Acute kidney injury after laparoscopic radical nephrectomy: role of the renin-angiotensin system and the predictive value of its activation status

doi:10.12122/j.issn.1673-4254.2024.11.19

Abstract

Abstract:

Objective To investigate the role of the renin-angiotensin system (RAS) in the pathogenesis of acute kidney injury (AKI) after laparoscopic radical nephrectomy (LRN) and the predictive value of RAS activation status for AKI. Methods Eighty-two patients undergoing LRN at the Third Medical Center of General Hospital of PLA from December, 2023 to March, 2024 were enrolled, including 57 with postoperative AKI and 25 without AKI according to KDIGO criteria. Blood and urine samples were collected from the patients before and at 24 h after the operation for analyzing the correlation of urinary aldosterone, plasma ACE2, Ang1-7, Nrf-2, and IL-10 levels with postoperative AKI. Univariate and multivariate logistic regression analyses and ROC curve were employed to identify the risk factors for postoperative AKI and their predictive value for AKI. Results Compared with those without postoperative AKI, the patients with AKI had significantly higher postoperative urinary aldosterone levels and lower plasma ACE 2, Ang 1-7, Nrf-2, and IL-10 levels (P<0.05). Postoperative urinary aldosterone level was positively correlated with AKI and negatively with estimated glomerular filtration rate (eGFR) (P<0.05); plasma levels of ACE 2, Nrf-2, and IL-10 were all negatively correlated with AKI and positively with eGFR. Urinary aldosterone was a risk factor and plasma ACE 2, Ang 1-7, Nrf-2 and IL-10 were protective factors for AKI, and among them urinary aldosterone was an independent risk factor (AUC=0.651) and plasma Nrf-2 was an independent protective factor (AUC=0.679). The unconventional RAS pathway indices had an AUC of 0.758, and aldosterone combined with the unconventional pathway indices had an AUC of 0.788 for predicting postoperative AKI. Conclusion Activation of the conventional RAS pathway and suppression of the unconventional pathway contribute to AKI following LRA possibly by affecting eGFR. Aldosterone combined with the unconventional pathway indicators can predict the occurrence of AKI after LRN.

Key words: acute kidney injury, radical nephrectomy, renin-angiotensin system

Jiaxin LI, Yi LIU, Xiangjie LIU, Longhe XU, Yongzhe LIU. Acute kidney injury after laparoscopic radical nephrectomy: role of the renin-angiotensin system and the predictive value of its activation status[J]. Journal of Southern Medical University, 2024, 44(11): 2220-2226.

