Уромодулин сыворотки как ранний биомаркер атрофии канальцев и интерстициального фиброза у пациентов с гломерулопатиями

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Аннотация

Цель исследования. Оценить значимость концентрации уромодулина (белка Тамма–Хорсфалла – ТХБ) в сыворотке крови как биомаркера тубулярной атрофии (ТА) и интерстициального фиброза (ИФ) почек у пациентов с гломерулопатиями.
Материалы и методы. Обследовано 84 человека с гломерулопатиями и 11 практически здоровых лиц (контроль). У всех измерены концентрации уромодулина в сыворотке крови (Sumo) и моче (Uumo), установлены показатели почечной экскреции этого белка, величины расчетной скорости клубочковой фильтрации (рСКФ) и проведена полуколичественная оценка нефробиоптата.
Результаты и обсуждение. Sumo снижалась при минимальной выраженности ТА или ИФ, когда величины рСКФ еще остаются нормальными. Вариации таких показателей экскреции ТХБ, как Uumo, суточная экскреция и отношение уромодулин мочи / креатинин мочи, в зависимости от степени атрофии или фиброза аналогичного тренда не проявлялись.
Заключение. Sumo перспективна в качестве раннего биомаркера фиброзно-атрофических повреждений почек. Параметры ренальной экскреции ТХБ таким свойством, скорее всего, не обладают. Причиной запаздывания снижения Uumo при прогрессировании хронической болезни почек по сравнению с уменьшением Sumo, по-видимому, является необходимость поддерживать приемлемую Uumo для противодействия инфицированию мочевыводящих путей и камнеобразованию.

Ключевые слова: уромодулин, белок Тамма–Хорсфалла, концентрация, сыворотка крови, моча, гломерулопатии.

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Aim. To assess the significance of the serum uromodulin (Tamm–Horsfall protein – THP) concentration (Sumo) as an early biomarker of tubular atrophy (TA) and interstitial renal fibrosis (IF) in patients with glomerulopathies.
Materials and methods. 84 patients with glomerulopathy and 11 practically healthy persons (control) were examined. Uromodulin concentrations in serum and urine (Uumo) were measured, renal excretion of this protein and the estimated glomerular filtration rate (eGFR) were established. A semi-quantitative assessment of nephrobioptates was performed.
Results and discussion. Sumo decreases with a minimum expression of tubular atrophy (TA) or interstitial fibrosis (IF), when the values of eGFR still remain normal. Variations of such excretory parameters of THP as Uumo, daily excretion, and ratio: urinary uromodulin / urinary creatinine, did not manifest a similar trend.
Conclusion. Sumo is promising as an early biomarker of fibrotic and atrophic renal damage. The parameters of renal excretion of THP do not seem to have this property. The reason for the delay in the decline of Uumo in the progression of CKD as compared to the decrease in Sumo seems to be the need to maintain a sufficient Uumo to counteract urinary tract infection and stone formation.

Key words: uromodulinб Tamm–Horsfall protein, serum, concentration, kidney diseases.

