Attia says he CURRENTLY is not taking rapamycin
Interesting. Talked about potential kidney damage.
https://x.com/60Minutes/status/1986131399754027316
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He says: “I’m not taking it at the moment, but I’ve taken it on and off…over the past 7 years”
It doesn’t sound like his position on it has changed at all.
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No. But Am surprised that he said last time he took rapa he had terrible mouth sore throughout. The kidney thing so is new.
Also Brad Stanfield’s rapa study should be out any minute now?
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Rapamycin-associated nephropathy; a short look at the new findings
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A summary of the paper and the risks and testing protocol for early identification (though risk is low, and unheard of in health populations doing periodically).
CGPT5.1
Here’s the straight answer, broken into: (1) what this paper actually says, (2) what the broader literature shows about how often kidney problems happen with sirolimus, and (3) how to monitor so you catch trouble early.
1. What the attached paper actually says
Citation: Nasri et al., “Rapamycin-associated nephropathy; a short look at the new findings,” J Ren Endocrinol 2024.
This is a brief narrative review, not original clinical data. It summarizes known kidney toxicity patterns attributed to rapamycin/sirolimus, mainly in transplant and proteinuric kidney disease settings.
Core message
Rapamycin-associated nephropathy (RAN) is described as:
-
Clinical picture
- Proteinuria (can be heavy/nephrotic)
- Decline in glomerular filtration rate (GFR)
- Sometimes acute kidney injury (AKI)
-
Histopathology / lesions described
- Tubulointerstitial damage: interstitial fibrosis, tubular atrophy or dilatation, tubulointerstitial inflammation.
- Glomerular damage: collapsing focal segmental glomerulosclerosis (FSGS) with glomerular tuft collapse and proliferation of podocytes/epithelial cells.
- Cast nephropathy: intratubular cast formation, especially with tacrolimus + rapamycin or in protein-overload conditions.
- Vascular injury: endothelial cell injury, inflammatory cell infiltration, and thrombosis of renal vessels.
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Mechanisms they emphasize
- mTOR inhibition → impaired cell growth and repair → susceptibility to injury.
- Accumulation of autophagosomes in tubular cells → oxidative stress, apoptosis, fibrosis, and tubular atrophy.
-
Risk factors listed
- High dose, long-term use
- Diabetes, hypertension, obesity
- Age >60 years
- Black race
- Pre-existing kidney disease / chronic glomerulopathies
-
Diagnosis / management
- Diagnosis: new or worsening proteinuria + GFR decline; confirmed by biopsy showing interstitial fibrosis & tubular atrophy ± FSGS and casts.
- Management options:
- Dose reduction or discontinuation of rapamycin
- Corticosteroids
- ACE inhibitors / ARBs
- Alternative immunosuppressants
- Prognosis: if not addressed, can progress to end-stage renal disease.
Bottom line from the paper: RAN is real, pathologically distinct (often FSGS-like + cast nephropathy), and strongly linked to high doses, long exposure, and pre-existing kidney vulnerability. But the paper does not provide hard incidence numbers.
2. Kidney risks of rapamycin/sirolimus – and how common they are
Nearly all quantitative data come from transplant / high-dose sirolimus use or from patients with pre-existing glomerular disease. There is essentially no robust incidence data for low-dose, intermittent “longevity-style” rapamycin in people with normal kidneys.
Specific kidney risks (from this paper + broader literature)
- New or worsening proteinuria
- Very consistently reported after conversion to sirolimus in kidney and heart transplant patients.
- Often non-nephrotic, but nephrotic-range proteinuria and full nephrotic syndrome are documented, frequently with collapsing FSGS on biopsy.
- Collapsing FSGS and glomerulosclerosis
- High sirolimus levels have been linked to de novo collapsing FSGS even in patients without prior FSGS or calcineurin nephropathy.
- In patients with existing FSGS, sirolimus therapy has repeatedly been associated with worsening proteinuria and nephrotoxicity, especially when disease is longstanding and proteinuric.
- Acute kidney injury (AKI) and “rapamycin nephrotoxicity” in native kidneys
- Fervenza et al. reported AKI + heavy proteinuria in patients with chronic glomerulopathies started on rapamycin; kidney function improved after stopping the drug in some cases.
- Experimental models show rapamycin can worsen renal function and increase intratubular cast formation in protein-overload nephropathy.
- Delayed graft function / cast nephropathy in transplants
- Delayed graft function with prominent cast nephropathy has been described with tacrolimus + rapamycin.
- Chronic interstitial fibrosis / tubular atrophy and vascular injury
- Chronic sirolimus exposure is linked to tubular atrophy, interstitial fibrosis, glomerulosclerosis, and vascular rarefaction/ endothelial injury – in line with what the review describes as RAN.