Figures/Tables 6

References 33

1	Susantitaphong P, Cruz DN, Cerda J, et al. World incidence of AKI: a meta-analysis[J]. Clin J Am Soc Nephrol, 2013, 8(9): 1482-93.
2	Hur M, Park SK, Yoo S, et al. The association between intraoperative urine output and postoperative acute kidney injury differs between partial and radical nephrectomy[J]. Sci Rep, 2019, 9(1): 760.
3	Iwai M, Horiuchi M. Devil and angel in the renin-angiotensin system: ace-angiotensin II-AT1 receptor axis vs. ACE2-angiotensin-(1-7)-Mas receptor axis[J]. Hypertens Res, 2009, 32(7): 533-6.
4	Sharma N, Anders HJ, Gaikwad AB. Fiend and friend in the renin angiotensin system: an insight on acute kidney injury[J]. Biomed Pharmacother, 2019, 110: 764-74.
5	Martín-Fernández B, Rubio-Navarro A, Cortegano I, et al. Aldosterone induces renal fibrosis and inflammatory M1-macrophage subtype via mineralocorticoid receptor in rats[J]. PLoS One, 2016, 11(1): e0145946.
6	Fang F, Liu GC, Zhou XH, et al. Loss of ACE2 exacerbates murine renal ischemia-reperfusion injury[J]. PLoS One, 2013, 8(8): e71433.
7	Abdel-Hakeem EA, Abdel Hafez SMN, Kamel BA, et al. Angiotensin 1-7 mitigates rhabdomyolysis induced renal injury in rats via modulation of TLR-4/NF-kB/iNOS and Nrf-2/heme-oxygenase-1 signaling pathways[J]. Life Sci, 2022, 303: 120678.
8	Cheruku SR, Raphael J, Neyra JA, et al. Acute kidney injury after cardiac surgery: prediction, prevention, and management[J]. Anesthesiology, 2023, 139(6): 880-98.
9	Franzén S, Semenas E, Taavo M, et al. Renal function during sevoflurane or total intravenous propofol anaesthesia: a single-centre parallel randomised controlled study[J]. Br J Anaesth, 2022, 128(5): 838-48.
10	Kim NY, Chae D, Lee J, et al. Development of a risk scoring system for predicting acute kidney injury after minimally invasive partial and radical nephrectomy: a retrospective study[J]. Surg Endosc, 2021, 35(4): 1626-35.
11	Ellis RJ, del Vecchio SJ, Ng KL, et al. Factors associated with acutely elevated serum creatinine following radical tumour nephrectomy: the Correlates of Kidney Dysfunction-Tumour Nephrectomy Database study[J]. Transl Androl Urol, 2017, 6(5): 899-909.
12	Blasi ER, Rocha R, Rudolph AE, et al. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats[J]. Kidney Int, 2003, 63(5): 1791-800.
13	Rafiq K, Hitomi H, Nakano D, et al. Pathophysiological roles of aldosterone and mineralocorticoid receptor in the kidney[J]. J Pharmacol Sci, 2011, 115(1): 1-7.
14	Otsuka H, Abe M, Kobayashi H. The effect of aldosterone on cardiorenal and metabolic systems[J]. Int J Mol Sci, 2023, 24(6): 5370.
15	Dudoignon E, Moreno N, Deniau B, et al. Activation of the renin-angiotensin-aldosterone system is associated with Acute Kidney Injury in COVID-19[J]. Anaesth Crit Care Pain Med, 2020, 39(4): 453-5.
16	Cheungpasitporn W, Thongprayoon C, Srivali N, et al. Preoperative renin-angiotensin system inhibitors use linked to reduced acute kidney injury: a systematic review and meta-analysis[J]. Nephrol Dial Transplant, 2015, 30(6): 978-88.
17	Nakamura Y, Kobayashi H, Tanaka S, et al. Association between plasma aldosterone and markers of tubular and glomerular damage in primary aldosteronism[J]. Clin Endocrinol, 2021, 94(6): 920-6.
18	Donoghue M, Hsieh F, Baronas E, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9[J]. Circ Res, 2000, 87(5): E1-9.
19	Simões E Silva AC, Teixeira MM. ACE inhibition, ACE2 and angiotensin‑(1-7) axis in kidney and cardiac inflammation and fibrosis[J]. Pharmacol Res, 2016, 107: 154-62.
20	Wong DW, Oudit GY, Reich H, et al. Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury[J]. Am J Pathol, 2007, 171(2): 438-51.
21	Bae EH, Konvalinka A, Fang F, et al. Characterization of the intrarenal renin-angiotensin system in experimental alport syndrome[J]. Am J Pathol, 2015, 185(5): 1423-35.
22	Bae EH, Fang F, Williams VR, et al. Murine recombinant angiotensin-converting enzyme 2 attenuates kidney injury in experimentalAlport syndrome[J]. Kidney Int, 2017, 91(6): 1347-61.
23	Lu W, Kang J, Hu K, et al. Angiotensin-(1-7) relieved renal injury induced by chronic intermittent hypoxia in rats by reducing inflammation, oxidative stress and fibrosis[J]. Braz J Med Biol Res, 2017, 50(1): e5594.
24	Zhu Y, Xu DL, Deng F, et al. Angiotensin (1-7) attenuates sepsis-induced acute kidney injury by regulating the NF‑κB pathway[J]. Front Pharmacol, 2021, 12: 601909.
25	Wei W, Ma N, Fan XY, et al. The role of Nrf2 in acute kidney injury: novel molecular mechanisms and therapeutic approaches[J]. Free Radic Biol Med, 2020, 158: 1-12.
26	Guerrero-Hue M, Rayego-Mateos S, Vázquez-Carballo C, et al. Protective role of Nrf2 in renal disease[J]. Antioxidants, 2020, 10(1): 39.
27	Liu MC, Grigoryev DN, Crow MT, et al. Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice[J]. Kidney Int, 2009, 76(3): 277-85.
28	Nezu M, Souma T, Yu L, et al. Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression[J]. Kidney Int, 2017, 91(2): 387-401.
29	Li JW, Li L, Wang S, et al. Resveratrol alleviates inflammatory responses and oxidative stress in rat kidney ischemia-reperfusion injury and H₂O₂-induced NRK-52E cells via the Nrf2/TLR4/NF-κB pathway[J]. Cell Physiol Biochem, 2018, 45(4): 1677-89.
30	Sakai KJ, Nozaki Y, Murao Y, et al. Protective effect and mechanism of IL-10 on renal ischemia-reperfusion injury[J]. Lab Invest, 2019, 99(5): 671-83.
31	Wei W, Zhao YB, Zhang Y, et al. The role of IL-10 in kidney disease[J]. Int Immunopharmacol, 2022, 108: 108917.
32	Verma SK, Garikipati VNS, Krishnamurthy P, et al. Interleukin-10 inhibits bone marrow fibroblast progenitor cell-mediated cardiac fibrosis in pressure-overloaded myocardium[J]. Circulation, 2017, 136(10): 940-53.
33	Tibi S, Zeynalvand G, Mohsin H. Role of the renin angiotensin aldosterone system in the pathogenesis of sepsis-induced acute kidney injury: a systematic review[J]. J Clin Med, 2023, 12(14): 4566.