Список литературы

1. Rampoldi L, Scolari F, Amoroso A, et al. The rediscovery of uromodulin (Tamm–Horsfall protein): from tubulointerstitial nephropathy to chronic kidney disease. Kidney Int. 2011;80:338-47. doi: 10.1038/ ki.2011.134
2. Mount DB. Thick ascending limb of the loop of Henle. Clin J Am Soc Nephrol. 2014;9:1974-86. doi: 10.2215/CJN.04480413
3. Lhotta K. Uromodulin and chronic kidney disease. Kidney Blood Press Res. 2010;33(5):393-8. doi: 10.1159/000320681
4. El-Achkar TM, Wu XR. Uromodulin in kidney injury: an instigator, bystander, or protector? Am J Kidney Dis. 2012;59:452-61. doi: 10.1053/ j.ajkd.2011.10.054
5. Зверев Я.Ф., Жариков А.Ю., Брюханов В.М., Лампатов В.В. Модуляторы оксалатного нефролитиаза. Ингибиторы кристаллизации. Нефрология. 2010;14(1):29-49 [Zverev YaF, Zharikov AYu, Bryuhanov VM, Lampatov VV. Modulators of oxalate nephrolithiasis. Crystallization Inhibitors. Nefrologiya. 2010;14(1):29-49 (In Russ.)].
6. Youhanna S, Weber J, Beaujean V, et al. Determination of uromodulin in human urine: inﬂuence of storage and processing. Nephrol Dial Transplant. 2014;29:136-45. doi: 10.1093/ndt/gft345
7. Prajczer S, Heidenreich U, Pfaller W, et al. Evidence for a role of uromodulin in chronic kidney disease progression. Nephrol Dial Transplant. 2010;25:1896-903. doi: 10.1093/ndt/gfp748
8. Garimella PS, Biggs ML, Katz R, et al. Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults. Kidney Int. 2015;88:1126–34. doi: 10.1038/ki.2015.192
9. Shlipak MG, Li Y, Fox C, et al. Uromodulin concentrations are not associated with incident CKD among persons with coronary artery disease. BMC Nephrol. 2011;12:2. doi: 10.1186/1471-2369-12-2
10. Zhou J, Chen Y, Liu Y, et al. Urinary uromodulin excretion predicts progression of chronic kidney disease resulting from IgA nephropathy. PLoS One. 2013;8:e71023. doi: 10.1371/journal.pone.0071023
11. Kottgen A, Hwang SJ, Larson MG, et al. Uromodulin levels associate with common UMOD variant and risk for incident CKD. J Am Soc Nephrol. 2010;21:337-44. doi: 10.1681/ASN.2009070725
12. Risch L, Lhotta K, Meier D, Medina-Escobar P, et al. The serum uromodulin level is associated with kidney function. Clin Chem Lab Med. 2014;52(12):1755-61. doi: 10.1515/cclm-2014-0505
13. Fedak D, Kuźniewski M, Fugiel A, et al. Serum uromodulin concentrations correlate with glomerular filtration rate in patients with chronic kidney disease. Pol Arch Intern Med. 2016;126(12):995-1004. doi: 10. 20452/pamw.3712
14. Steubl D, Block M, Herbst H, et al. Plasma uromodulin correlates with kidney function and identifies early stages in chronic kidney disease patients. Medicine. 2016;95:e3011. doi: 10.1097/MD. 000000000000 3011
