mTOR Inhibitors

Glomerular Injury / Proteinuria.

Everolimus commonly causes all-grade proteinuria, with high-grade uncommon; mTOR-inhibitor proteinuria/FSGS is well described. Temsirolimus case-level only.

Source: Vollenbröker et al., Am J Physiol Renal Physiol 2008; Letavernier et al., 2008

Reported injury signatures: Glomerular Injury / Proteinuria, Acute Tubular Necrosis, Thrombotic Microangiopathy.

1. Glomerular Injury / ProteinuriaPrimary~96%Proteinuria in 96% (44/46) of everolimus-treated first-line metastatic RCC patients (overall 81% across VEGF/mTOR agents), the great majority grade 1-2 and managed by continued monitoring; reflects mTOR-inhibitor podocyte/slit-diaphragm injury. High-grade (grade 3-4) proteinuria is uncommon.
2. Acute Tubular NecrosisSecondary
3. Thrombotic MicroangiopathyRare

Subacute (~1–6 weeks) — Develops over weeks to months of therapy.

• Pre-existing CKD / proteinuria

• Check a baseline urine protein/creatinine ratio before starting or converting from a calcineurin inhibitor — the baseline gates initiation and anchors later attribution

• Quantify proteinuria at baseline and serially (spot urine protein/creatinine or albumin/creatinine ratio) — mTOR-inhibitor proteinuria can be heavy/nephrotic and is the dominant renal signal
• Check serum creatinine/eGFR before starting and periodically; an unexpected rise should prompt evaluation rather than a level-driven dose increase
• Screen for thrombotic microangiopathy when creatinine rises with new anemia or thrombocytopenia — order CBC with smear (schistocytes), LDH, and haptoglobin, especially in combination with calcineurin inhibitors or VEGF-pathway agents
• Monitor sirolimus/everolimus trough levels in transplant recipients to keep exposure in target range and limit dose-dependent glomerular injury
• Reassess proteinuria and renal function after any dose change or after switching from a calcineurin inhibitor, since de novo or worsening proteinuria often emerges after conversion

• ZEUS — early conversion from cyclosporine to everolimus after kidney transplant improved measured GFR at 12 months, but the everolimus arm showed more proteinuria, illustrating the trade-off between escaping CNI nephrotoxicity and incurring mTOR-inhibitor glomerular effects.
• RECORD-1 — registrational placebo-controlled phase 3 of everolimus in VEGF-refractory metastatic RCC; established efficacy and characterized the class adverse-event profile including proteinuria.
• Global ARCC trial (Hudes et al.) — temsirolimus vs interferon-alfa in poor-prognosis advanced RCC, the registrational study for temsirolimus that defined its tolerability/toxicity profile.
• Sirolimus conversion/de novo series in kidney transplantation — multiple cohorts linked sirolimus to new-onset or worsening proteinuria and biopsy-proven FSGS-pattern podocyte injury, anchoring the mechanistic glomerular signal of the class.

• The dominant renal toxicity is proteinuria from podocyte injury (FSGS-pattern), not a filtration/clearance problem — so the class is generally mild and reversible, and management is dose reduction or withdrawal, not renal dose-capping.
• Proteinuria is frequently unmasked or worsened when patients are converted from a calcineurin inhibitor to an mTOR inhibitor, a classic transplant scenario — check a baseline UPCR before and after conversion.
• mTOR inhibitors can also impair tubular recovery and have been associated with delayed graft function and acute tubular injury, so they are usually avoided early post-transplant while tubules are healing.
• Thrombotic microangiopathy is an uncommon but serious class effect, with risk amplified by concurrent calcineurin inhibitors or VEGF-pathway agents — keep it on the differential for any creatinine rise plus cytopenias.

Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.

• 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 (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsEvaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.Kidney Int · PMID 38519239
• 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