Evaluation of the cisplatin nephrotoxicity using the urinary neutrophil
               gelatinase-associated lipocalin (NGAL) in patients with head and neck
               cancer

Peres, Luis Alberto Batista; Cunha Júnior, Ademar Dantas da; Assumpção, Rosangela Aparecida Botinha; Schäfer, Alex Júnior; Silva, Aline Liene da; Gaspar, Arianne Ditzel; Scarpari, Deborah Francisca; Alves, Julia Barazetti Ferrari; Girelli Neto, Rodolfo; Oliveira, Thaís Figueiredo Teodoro de

doi:10.5935/0101-2800.20140041

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Brazilian Journal of Nephrology

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Original Articles • J Bras Nefrol 36 (3) • Jul-Sep 2014 • https://doi.org/10.5935/0101-2800.20140041 copy

Evaluation of the cisplatin nephrotoxicity using the urinary neutrophil gelatinase-associated lipocalin (NGAL) in patients with head and neck cancer

Authorship SCIMAGO INSTITUTIONS RANKINGS

Introduction:

Acute kidney injury (AKI) in patients receiving cisplatin is common, therefore the evaluation of renal function in patients on use of nephrotoxic drugs is fundamental.

Objective:

To evaluate the incidence of AKI and the role of lipocalin associated to neutrophil gelatinase (NGAL) in the monitoring of renal function in patients with head and neck cancer (HNC) who received cisplatin.

Methods:

We prospectively studied 50 patients with HNC treated with three sessions of cisplatin. Blood and urine were collected 24 hours before cisplatin, 24 hours after infusion, 48 hours after each application and 35 days after the end of treatment (urine NGAL, C-reactive protein, creatinine, glomerular filtration rate, plasma lactate dehydrogenase and magnesium).

Results:

AKI was observed in 78% of patients. There was increase in creatinine, and decrease in GFR after each cycle of cisplatin, and increased urine NGAL. Positive association was observed between the levels of NGAL, creatinine and C-reactive protein. It was observed an increase in creatinine, NGAL, C-reactive protein and decreased GFR in AKI patients compared to patients without AKI.

Conclusion:

AKI was noted in 78% of patients with HNC treated with cisplatin and showed the correlation of NGAL with creatinine and GFR in demonstrating renal injury. NGAL levels may be elevated compared to baseline levels, even before the use of cisplatin.

acute kidney injury; cisplatin; lipocalins

Variable		n (%)
Age (years - mean ± SD)	58.5 ± 9.1	50 (100%)
Gender	Male	40 (80%)
Gender	Female	10 (20%)
Histopathology	Adenocarcinoma	2 (4%)
	Adenoid cystic carcinoma	1 (2%)
	Squamous cell carcinoma	47 (94%)
Tumor site	Oral cavity	7 (14%)
	Oropharynx	22 (44%)
	Larynx	10 (20%)
	Other	11 (22%)
Staging	III	15 (30%)
Staging	IV	35 (70%)
	Mean ± SD
Creatinine (mg/dL)	0.83 ± 0.23
GFR (ml/min/1.73 m²)	108.3 ± 35.5
Urea (mg/dL)	30.1 ± 8.9
NGAL (μg/L)	25.0 ± 22.3
Magnesium (mg/dL)	2.0 ± 0.2
Sodium (mEq/L)	136.4 ± 3.7
Potassium (mEq/L)	4.4 ± 0.4
Calcium (mg/dL)	9.2 ± 0.6
CRP (mg/dL)	2.3 ± 4.0
LDH (U/L)	199.8 ± 70.4
Hemoglobin (g/dL)	13.0 ± 1.6
Segmented (cells/mm³)	6151.0 ± 2953.2
Lymphocytes (cells/mm³)	1898.1 ± 691.1
Albumin (g/dL)	5.2 ± 6.2
GPT (U/L)	84.8 ± 32.4
Alkaline phosphatase (U/L)	9.2 ± 0.5

Variables	D0	D1	D3	D21	D22	D24	D42	D43	D45	D78
Mg (mg/dl)	1.99	1.84	1.92	1.77	1.64^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;	1.72^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;	1.49^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;	1.44^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;	1.49^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;	1.43^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;
Cr (mg/dl)	0.81	0.84	1.11^• l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	1.01	0.99	1.40^• l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	1.03	0.95	1.21^• l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	1.11^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;
GRF (ml/min/1.73 m²)	100.7	90.01	70.75^• l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	76.10	80.6	52.84^• l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	75.24	85.07	54.20^• l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	71.02^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;
Urea (mg/dL)	30.05	26.00	46.00^• l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	37.70	30.9	54.05^• l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	40.60	34.70	60.25^• l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	40.95^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;
NGAL (μg/L)	20.10	10.00^l l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	37.95^!! !! p < 0.05 (Dunn's post test following the Kruskal-Wallis test) on D1;	55.60^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;	16.85^l l p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative 48 hours after cisplatin infusion (D3, D24, D45) and 24 hours before cisplatin infusion (D21, D42). Cr: Creatinine;	69.90^‡ • p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative to values 24 hours before each cycle (D0, D21, D42) and within 24 hours of cisplatin infusion (D1, D22, D43);	57.50^‡ • p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative to values 24 hours before each cycle (D0, D21, D42) and within 24 hours of cisplatin infusion (D1, D22, D43);	16.55	45.00^‡ • p < 0.05 (Dunn's post test following the Kruskal-Wallis test) relative to values 24 hours before each cycle (D0, D21, D42) and within 24 hours of cisplatin infusion (D1, D22, D43);	37.40^!! !! p < 0.05 (Dunn's post test following the Kruskal-Wallis test) on D1;
CRP (mg/dl)	0.98	0.93	1.08	1.91	3.00	1.68	4.74^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;	4.55^† † p < 0.05 (Dunn's post test following the Kruskal-Wallis test): relative to D0 and D1;	2.64	2.37

