a) What is stem cell? Discuss its role in regeneration of failing kidney. [5] b) Briefly discuss present status of immuno-tolerance in kidney transplantation. [5]
Definition
Stem cells are undifferentiated cells capable of self-renewal and differentiation into specialized cell types, playing a key role in tissue repair and regeneration (Harrison's 21e, Ch. 265).
Etiopathogenesis
In kidney injury, loss of functional nephron units triggers endogenous repair mechanisms. Stem cells contribute by homing to injured sites, differentiating into renal tubular epithelial cells, podocytes, or endothelial cells, and secreting paracrine factors that modulate inflammation and fibrosis. Various types include:
| Stem Cell Type | Source | Role in Kidney Regeneration |
|---|---|---|
| Mesenchymal Stem Cells (MSCs) | Bone marrow, adipose tissue | Anti-inflammatory, anti-fibrotic, differentiate into renal lineages |
| Hematopoietic Stem Cells (HSCs) | Bone marrow | Mainly immunomodulation and repair via paracrine effects |
| Induced Pluripotent Stem Cells (iPSCs) | Reprogrammed somatic cells | Potential for generating all nephron components in vitro |
| Renal Progenitor Cells | Resident renal tubular cells | Intrinsic regeneration of tubular epithelium following injury |
(Harrison's 21e, Ch. 265; Brenner & Rector's The Kidney, 11th edition)
Clinical Features
No direct clinical features of stem cells; their application is experimental in conditions like chronic kidney disease (CKD) or acute kidney injury (AKI).
Diagnosis
Assessment involves experimental biomarkers and imaging to evaluate renal function improvement post-stem cell therapy; no standard diagnostic criteria.
Management
Stem cell therapy is investigational. Approaches include:
- Autologous or allogenic MSC infusion via intravenous or intra-arterial routes.
- Pre-clinical and Phase I/II trials showing safety and preliminary efficacy in AKI and CKD.
- Challenges include cell homing efficiency, differentiation control, and immunogenicity.
(Harrison's 21e, Ch. 265)
Recent Advances
- Use of iPSCs to generate kidney organoids for modeling diseases and personalized therapy.
- Combination therapies integrating stem cells with biomaterials for enhanced renal repair.
- Genetic modification of stem cells to improve engraftment and anti-fibrotic effects.
- Ongoing clinical trials exploring MSCs in diabetic nephropathy and AKI (recent 3-5 years).
(Harrison's 21e, Ch. 265; Brenner & Rector's The Kidney, 11th edition)
Key Points for Exam
- Define stem cells: self-renewal and differentiation.
- Types of stem cells relevant to kidney regeneration (MSC, HSC, iPSC, renal progenitors).
- Mechanisms: differentiation + paracrine anti-inflammatory and anti-fibrotic effects.
- Current status: experimental with ongoing clinical trials.
- Potential future therapies include kidney organoids from iPSCs.
Definition
Immuno-tolerance in kidney transplantation refers to a state where the recipient's immune system accepts the allograft without continuous immunosuppression (Harrison's 21e, Ch. 277).
Etiopathogenesis
Tolerance involves complex immunological mechanisms:
| Mechanism | Description |
|---|---|
| Central Tolerance | Deletion of donor-reactive T cells in thymus |
| Peripheral Tolerance | Regulatory T cells (Tregs) suppress alloreactive T cells |
| Chimerism | Mixed donor-recipient hematopoietic cell populations promoting tolerance |
| Clonal Anergy/Exhaustion | Functional inactivation or deletion of reactive clones |
Immunosuppressants block effector responses but do not induce true tolerance (Harrison's 21e, Ch. 277).
Clinical Features
Tolerance allows stable graft function without rejection or immunosuppression-related toxicity.
Diagnosis
Operational tolerance is retrospectively diagnosed by stable graft function after immunosuppressant withdrawal, absence of donor-specific antibodies (DSA), and immune monitoring. Biomarker panels under study include:
| Biomarker Category | Examples | Clinical Utility |
|---|---|---|
| Cellular markers | Increased Tregs, Tr1 cells | Predict tolerance |
| Molecular signatures | Regulatory gene expression | Emerging diagnostic tools |
| DSA Detections | Negative or low DSA | Indicates low immunologic risk |
(Harrison's 21e, Ch. 277)
Management
- Standard immunosuppression remains the norm.
- Experimental protocols:
- Hematopoietic stem cell transplantation with non-myeloablative conditioning to induce chimerism.
- Use of Treg cell adoptive therapies.
- Costimulatory blockade agents (abatacept, belatacept) facilitate tolerance.
- Immunosuppression minimization or withdrawal attempted in select stable patients within clinical trials.
Recent Advances
- Successful induction of mixed chimerism using combined kidney and bone marrow transplantation in select centers (e.g., Stanford protocol).
- Enhanced understanding of Treg biology as a cellular therapy.
- Development of non-invasive immune monitoring assays to identify tolerant patients.
- Use of costimulation blockade agents improving long-term graft survival with lower toxicity.
(Harrison's 21e, Ch. 277)
Key Points for Exam
- Definition of immuno-tolerance: graft acceptance without immunosuppression.
- Central and peripheral mechanisms with emphasis on Tregs and chimerism.
- Operational tolerance diagnosed clinically and via biomarkers.
- Current experimental induction strategies: mixed chimerism, Treg therapy, costimulatory blockade.
- Routine clinical use limited; immunosuppression is standard of care.
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