Exploring Rapamycin with RENOLOGY

by Robin Rose MD 4/10/25

Because CKD is a progeric condition ( which means accelerated aging) the world of longevity medicine has great appeal.

There’s current excitement about RAPAMYCIN and its mTOR inhibition - doctors and patients want it.

Recently I’ve seen some suggestions that prolonged inhibition of mTOR may not be the best route to kidney success —::> and in fact rapamycin may have negative potential effects in general.

I have gathered some info and some thoughts to share.- because choosing wisely is what we do.

🔆FIRST what is mTOR🔆

The mTOR (mechanistic target of rapamycin) pathway is a central regulator of cell growth, proliferation, and metabolism.

In CKD, dysregulation of this pathway can lead to fibrosis, glomerular hypertrophy, inflammation, and cystic kidney disorders.

Research has shown that targeted inhibition of mTOR—particularly mTORC1—offers renal-protective effects in specific disease contexts.

🔆Benefits of mTOR Inhibition in CKD 🔆

1. Slowing CKD Progression

🧬 mTOR contributes to CKD progression by promoting mesangial cell proliferation and tubular hypertrophy.

🧬 Rapamycin has been shown to reduce proteinuria and renal injury in multiple models.[Lieberthal, W., & Levine, J. S. (2009). JASN, 20(12), 2431–2436.]

2. Inhibiting Renal Fibrosis

🧬mTOR inhibitors can downregulate TGF-β1 and reduce extracellular matrix accumulation —::> mitigating tubulointerstitial fibrosis. [Chao, C. T., et al. (2021). IJMS, 22(18), 10084.]

3. Modulating Autophagy and Cellular Senescence

🧬 mTOR inhibition activates autophagy [protective in tubular cells under oxidative stress].

🧬 It also suppresses senescence pathways [exaggerated in aging kidneys]. [Ma, M. K. et al. (2018). Transplantation, 102(2), S7–S15]

4. Therapy in Polycystic Kidney Disease (PKD)

🧬mTOR inhibitors slow cyst growth in autosomal dominant PKD (ADPKD).

🧬 therapeutic efficacy is modest unless started early [Torres, V. E., et al. (2010). CJASN, 5(7), 1330–1339]

5. Reducing Ischemia-Reperfusion Injury

🧬rapamycin reduces apoptosis, inflammation, and p53 expression after acute kidney injury (AKI) [relevant in acute-on-CKD events] [Apoptosis, 15(9), 1211–1221]

6. Other miscellaneous benefits

🧬Podocyte preservation—::> Prevents podocyte hypertrophy and loss

🧬Oxidative stress —::> Reduces ROS and mitochondrial dysfunction

🧬Glomerular sclerosis —::> Inhibits ECM deposition and mesangial expansion

Much of research focuses on inhibiting the mTOR pathway to slow CKD progression,

👉🏿BUT—::> it’s important to recognize that mTOR activity is ::not inherently bad :: in fact, basal and regulated mTOR signaling is essential for kidney development, nephron maintenance, and recovery from acute injuries.

Dysregulation —not simple activation— is the real issue in pathology.

🔆Exploring mTOR’s Benefits in Kidney🔆

The mTOR pathway, especially its two complexes (mTORC1 and mTORC2), supports renal homeostasis in several critical ways:

1. mTORC1 Supports Tubular Recovery Post-Injury

🧬 basal mTORC1 signaling is needed for normal tubular cell metabolism

🧬complete inhibition impairs renal repair after ischemic injury. [Grahammer F, et al. (2021)]

2. mTORC2 Maintains Glomerular Barrier Integrity

🧬mTORC2 regulates cytoskeletal stability in podocytes, reducing glomerular leakiness and proteinuria in early CKD. [Huynh C. et al., (2023)]

3. Nephron Development Requires mTOR Signaling

🧬 mTOR is vital during kidney organogenesis, influencing nephron endowment and long-term renal function. [_Rogers N.M. et al. (2016)]

4. Metabolic Adaptation in CKD

🧬mTOR activity is linked to metabolic reprogramming in CKD model —::> this allows adaptive energy responses and reduces cell death.

[Zhu Z. et al. (2022)].

5. Cell Growth & Nutrient Sensing

🧬mTOR mediates amino acid sensing and regulates glomerular cell hypertrophy in a controlled manner, supporting glomerular function. [Chao, CT et al. (2021)]

6. Beneficial Functions of mTOR in the Kidney

   🧬Cytoskeletal integrity in podocytes —::> mTORC2 promotes actin stability, key to glomerular filtration

   🩺mTORC2 Maintains Glomerular Barrier Integrity —::> regulates cytoskeletal stability in podocytes, reducing glomerular leakiness and proteinuria in early CKD. [Huynh C. et al., (2023)]

🔆SO WHAT TO THINK ABOUT USING RAPAMYCIN OR NOT IN CKD 🔆

The mTOR pathway is essential for kidney health —::> it plays pivotal roles in development, cell survival, and recovery.

