Sorafenib
Nexavar · VEGFR TKI
Anti-angiogenic hypertension and proteinuria; occasional TMA.
HTNGLOMTMA
Moderate69% phenotype match
mTOR inhibitor
Everolimus
Afinitor · EVE
mTOR inhibitor · approved 2009 · 8 citations
Aging evidence· through 2020
Emerging evidence6/9 · 6 signals▾
- 8 citations
- Deep literature (12+ refs)
- Accrued over 12+ years
- Beyond single case reports
- High-impact journal
- Landmark reference
- Registrational / key trials
- Current through 2020
- 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 oral rapalog whose podocytes pay in protein — glomerular proteinuria and secondary FSGS, with occasional thrombotic microangiopathy.
ModerateTargeted therapy (mTOR rapalog), late 2000s
Advanced renal cell carcinoma after failure of a VEGF-targeted tyrosine-kinase inhibitor (sunitinib/sorafenib)Progressive pancreatic and GI/lung neuroendocrine tumorsHR-positive, HER2-negative advanced breast cancer (with exemestane) after letrozole/anastrozole failureSubependymal giant-cell astrocytoma (SEGA) and renal angiomyolipoma in tuberous sclerosis complexTSC-associated refractory seizures (Afinitor Disperz)
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Signature kidney injury
Signature lesion
Proteinuria is a recognized but variably reported class effect of mTOR inhibitors; a clean everolimus-monotherapy incidence in oncology is not well quantified, and most nephrotic-range and biopsy-proven FSGS data are extrapolated from the sirolimus/transplant literature. New or worsening proteinuria is common but usually low-grade with preserved GFR, while heavy proteinuria and overt podocytopathy are uncommon. In a phase II trial that combined everolimus with bevacizumab in metastatic RCC, grade 3-4 proteinuria reached 25% and forced discontinuation in several patients — but that figure reflects the added anti-VEGF effect and substantially overstates everolimus given alone. Thrombotic microangiopathy is rare and drawn mainly from case reports, typically with concomitant calcineurin-inhibitor or anti-VEGF exposure.Source: Hainsworth JD et al., J Clin Oncol 2010 (PMID 20368560): 25% grade 3-4 proteinuria with everolimus + bevacizumab — a combination figure that overstates everolimus monotherapy; no clean single-agent oncology incidence is well established.
Onset & rechallenge
Time to injurySubacute (~1–6 weeks)
Proteinuria emerges over the first weeks to months; thrombotic microangiopathy usually within weeks to months, often with concurrent calcineurin-inhibitor or anti-VEGF exposure.
Distilled from: “Subacute — proteinuria typically emerges over the first weeks to months of therapy; thrombotic microangiopathy usually appears within weeks to months, often in the setting of concurrent calcineurin-inhibitor or anti-VEGF exposure.” · PMID 18631865
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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.
Endothelial injury with microvascular thrombi, hemolysis and thrombocytopenia — gemcitabine, mitomycin C, anti-VEGF.
Renal electrolyte derangement — magnesium/potassium/calcium wasting (cisplatin, anti-EGFR antibodies) or retention (FGFR-inhibitor hyperphosphatemia, tumor-lysis hyperkalemia/hyperphosphatemia).
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityModerate
ReversibilityVariable
Evidence0 refs
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Vasculature / 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.
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Kidney injury
Mechanism of kidney injury
mTORC1 signaling is required for the compensatory podocyte hypertrophy that maintains coverage of the glomerular filtration barrier after podocyte stress or loss; pharmacologic mTOR inhibition impairs this repair program, producing foot-process effacement, podocyte depletion, secondary focal segmental glomerulosclerosis, and proteinuria (Puelles 2019; Letavernier 2008). mTOR blockade also downregulates podocyte VEGF-A and slit-diaphragm proteins (e.g., nephrin) and impairs glomerular endothelial repair, promoting endothelial injury and thrombotic microangiopathy — a risk amplified by concurrent calcineurin inhibitors or anti-VEGF agents. Proximal-tubular effects drive renal phosphate, potassium, and magnesium wasting, producing the electrolyte disturbances seen with this class.
Clinical presentation
Most often new or rising proteinuria detected on dipstick or urine albumin/protein-to-creatinine ratio, usually with preserved or only slowly declining GFR; occasionally nephrotic-range proteinuria with edema and hypoalbuminemia. When biopsied (uncommon in oncology), the lesion is a podocytopathy with foot-process effacement and secondary FSGS. Thrombotic microangiopathy presents as rising creatinine with microangiopathic hemolytic anemia (schistocytes, elevated LDH, low haptoglobin), thrombocytopenia, and sometimes hypertension. Electrolyte manifestations include hypophosphatemia, hypokalemia, and hypomagnesemia.
