mTOR inhibitors (everolimus · temsirolimus)
mTOR inhibitor
Podocyte injury → proteinuria and FSGS.
GLOMATN
Mild82% phenotype match
mTOR inhibitor
Temsirolimus
Torisel · TEM
mTOR inhibitor · approved 2007 · 8 citations
Dated evidence· through 2016
Emerging evidence4/9 · 5 signals▾
- 8 citations
- Deep literature (12+ refs)
- Accrued over 9+ years
- Beyond single case reports
- High-impact journal
- Landmark reference
- Registrational / key trials
- Current through 2016
- Real-world FAERS signal
Grades the strength of the evidence base (volume, journal quality, landmark trials, recency, real-world corroboration) — not the drug's severity. A rule-based summary, not a formal certainty appraisal.
The IV rapalog whose kidney signal is podocyte proteinuria — real for the class, thinly quantified for the drug.
MildmTOR inhibitor
Advanced (poor-prognosis) renal cell carcinomaRelapsed/refractory mantle cell lymphoma (EU approval)
§01
Signature kidney injury
Signature lesion
Not firmly quantified for temsirolimus specifically. Proteinuria is the recognized mTOR-inhibitor glomerular signal, but for temsirolimus it is documented mostly at the class/case level rather than in drug-specific renal endpoints (everolimus proteinuria runs high yet is usually grade 1-2 — e.g., 96% all-grade in one first-line mRCC cohort). In the pivotal temsirolimus ARCC trial, metabolic lab abnormalities (hyperglycemia, hyperlipidemia, hypophosphatemia) dominated and frank nephrotoxicity was uncommon; drug-specific AKI and nephrotic syndrome appear only in case reports.Source: Not firmly quantified for temsirolimus; class/context from Land et al., J Oncol Pharm Pract 2014 (everolimus) and case-level Heras et al., Nefrologia 2009.
Onset & rechallenge
Time to injurySubacute (~1–6 weeks)
Typically weeks to months into weekly dosing; not firmly characterized for temsirolimus.
Distilled from: “Subacute — typically weeks to months into weekly dosing; not firmly characterized for temsirolimus.” · PMID 17538086
§02
Renal toxicities, ranked
This agent's kidney lesions ordered by prominence — the #1 signature lesion first, then secondary and rare patterns. Cited incidence is shown where a citable figure exists; otherwise the tier stands qualitatively.
Damage to the filtration barrier — podocyte injury, FSGS and protein leak from VEGF and mTOR blockade.
Renal electrolyte derangement — magnesium/potassium/calcium wasting (cisplatin, anti-EGFR antibodies) or retention (FGFR-inhibitor hyperphosphatemia, tumor-lysis hyperkalemia/hyperphosphatemia).
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityMild
ReversibilityVariable
Evidence0 refs
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Proximal Tubule
Distal Tubule / Collecting Duct
Glomerular Injury / Proteinuria
Damage to the filtration barrier — podocyte injury, FSGS and protein leak from VEGF and mTOR blockade.
§03
Kidney injury
Mechanism of kidney injury
Inferred largely from the sirolimus/everolimus class (temsirolimus is a sirolimus prodrug): mTORC1 (and secondary mTORC2) inhibition in podocytes down-regulates slit-diaphragm proteins (nephrin, TRPC6) and the Nck/actin cytoskeleton, and disrupts the autophagic flux podocytes depend on for maintenance and repair — producing proteinuria and FSGS-type lesions. Reduced VEGF signaling with an antiproliferative effect on glomerular endothelium can add a thrombotic-microangiopathy-like component. Proximal-tubular phosphate wasting contributes to the class-typical hypophosphatemia.
Clinical presentation
Usually asymptomatic proteinuria found on urinalysis or urine protein/creatinine ratio, occasionally nephrotic-range with edema; sometimes a modest creatinine rise. Rare acute kidney injury is reported at case level. Hypophosphatemia (and less often hypokalemia) plus the metabolic derangements hyperglycemia and hyperlipidemia are common lab findings, distinct from primary renal parenchymal injury.
Management
Quantify proteinuria with a UPCR/UACR. Low-grade proteinuria can usually be continued with monitoring; add an ACEi or ARB for its antiproteinuric effect. Reduce dose or hold for grade 3-4 or nephrotic-range proteinuria or a rising creatinine, and discontinue for persistent nephrotic syndrome or progressive decline. Refer to nephrology and consider biopsy for nephrotic-range proteinuria or atypical AKI. Replace phosphate and manage hyperglycemia/hyperlipidemia. For rare AKI, hold the drug and correct prerenal/GI-loss contributors with supportive care.Lesion-level management framework
Risk factors
- Pre-existing CKD or baseline proteinuria
- Reduced renal mass (post-nephrectomy / solitary kidney in RCC)
- Diabetes or hypertension
- Prior or concurrent VEGF-pathway-targeted therapy
- Hypoalbuminemia
Prevention
- Baseline and periodic urinalysis / urine protein-to-creatinine ratio
- Baseline renal function (creatinine, eGFR) before and during therapy
- Monitor serum phosphate, glucose and lipids
- Optimize blood pressure and avoid concurrent nephrotoxins
Anticancer mechanism· how it treats cancer
Temsirolimus is an IV ester prodrug of sirolimus (rapamycin). It binds FKBP-12, and the complex inhibits mTORC1, lowering HIF-1alpha/VEGF and cyclin D1 to arrest tumor cells in G1 and blunt angiogenesis.