—::> Complete inhibition of mTOR can be harmful. particularly during repair or in aging kidneys.

🌈AGAIN—::> modulating rather than suppressing mTOR is a more appropriate strategy in CKD management🌈

🔆mTOR Pathway in EARLY Stage 2 CKD: Beneficial Roles in Tubular Health and Function🔆

In stage 2, mTORC1 and mTORC2 are not yet overactivated —::> they play a protective metabolic role in tubular energy maintenance and electrolyte transport. —::> Suppression at this stage may be counterproductive unless there is pathological overactivity.

🧬While hyperactivation of the mTOR pathway is implicated in CKD progression, evidence shows us that physiological levels of mTOR signaling [especially in stage 2 ] are beneficial for tubular repair, energy metabolism, and epithelial cell integrity.

🧬In early CKD, regulated mTOR activity in tubular epithelial cells helps prevent maladaptive responses and promotes cellular survival and adaptation.

🌈The tubules are where the action is in stage 2! 🌈

🧬mTOR Maintains Electrolyte and Solute Reabsorption. —::> mTORC1 regulates the expression of transporters in the proximal tubule (e.g., NHE3, Na+/K+ ATPase), ensuring electrolyte homeostasis during mild dysfunction. [ Grahammer & Huber (2021)]

🧬In early CKD, mTOR supports selective autophagy to remove damaged organelles while preserving energy production—critical for ATP-demanding tubule cells. [ Lin et al. (2019)]

🧬Prevents Early EMT and Fibrotic Transition

—::> Moderate mTOR signaling maintains epithelial integrity and prevents tubular epithelial cells from undergoing partial epithelial-mesenchymal transition (EMT)—a precursor to fibrosis. [Chao et al. (2021)]

🧬Supports Mitochondrial Biogenesis in Tubular Cells —::> mTORC1 facilitates PGC-1α-dependent mitochondrial generation in tubular cells [a mechanism that’s protective against hypoxic damage in early CKD]. [Zhu et al. 2022]

🔆Rapamycin Can Hurt CKD - Key Adverse Effects🔆

Although rapamycin (sirolimus) and other mTOR inhibitors offer therapeutic potential in CKD, especially for slowing fibrosis or treating polycystic kidney disease, they can exacerbate or contribute to renal dysfunction under certain conditions—especially when used inappropriately or without mindful patient selection.

1. Proteinuria Aggravation

🧬One of the most consistent adverse effects is the exacerbation of proteinuria —::> especially in patients with preexisting glomerular damage.

🧬Rapamycin interferes with podocyte homeostasis and slit diaphragm structure, potentially increasing albuminuria. [Zaza et al. (2013)]

2. Delayed Renal Repair & Tubular Recovery

🧬 In acute or early-stage CKD, rapamycin may inhibit the regeneration of tubular epithelial cells [especially when repair requires mTORC1 activity]

🧬This can delay recovery from ischemia-reperfusion injury or nephrotoxic insults [ Rogers et al. (2016)]

3. Endothelial effects

🧬 Rapamycin can inhibit endothelial cell proliferation [needed for glomerular repair, especially post-injury]

🧬This can lead to capillary dropout —::> worsening hypoxia and chronic progression. [Huber & Grahammer (2011)]

5. Dose-Dependent Toxicity

🧬 Adverse effects are strongly dose-dependent.

🧬Low-dose rapamycin (e.g., <2 mg/day) in pilot studies showed fewer renal complications -::> standard/high doses were associated with GFR decline. [Schold et al. (2014)]

6. Additional concerns

   🧬Hyperlipidemia -::> Elevates CV risk in a high-risk group

   🧬Impaired wound healing -::> Especially problematic in diabetics

   🧬Mouth ulcers, skin rashes -::> Common and dose-limiting

   🧬Anemia and leukopenia -::> Can exacerbate CKD-related cytopenias

🔆A DEEPER DIVE INTO mTOR & TUBULES🔆

🔆mTOR–AMPK–PGC-1α Signaling 🔆

1. Baseline (Healthy State)

🧬mTORC1: Promotes protein synthesis, cell growth, and mitochondrial biogenesis (mild).

🧬 AMPK: Energy sensor—keeps mTOR in check; promotes autophagy and FA oxidation.

🧬PGC-1α: Drives mitochondrial biogenesis, antioxidant defense.

