Gender-Specific Renal Function and Urinary Syndrome in Patients with Liver Cirrhosis of Alcoholic Etiology: Observational Study

Background. Gender has now been proven to have a significant impact on the development, course and outcome of a large number of diseases, including alcoholic liver disease. Alcohol consumption is one of the leading risk factors for various diseases. Alcohol-related diseases cause 10% of all deaths worldwide among young and middle-aged people. The occurrence of renal dysfunction in cirrhosis of the liver is an integral part of the natural course of the disease. At the moment, the diagnosis of gender-specific renal dysfunction that occurs against the background of liver cirrhosis is essential for the development of effective treatment strategies and the improvement of survival.

Objectives. The study is aimed at identifying the features of the gender-specific renal function and urinary syndrome in patients with liver cirrhosis of alcoholic etiology and assessing the comprehensive prognostic significance of the indicators of common urine analysis in the diagnosis of renal dysfunction.

Methods. An observational study was carried out using data from medical records of 158 patients with alcoholic liver cirrhosis (95 men and 63 women), aged 36 to 72 years, who were inpatients between February 2016 and March 2020. Physical examination and laboratory diagnostic data were taken into account. Binary predictors of renal dysfunction progression in patients with alcoholic liver cirrhosis were determined based on the analysis of descriptive statistics. Statistical data processing was performed using computer program Statistica 10 (StatSoft, Inc., USA) and standard Microsoft Excel software package (Microsoft Office 2016). Non-parametric statistical methods were used to describe the results. Quantitative results were analyzed using the Mann-Whitney test; comparison of two samples by a qualitatively defined feature was performed by means of the Fisher angular transformation method. Differences were considered significant at p ˂ 0.05. A multilayer neural network function from the Statistica 10 Neural Networks software was used to construct a classification scheme for renal dysfunction (yes/no). Neural network performance was assessed using descriptive and inductive statistics, calculating sensitivity, specificity, performing ROC analysis and constructing cumulative gains charts.

Results. A renal function test revealed a significant decrease in glomerular filtration rate (p = 0.029) and a significant increase in urinary albumin/creatinine ratio (p < 0.0001) in women with alcoholic liver cirrhosis as compared with men. Women are also reported to have a high incidence of proteinuria, leukocyturia and bacteriuria. According to ROC-analysis, the urinalysis indicators have a high prognostic significance in identifying renal dysfunction in men and women with alcoholic liver cirrhosis (AUROC = 0.902 and sensitivity 81.82%, AUROC = 0.881 and sensitivity 75.00%, respectively).

Conclusion. Renal dysfunction develops earlier and occurs twice as often in women with alcoholic cirrhosis than in men of the same age. The application of a neural network mechanism to predict renal dysfunction in men and women with alcoholic liver cirrhosis according to the indicators of urinalysis provides a high prognostic ability.

1. Grego S., Pasotti E., Moccetti T., Maggioni A.P. “Sex and gender medicine”: il principio della medicina di genere [Sex and gender medicine: the foundation of gender medicine]. G. Ital. Cardiol. (Rome). 2020; 21(8): 602–606 (Italian). DOI: 10.1714/3405.33894.

2. Durazzo M., Belci P., Collo A., Prandi V., Pistone E., Martorana M., Gambino R., Bo S. Gender specific medicine in liver diseases: a point of view. World J. Gastroenterol. 2014; 20(9): 2127–2135. DOI: 10.3748/wjg.v20.i9.2127

3. Rubin J.B., Srisengfa Y.T., Albhaisi S., Acharya C., Nangia G., Shaikh T., Thacker L.R., Reddy K.R., Tandon P., Bajaj J.S., Lai J.C. Hospitalized Women With Cirrhosis Have More Nonhepatic Comorbidities and Associated Complications Than Men. Clin. Gastroenterol. Hepatol. 2020; 18(13): 3046–3048. DOI: 10.1016/j.cgh.2019.09.043

4. Peacock A., Leung J., Larney S., Colledge S., Hickman M., Rehm J., Giovino G.A., West R., Hall W., Griffiths P., Ali R., Gowing L., Marsden J, Ferrari AJ, Grebely J, Farrell M, Degenhardt L. Global statistics on alcohol, tobacco and illicit drug use: 2017 status report. Addiction. 2018; 113(10): 1905–1926. DOI: 10.1111/add.14234

5. GBD 2017 Cirrhosis Collaborators. The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol. Hepatol. 2020; 5(3): 245–266. DOI: 10.1016/S2468-1253(19)30349-8

6. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. J. Hepatol. 2018; 69(1): 154–181. DOI: 10.1016/j.jhep.2018.03.018