15. Scherberich JE, Gruber R, Nockher WA, et al. Serum uromodulin –
a marker of kidney function and renal parenchymal integrity. Nephrol Dial Transplant. 2017 Feb 16. doi: 10.1093/ndt/gfw422
16. National Kidney Foundation. Glomerular Filtration Rate (GFR) Calculators. Доступно по ссылке: https://www.kidney.org/professionals/ KDOQI/gfr (Ссылка активна на 27.11.2017).
17. Рубанович А.В. Статистика множественных сравнений в ассоциативных исследованиях полиморфизма ДНК: Кошмар Бонферрони [Rubanovich AV. Statistics of multiple comparisons in associative studies of DNA polymorphism: The Nightmare of Bonferroni (In Russ.)]. Доступно по ссылке: http://www.myshared.ru/slide/45790/ (Ссылка активна на 27.11.2017).
18. Паклин Н. Логистическая регрессия и ROC-анализ – математический аппарат. Доступно по ссылке: https://basegroup.ru/community/articles/logistic (Ссылка активна на 27.11.2017) [Paklin N. Logistic regression and ROC analysis – mathematical apparatus (In Russ.). Available from: https://basegroup.ru/community/articles/logistic].
19. Смирнов А.В., Хасун М., Каюков И.Г. и др. Уромодулин и выраженность тубулоинтерстициальных повреждений у пациентов с нефропатиями. Нефрология. 2015;19(2):49-54 [Smirnov AV, Hasun M, Kayukov IG, et al. Uromodulin and severity of tubulointerstitial lesions in patients with nephropathies. Nefrologiya. 2015;19(2):49-54 (In Russ.)].
20. Bohle A, Mackensen-Haen S, von Gise H, et al. The consequences of tubulo-interstitial changes for renal function in glomerulopathies.
A morphometric and cytological analysis. Pathol Res Pract. 1990;186(1):135-44. doi: 10.1016/S0344-0338(11)81021-6
21. Mackensen-Haen S, Bohle A, Christensen J, et al. The consequences for renal function of widening of the interstitium and changes in the tubular epithelium of the renal cortex and outer medulla in various renal diseases. Clin Nephrol. 1992;37(2):70-7.
22. Pak J, Pu X, Zhang ZT, et al. Tamm–Horsfall protein binds to type 1 ﬁmbriated Escherichia coli and prevent E. coli from binding to uroplakin Ia and Ib receptors. J Biol Chem. 2001;276:9924-30.
doi: 10.1074/jbc.M008610200
23. Rafﬁ HS, Bates JM Jr, Laszik Z, et al. Tamm–Horsfall protein protects against urinary tract infection by Proteus mirabilis. J Urol. 2009;181:2332-8. doi: 10.1016/j.juro.2009.01.014
24. Seraﬁni-Cessa F, Monti A, Cavallone D. N-glycans carried by Tamm– Horsfall glycoprotein have a crucial role in the defense against urinary tract diseases. Glycoconjugate J. 2005;22:383-94.
25. Mo L, Huang HY, Zhu XH, et al. Tamm–Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. Kidney Int. 2004;66:1159-66. doi: 10.1111/j.1523-1755.2004. 00867.x