Management
Quantify proteinuria (UACR or 24-h) and start or optimize RAAS blockade (ACE inhibitor/ARB) with blood-pressure control. Low-grade proteinuria can usually be continued with close monitoring; nephrotic-range or progressively rising proteinuria warrants dose reduction or discontinuation, after which glomerular injury frequently improves. For suspected thrombotic microangiopathy, stop everolimus (and reduce or stop a concomitant calcineurin inhibitor), give supportive care, and involve hematology — drug-associated TMA is generally managed by withdrawal of the offending agent rather than complement blockade. Replace phosphate, potassium, and magnesium as needed. Refer to nephrology for significant or persistent proteinuria, unexplained GFR decline, or consideration of biopsy.Lesion-level management framework
Risk factors
- Pre-existing CKD, baseline proteinuria, or diabetic nephropathy
- Concurrent anti-VEGF agent (bevacizumab, VEGF-TKI) — additive proteinuria
- Concurrent calcineurin inhibitor (tacrolimus/cyclosporine) — additive TMA risk
- Higher drug exposure / elevated troughs (transplant setting)
- Reduced nephron mass (prior nephrectomy in RCC patients)
- Poorly controlled hypertension
- Conversion from a calcineurin inhibitor to an mTOR inhibitor in transplant recipients
Prevention
- Baseline urinalysis and quantified proteinuria (UACR or spot protein:creatinine) plus serum creatinine before starting
- Serial monitoring of proteinuria and creatinine on treatment
- Baseline and ongoing blood-pressure control, favoring ACE inhibitor / ARB in patients who develop proteinuria
- Avoid unnecessary co-administration with anti-VEGF agents and keep calcineurin-inhibitor levels controlled to limit additive glomerular/endothelial injury
- Therapeutic drug monitoring where applicable (transplant)
- Baseline and periodic phosphate, potassium, and magnesium
Anticancer mechanism· how it treats cancer
Oral rapamycin analog (rapalog) that binds FKBP-12 to inhibit mTOR complex 1 (mTORC1), blocking downstream S6K1/4E-BP1 signaling. This arrests G1/S cell-cycle progression, suppresses protein synthesis and proliferation, and reduces HIF-1alpha-driven VEGF production, adding an anti-angiogenic effect.
Note · Educational content, not medical advice. Everolimus (Afinitor) is the oncology/TSC brand; the same molecule is marketed as Zortress (lower, trough-guided doses) for transplant immunosuppression, where much of the proteinuria/FSGS and TMA literature originates. Because a clean single-agent oncology incidence for glomerular injury is not well established, incidencePct is left null and quantified figures are attributed to their specific (often combination) trial contexts.
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Clinical depth
Renal dose adjustment
No renal-function-based dose adjustment is defined — everolimus is hepatically metabolized (CYP3A4/P-glycoprotein) and its pharmacokinetics are not meaningfully altered by renal impairment, so dosing is instead adjusted for hepatic impairment, CYP3A drug interactions, and toxicity. When nephrotoxicity (heavy proteinuria or TMA) develops, dose interruption/reduction or discontinuation is the lever, not a renal-clearance-based reduction.
Dialyzability & ESKD dosing
Not meaningfully dialyzable and no supplemental post-dialysis dosing is defined: everolimus has a large apparent volume of distribution, is substantially protein-bound (~74%), and is extensively metabolized, so hemodialysis is not expected to remove significant drug. Data in dialysis patients are limited.
Differential diagnosis
Separate mTOR-inhibitor podocytopathy/proteinuria from: anti-VEGF-agent proteinuria and TMA when everolimus is combined with bevacizumab or a VEGF-TKI; calcineurin-inhibitor nephrotoxicity and CNI-associated TMA in transplant recipients; diabetic nephropathy and hypertensive glomerulosclerosis; underlying malignancy-associated glomerulopathy; and other causes of AKI (prerenal, contrast, obstruction). For a TMA picture, consider complement-mediated atypical HUS, TTP, malignancy-associated TMA, and calcineurin-inhibitor TMA as competing/contributing causes.
Monitoring
- Baseline and periodic urinalysis with quantified proteinuria (UACR or spot protein:creatinine)
- Serum creatinine / eGFR
- Blood pressure
- CBC with smear, LDH, and haptoglobin if TMA is suspected (schistocytes, thrombocytopenia)
- Serum phosphate, potassium, and magnesium
- Everolimus trough concentrations in the transplant setting
- Fasting glucose and lipids (associated metabolic adverse effects)
Key trials & series
- RECORD-1 — registrational phase III of everolimus in advanced clear-cell RCC after VEGF-TKI failure, establishing efficacy and the tolerability/safety profile that underpins AE management guidance
- RECORD-4 (Motzer 2015, PMID 26681676) — prospective second-line everolimus in metastatic RCC confirming PFS benefit with a safety profile consistent with prior experience
- BOLERO-2 — phase III of everolimus plus exemestane in HR-positive advanced breast cancer (source of much real-world AE-management experience)
- Everolimus + bevacizumab phase II in advanced RCC (Hainsworth 2010, PMID 20368560) — 25% grade 3-4 proteinuria, illustrating additive glomerular toxicity when combined with an anti-VEGF agent
Clinical pearls
- The signature renal lesion is glomerular, not tubular: think podocyte injury with proteinuria and secondary FSGS — check a urine protein ratio before and during therapy, don't just track creatinine.