2. CKD Stage 2–3 (Mild to Moderate Injury)

🧬mTORC1 (moderate activation): Supports tubular repair, transport protein expression (ie NHE3).

🧬 AMPK (downregulated in metabolic syndrome): Reduced fatty acid oxidation and mitochondrial repair.

🧬 PGC-1α (partially suppressed): Leads to early mitochondrial dysfunction and oxidative stress.

3. Stage 4–5 CKD and Tubular Pathology

🧬 hyperactivation of mTORC1 in tubular epithelial cells (TECs) accelerates renal fibrosis, tubular atrophy, and epithelial-to-mesenchymal transition (EMT)

🧬 mTOR influences glycolytic shifts, cellular senescence, and maladaptive repair, particularly under hypoxic and inflammatory conditions typical in late-stage CKD.

🧬 But —::> complete suppression of mTOR impairs tubular regeneration and homeostasis.

🧬 Thus, stage-specific modulation is key to therapeutic targeting.

🔆MONITORING🔆

🧬Monitoring rapamycin therapy in CKD requires a targeted lab panel and clinical vigilance

🧬dosing needs to balance mTOR modulation without worsening kidney function, lipids, or immune suppression.

Testing

✔️Serum Creatinine & eGFR

Baseline, then every 2–4 weeks

Detect renal toxicity, dose-related decline

✔️Urine Protein-to-Creatinine Ratio (UPCR)

Baseline, monthly

Monitor worsening proteinuria (if >0.5 g/day)

✔️CBC (WBC, Platelets, Hemoglobin)

Baseline, then monthly

Detect cytopenias

(anemia, leukopenia, thrombocytopenia)

✔️Liver Function Tests (ALT, AST)

Every 1–2 months

Detect hepatic metabolism abnormalities

✔️Lipid Profile (LDL, HDL, TG)

Every 6–8 weeks initially

Rapamycin frequently raises LDL and triglycerides

✔️Blood Glucose/HbA1c

Every 3–6 months

Monitor for insulin resistance, esp in diabetics

✔️C-reactive protein (optional)

Baseline and PRN

Track low-grade inflammation

Track unexpected systemic responses

✔️Rapamycin Trough Level (ng/mL)

Target: 3–6 ng/mL (low dose CKD)

>8–12 ng/mL only in transplant

🔆Red Flags for Immediate Dose Adjustment or Discontinuation🔆

🧬 Proteinuria increase >50% from baseline

🧬 Serum creatinine rise >30% within 2 weeks

🧬New-onset hyperlipidemia requiring statin

🧬Mouth ulcers, rash, poor wound healing

🧬 Platelet count <100k or WBC <3.5k

🔆Rapamycin Side Effects in CKD 🔆

🧬Renal & Metabolic

• Worsening proteinuria

• Elevated serum creatinine (in susceptible patients)

• Hyperlipidemia (↑ LDL, triglycerides)

• Hyperglycemia / insulin resistance

🧬Hematologic

• Anemia

• Leukopenia / neutropenia

• Thrombocytopenia

🧬Dermatologic / Mucosal

• Mouth ulcers (aphthous)

• Delayed wound healing

• Skin rash or acneiform lesions

🧬Gastrointestinal

• Nausea, diarrhea, abdominal discomfort

🧬Infectious Risk

• Increased susceptibility to infections

(especially viral and fungal)

🧬Pulmonary

• Non-infectious pneumonitis (rare but serious)

🧬Other

• Fatigue

• Headache

• Menstrual irregularities

• Poor surgical recovery

🌈Be aware 🌈

🌈Be prepared🌈

🔆 Options other than Rapa for CKD 🔆

✔️Rapamycin isn’t the only way to tap into mTOR’s regulatory network.

For CKD patients at risk of rapamycin-related toxicity, we can consider AMPK activators (ie. metformin, berberine), antioxidants, or senolytics that indirectly target the same stress pathways —::> but with fewer renal side effects.

🧬Metformin

Activates AMPK → inhibits mTOR

Reduces fibrosis, improves autophagy

🧬Berberine

AMPK activator, antioxidant

Protects mitochondria in DN, CKD models

🧬Resveratrol

SIRT1 activation → inhibits mTOR indirectly

Lowers inflammation in renal tissue

🧬Curcumin

Downregulates mTOR and TGF-β

Anti-fibrotic and antioxidant

🧬Spermidine

Autophagy enhancer, mTORC1 modulator

Improves renal aging and mitochondrial health

🔆Mitochondria- targeting 🔆

🧬MitoQ

Mitochondrial antioxidant

Reduces renal oxidative damage

🧬Coenzyme Q10 (ubiquinone)

