Assessment of novel biomarkers of renal dysfunction associated with lower urinary tract symptoms in men with benign prostatic hyperplasia

Introduction. The problem of diagnostics and treatment of patients with complex lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH) remains highly relevant. Clinical diagnostic methods do not always allow timely prediction of changes in renal, upper and lower urinary tract function with different types of treatment intervention. The search for potential biomarkers allowing minimally invasive assessment of the bladder and renal function condition seems to be a promising direction of scientific research.

Objective. To identify potential urine and serum biomarkers allowing to assess renal function in patients with LUTS/BPH.

Materials & methods. The study included 69 patients with LUTS/BPH and subsequently divided them into two groups. Group 1 included 48 patients with moderate LUTS who received combination therapy with alpha-1 adrenergic blockers (AABs) and 5-alpha reductase inhibitors (5ARIs). Group 2 included 21 patients with severe LUTS/BPH. Patients of group 2 underwent surgical treatment: transurethral resection of the prostate. In addition to standard research methods (IPSS, voiding diaries, laboratory, urodynamic and radiation techniques), to search for potential biomarkers in serum and urine, concentrations of: insulin-like growth factor binding protein-7 (IGFBP7), B-Cross Laps, Cystatin C, OPN, trefoil factor (TFF3), uromodulin, Clusterin, lactate dehydrogenase (LDH). The follow-up period for patients was 12 months.

Results. The study noted that IGFBP7, Cystatin C, TFF3 in the blood serum, as well as LDH, Clusterin in the urine are associated with the severity of LUTS/BPH. Serum biomarker levels were initially higher in patients with severe LUTS compared to patients with moderate LUTS (group 1). The levels of these substrates decreased in patients of all groups during treatment (conservative therapy, surgical interventions for BPH). When assessing urinary biomarkers, the greatest decrease in Clusterin level by the end of follow-up was registered in group 1 patients, the least pronounced in group 2 patients. The initial value of LDH was twice higher in group 2 vs group 1 and progressively decreased after surgical treatment of bladder outlet obstruction.

Conclusion. Biomarkers used to assess renal dysfunction in the development of LUTS/BPH are a promising area of scientific research. Panels of new markers will enable to predict renal dysfunction in patients with moderate-to-severe LUTS, which will improve the quality of medical care for this category of patients.

1. Zemskova S.S., Shabunina V.I., Gertner L.V., Muchin V.B., Iljina E.B., Korjakin A.V. Influence of surgical and conservative treatment of diseases urogenital at reactivity immunologic of patients. Journal of Experimental and Clinical Surgery. 2010;3(4):408-414. (In Russian). DOI: 10.18499/2070-478X-2010-3-4-408-414

2. Vasconcelos CTM, Gomes MLS, Geoffrion R, Saboia DM, Bezerra KC, Vasconcelos Neto JA.Pessary evaluation for genital prolapse treatment: From acceptance to successful fitting. Neurourol Urodyn. 2020;39(8):2344-2352. DOI: 10.1002/nau.24493

3. Apolihin O.I., Komarova V.A., Nikushina A.A., Sivkov A.V. Prostate diseases in the Russian Federation: statistical data for 2008-2017. Experimental and clinical urology. 2019;4:114-121. (In Russian). DOI: 10.29188/2222-8543-2019-11-2-4-12

4. Koroteev M.A., Korenkov D.G., Mikhailichenko V.V. Early prevention of infectious and inflammatory complications of transurethral resection of benign prostatic hyperplasia. Andrology and Genital Surgery. 2008(2):55-61. (In Russian).

5. Wong A, Mahmalji W. The role of Rezūm ™ team ablation of the prostate in the treatment of patients with acute urinary retention secondary to benign prostatic hyperplasia. A single center, single surgeon case series and literature review. Aging Male. 2020;23(5):1620-1626. DOI: 10.1080/13685538.2021.1901273

6. Dudarev V.A., Koshmelev A.A., Starcev V.Yu. Frequency and causes of complications of benign prostatic hyperplasia, by the research of residents of the region of Russia (Zabaykalsky territory). Transbaikalian Medical Bulletin. 2017;2:161-169. (In Russian). eLIBRARY ID: 29409312; EDN: YTOQZV

7. Startsev V.Yu., Dudarev V.A., Koshmelev A.A. Causes of complications of prostatic hyperplasia in residents of the Russian region. Urology reports. 2017;7(S):101-102. (In Russian). eLIBRARY ID: 29246515; EDN: YQAATP

8. Swavely NR, Speich JE, Stothers L, Klausner AP. New Diagnostics for Male Lower Urinary Tract Symptoms. Curr Bladder Dysfunct Rep. 2019;14:90-97. DOI: 10.1007/s11884-019-00511-0

