Everolimus

Glomerular Injury / Proteinuria.

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.

Reported injury signatures: Glomerular Injury / Proteinuria, Thrombotic Microangiopathy, Electrolyte Disturbance.

1. Glomerular Injury / ProteinuriaPrimary
2. Thrombotic MicroangiopathySecondary
3. Electrolyte DisturbanceSecondary

Subacute (~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.

• 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

• 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

• 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)

• 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

• 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.

• ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides 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.Nat Rev Nephrol · PMID 41361704
• SIRM (2022) — SIRM-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)Recommends 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.Radiol Med · PMID 35303246
• KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies 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.Kidney Int · PMID 33126977
• KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses 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.Kidney Int · PMID 33276867
• ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides 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.EClinicalMedicine · PMID 40290844
• ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree 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.EClinicalMedicine · PMID 40290845
• ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes 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.EClinicalMedicine · PMID 40290846
• KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/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.Crit Care · PMID 23394211
• KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides 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.Kidney Int · PMID 34556300
• KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates 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.Kidney Int · PMID 38388147
• KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates 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.Kidney Int · PMID 38182299
• KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages 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.Kidney Int · PMID 40975525