How often do these problems actually happen?
Again: these numbers are from transplant/high-dose settings (troughs typically 8–20 ng/mL, often combined with CNIs). Extrapolating them to low-dose longevity dosing is speculative.
2.1 Proteinuria (any degree)
- A systematic review/meta-analysis of 29 RCTs (5,747 kidney transplant recipients) comparing continued calcineurin inhibitor (CNI) vs conversion to mTOR inhibitors (sirolimus/everolimus) showed:
- Relative risk of proteinuria with mTORi ≈ 1.87 (95% CI 1.34–2.59) vs staying on CNI.
- In clinical series of kidney transplant patients switched to sirolimus:
- Incidence of proteinuria varies from ~15% up to >40%, depending on how proteinuria is defined. A review of post-transplant proteinuria notes that when higher thresholds are used, incidence still remains around 10–30%, and is considered “very frequent.”
- One sirolimus-based, CNI-free regimen reported proteinuria in about 7% of patients, but this was a relatively small cohort with careful selection.
- After conversion from azathioprine to sirolimus in renal transplant recipients:
- Mean 24 h protein excretion rose from 0.37 ± 0.34 g/day to 1.81 ± 1.73 g/day at ~1 year.
- All seven patients who already had proteinuria worsened; none with zero baseline proteinuria developed new proteinuria in that small cohort.
Takeaway: In transplant/high-dose settings, roughly 15–40% of patients will develop some degree of new or worsened proteinuria after switching to sirolimus, especially if they already had proteinuria or CKD.
2.2 Nephrotic-range proteinuria / collapsing FSGS
- Case series of de novo nephrotic syndrome and collapsing FSGS on sirolimus exist, but numbers are small (e.g., three clearly documented patients with high sirolimus troughs and no prior FSGS/CAN in Letavernier et al.).
- In larger series and RCTs, nephrotic-range proteinuria is uncommon but significant – typically a small subset of the 15–40% who develop any proteinuria. Many reports are case series rather than precise incidence estimates.
A reasonable practical ballpark from the literature:
- Any proteinuria: ~15–40%
- Nephrotic-range / FSGS-type lesions: probably <5–10% in high-risk, transplant-type populations, but exact numbers are not well quantified.
2.3 Acute kidney injury (AKI) and overt “rapamycin nephrotoxicity”
- AKI with rapamycin in native kidneys (chronic glomerulopathy patients) is described mainly as small case series – clear signal, but rare relative to total sirolimus exposure.
- In the big meta-analysis, mTORi regimens overall did not show a major increase in graft loss or death vs CNIs, but had higher discontinuation rates due to adverse events, with proteinuria being one of the prominent reasons.
2.4 Key modifiers of risk
Across the data:
- Pre-existing proteinuria / CKD strongly predicts bad outcomes after switching to sirolimus. Patients with baseline proteinuria <~800 mg/day have a much better chance of improved function; above that threshold risk increases substantially.
- Older age, diabetes, hypertension, obesity, Black race, and pre-existing glomerular disease all show up repeatedly as risk factors – in line with the paper’s list.
- Combination with calcineurin inhibitors (cyclosporine/tacrolimus) and high sirolimus trough levels clearly amplify nephrotoxicity. Rapamune’s own label explicitly warns about decline in renal function when combined with cyclosporine and recommends close monitoring.
3. Practical testing / monitoring protocol to catch kidney issues early
This is the part you actually care about in a longevity or off-label context.
Important caveat: all formal guidance comes from transplant and CKD practice, not from low-dose, intermittent rapamycin in otherwise healthy people. Below is a conservative, safety-oriented monitoring scheme derived from:
- KDIGO 2024 CKD guidelines on eGFR and albuminuria monitoring.
- Drug labeling for Rapamune, which stresses renal function monitoring, especially with cyclosporine.
- The risk profile described in the attached paper and mTORi trials.
3.1 Before starting rapamycin
Baseline work-up (non-negotiable if you’re being serious about risk control):
- Serum labs
- Serum creatinine → calculate eGFR (CKD-EPI 2021).
- Optional but useful: cystatin C to confirm GFR if borderline.
- Electrolytes, fasting glucose, HbA1c, lipids (rapa impacts metabolic status).
- Urine
- Spot urine albumin-to-creatinine ratio (uACR) .
- Spot urine protein-to-creatinine ratio (uPCR) if available.
- Basic urinalysis with dipstick and microscopy (look for protein, blood, casts).
- Blood pressure
- Home BP (morning + evening) for at least a week to establish baseline.