Characteristics	AKI group (n=57)	Non-AKI group (n=25)	t /χ²/Z	P
Age (year)	59.65±9.71	58.32±8.59	0.58	0.56
Gender (male/female)	41/16	11/14	5.84	0.02
BMI (kg/m²)	25.58±3.29	25.04±2.60	-0.72	0.48
Smoking [n (%)]	16 (28.1%)	6 (4%)	0.15	0.70
Alcohol consumption[n (%)]	12 (21.1%)	8 (32%)	1.13	0.29
Combined disease [n (%)]
Diabetes	6 (10.5%)	2 (8%)	0.13	0.72
Cardiovascular disease	3 (5.3%)	1 (4%)	0.06	0.81
blood volume	100 (50, 200)	100 (50, 250)	-0.67	0.50
urine output	100 (50, 175)	100 (50, 100)	-0.85	0.40
Crystalloid solution (mL)	1000 (1000, 1500)	1500 (1000, 1500)	-1.57	0.12
Surgery time (min)	160 (111.5, 222)	170 (111.5, 195)	-0.08	0.94
sCr (mmol/L)	70.29±11.67	65.48±12.59	-1.68	0.09
eGFR (mL/min/1.73 m² )	94.42±12.97	97.68±15.89	0.54	0.60

Characteristics	AKI group (n=57)	Non-AKI group (n=25)	t /χ²/Z	P
Age (year)	59.65±9.71	58.32±8.59	0.58	0.56
Gender (male/female)	41/16	11/14	5.84	0.02
BMI (kg/m²)	25.58±3.29	25.04±2.60	-0.72	0.48
Smoking [n (%)]	16 (28.1%)	6 (4%)	0.15	0.70
Alcohol consumption[n (%)]	12 (21.1%)	8 (32%)	1.13	0.29
Combined disease [n (%)]
Diabetes	6 (10.5%)	2 (8%)	0.13	0.72
Cardiovascular disease	3 (5.3%)	1 (4%)	0.06	0.81
blood volume	100 (50, 200)	100 (50, 250)	-0.67	0.50
urine output	100 (50, 175)	100 (50, 100)	-0.85	0.40
Crystalloid solution (mL)	1000 (1000, 1500)	1500 (1000, 1500)	-1.57	0.12
Surgery time (min)	160 (111.5, 222)	170 (111.5, 195)	-0.08	0.94
sCr (mmol/L)	70.29±11.67	65.48±12.59	-1.68	0.09
eGFR (mL/min/1.73 m² )	94.42±12.97	97.68±15.89	0.54	0.60

Variable	Time	AKI group (n=57)	Non-AKI group (n=25)	P
Urinary aldosterone (pg/mL)	T₁	362.63±53.87	381.27±38.26	0.122
Urinary aldosterone (pg/mL)	T₂	433.65±44.95	407.34±51.29	0.022
Plasma ACE 2 (pg/mL)	T₁	219.74±29.84	210.82±33.05	0.233
Plasma ACE 2 (pg/mL)	T₂	210.88±36.68	230.60±35.13	0.026
Plasma Ang 1-7 (pg/mL)	T₁	176.15±24.46	172.63±24.71	0.551
Plasma Ang 1-7 (pg/mL)	T₂	191.71±31.22	206.82±25.45	0.036
Plasma Nrf-2 (ng/mL)	T₁	1024.12±245.77	978.27±204.63	0.417
Plasma Nrf-2 (ng/mL)	T₂	1213.26±177.50	1314.99±172.10	0.018
Plasma IL-10 (pg/mL)	T₁	361.55±41.98	360.01±42.52	0.879
Plasma IL-10 (pg/mL)	T₂	331.06±40.14	351.49±40.67	0.038

Variable	Time	AKI group (n=57)	Non-AKI group (n=25)	P
Urinary aldosterone (pg/mL)	T₁	362.63±53.87	381.27±38.26	0.122
Urinary aldosterone (pg/mL)	T₂	433.65±44.95	407.34±51.29	0.022
Plasma ACE 2 (pg/mL)	T₁	219.74±29.84	210.82±33.05	0.233
Plasma ACE 2 (pg/mL)	T₂	210.88±36.68	230.60±35.13	0.026
Plasma Ang 1-7 (pg/mL)	T₁	176.15±24.46	172.63±24.71	0.551
Plasma Ang 1-7 (pg/mL)	T₂	191.71±31.22	206.82±25.45	0.036
Plasma Nrf-2 (ng/mL)	T₁	1024.12±245.77	978.27±204.63	0.417
Plasma Nrf-2 (ng/mL)	T₂	1213.26±177.50	1314.99±172.10	0.018
Plasma IL-10 (pg/mL)	T₁	361.55±41.98	360.01±42.52	0.879
Plasma IL-10 (pg/mL)	T₂	331.06±40.14	351.49±40.67	0.038

Characteristics	r	P
Urinary aldosterone (pg/mL)	-0.294	0.007
Plasma ACE 2 (pg/mL)	0.241	0.029
Plasma Ang 1-7 (pg/mL)	0.179	0.108
Plasma Nrf-2 (ng/mL)	0.274	0.013
Plasma IL-10 (pg/mL)	0.293	0.008