Surgery is the gold standard for treating localized Renal Cell Carcinoma (RCC). While oncological outcomes are similar between radical nephrectomy (RN) and nephron-sparing surgery (NSS), the incidence of hypertension and/or chronic kidney disease (CKD) is significantly higher long-term after RN. CKD impacts quality of life and has significant health-economic implications, increasing the risk of cardiovascular events and renal failure. Lower estimated Glomerular Filtration Rate (eGFR) after renal surgery is associated with poorer survival, emphasizing the importance of preserving renal function. Current guidelines strongly favor partial nephrectomy (PN) for T1 tumors, especially in elderly or comorbid patients. Patients undergoing kidney surgery may have pre-existing CKD, and perioperative acute kidney injury (AKI) can worsen renal recovery. Postoperative AKI, occurring in up to 41% of PN patients, is a serious complication often diagnosed late and underestimated. In PN patients, AKI is linked to long-term CKD, prolonged hospital stays, cardiovascular events, mortality, and tumor relapse. Current AKI diagnostic criteria rely on serum creatinine (sCr), an inaccurate marker influenced by non-renal factors, with delayed increase and potential masking by hemodilution. Several new urinary and serum biomarkers offer improved AKI detection and CKD prediction. Early AKI detection is helpful, but early prediction of long-term eGFR decline is even more crucial. This study aimed to identify serum and urinary AKI markers predicting long-term GFR decline after robotic NSS. Various biomarkers were selected to represent different nephron injury sites and mechanisms (Figure 1). The biomarker kinetics within 24 h post-surgery and their AKI predictive capacity were also explored.

Existing literature highlights the limitations of serum creatinine (sCr) in accurately and timely diagnosing acute kidney injury (AKI) after partial nephrectomy (PN) or radical nephrectomy (RN). Studies have suggested the potential of biomarkers like serum cystatin C and urinary NGAL as early predictors of AKI post-surgery. However, many studies used non-validated AKI definitions and often lacked postoperative urinary output assessment. Furthermore, long-term kidney function after nephron-sparing surgery (NSS) and comprehensive comparisons of various AKI biomarkers are frequently absent in the literature. Promising biomarkers such as the NephroCheck test, acanthocytes in urinary sediment, and kineticGFR haven't been extensively explored in the context of NSS. This gap in the literature motivated the current study to comprehensively evaluate a panel of biomarkers for both early AKI detection and long-term GFR decline prediction after robotic PN.

This monocentric prospective observational study enrolled patients undergoing robotic NSS for suspected localized RCC at Careggi University Hospital between May 2017 and October 2017. Inclusion criteria included age >18 years, clinical evidence of a sporadic solid renal mass (T1, N0, M0), and at least two risk factors for long-term GFR decline (age >70 years, preoperative anemia, chronic heart failure (NYHA >2), diabetes, preoperative CKD). Patients with insufficient preoperative sCr values or preoperative eGFR <30 mL/min/1.73 m² were excluded. Data included demographics, clinical information, anesthesiologic and surgical variables. Postoperative AKI (according to KDIGO criteria) was assessed using sCr increase ≥0.3 mg/dL within 48 h or a 1.5-fold sCr increase within 7 days, or urine output <0.5 mL/kg/h for at least 6 h. Blood and urine samples were collected preoperatively and postoperatively (4 h, 10 h, 24 h, 48 h). Parameters analyzed included kineticGFR, hourly urinary output, plasma sCr, cystatin C, NGAL, urine protein, albumin, creatinine, NGAL, [TIMP-2] × [IGFBP7] (NephroCheck), and acanthocytes. Kidney function was reassessed up to 24 months postoperatively to evaluate long-term eGFR decline. Statistical analysis included ROC curves, univariate and multivariate logistic regression, Pearson correlation, and multiple linear regression with backward selection. A p-value <0.05 indicated significance. The study adhered to the Declaration of Helsinki, with ethics committee approval (BIO.16.015) and informed consent obtained from all participants.

Thirty-eight patients were included, with 16 (42%) developing clinical AKI. The 24-month eGFR decline was significantly greater in patients with postoperative AKI (−20.75 vs. −7.20 mL/min, p<0.0001). Multivariate linear regression showed that kineticGFR at 4 h (p=0.008) and NephroCheck at 10 h (p=0.001) were efficient predictors of postoperative AKI and long-term eGFR decline, outperforming sCr (R² 0.33 vs. 0.04). NephroCheck increase >0.3 was observed in 81% of AKI patients and 27% of non-AKI patients at 4 h, and 88% and 27% at 10h, respectively. Serum cystatin C increase ≥10% within 24 h was seen in 50% of AKI and 5% of non-AKI patients at 10 h. KineticGFR reduction ≥50% at 4 h occurred in 56% of AKI and 18% of non-AKI patients. KineticGFR and serum cystatin C showed high specificity for AKI prediction, while NephroCheck had high sensitivity. Postoperative serum and urinary NGAL, acanthocytes, and albuminuria were not significant predictors of AKI or long-term GFR decline. The median eGFR decline at 24 months was -11.5 mL/min, significantly greater in patients with AKI. Multiple linear regression confirmed NephroCheck at 10 h and kineticGFR at 4 h as independent predictors of 24-month eGFR decline. Only uNGAL, NephroCheck, and kineticGFR predicted long-term eGFR decline. KineticGFR at 4 h and urinary NephroCheck at 10 h predicted long-term GFR decline more efficiently than sCr (R² 0.33 vs. 0.04). The same model also efficiently predicted AKI, but 12-24 h earlier than sCr.

Early identification of patients susceptible to AKI and CKD post-renal tumor surgery is crucial for timely intervention and nephroprotection. This study demonstrated that urinary NephroCheck at 10 h and kineticGFR at 4 h post-robotic NSS were superior to sCr in predicting long-term eGFR decline and AKI diagnosis. Given sCr's limitations, a multiparametric approach is needed to assess postoperative kidney insult. Biomarkers provide earlier insight into AKI development and pathophysiology. Our study used a comprehensive panel of biomarkers, including the novel NephroCheck test, acanthocytes, and kineticGFR, unlike most previous studies. While many biomarkers were associated with clinical AKI, only a few predicted long-term GFR decline. The study aimed to identify biomarkers that improve AKI and long-term GFR decline prediction compared to standard sCr assessment. Postoperative sCr was an inaccurate predictor of long-term eGFR decline, while only uNGAL, NephroCheck, proteinuria, and kineticGFR significantly predicted it. The predictive model combining NephroCheck at 10 h and kineticGFR at 4 h identified AKI as efficiently as sCr but much earlier, allowing for timely nephroprotective strategies. This model included biomarkers of both kidney dysfunction and damage, aligning with recent consensus statements recommending a combined approach using damage and functional biomarkers along with clinical information.

Peri-operative blood and urine biomarkers can identify patients at higher risk for adverse long-term kidney outcomes. This study, the first to investigate NephroCheck and kineticGFR in urology, supports their potential role in NSS patients. NephroCheck and kineticGFR, readily available clinically, show promise for early AKI and long-term GFR decline prediction after PN. In NSS patients, they may improve diagnostic accuracy by complementing sCr.

The study's limitations include its monocentric design with a relatively small sample size (38 patients), limiting generalizability. Further multicenter studies with larger cohorts are needed to validate these findings. The clinical effectiveness and cost-effectiveness of these biomarkers still need to be proven before widespread implementation in urologic surgery.