- Risk stratification
- High-risk if:
- eGFR <60 (CKD G3+)
- uACR ≥30 mg/g (albuminuric)
- Diabetes, uncontrolled hypertension, obesity, age >60, Black race
- Any known primary glomerular disease
If someone already has significant proteinuria (e.g., ≥800 mg/day equivalent) or clear CKD, conversion data strongly suggest they are poor candidates for mTORi monotherapy; nephrology input is mandatory.
3.2 Early monitoring after starting rapamycin
Goal = catch new proteinuria or a GFR drop early, before you’re stuck with irreversible fibrosis.
A cautious schedule for a non-transplant, off-label setting:
-
At ~4 weeks after starting or changing dose
- Serum creatinine & eGFR
- uACR ± uPCR
- Urinalysis
- BP check (clinic or well-documented home logs)
- Repeat at 3 months Same panel as above.
- For high-risk patients (any CKD, diabetes, HTN, strong family history, etc.), I’d treat it like a nephrotoxic drug:
- Check monthly for first 3 months, then space out if rock-stable.
3.3 Ongoing long-term monitoring (if stable)
If things look clean after the first 3–6 months:
-
Every 6–12 months :
- Serum creatinine/eGFR
- uACR (± uPCR)
- Urinalysis
- BP
- This is stricter than KDIGO’s minimum of annual eGFR + albuminuria for CKD patients, and more aligned with drug-toxicity monitoring.
3.4 “Red flag” thresholds – when to worry and what to do
These are practical triggers that should prompt immediate reassessment of rapamycin and ideally a nephrology consult:
- New proteinuria
- uACR rises from <30 mg/g → ≥30 mg/g on repeat testing, especially if:
- It continues to rise on repeat within a few weeks, or
- uACR ≥300 mg/g or uPCR suggests ≥0.5–1 g/day protein.
- Any nephrotic-range signal (uPCR ≈ >3.5 g/day equivalent, or dipstick 3+ with edema, low albumin, hyperlipidemia) is an emergency-level red flag.
- GFR decline
- KDIGO 2024 suggests any >30% drop in eGFR within 3 months after starting a new agent should trigger evaluation.
- For rapamycin specifically, I’d be very cautious with:
- ≥20–30% fall in eGFR vs baseline, sustained on repeat.
- Or an AKI pattern (rise in creatinine ≥0.3 mg/dL within 48 h or 1.5× baseline within 7 days).
- Unexpected hypertension or edema
- New or worsening BP, especially alongside proteinuria, fits an FSGS / nephrotic picture.
Immediate steps when you hit one of these:
- Repeat labs quickly (within 1–2 weeks, or sooner if AKI suspected).
- Review:
- Rapamycin dose and trough levels (if available).
- Concomitant nephrotoxins (NSAIDs, CNIs, contrast, etc.).
- Volume status and BP control.
-
Strongly consider holding or reducing rapamycin while evaluating, especially if:
- Nephrotic-range proteinuria,
- Rapid eGFR drop, or
- Clear AKI pattern.
- If abnormalities persist or are severe → kidney biopsy to differentiate RAN (collapsing FSGS / cast nephropathy / interstitial fibrosis) from other causes.
3.5 Simple “monitoring protocol” summary
If you want a short, operational checklist:
Before rapa
- Creatinine + eGFR, ± cystatin C
- uACR ± uPCR + full urinalysis
- BP profile
- Flag CKD/proteinuria/diabetes/HTN/age>60/Black race
After starting / dose change
- Labs at 4 weeks: creatinine/eGFR, uACR/uPCR, urinalysis, BP
- Labs at 3 months
- If high-risk: labs monthly for first 3 months
Long-term if stable
- Creatinine/eGFR + uACR and urinalysis every 6–12 months
- BP at every clinical touchpoint or via home monitoring
Stop / reduce & call nephrology if:
- New persistent proteinuria (uACR ≥30 mg/g rising on repeat)
- uACR ≥300 mg/g or uPCR suggesting ≥0.5–1 g/day
- eGFR drop ≥30% from baseline within a few months
- Any AKI or nephrotic syndrome picture
Reality check
- The kidney toxicity signal is real, but it has been documented almost entirely at higher, continuous immunosuppressive doses, often in conjunction with CNIs or on background CKD/proteinuria.
- For low-dose intermittent “longevity” use in people with normal kidneys , we simply do not have robust, long-term incidence data – so the safest assumption is: treat it like a drug that can unmask or worsen subclinical kidney disease, and watch the kidneys properly.
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My kidneys are in great shape after 2-3 years of weekly Rapamycin dosing. My eGFR is 108.
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Yes, research says it repairs gonads and kidneys. Certainly, issues would be noted in kidney/organ recipients after past decades of use.
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The key here is that mTOR does good things as well as bad ones. Hence the lowness of the trough is a positive.
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