9. Cho KJ, Koh JS, Choi J, Kim JC. Changes in Adenosine Triphosphate and Nitric Oxide in the Urothelium of Patients with Benign Prostatic Hyperplasia and Detrusor Underactivity. J Urol. 2017;198(6):1392-1396. DOI: 10.1016/j.juro.2017.06.080

10. Dudarev V.A., Startsev V.Yu. Factors predicting the development of urinary tract disorders in prostatic hyperplasia in elderly men. Urologija. 2018;6:150-154. (In Russian). DOI: 10.18565/urology.2018.6.150-154

11. Gharaee-Kermani M, Macoska JA. Promising molecular targets and biomarkers for male BPH and LUTS. Curr Urol Rep. 2013;14(6):628-637. DOI: 10.1007/s11934-013-0368-z

12. Young S, Gasparetto A, Jalaeian H, Golzarian J. Biomarkers in the setting of benign prostatic hyperplasia-induced lower urinary tract symptoms: what an interventional radiologist needs to know. Br J Radiol. 2020;93(1114):20200484. DOI: 10.1259/bjr.20200484

13. Ma J, Gharaee-Kermani M, Kunju L, Hollingsworth JM, Adler J, Arruda EM, Macoska JA. Prostatic fibrosis is associated with lower urinary tract symptoms. J Urol. 2012;188(4):1375-1381. DOI: 10.1016/j.juro.2012.06.007

14. Rodriguez-Nieves JA, Macoska JA. Prostatic fibrosis, lower urinary tract symptoms, and BPH. Nat Rev Urol. 2013;10(9):546-550. DOI: 10.1038/nrurol.2013.149

15. Gheinani AH, Kiss B, Moltzahn F, Keller I, Bruggmann R, Rehrauer H, Fournier CA, Burkhard FC, Monastyrskaya K. Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction. JCI Insight. 2017;2(2):e89560. DOI: 10.1172/jci.insight.89560

16. Akhokhov Z.M., Ismailov R.S., Kogan M.I. MicroRNAs as molecular biological markers of benign hyperplasia and prostate cancer differentiation. Urology Herald. 2023;11(3):98-107. (In Russian). DOI: 10.21886/2308-6424-2023-11-3-98-107

17. Kirpatovsky V.I., Mudraya I.S., Fedyakov R.P., Golovanov S.A., Drozhzheva V.V., Chernikov D.U., Eliseev D.E., Nadtochy O.N., Syromyatnikova E.V. Enzymuria as a marker of bladder damage in acute urinary retention V. Experimental and clinical urology. 2012;1:20-23. (In Russian). eLIBRARY ID: 17775523; EDN: OYZNNP

18. Kobalava ZhD, Villeval’de SV, Efremovtseva MA, Moiseev VS. Biomarkers of acute kidney injury: Current views and prospects. Terapevticheskii Arkhiv. 2014;86(6):88-93. (In Russian). eLIBRARY ID: 22372998; EDN: SVPHNF

19. Kirpatovskiy V.I., Orlova E.V., Kharlamova L.A., Golovanov S.A., Drozhzheva V.V., Frolova E.V. The significance of dynamic detection of Cystatin C concentration in the blood as a marker of the risk of transition of acute kidney injury to chronic renal failure and the effectiveness of nephroprotective therapy. Experimental and Clinical Urology. 2021;14(4):20-29. (In Russian). DOI: 10.29188/2222-8543-2021-14-4-20-29

20. Mello MF, de Bessa J Júnior, Reis ST, Kondo EY, Yu L, Dénes FT, Lopes RI. Evaluating TIMP-2 and IGFBP-7 as a predictive tool for kidney injury in ureteropelvic junction obstruction. Int Braz J Urol. 2022;48(2):284-293. DOI: 10.1590/S1677-5538.IBJU.2021.0340

21. Nalesso F, Cattarin L, Gobbi L, Fragasso A, Garzotto F, Calò LA. Evaluating Nephrocheck® as a Predictive Tool for Acute Kidney Injury. Int J Nephrol Renovasc Dis. 2020;13:85-96. DOI: 10.2147/IJNRD.S198222

22. Devarajan P. Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of kidney disease. Scand J Clin Lab Invest Suppl. 2008;241:89-94. DOI: 10.1080/00365510802150158

23. Prokopyeva N.E., Novikova V.P. Recent biomarkers of renal injure. Medicine: Theory and Practice, 3(3 app), 29-35. (In Russian) eLIBRARY ID: 36546415; EDN: YPURYT

24. Astor BC, Köttgen A, Hwang SJ, Bhavsar N, Fox CS, Coresh J. Trefoil factor 3 predicts incident chronic kidney disease: a case-control study nested within the Atherosclerosis Risk in Communities (ARIC) study. Am J Nephrol. 2011;34(4):291-297. DOI: 10.1159/000330699