7. Kim D.K., Kim Y.H., Jang H.H., Park J., Kim J.R., Koh M., Jeong W.I., Koo S.H., Park T.S., Yun C.H., Park S.B., Chiang J.Y.L., Lee C.H., Choi H.S. Estrogen-related receptor γ controls hepatic CB1 receptor-mediated CYP2E1 expression and oxidative liver injury by alcohol. Gut. 2013; 62(7): 1044–1054. DOI: 10.1136/gutjnl-2012-303347

8. Bataller R., Cabezas J., Aller R., Ventura-Cots M., Abad J., Albillos A., Altamirano J., Arias-Loste M.T., Bañares R., Caballería J., Caballería L., Carrión J.A., Diago M., Fernández Rodríguez C., Gallego R., García-Cortes M., García-Monzón C., Genescà J., Ginés P., Hernandez-Guerra M., Jorquera F., Lligoña A., Molina E., Pareja M.J., Planas R., Tomé S., Salmerón J., Romero-Gómez M. Alcohol-related liver disease. Clinical practice guidelines. Consensus document sponsored by AEEH. Gastroenterol. Hepatol. 2019; 42(10): 657–676 (English, Spanish). DOI: 10.1016/j.gastrohep.2019.09.006

9. Ivashkin V.T., Mayevskaya M.V., Pavlov C.S., Sivolap Yu.P., Lunkov V.D., Zharkova M.S., Maslennikov R.V. Management of adult patients with alcoholic liver disease: clinical guidelines of the Russian Scientific Liver Society. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2017; 27(6): 20–40 (In Russ., English abstract). DOI: 10.22416/1382-4376-2017-27-6-20-40

10. Milic J., Glisic M., Voortman T., Borba L.P., Asllanaj E., Rojas L.Z., Troup J., Kiefte-de Jong J.C., van Beeck E., Muka T., Franco O.H. Menopause, ageing, and alcohol use disorders in women. Maturitas. 2018; 111: 100–109. DOI: 10.1016/j.maturitas.2018.03.006

11. Huelin P., Piano S., Solà E., Stanco M., Solé C., Moreira R., Pose E., Fasolato S., Fabrellas N., de Prada G., Pilutti C., Graupera I., Ariza X., Romano A., Elia C., Cárdenas A., Fernández J., Angeli P., Ginès P. Validation of a Staging System for Acute Kidney Injury in Patients With Cirrhosis and Association With Acute-on-Chronic Liver Failure. Clin. Gastroenterol. Hepatol. 2017; 15(3): 438–445.e5. DOI: 10.1016/j.cgh.2016.09.156

12. Parke C.Y., Martin P., Bunnapradist S. Renal dysfunction in cirrhosis. Clin. Liver Dis. (Hoboken). 2015; 5(6): 150–153. DOI: 10.1002/cld.485

13. Lum E.L., Homkrailas P., Bunnapradist S. Evaluation of Renal Disease in Patients With Cirrhosis. J. Clin. Gastroenterol. 2020; 54(4): 314–321. DOI: 10.1097/MCG.0000000000001325

14. Mikhailova Z.D., Pivovarov D.V., Pivovarova A.R. Kidney as a Target Organ in Cardiac Oncology. Kuban Scientific Medical Bulletin. 2020; 27(3): 92–104 (In Russ., English abstract). DOI: 10.25207/1608-6228-2020-27-3-92-104

15. Angeli P., Garcia-Tsao G., Nadim M.K., Parikh C.R. News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the International Club of Ascites (ICA) consensus document. J. Hepatol. 2019; 71(4): 811–822. DOI: 10.1016/j.jhep.2019.07.002

16. Huelin P., Solà E., Elia C., Solé C., Risso A., Moreira R., Carol M., Fabrellas N., Bassegoda O., Juanola A., de Prada G., Albertos S., Piano S., Graupera I., Ariza X., Napoleone L., Pose E., Filella X., Morales-Ruiz M., Rios J., Fernández J., Jiménez W., Poch E., Torres F., Ginès P. Neutrophil Gelatinase-Associated Lipocalin for Assessment of Acute Kidney Injury in Cirrhosis: A Prospective Study. Hepatology. 2019; 70(1): 319–333. DOI: 10.1002/hep.30592

17. Kim T.H., Lee H.A., Seo Y.S., Lee Y.R., Yim S.Y., Lee Y.S., Suh S.J., Jung Y.K., Kim J.H., An H., Yim H.J., Yeon J.E., Byun K.S., Um S.H.; Korean Study Group of Portal Hypertension. Assessment and prediction of acute kidney injury in patients with decompensated cirrhosis with serum cystatin C and urine N-acetyl-β-D-glucosaminidase. J. Gastroenterol. Hepatol. 2019; 34(1): 234–240. DOI: 10.1111/jgh.14387

18. Rognant N., Lemoine S. Evaluation of renal function in patients with cirrhosis: where are we now? World J. Gastroenterol. 2014; 20(10): 2533–2541. DOI: 10.3748/wjg.v20.i10.2533