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1. Rampoldi L, Scolari F, Amoroso A, et al. The rediscovery of uromodulin (Tamm–Horsfall protein): from tubulointerstitial nephropathy to chronic kidney disease. Kidney Int. 2011;80:338-47. doi: 10.1038/ ki.2011.134
2. Mount DB. Thick ascending limb of the loop of Henle. Clin J Am Soc Nephrol. 2014;9:1974-86. doi: 10.2215/CJN.04480413
3. Lhotta K. Uromodulin and chronic kidney disease. Kidney Blood Press Res. 2010;33(5):393-8. doi: 10.1159/000320681
4. El-Achkar TM, Wu XR. Uromodulin in kidney injury: an instigator, bystander, or protector? Am J Kidney Dis. 2012;59:452-61. doi: 10.1053/ j.ajkd.2011.10.054
5. [Zverev YaF, Zharikov AYu, Bryuhanov VM, Lampatov VV. Modulators of oxalate nephrolithiasis. Crystallization Inhibitors. Nefrologiya. 2010;14(1):29-49 (In Russ.)].
6. Youhanna S, Weber J, Beaujean V, et al. Determination of uromodulin in human urine: inﬂuence of storage and processing. Nephrol Dial Transplant. 2014;29:136-45. doi: 10.1093/ndt/gft345
7. Prajczer S, Heidenreich U, Pfaller W, et al. Evidence for a role of uromodulin in chronic kidney disease progression. Nephrol Dial Transplant. 2010;25:1896-903. doi: 10.1093/ndt/gfp748
8. Garimella PS, Biggs ML, Katz R, et al. Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults. Kidney Int. 2015;88:1126–34. doi: 10.1038/ki.2015.192
9. Shlipak MG, Li Y, Fox C, et al. Uromodulin concentrations are not associated with incident CKD among persons with coronary artery disease. BMC Nephrol. 2011;12:2. doi: 10.1186/1471-2369-12-2
10. Zhou J, Chen Y, Liu Y, et al. Urinary uromodulin excretion predicts progression of chronic kidney disease resulting from IgA nephropathy. PLoS One. 2013;8:e71023. doi: 10.1371/journal.pone.0071023
11. Kottgen A, Hwang SJ, Larson MG, et al. Uromodulin levels associate with common UMOD variant and risk for incident CKD. J Am Soc Nephrol. 2010;21:337-44. doi: 10.1681/ASN.2009070725
12. Risch L, Lhotta K, Meier D, Medina-Escobar P, et al. The serum uromodulin level is associated with kidney function. Clin Chem Lab Med. 2014;52(12):1755-61. doi: 10.1515/cclm-2014-0505
13. Fedak D, Kuźniewski M, Fugiel A, et al. Serum uromodulin concentrations correlate with glomerular filtration rate in patients with chronic kidney disease. Pol Arch Intern Med. 2016;126(12):995-1004. doi: 10. 20452/pamw.3712
14. Steubl D, Block M, Herbst H, et al. Plasma uromodulin correlates with kidney function and identifies early stages in chronic kidney disease patients. Medicine. 2016;95:e3011. doi: 10.1097/MD. 000000000000 3011
15. Scherberich JE, Gruber R, Nockher WA, et al. Serum uromodulin –
a marker of kidney function and renal parenchymal integrity. Nephrol Dial Transplant. 2017 Feb 16. doi: 10.1093/ndt/gfw422
16. National Kidney Foundation. Glomerular Filtration Rate (GFR) Calculators. Доступно по ссылке: https://www.kidney.org/professionals/ KDOQI/gfr (Ссылка активна на 27.11.2017).
17. [Rubanovich AV. Statistics of multiple comparisons in associative studies of DNA polymorphism: The Nightmare of Bonferroni (In Russ.)]. Доступно по ссылке: http://www.myshared.ru/slide/45790/ (Ссылка активна на 27.11.2017).
18. [Paklin N. Logistic regression and ROC analysis – mathematical apparatus (In Russ.). Available from: https://basegroup.ru/community/articles/logistic].
19. [Smirnov AV, Hasun M, Kayukov IG, et al. Uromodulin and severity of tubulointerstitial lesions in patients with nephropathies. Nefrologiya. 2015;19(2):49-54 (In Russ.)].
20. Bohle A, Mackensen-Haen S, von Gise H, et al. The consequences of tubulo-interstitial changes for renal function in glomerulopathies.
A morphometric and cytological analysis. Pathol Res Pract. 1990;186(1):135-44. doi: 10.1016/S0344-0338(11)81021-6
21. Mackensen-Haen S, Bohle A, Christensen J, et al. The consequences for renal function of widening of the interstitium and changes in the tubular epithelium of the renal cortex and outer medulla in various renal diseases. Clin Nephrol. 1992;37(2):70-7.
22. Pak J, Pu X, Zhang ZT, et al. Tamm–Horsfall protein binds to type 1 ﬁmbriated Escherichia coli and prevent E. coli from binding to uroplakin Ia and Ib receptors. J Biol Chem. 2001;276:9924-30.
doi: 10.1074/jbc.M008610200
23. Rafﬁ HS, Bates JM Jr, Laszik Z, et al. Tamm–Horsfall protein protects against urinary tract infection by Proteus mirabilis. J Urol. 2009;181:2332-8. doi: 10.1016/j.juro.2009.01.014
24. Seraﬁni-Cessa F, Monti A, Cavallone D. N-glycans carried by Tamm– Horsfall glycoprotein have a crucial role in the defense against urinary tract diseases. Glycoconjugate J. 2005;22:383-94.
25. Mo L, Huang HY, Zhu XH, et al. Tamm–Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. Kidney Int. 2004;66:1159-66. doi: 10.1111/j.1523-1755.2004. 00867.x

Авторы

А.В. Смирнов, М. Хасун, И.Г. Каюков, О.В. Галкина, В.Г. Сиповский, М.М. Парастаева,
Е.О. Богданова

ФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. академика И.П. Павлова» Минздрава
России, Санкт-Петербург, Россия

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A.V. Smirnov, M. Khasun, I.G. Kayukov, O.V. Galkina, V.G. Sipovski, M.M. Parastaeva, E.O. Bogdanova

Academician I.P. Pavlov First St. Petersburg State Medical University, Ministry of Health of Russia, St. Petersburg, Russia

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