Note · IV ester prodrug of sirolimus; renal profile largely extrapolated from the sirolimus/everolimus class. Temsirolimus-specific renal incidence is not firmly quantified — claims are hedged to case-level and class evidence.
§04
Clinical depth
Renal dose adjustment
No specific renal dose adjustment is recommended in the label — temsirolimus and its active metabolite sirolimus are cleared by hepatic CYP3A4 metabolism and biliary excretion, not renal elimination, so renal impairment does not mandate a dose change (efficacy/safety in severe renal impairment are not established; use caution). Hepatic impairment, not renal, drives dose reduction (and severe hepatic impairment is a contraindication). Standard RCC dosing is 25 mg IV weekly.
Dialyzability & ESKD dosing
Not meaningfully dialyzable. Sirolimus (the active moiety) has a large volume of distribution, extensive tissue and erythrocyte partitioning, and high protein/lipoprotein binding, so hemodialysis is not expected to remove clinically significant amounts; direct data are limited.
Differential diagnosis
Separate drug-induced podocytopathy/proteinuria from RCC-associated paraneoplastic glomerulopathy (membranous nephropathy, minimal-change disease), diabetic nephropathy, and hypertensive nephrosclerosis. In sequenced RCC regimens, concurrent or prior VEGF-pathway inhibitors can cause overlapping proteinuria/TMA. For an acute creatinine rise, weigh prerenal azotemia from GI losses/dehydration and ischemic/contrast ATN. Hypophosphatemia has its own differential (poor intake, other tubular toxins).
Monitoring
- Baseline and periodic urinalysis / UPCR or UACR for proteinuria
- Serum creatinine and eGFR
- Serum phosphate and potassium
- Fasting glucose and lipid panel (metabolic class effects)
- Blood pressure
Key trials & series
- GLOBAL ARCC (Hudes et al., NEJM 2007) — pivotal phase 3 in poor-prognosis metastatic RCC establishing 25 mg IV weekly; hyperglycemia, hyperlipidemia and hypophosphatemia were prominent while frank nephrotoxicity was uncommon and renal-specific proteinuria was not systematically captured
- Phase 3 mantle-cell-lymphoma program — higher 175/75 mg dosing with a different, mostly hematologic/GI safety profile (Bouabdallah et al., Curr Opin Oncol 2013)
Clinical pearls
- Temsirolimus is the IV ester prodrug of sirolimus — its renal footprint is inferred mainly from the sirolimus/everolimus class literature rather than temsirolimus-specific trials.
- Proteinuria (podocyte slit-diaphragm down-regulation plus autophagy disruption, with FSGS in some cases) is the signature mTOR-inhibitor renal signal, but the temsirolimus-specific incidence is not firmly quantified — hedge.
- The pivotal ARCC trial foregrounded hyperglycemia, hyperlipidemia and hypophosphatemia; frank nephrotoxicity was uncommon and creatinine changes modest.
- No renal dose adjustment is required (hepatic metabolism and biliary excretion); hepatic impairment drives dose changes instead.
- An ACEi/ARB plus dose reduction usually controls proteinuria; nephrotic-range proteinuria or a rising creatinine warrants holding the drug and nephrology input.
- Watch for additive glomerular injury when temsirolimus is sequenced with VEGF-pathway agents in RCC.
Beyond the kidney — non-renal toxicities· 4 organ systems
Class-level context for the major non-renal toxicities of mtor inhibitors.
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Non-infectious pneumonitis
Endocrine
Thyroiditis, hypophysitis, diabetes
- Hyperglycemia, hyperlipidemia
Gastrointestinal
Diarrhea, colitis, mucositis, perforation
- Stomatitis
Immune / Infusion
CRS, infusion reactions, irAEs, anaphylaxis
- Immunosuppression / infection
§05
References
8 peer-reviewed references. Citation metadata via PubMed / NLM.
Evidence accrual
8 references · 2007–2016 · 2 since 2014Citations per year in this profile — a proxy for how actively the agent's renal literature is accruing. Recent years are highlighted. Reflects curation depth, not a systematic bibliometric count.
