Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
AKT inhibitor
Capivasertib
Truqap · Capi
An AKT inhibitor for breast cancer — AKI tends to ride on its diarrhea and hyperglycemia.
ModerateAKT inhibitor · approved 2023
HR-positive HER2-negative advanced breast cancer (PIK3CA/AKT1/PTEN-altered)
Signature kidney injury
Prerenal / Hemodynamic AKI
Diarrhea and hyperglycemia are the characteristic on-target toxicities (diarrhea very common; hyperglycemia frequent, occasionally severe). AKI, when it occurs, is largely a downstream pre-renal consequence of diarrhea-related volume loss and osmotic/metabolic disturbance; direct renal incidence is not well quantified. Rash is common but not nephrotoxic.
Source: Turner et al., N Engl J Med 2023 (CAPItello-291)
Mechanism of kidney injury
AKT inhibition is mechanistically tied to two on-target effects with renal consequences. (1) Loss of AKT-dependent insulin signaling causes hyperglycemia (occasionally severe, with osmotic diuresis, dehydration and rarely DKA-like states), driving pre-renal volume depletion and electrolyte loss. (2) AKT blockade in gut epithelium produces secretory diarrhea; the resulting hypovolemia leads to pre-renal azotemia that can progress to ischemic tubular injury if severe. The kidney is injured indirectly via GI and metabolic toxicity rather than by a direct tubular toxin.
Clinical presentation
Rising creatinine in the context of diarrhea and hyperglycemia, with pre-renal indices (low FeNa, concentrated urine) early; hyperglycemia and electrolyte shifts (hypokalemia, hyponatremia) on labs. Resolves with rehydration and metabolic control.
Onset
Early in therapy, tracking diarrhea/hyperglycemia (first cycles).
Reversibility
Reversible
Anticancer mechanism
Potent pan-AKT (AKT1/2/3) ATP-competitive serine/threonine kinase inhibitor that blocks PI3K–AKT–mTOR signaling downstream of common oncogenic alterations. Approved with fulvestrant for HR-positive HER2-negative advanced breast cancer harboring PIK3CA, AKT1 or PTEN alterations.
Management
Aggressive supportive care for diarrhea and hyperglycemia with volume and electrolyte repletion; hold/dose-reduce per label for grade ≥3 toxicity. Treat hyperglycemia (hydration, antihyperglycemics, insulin if severe). Supportive AKI care; renal function recovers with restoration of volume and glycemic control.
Risk factors
- Severe diarrhea / volume depletion
- Diabetes or baseline hyperglycemia
- Pre-existing CKD
- Concurrent nephrotoxins or diuretics
Prevention
- Prompt antidiarrheal therapy (loperamide) and aggressive oral/IV rehydration
- Baseline and on-treatment glucose monitoring; manage hyperglycemia early
- Creatinine and electrolyte monitoring
- Patient education to report diarrhea early
Note · Renal injury is mostly secondary to gastrointestinal and metabolic toxicity rather than a direct nephrotoxic effect; the key to renal protection is rapid management of diarrhea and hyperglycemia.
Clinical depth
Renal dose adjustment
No dedicated renal dose adjustment for mild–moderate impairment; severe impairment/ESKD not well studied. Dose modification is driven by GI/metabolic toxicity grade. Capivasertib is given on an intermittent (4-days-on/3-days-off) schedule.
Dialyzability & ESKD dosing
Hepatically metabolized small molecule (CYP3A4); dialyzability not well characterized and unlikely to be the management lever. In advanced CKD, focus on volume/glucose management.
Differential diagnosis
Pre-renal AKI from diarrhea/hyperglycemic osmotic diuresis vs intrinsic tubular injury (the former corrects rapidly with volume) vs concurrent nephrotoxin; check glucose and volume status before attributing AKI to a direct renal lesion.
Monitoring
- Fasting glucose/HbA1c at baseline and periodically
- Stool frequency and hydration status
- Serum creatinine and electrolytes (K, Na) each cycle
- Blood pressure
Key trials & series
- CAPItello-291 (Turner NEJM 2023) phase III with fulvestrant
- CAPItello-290/-281 program (broader development)
Clinical pearls
- Protect the kidney by treating the diarrhea and hyperglycemia fast — the AKI is downstream volume/metabolic, not a tubular toxin.
- Severe hyperglycemia from AKT inhibition can cause osmotic diuresis and pre-renal AKI; monitor glucose proactively.
- The intermittent 4-on/3-off schedule helps mitigate cumulative GI toxicity.
- Rehydration and glycemic control reverse the creatinine rise in most cases.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Injury signatures
Prerenal / Hemodynamic AKIElectrolyte Wasting
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkCapivasertib in Hormone Receptor-Positive Advanced Breast Cancer.Turner NC et al. · N Engl J Med 2023 · PMID 37256976Pivotal CAPItello-291 trial detailing diarrhea and hyperglycemia as the principal toxicities.PMIDConventional Chemotherapy Nephrotoxicity.Gupta S et al. · Adv Chronic Kidney Dis 2021 · PMID 35190107Onconephrology reference for pre-renal/volume-depletion AKI mechanisms.PMIDRenal Side Effects of Novel Molecular Targeted Oncologic Agents.Fenoglio R et al. · G Ital Nefrol 2023 · PMID 38007829Onconephrology overview of renal effects of novel targeted agents, supporting that AKT-inhibitor AKI is largely secondary rather than a direct lesion.PMIDCurrent Trends in Anti-Cancer Molecular Targeted Therapies: Renal Complications and Their Histological Features.Tonooka A et al. · J Nippon Med Sch 2021 · PMID 34840210Histologic survey of targeted-therapy renal complications giving context to the absence of a defined AKT-inhibitor lesion.PMIDDrug-induced rise in serum creatinine: cystatin C to the rescue? Evidence, pitfalls and knowledge gaps.Van Regemorter E et al. · Eur J Intern Med 2025 · PMID 41224604Reviews drug-related creatinine rises across targeted agents and the cystatin-C approach to distinguish true from apparent AKI.PMIDManagement of euvolemic hyponatremia attributed to SIADH in the hospital setting.Peri A et al. · Minerva Endocrinol 2014 · PMID 24513602Approach to drug- and illness-related hyponatremia, relevant to the electrolyte shifts (hyponatremia/hypokalemia) accompanying capivasertib diarrhea.
Related agents
Other agents sharing the same signature kidney injury.