19. Lazebnik L.B., Golovanova E.V., Tarasova L.V., Krivosheev A.B., Sas E.I., Eremina E.Yu., Trukhan D.I., Hlynova O.V., Tsyganova Yu.V. Adult Alcoholic Liver Disease. Experimental and Clinical Gastroenterology. 2020; 174(2): 4–28 (In Russ., English abstract). DOI: 10.31146/1682-8658-ecg-174-2-4-28

20. Dronov S.V., Fomenko A.P. A method for estimating the predictive power of a binary indicator. Izvestiya of Altai State University. 2017; 4(96): 89–93 (In Russ., English abstract). DOI: 10.14258/izvasu(2017)4-15

21. Lazarenko V.A., Antonov A.E., Markapuram V.K., Awad K. Experience of neuronet diagnosis and prediction of peptic ulcer disease by results of risk factors’ analysis. Bulletin of Siberian Medicine. 2018; 17(3): 88–95 (In Russ., English abstract). DOI: 10.20538/1682-0363-2018-3-88-95

22. Weaver R.G., James M.T., Ravani P., Weaver C.G.W., Lamb E.J., Tonelli M., Manns B.J., Quinn R.R., Jun M., Hemmelgarn B.R. Estimating Urine Albumin-to-Creatinine Ratio from Protein-to-Creatinine Ratio: Development of Equations using Same-Day Measurements. J. Am. Soc. Nephrol. 2020; 31(3): 591–601. DOI: 10.1681/ASN.2019060605

23. Mejia J.R., Fernandez-Chinguel J.E., Dolores-Maldonado G., Becerra-Chauca N., Goicochea-Lugo S., Herrera-Añazco P., Zafra-Tanaka J.H., Taype-Rondan A. Diagnostic accuracy of urine dipstick testing for albumin-to-creatinine ratio and albuminuria: A systematic review and meta-analysis. Heliyon. 2021; 7(11): e08253. DOI: 10.1016/j.heliyon.2021.e08253

24. Tran A.C., Melchinger H., Weinstein J., Shaw M., Kent C., Perazella M.A., Wilson F.P., Parikh C.R., Moledina D.G. Urine testing to differentiate glomerular from tubulointerstitial diseases on kidney biopsy. Pract. Lab. Med. 2022; 30: e00271. DOI: 10.1016/j.plabm.2022.e00271

25. Hamadah A.M., Gharaibeh K., Mara K.C., Thompson K.A., Lieske J.C., Said S., Nasr S.H., Leung N. Urinalysis for the diagnosis of glomerulonephritis: role of dysmorphic red blood cells. Nephrol. Dial. Transplant. 2018; 33(8): 1397–1403. DOI: 10.1093/ndt/gfx274

26. Yoo J.J., Kim S.G., Kim Y.S., Lee B., Lee M.H., Jeong S.W., Jang J.Y., Lee S.H., Kim H.S., Kim Y.D., Cheon G.J. Estimation of renal function in patients with liver cirrhosis: Impact of muscle mass and sex. J. Hepatol. 2019; 70(5): 847–854. DOI: 10.1016/j.jhep.2018.12.030

27. Fagundes C., Barreto R., Guevara M., Garcia E., Solà E., Rodríguez E., Graupera I., Ariza X., Pereira G., Alfaro I., Cárdenas A., Fernández J., Poch E., Ginès P. A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J. Hepatol. 2013; 59(3): 474–481. DOI: 10.1016/j.jhep.2013.04.036

28. Ohashi N., Tsuji N., Naito Y., Iwakura T., Isobe S., Ono M., Fujikura T., Tsuji T., Sakao Y., Yasuda H., Kawamura K., Sakaguchi T., Kato A., Fujigaki Y. Relationship between urinary fractional excretion of sodium and life prognosis in liver cirrhosis patients. Hepatol. Res. 2013; 43(11): 1156–1162. DOI: 10.1111/hepr.12068

29. Béjar-Serrano S., Del Pozo P., Fernández-de la Varga M., Benlloch S. Multidrug-resistant bacterial infections in patients with liver cirrhosis in a tertiary referral hospital. Gastroenterol. Hepatol. 2019; 42(4): 228–238 (English, Spanish). DOI: 10.1016/j.gastrohep.2018.07.017

30. Bessonov P.D., Borzunov I.V., Bessonova E.N. Urinary tract infections in patients with decompensated liver cirrhosis, listed for liver transplantation. Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2017; 27(5): 57–64 (In Russ., English abstract). DOI: 10.22416/1382-4376-2017-27-5-57-64

31. Piotrowski D., Sączewska-Piotrowska A., Jaroszewicz J., Boroń-Kaczmarska A. Lymphocyte-To-Monocyte Ratio as the Best Simple Predictor of Bacterial Infection in Patients with Liver Cirrhosis. Int. J. Environ. Res. Public Health. 2020; 17(5): 1727. DOI: 10.3390/ijerph17051727