- 1.LandmarkTemsirolimus, interferon alfa, or both for advanced renal-cell carcinoma.Hudes G et al. · N Engl J Med · 2007 · PMID 17538086Pivotal phase 3 (Global ARCC) registrational trial in poor-prognosis metastatic RCC; metabolic lab abnormalities (hyperglycemia, hyperlipidemia, hypophosphatemia) prominent while frank nephrotoxicity was uncommon.
- 2.LandmarkInhibition of MTOR disrupts autophagic flux in podocytes.Cinà DP et al. · J Am Soc Nephrol · 2011 · PMID 22193387Podocyte-selective mTOR loss and rapamycin disrupt autophagic flux, causing proteinuria — core mechanism of mTOR-inhibitor glomerular injury.
- 3.LandmarkmTOR regulates expression of slit diaphragm proteins and cytoskeleton structure in podocytes.Vollenbröker B et al. · Am J Physiol Renal Physiol · 2008 · PMID 19019920Molecular basis of mTOR-inhibitor proteinuria/FSGS — rapamycin down-regulates nephrin/TRPC6 and the podocyte cytoskeleton.
- 4.mToR inhibitors-induced proteinuria: mechanisms, significance, and management.Letavernier E et al. · Transplant Rev (Orlando) · 2008 · PMID 18631865Review linking mTOR inhibition to podocyte injury/FSGS and framing significance and management of the class proteinuria.
- 5.Proteinuria with first-line therapy of metastatic renal cell cancer.Land JD et al. · J Oncol Pharm Pract · 2016 · PMID 25505255Class incidence context in mRCC — high all-grade but mostly grade 1-2 proteinuria (everolimus 96%), supporting continued monitoring for low-grade events.
- 6.Strategies for the management of adverse events associated with mTOR inhibitors.Kaplan B et al. · Transplant Rev (Orlando) · 2014 · PMID 24685370Practical incidence and management guidance for mTOR-inhibitor proteinuria and nephrotoxicity across oncology and transplant use.
- 7.[Acute renal failure in a patient with renal carcinoma treated with temsirolimus].Heras M et al. · Nefrologia · 2009 · PMID 19936012Temsirolimus-specific case of acute renal failure in RCC — the drug-level (case) evidence behind the AKI signal.
- 8.Temsirolimus in the treatment of mantle cell lymphoma: frequency and management of adverse effects.Bouabdallah K et al. · Curr Opin Oncol · 2013 · PMID 23388840Temsirolimus-specific adverse-event frequency and management, including the higher 175/75 mg MCL dosing and its distinct safety profile.
Guidelines & consensus· 12
General onco-nephrology references
ADQIThe nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupNat Rev Nephrol 2026 · PMID 41361704Provides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.SIRMSIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Radiol Med 2022 · PMID 35303246Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.KDIGOKDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerKidney Int 2020 · PMID 33126977Identifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.KDIGOKDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationKidney Int 2020 · PMID 33276867Addresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.ADDIKDIntegrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceEClinicalMedicine 2025 · PMID 40290844Provides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.ADDIKDAligning kidney function assessment in patients with cancer to global practices in internal medicineEClinicalMedicine 2025 · PMID 40290845Three consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.ADDIKDA methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEClinicalMedicine 2025 · PMID 40290846Establishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.KDIGODiagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Crit Care 2013 · PMID 23394211Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.KDIGOExecutive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesKidney Int 2021 · PMID 34556300Provides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisKidney Int 2024 · PMID 38388147Updates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.KDIGOExecutive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisKidney Int 2024 · PMID 38182299Updates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.KDIGOExecutive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Kidney Int 2025 · PMID 40975525Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.
Where Temsirolimus sits in nephrotoxicity space — each dot is an anti-cancer agent, positioned so neighbors share a kidney-injury phenotype.
Phenotype-similar agents· nearest neighbors in nephrotoxicity space
Profile
Sirolimus
Rapamune · mTOR inhibitor
Proteinuria, cast nephropathy, delayed graft recovery.
GLOMATN
Moderate77% phenotype match
Erlotinib
Tarceva · EGFR TKI
Rare minimal-change disease and AKI.
GLOMATN
Mild71% phenotype match
Everolimus
Afinitor · mTOR inhibitor
Podocyte injury with proteinuria/FSGS; occasional thrombotic microangiopathy.
GLOMTMALYTE
Moderate63% phenotype match
Bleomycin
Blenoxane · Antitumor antibiotic
Renally excreted (~2/3 in urine); half-life rises exponentially below CrCl 25-35 — exposure/clearance issue amplifying pulmonary toxicity, not a direct nephrotoxin.
PREATNLYTE
Mild62% phenotype match
Carboplatin
Paraplatin · Platinum agent
Kidney-sparing; GFR-dosed by the Calvert formula.
ATNLYTE
Mild60% phenotype match
Nearest agents by kidney-injury phenotype (shared injuries, nephron target, severity, class) — a similarity approximation, not a claim of shared drug identity or mechanism.