Sorafenib

The injury is on-target interruption of physiologic VEGF signaling in the glomerulus. Podocytes constitutively secrete VEGF-A that acts on VEGFR2 of the adjacent fenestrated glomerular endothelium to maintain the filtration barrier; blocking this axis reduces endothelial nitric oxide and prostacyclin, causing vasoconstriction, microvascular rarefaction and salt-sensitive hypertension, and injures the endothelium. Loss of podocyte-derived VEGF signaling downregulates nephrin and other slit-diaphragm proteins, producing proteinuria, and severe endothelial injury can precipitate a renal-limited thrombotic microangiopathy. Conditional deletion of VEGF from mouse podocytes reproduces a thrombotic glomerular injury, establishing that local VEGF loss alone is sufficient (Eremina 2008). Mechanistic reviews note that receptor tyrosine-kinase inhibitors such as sorafenib biopsy preferentially as glomerulopathies (minimal change disease / FSGS) rather than the pure TMA characteristic of anti-VEGF antibodies, while inhibition of the downstream RAF/MAPK/ERK arm may add tubulointerstitial injury (Estrada 2019). Animal models of sorafenib show hypertension, proteinuria and glomerular nephrin loss, supporting a direct glomerular mechanism.

Most patients present with new or worsening hypertension, frequently in the first weeks of therapy, and asymptomatic dipstick proteinuria detected on routine monitoring. A minority develop nephrotic-range proteinuria with edema, hypoalbuminemia and hyperlipidemia. The severe end of the spectrum is renal thrombotic microangiopathy — a rising creatinine/AKI with microangiopathic hemolytic anemia (schistocytes, low haptoglobin, elevated LDH) and thrombocytopenia — and, on biopsy, endothelial injury and glomerular capillary changes often accompanied by acute tubular injury. Serum phosphate should be watched, as hypophosphatemia was more frequent than placebo in the registrational hepatocellular-carcinoma trial.

Hypertension is managed with standard antihypertensives and rarely requires stopping the drug; ACE inhibitors or ARBs are preferred for their renoprotective and antiproteinuric effect, especially when proteinuria coexists. For proteinuria, monitor quantitatively, add/optimize RAAS blockade, and dose-reduce or interrupt therapy for nephrotic-range or progressively worsening proteinuria, with nephrology referral. For thrombotic microangiopathy the mainstay is holding or discontinuing sorafenib plus supportive care; plasma exchange is generally ineffective because this is not classic TTP. Discontinuation commonly reverses the anemia, hypertension and proteinuria (Usui 2014), though some proteinuria/renal dysfunction persists and rare TMA cases progress to end-stage renal disease. Because sorafenib is comparatively less nephrotoxic than some other VEGFR TKIs, switching a patient with anti-VEGF nephrotic syndrome from a more nephrotoxic agent (e.g., lenvatinib) to sorafenib has improved proteinuria while maintaining tumor control (Yang 2020).Lesion-level management framework

No specific renal dose adjustment is established. Sorafenib is cleared predominantly by hepatic metabolism (CYP3A4 oxidation and UGT1A9 glucuronidation) with only a minor fraction of the dose eliminated renally, so mild-to-moderate renal impairment has little effect on exposure and the standard 400 mg twice-daily dose is used. Data in severe impairment and dialysis are limited; modify dose primarily for toxicity (uncontrolled hypertension, nephrotic-range proteinuria, other grade 3-4 events) rather than for eGFR.

Not meaningfully dialyzable. Sorafenib is very highly protein-bound (~99.5%) with a large apparent volume of distribution and minimal renal excretion, so hemodialysis is not expected to remove appreciable drug; small case experience suggests hemodialysis patients can receive standard dosing (started conservatively and titrated), without regard to dialysis timing.

Essential or pre-existing hypertension and CKD; proteinuria/TMA from a co-administered anti-VEGF agent or other TKI; other causes of thrombotic microangiopathy (gemcitabine, calcineurin inhibitors, malignancy-associated TMA, TTP/HUS); prerenal azotemia from sorafenib-associated diarrhea/volume loss; contrast- or sepsis-related ATN; progression of the underlying malignancy; and, in hepatocellular-carcinoma patients, hepatorenal physiology confounding the renal picture.