Can nephrons be rejuvenated?

Nephron Rejuvenation: Current Evidence and Possibilities

Currently, nephrons cannot be fully rejuvenated once damaged, but nephron-sparing approaches can preserve existing nephron function and some experimental therapies show promise for partial regeneration.

Current Clinical Approaches to Nephron Preservation

Nephron-Sparing Surgery

• Partial nephrectomy (nephron-sparing surgery) is the preferred approach for treating renal tumors when feasible, particularly for:

  • Small unilateral tumors (T1a and selected T1b)
  • Patients with renal insufficiency
  • Bilateral renal masses
  • Familial renal cell cancer 1

• Nephron-sparing surgery has well-established oncologic outcomes comparable to radical nephrectomy while preserving renal function 1

• When compared with radical nephrectomy, partial nephrectomy achieves:

  • Preserved renal function
  • Decreased overall mortality
  • Reduced frequency of cardiovascular events 1

Optimal Surgical Techniques

• The goals of nephron-sparing surgery should be optimal tumor control while minimizing ischemia time to ideally <30 minutes 1

• Laparoscopic, robotic, and open partial nephrectomy all offer comparable outcomes when performed by skilled surgeons 1

Limitations of Current Approaches

While nephron-sparing approaches help preserve existing nephron function, they do not truly "rejuvenate" damaged nephrons. Once nephrons are damaged beyond a certain point, current clinical medicine cannot fully restore their function.

Key limitations include:

• Nephron formation in humans is limited to embryonic kidney development with no new nephrons formed after birth 2
• Although kidneys possess capacity for self-repair of certain segments, complete nephron loss from acute or chronic injury is generally considered irreversible 2

Experimental Approaches to Nephron Regeneration

Cellular Dedifferentiation

• Research in zebrafish models has shown that 4-(phenylthio)butanoic acid (PTBA), a histone deacetylase inhibitor, enhances renal recovery by:
  • Increasing reactivation of renal progenitor genes
  • Enhancing dedifferentiation of renal tubular epithelial cells
  • Reducing kidney injury markers
  • Lowering inflammatory responses 3

Stem Cell Approaches

• Human pluripotent stem cells (PSCs) show promise for regenerating nephron progenitor cells:
  • Differentiation protocols can generate cells expressing nephron progenitor cell markers
  • These cells can assemble into three-dimensional nephron-like structures 2
  • Both embryonic stem cells and induced pluripotent stem cells are being investigated 4

Reversing Renal Fibrosis

• Degradation of interstitial matrix proteins may be feasible, especially before interstitial scarring becomes highly organized 5
• Removing interstitial myofibroblasts (major source of fibrosis-associated matrix proteins) is another potential approach 5
• Recent advances in matrix biology, developmental biology, angiogenesis, and stem cell research have identified new therapeutic targets 5, 6

Challenges in Nephron Regeneration

The greatest therapeutic challenges include:

1. Inability to regenerate intact functional nephrons where they have been destroyed 5
2. Loss of peritubular capillaries and tubules that underlie declining renal function 5
3. Ensuring long-term maintenance and stability of regenerated cells 4
4. Safety concerns regarding potential tumorigenicity of stem cell-derived tissues 4

Clinical Implications

While complete nephron rejuvenation remains elusive in current clinical practice, several approaches can help preserve kidney function:

1. Prioritize nephron-sparing approaches whenever possible 1, 7
2. Consider partial nephrectomy for small renal tumors to preserve renal function 1, 7
3. Minimize ischemia time during renal surgeries 1
4. Regular monitoring of renal function in patients with kidney disease 7

Future Directions

The successful recreation of human nephrons from pluripotent stem cells would offer a novel therapeutic approach to treating patients with kidney disease 2. Ongoing research focuses on:

• Improving long-term maintenance and stability of regenerated cells 4
• Testing the ability of regenerated cells to integrate into three-dimensional kidney structures 2
• Developing bioengineered structures or scaffolds with appropriate matrix materials 2