- mTOR is protective for stressed podocytes; inhibiting it blocks the compensatory hypertrophy that maintains the filtration barrier, which is why proteinuria is a mechanism-based class effect (Puelles 2019; Letavernier 2008).
- Proteinuria usually responds to RAAS blockade, dose reduction, or drug withdrawal — most low-grade proteinuria does not require stopping the drug, but nephrotic-range proteinuria should.
- Watch for additive glomerular toxicity when everolimus is combined with anti-VEGF agents (bevacizumab, VEGF-TKIs) — the 25% grade 3-4 proteinuria figure comes from a bevacizumab combination and overstates everolimus alone.
- Thrombotic microangiopathy is rare and usually appears alongside a calcineurin inhibitor or anti-VEGF drug; screen with LDH, haptoglobin, platelets, and a smear when creatinine rises unexpectedly, and manage primarily by stopping the culprit(s).
- No renal-clearance dose adjustment exists (hepatic metabolism), and the drug is not dialyzable — the management lever for nephrotoxicity is dose interruption/reduction, not renal dosing.
- Don't forget the electrolytes: proximal-tubular wasting can produce hypophosphatemia, hypokalemia, and hypomagnesemia.
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
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References
8 peer-reviewed references. Citation metadata via PubMed / NLM.
Evidence accrual
8 references · 2008–2020 · 3 since 2018Citations 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.LandmarkmToR inhibitors-induced proteinuria: mechanisms, significance, and management.Letavernier E, Legendre C. · Transplant Rev (Orlando) · 2008 · PMID 18631865Foundational review of the mechanism (podocyte injury, FSGS), significance, and management of mTOR-inhibitor-induced proteinuria.
- 2.LandmarkmTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans.Puelles VG, et al. · JCI Insight · 2019 · PMID 31534053Mechanistic evidence that mTOR signaling drives protective compensatory podocyte hypertrophy; pharmacologic mTOR inhibition during podocyte loss caused albuminuria and glomerulosclerosis.
- 3.Strategies for the management of adverse events associated with mTOR inhibitors.Kaplan B, Qazi Y, Wellen JR. · Transplant Rev (Orlando) · 2014 · PMID 24685370Reviews incidence, mechanism, and practical management of mTOR-inhibitor adverse events including proteinuria, nephrotoxicity, and electrolyte disturbances.
- 4.LandmarkPhase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma.Hainsworth JD, et al. · J Clin Oncol · 2010 · PMID 20368560Quantifies proteinuria risk: grade 3-4 proteinuria in 25% with everolimus plus bevacizumab, causing discontinuation in several patients — the anchor for the (combination-inflated) incidence.
- 5.LandmarkPhase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4).Motzer RJ, et al. · Ann Oncol · 2015 · PMID 26681676Prospective second-line everolimus RCC trial confirming efficacy and characterizing the everolimus safety profile in the registrational indication.
- 6.Small intestinal thrombotic microangiopathy following kidney transplantation diagnosed by balloon-assisted enteroscopy.Nishio M, et al. · Ann Gastroenterol · 2020 · PMID 33414631Case documenting everolimus-induced thrombotic microangiopathy that resolved on drug discontinuation, supporting the TMA association.
- 7.An Atypical Presentation of Thrombotic Microangiopathy After Lung Transplant: A Case Report.Menezes MDM, et al. · Transplant Proc · 2019 · PMID 31155208Renal TMA in which kidney function only recovered once everolimus was stopped, illustrating everolimus-associated (often CNI-combined) endothelial injury.
- 8.Everolimus in the treatment of renal cell carcinoma and neuroendocrine tumors.Chan HY, Grossman AB, Bukowski RM. · Adv Ther · 2010 · PMID 20623346Reviews the RECORD-1 registrational program and indications underpinning everolimus approval and clinical use.
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 Everolimus 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
Temsirolimus
Torisel · mTOR inhibitor
Proteinuria and glomerular effects; less firmly quantified than everolimus.
GLOMLYTEATN
Mild63% phenotype match
Doxorubicin
Adriamycin · Anthracycline
Experimental podocyte model; clinical proteinuria rare.
GLOMTMA
Mild58% phenotype match
Mitomycin C
Mutamycin · Antitumor antibiotic
Prototype dose-dependent TMA.
TMAGLOM
Severe58% phenotype match
Pazopanib
Votrient · VEGFR TKI
VEGFR-TKI; hypertension, proteinuria, TMA.
GLOMHTNTMA
Moderate57% phenotype match
Axitinib
Inlyta · VEGFR TKI
Potent VEGFR-TKI; hypertension and proteinuria dominate.
HTNGLOMTMA
Moderate57% 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.