Novel Biomarkers for Early Detection of Acute Kidney Injury and Prediction of Long-Term Kidney Function Decline after Partial Nephrectomy

The study addresses the need for early and accurate detection of postoperative acute kidney injury (AKI) and prediction of long-term kidney function decline in patients undergoing nephron-sparing surgery (NSS) for localized renal cell carcinoma. Although NSS preserves renal parenchyma compared to radical nephrectomy, postoperative AKI is common and associated with worse long-term outcomes, including chronic kidney disease, cardiovascular events, mortality, and tumor relapse. Conventional reliance on serum creatinine is limited by delayed rise and non-renal influences. The research tests whether novel serum and urinary biomarkers, reflecting different sites and mechanisms of kidney injury, can more promptly detect AKI and better predict long-term decline in estimated glomerular filtration rate (eGFR) than creatinine. The primary goal is to identify biomarkers that efficiently predict long-term GFR decline after robotic NSS and to characterize their early postoperative kinetics.

The authors note evidence that partial nephrectomy is associated with better long-term renal outcomes than radical nephrectomy, yet AKI remains frequent after renal surgery and correlates with CKD and adverse outcomes. Consensus criteria (RIFLE, KDIGO) standardized AKI definitions but rely on serum creatinine, which has significant limitations including delayed changes and hemodilution effects. Prior systematic reviews suggested cystatin C and urinary NGAL as promising early AKI predictors after nephrectomy, though many studies lacked validated AKI definitions and long-term follow-up. Biomarkers such as NephroCheck ([TIMP-2]×[IGFBP7]), acanthocytes in urinary sediment, and kineticGFR had not been comprehensively evaluated in the NSS setting. The study positions itself to fill these gaps by testing a broad panel of biomarkers for both early AKI detection and long-term renal outcome prediction.

Design: Monocentric, prospective observational study at Careggi University Hospital (Florence, Italy). Enrollment: All consecutive adults (>18 years) scheduled for robotic nephron-sparing surgery (NSS) for suspected localized RCC (T1, N0, M0) from May to October 2017. Inclusion required at least two risk factors for long-term GFR decline (age >70 years, preoperative anemia, chronic heart failure NYHA >2, diabetes, preoperative CKD per KDIGO). Exclusions: Fewer than two preoperative serum creatinine (sCr) values, or preoperative eGFR <30 mL/min/1.73 m2. Data and sampling: Demographic, clinical, anesthesiologic, and surgical variables were collected. Blood and urine were sampled preoperatively and at 4 h, 10 h, 24 h, and 48 h postoperatively (day/night). Biomarkers measured included: serum creatinine, cystatin C, NGAL; kineticGFR; urinary NGAL; protein, albumin, creatinine; [TIMP-2]×[IGFBP7] via NephroCheck; acanthocytes in urinary sediment. Urine output was recorded hourly. AKI definition: Per KDIGO—sCr increase ≥0.3 mg/dL within 48 h or ≥1.5× baseline within 7 days, or urine output <0.5 mL/kg/h for ≥6 h. Clinical AKI was adjudicated using sCr and urine output. Follow-up: eGFR (CKD-EPI) reassessed up to 24 months postoperatively. Primary outcome: eGFR decline at 24 months. Only patients with complete renal function evaluation at 12 and 24 months were included in outcome analyses. Ethics: Conducted per the Declaration of Helsinki; regional ethics approval (BIO.16.015). Written informed consent obtained. Statistics: Data reported as median (IQR) or counts (%). ROC analysis and univariate logistic regression assessed biomarkers’ prediction of AKI and eGFR decline; odds ratios and AUCs reported with 95% CIs. Pearson correlation assessed associations with 24-month eGFR decline. Biomarkers with p<0.1 in univariate analyses entered predictive models for eGFR decline; models were compared to sCr’s predictive capability. The same model was tested for AKI prediction. Multiple linear regression with backward selection included predictive biomarkers and known risk factors to identify independent predictors of 24-month eGFR decline. Two-sided p<0.05 deemed significant.

