes actions by MSC secretory factors.
International Journal of Molecular Sciences - Packham D.K. (2016) "Clinical Trial of MPC Therapy" Preliminary study of MSC treatment for diabetic nephropathy.
EBioMedicine - Habiba U.E. (2024) "WJ-MSC Case Report" Demonstrates improvement in renal function in patients with end-stage renal failure.
F1000Research