Variable	AKI (n = 39)	No AKI (n = 11)	p -value	Residual kidney disease (n = 16)	No residual kidney disease (n = 11)	p -value
Age (years)	58.1 ± 8.9	60.3 ± 9.5	0.725^† † p -value from Student's f-test;	59.3 ± 9.6	60.8 ± 9.5	0.342^† † p -value from Student's f-test;
Males (n)	31 (79%)	10 (90%)	0.807^* * p -value from Fisher's exact test;	11 (68%)	10 (90%)	0.771^* * p -value from Fisher's exact test;
Body surface area (m²)	1.6 ± 0.3	1.56 ± 0.16	0.325^‡ ‡ p -value from Mann-Whitney U test.	1.71 ± 0.23	1.5 ± 0.16	0.126^‡ ‡ p -value from Mann-Whitney U test.
Creatinine (mg/dL)	0.80 ± 0.18	0.88 ± 0.35	0.914^† † p -value from Student's f-test;	1.60 ± 0.48	0.8 ± 0.2	< 0.0001^† † p -value from Student's f-test;
GFR (ml/min/1.73 m²)	109.2 ± 34.5	103.7 ± 38.9	0.350^‡ ‡ p -value from Mann-Whitney U test.	46.38 ± 10.28	104.6 ± 40.1	0.0010^‡ ‡ p -value from Mann-Whitney U test.
Urea (mg/dL)	29.93 ± 9.1	30.4 ± 7.9	0.476^† † p -value from Student's f-test;	65.6 ± 35.0	50.48 ± 38.03	0.135^‡ ‡ p -value from Mann-Whitney U test.
NGAL (μg/L)	24.5 ± 23.93	27.5 ± 9.4	0.209^‡ ‡ p -value from Mann-Whitney U test.	97.34 ± 93.67	56.0 ± 54.01	0.1228^‡ ‡ p -value from Mann-Whitney U test.
Magnesium (mg/dL)	1.96 ± 0.25	2.02 ± 0.20	0.085^† † p -value from Student's f-test;	1.63 ± 0.31	1.5 ± 0.2	0.316^‡ ‡ p -value from Mann-Whitney U test.
Sodium (mEq/L)	136 ± 3.4	136.88 ± 4.7	0.865^‡ ‡ p -value from Mann-Whitney U test.	132.7 ± 4.8	133.2 ± 3.9	0.891^‡ ‡ p -value from Mann-Whitney U test.
Potassium (mEq/L)	4.3 ± 0.37	4.76 ± 0.37	0.848^† † p -value from Student's f-test;	4.8 ± 0.9	4.4 ± 0.38	0.640^‡ ‡ p -value from Mann-Whitney U test.
Calcium (mg/dL)	9.1 ± 0.52	9.6 ± 0.72	0.200^‡ ‡ p -value from Mann-Whitney U test.	9.0 ± 0.7	8.7 ± 0.4	0.427^† † p -value from Student's f-test;
CRP (mg/dL)	2.23 ± 3.92	2.6 ± 4.4	0.982^‡ ‡ p -value from Mann-Whitney U test.	5.2 ± 5.0	2.5 ± 1.8	0.192^‡ ‡ p -value from Mann-Whitney U test.
LDH (U/L)	202.7 ± 76.1	196.6 ± 35.5	0.742^‡ ‡ p -value from Mann-Whitney U test.	188.4 ± 43.1	195 ± 85.7	0.841^‡ ‡ p -value from Mann-Whitney U test.
Hemoglobin (g/dL)	13.1 ± 1.6	12.3 ± 1.2	0.326^† † p -value from Student's f-test;	10.19 ± 1.46	10.8 ± 0.68	0.420^† † p -value from Student's f-test;
Segmented (cells/mm³)	5974.02 ± 3003.1	6859.1 ± 2793.6	0.147^‡ ‡ p -value from Mann-Whitney U test.	5013.5 ± 3727	2957 ± 813	0.183^† † p -value from Student's f-test;
Lymphocytes (cells/mm³)	1819.8 ± 733.5	1821.4 ± 521.37	0.370^† † p -value from Student's f-test;	852.1 ± 359.3	745 ± 438	0.438^† † p -value from Student's f-test;
Albumin (g/dL)	4.2 ± 0.39	3.9 ± 0.32	0.400^† † p -value from Student's f-test;	3.7 ± 0.4	3.6 ± 0.4	0.828^† † p -value from Student's f-test;
GPT (U/L)	26.9 ± 15.8	22.27 ± 16.7	0.394^‡ ‡ p -value from Mann-Whitney U test.	23.9 ± 18.0	17.1 ± 9.0	0.473^† † p -value from Student's f-test;
Alkaline phosphatase (U/L)	87.8 ± 33.5	66.51 ± 15.3	0.063^‡ ‡ p -value from Mann-Whitney U test.	100.4 ± 30.8	85.6 ± 28.0	0.150^† † p -value from Student's f-test;

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[1] Correspondence to: Luis Alberto Batista Peres. State University of Western Paraná (UNIOESTE). Rua Vicente Machado, nº 2687, Country. Cascavel, PR, Brasil. CEP: 85813-250. E-mail: peres@certto.com.br