Electron transport & redox support

Used in diabetic nephropathy

🔆Senolytics🔆

🧬Fisetin

Clears senescent cells (early research in ckd)

🧬Quercetin + Dasatinib

Senolytic combo (early ) trials in fibrosis

🔆Indirect bioregulators🔆

🧬Melatonin

mTOR modulation via circadian and antioxidant pathways —::> May support kidney repair

🧬Oxytocin (peptide hormone)

Regulates Akt/mTOR balance in stress and inflammation —::> Kidney injury models show protective effects

🔆 Peptides and mTOR in CKD🔆

Several peptides and bioregulators can modulate the mTOR pathway [either directly or indirectly] acting on or near the mTOR pathway. These offer options to fine-tune mTOR activity —::> to support repair (mild activation) or reduce chronic overactivation (downregulation). In CKD or aging, this creates a therapeutic niche for balanced mTOR modulation without full inhibition.

1. Peptides That Inhibit or Downregulate mTOR

   
   

   🧬Thynosin beta-4

   Anti-inflammatory, reduces Akt/mTOR activation —::> Wound healing, fibrosis reduction

   
   

   🧬GHK-Cu

   Modulates gene expression; suppresses NF-κB, reducing mTOR indirectly —::> Skin, anti-aging, anti-fibrotic actions

   
   

   🧬Epithalon

   Bioregulator that activated telomerase, may modulate pineal signaling → downregulates mTOR via melatonin axis —::> Longevity peptide; neuroprotective

   
   

   🧬DSIP (Delta sleep-inducing peptide)

   Stress response peptide, may reduce metabolic overactivation of mTOR during inflammation

   —::> Sleep restoration, stress-related mTOR modulation

   
   

   🧬BPC-157

   Gut peptide with systemic anti-inflammatory effects; may indirectly suppress mTOR in chronic injury —::> Gut healing, AKI protection, tissue repair

   
   

2. Peptides That Activate or Support mTOR (Anabolic/Repair Role)

   
   

   🧬CJC-1295 + Ipamorelin

   Long-acting GHRH analogs; downstream mTOR activation —::> Anti-aging, muscle preservation

   
   

   🧬Follistatin peptides

   Myostatin inhibitor → mTOR promotion —::> Enhances muscle protein synthesis

   
   

3. Bioregulators and Epigenetic Peptides

   
   

   🧬These bioregulators normalize gene expression and cellular turnover, —::< with less dramatic mTOR activation/suppression than pharmacologic agents.

   
   

   🧬Vilon (thymic bioregulator peptide)

   May restore mTOR balance via immune normalization —::> Improves immune-tissue interaction

   
   

   🧬Livagen

   Liver-specific bioregulator peptide, with possible epigenetic mTOR modulation —::> Hepatorenal support

   
   

4. Combining Rapamycin with Peptides?

   
   

   🧬Yes, but with caution. Space peptides and rapamycin at least 4–6 hours apart to minimize overlap.

   
   

   🧬Several peptides complement or modulate the mTOR pathway without direct interference [ may even mitigate some side effects of rapamycin when dosed appropriately]

   
   

5. Clinical Strategy for Safe Co-Use

   🧬 Low-dose rapamycin (≤1 mg 2–3x/week) plus regenerative peptides (ie. BPC-157, GHK-Cu, Epitalon) may support:

     Mitochondrial health

    Endothelial function

   Wound repair (which rapa may impair)

    Anti-inflammatory balance

   
   

   🧬Avoid dual stimulation of mTOR (e.g., GHRH + rapamycin) [defeats the purpose].

   
   

🔆CONCLUSION : A Double-Edged Sword🔆

While rapamycin has ✔️anti-fibrotic, ✔️anti-proliferative, and ✔️immunomodulatory benefits -::>

it can be harmful to kidney function in patients with:

🧬Unresolved glomerular injury

🧬 Active tubular stress

🧬 Or when used in non-optimized doses

Personalizing care and renal monitoring are key.

Low-dose, time-limited use may mitigate many risks.

For CKD patients, always using the lowest effective rapamycin dose [and monitoring changes in proteinuria or creatinine] is safest.

There is allot more to learn about this topic- this is a good beginning to initiate the conversation. It is an introductory survey of the landscape - not medical advise - a diving board for further study in the journey and the scavenger hunt for manifesting and enjoying health.

We absolutely have to know the full spectrum of consequences to choose wisely - CKD is a conglomeration of deranged pathways and it is complicated - clinical decision making calls upon us to discover the personalized needs of each patient and know the risks and benefits —::> to keep our eye on the prize of KIDNEY SUCCESS. 🫶🏾