25. Tanaka K, Sugiyama H, Yamanari T, Mise K, Morinaga H, Kitagawa M, Onishi A, Ogawa-Akiyama A, Tanabe K, Eguchi J, Ohmoto Y, Shikata K, Wada J. Renal expression of trefoil factor 3 mRNA in association with tubulointerstitial fibrosis in IgA nephropathy. Nephrology (Carlton). 2018;23(9):855-862. DOI: 10.1111/nep.13444

26. Rinnert M, Hinz M, Buhtz P, Reiher F, Lessel W, Hoffmann W. Synthesis and localization of trefoil factor family (TFF) peptides in the human urinary tract and TFF2 excretion into the urine. Cell Tissue Res. 2010;339(3):639-647. DOI: 10.1007/s00441-009-0913-8

27. Huang JX, Blaskovich MA, Cooper MA. Cell- and biomarker-based assays for predicting nephrotoxicity. Expert Opin Drug Metab Toxicol. 2014;10(12):1621-1635. DOI: 10.1517/17425255.2014.967681

28. Jacobs RA, Meinild AK, Nordsborg NB, Lundby C. Lactate oxidation in human skeletal muscle mitochondria. Am J Physiol Endocrinol Metab. 2013;304(7):E686-94. DOI: 10.1152/ajpendo.00476.2012

29. Vaidya VS, Ferguson MA, Bonventre JV. Biomarkers of acute kidney injury. Annu Rev Pharmacol Toxicol. 2008;48:463-493. DOI: 10.1146/annurev.pharmtox.48.113006.094615

30. Polyanska M, Arner A, Malmquist U, Uvelius B. Lactate dehydrogenase activity and isoform distribution in the rat urinary bladder: effects of outlet obstruction and its removal. J Urol. 1993;150(2 Pt 1):543-545. DOI: 10.1016/s0022-5347(17)35543-x

31. Amdiy R.E., Al-Shukri S.K. Relation between urodynamic indexes and kidneys function in patients with benign prostate hyperplasia. Urology reports (St.-Petersburg). 2012;2(1):12-15. (In Russian). DOI: 10.17816/uroved2112-15

32. Rex N, Melk A, Schmitt R. Cellular senescence and kidney aging. Clin Sci (Lond). 2023;137(24):1805-1821. DOI: 10.1042/CS20230140

33. Lu CH, Wu HHH, Lin TP, Huang YH, Chung HJ, Kuo JY, Huang WJ, Lu SH, Chang YH, Lin ATL. Is intravesical prostatic protrusion a risk factor for hydronephrosis and renal insufficiency in benign prostate hyperplasia patients? J Chin Med Assoc. 2019;82(5):381-384. DOI: 10.1097/JCMA.0000000000000088

34. Luis-Lima S, Escamilla-Cabrera B, Negrín-Mena N, Estupiñán S, Delgado-Mallén P, Marrero-Miranda D, González-Rinne A, Miquel-Rodríguez R, Cobo-Caso MÁ, Hernández-Guerra M, Oramas J, Batista N, Aldea-Perona A, Jorge-Pérez P, González-Alayón C, Moreno-Sanfiel M, González-Rodríguez JA, Henríquez L, Alonso-Pescoso R, Díaz-Martín L, González-Rinne F, Lavín-Gómez BA, Galindo-Hernández J, Sánchez-Gallego M, González-Delgado A, Jiménez-Sosa A, Torres A, Porrini E. Chronic kidney disease staging with cystatin C or creatinine-based formulas: flipping the coin. Nephrol Dial Transplant. 2019;34(2):287-294. DOI: 10.1093/ndt/gfy086

35. Alaini A, Malhotra D, Rondon-Berrios H, Argyropoulos CP, Khitan ZJ, Raj DSC, Rohrscheib M, Shapiro JI, Tzamaloukas AH. Establishing the presence or absence of chronic kidney disease: Uses and limitations of formulas estimating the glomerular filtration rate. World J Methodol. 2017;7(3):73-92. DOI: 10.5662/wjm.v7.i3.73

36. Branten AJ, Vervoort G, Wetzels JF. Serum creatinine is a poor marker of GFR in nephrotic syndrome. Nephrol Dial Transplant. 2005;20(4):707-711. DOI: 10.1093/ndt/gfh719

37. Geißer D, Hetzel L, Westenfeld R, Boege F. Questionable Validity of Creatinine-Based eGFR in Elderly Patients but Cystatin C Is Helpful in First-Line Diagnostics. Geriatrics (Basel). 2023;8(6):120. DOI: 10.3390/geriatrics8060120

38. Clinical guidelines “Acute kidney injury.” Accessув September 11, 2023. (In Russian). https://rusnephrology.org/wp-content/uploads/2020/12/AKI_final.pdf.