- Cohort: 38 patients; arterial clamping in 60.5% with median warm ischemia time 20 (IQR 15–23) min. Clinical AKI occurred in 16/38 (42%): 81% KDIGO stage 1; 19% stage 2; none stage 3. AKI criteria: 3 by urine output, 9 by sCr, 4 by both. - Baseline differences: Preoperative serum NGAL was higher in patients who developed AKI (p=0.002). - Biomarker kinetics: KineticGFR nadir at 4 h; proteinuria and albuminuria peaked at 4 h; urinary NephroCheck and serum/urinary NGAL rose at 4 h and peaked at 10 h; sCr and cystatin C rose at 4 h and peaked at 24 h. - Early AKI prediction: At 4 h, NephroCheck increase >0.3 was present in 81% of AKI vs 27% of non-AKI patients; by 10 h it increased further among AKI patients. A cystatin C increase ≥10% within 24 h yielded OR 148.11 (95% CI 13.19–1662.9), AUC 0.95 (95% CI 0.87–1.00) for AKI prediction. A kineticGFR reduction ≥50% at 4 h occurred in 56% AKI vs 18% non-AKI patients. Using the lowest kineticGFR within 10 h: OR 6.64 (95% CI 1.54–28.66), AUC 0.72 (95% CI 0.57–0.87) for AKI prediction. Among biomarkers, kineticGFR and cystatin C showed highest specificity, NephroCheck highest sensitivity for AKI. Serum/urinary NGAL, acanthocytes, and albuminuria were not significant predictors of AKI. - Long-term renal function: Median eGFR decline was −4.9 mL/min at 6 months, −8.0 at 12 months, −8.5 at 18 months, and −11.5 mL/min at 24 months. Decline was greater with postoperative AKI: −20.75 vs −7.20 mL/min at 24 months (p<0.0001). In 8 patients without clinical or subclinical AKI (no kineticGFR ≥50% reduction and no NephroCheck >0.3), median 24-month decline was −1.8 mL/min, similar to healthy controls. - Predictors of 24-month eGFR decline: In multivariable linear regression, NephroCheck at 10 h (p<0.001) and kineticGFR at 4 h (p<0.01) independently predicted decline. Together they predicted 24-month decline efficiently (R2=0.33) and outperformed postoperative sCr (R2=0.04). Biomarkers significantly associated with long-term decline included urinary NGAL, NephroCheck, proteinuria, and kineticGFR; albuminuria was not. sCr at 24 h correlated weakly with 24-month decline (CC −0.25, p=0.119). - Model performance for AKI: KineticGFR at 4 h plus urinary NephroCheck at 10 h predicted AKI similarly to sCr (AUC 0.86 [0.75–0.98] vs 0.83 [0.70–0.97], p=0.66) but 12–24 h earlier.

The study demonstrates that a multiparametric strategy using both functional (kineticGFR) and damage (NephroCheck [TIMP-2]×[IGFBP7]) biomarkers identifies postoperative AKI earlier and predicts long-term renal function decline more accurately than serum creatinine in patients undergoing robotic partial nephrectomy. Given creatinine’s delayed response and susceptibility to non-renal factors, early biomarker-guided risk stratification could enable timely nephroprotective measures and closer surveillance. Notably, a considerable fraction of patients with significant 24-month eGFR decline did not meet clinical AKI criteria but were biomarker-positive, underscoring the clinical relevance of subclinical AKI. The combined use of kineticGFR at 4 h and NephroCheck at 10 h provided the best predictive performance for long-term decline and enabled earlier AKI diagnosis by up to a day compared with creatinine-based criteria. Preoperative serum NGAL and albuminuria may help identify patients predisposed to postoperative AKI. These findings align with consensus recommendations advocating integration of damage and functional biomarkers with clinical data to improve AKI diagnosis, risk stratification, and management.

Perioperative blood and urine biomarkers can identify patients at higher risk of adverse long-term renal outcomes after nephron-sparing surgery. This first urologic study evaluating NephroCheck and kineticGFR supports their utility for early (10 h) and very early (4 h) prediction of both AKI and long-term eGFR decline. Incorporating NephroCheck and kineticGFR into clinical practice alongside serum creatinine may improve diagnostic accuracy, enable earlier intervention, and potentially mitigate progression to CKD. Future research should validate these findings in larger, multicenter cohorts and assess the cost-effectiveness and clinical impact of biomarker-guided care pathways.

Single-center study with a small sample size (n=38), limiting generalizability and precision of estimates; external validation is needed. Although promising, the biomarkers’ clinical effectiveness, cost-effectiveness, and impact on patient management and outcomes in urologic surgery require further study. Some biomarkers showed mixed utility across endpoints, and comprehensive postoperative urine output assessment, while included here, is often lacking in routine practice.