nefrНефрологияNephrology (Saint-Petersburg)1561-62742541-9439Pavlov First Saint-Petersburg State Medical Universitynefr-237Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИ. КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯORIGINAL ARTICLES. CLINICAL INVESTIGATIONSИСПОЛЬЗОВАНИЕ КОМБИНИРОВАННОЙ ТЕРАПИИ ПЛАЗМАФЕРЕЗОМ, ВНУТРИВЕННЫМ ЧЕЛОВЕЧЕСКИМ ИММУНОГЛОБУЛИНОМ И РИТУКСИМАБОМ ДЛЯ ЛЕЧЕНИЯ ХРОНИЧЕСКОГО ОТТОРЖЕНИЯ ТРАНСПЛАНТИРОВАННОЙ ПОЧКИUSE OF COMBINED THERAPY BY PLASMAPHERESIS, HUMAN INTRAVENOUS IMMUNOGLOBULIN AND RITUXIMAB FOR CHRONIC RENAL ALLOGRAFT REJECTIONСтоляревичЕ. С.StolyarevichE. S.

Столяревич Екатерина Сергеевна, доктор медицинских наук 

123182, Москва, Щукинская ул., д. 1. 

Ekaterina S. Stolyarevich, MD, DMedSci. 

123182 Moscow, Shchukinskaya Str., d. 1

Stolyarevich@ya.ruАртюхинаЛ. Ю.ArtyukhinaL. Yu.

Артюхина Людмила Юрьевна 

123182, Москва, ул. Пехотная, д. 3. 

Ludmila Y. Artyukhina, MD 

123182, Moscow, Pehotnaya str., d. 3. 

rlyu-1404@yandex.ruИвановаЕ. С.IvanovaE. S.

Иванова Екатерина Сергеевна 

123182, Москва, ул. Пехотная, д. 3. 

Ekaterina S. Ivanova, MD 

123182, Moscow, Pehotnaya str., d. 3. 

katerineiv@mail.ruТомилинаН. А.TomilinaN. A.

Томилина Наталья Аркадьевна, доктор медицинских наук, профессор 

123182, Москва, Щукинская ул., д. 1. 

Prof. Natalia A. Tomilina, MD, DMedSci

123182, Moscow, Shchukinskaya Str., d. 1. 

natomilina@yandex.ruФедеральный научный центр трансплантологии и искусственных органов им. акад. В.И. Шумакова; Московский медико-стоматологический университет; Городская клиническая больница №52 Департамента здравоохранения г. Москвы, Московский городской нефрологический центрРоссияAcademician V.I. Shumakov Federal Research Center of Transplantology and Artificial Organs; Moscow University of Medicine and Dentistry; City Clinical Hospital №52 Department of Health in Moscow, Moscow City Nephrology CenterRussian FederationГородская клиническая больница №52 Департамента здравоохранения г. Москвы, Московский городской нефрологический центрРоссияCity Clinical Hospital №52 Department of Health in Moscow, Moscow City Nephrology CenterRussian Federation2016030320172066774Copyright © Столяревич Е.С., Артюхина Л.Ю., Иванова Е.С., Томилина Н.А., 20172017Столяревич Е.С., Артюхина Л.Ю., Иванова Е.С., Томилина Н.А.Stolyarevich E.S., Artyukhina L.Y., Ivanova E.S., Tomilina N.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nephrolog.ru/jour/article/view/237

ЦЕЛЬ – оценить эффективность использования комбинации внутривенного человеческого иммуноглобулина (ВВИГ) с плазмаферезом и ритуксимабом для лечения трансплантационной гломерулопатии в поздние сроки после трансплантации почки. ПАЦИЕНТЫ И МЕТОДЫ. В исследование было включено 50 пациентов с морфологически верифицированным диагнозом трансплантационной гломерулопатии, 24 из которых получали лечение плазмаферезом в сочетании с ВВИГ и ритуксимабом. Контрольную группу составили 26 пациентов, не получавших антигуморального лечения. РЕЗУЛЬТАТЫ. На момент постановки диагноза СКФ в исследуемой и контрольной группах не различалась (44,9 Ѓ} 21,3 и 41,2 Ѓ} 14,6 мл/мин, р =0,47), однако последующие темпы снижения функции трансплантата были ниже в группе получавших лечение по сравнению с контролем: –0,47 Ѓ} 0,6 мл/мин/мес и 1,31 Ѓ} 1,6 мл/мин/мес (p = 0,02). 3-летняя выживаемость трансплантатов, таким образом, составила 21,3% и 64,8% у пациентов, получавших лечение (р=0,01). ЗАКЛЮЧЕНИЕ. Наше исследование показало, что трансплантационная гломерулопатия, будучи наиболее частым вариантом хронического гуморального отторжения, характеризуется неблагоприятным прогнозом, который мало зависит от особенностей морфологической картины и активности процесса на момент постановки диагноза. Комплексное лечение, включающее сеансы плазмафереза, внутривенный человеческий иммуноглобулин и ритуксимаб, позволяет замедлить темпы прогрессирования хронического отторжения по крайней мере у части пациентов с хроническим гуморальным отторжением, выявленным в поздние сроки после АТП.

AIM – to evaluate efficiency of use of combined human intravenous immunoglobulin (IVIG) with plasmapheresis and rituximab for transplantation glomerulopathy in late period after kidney transplantation. PATIENTS AND METHODS. The study included 50 patients with morphologically verified transplantation glomerulopathy, 24 of which received plasmapheresis with IVIG and rituximab. Control group consisted of 26 patients without antihumoral treatment. RESULTS. At diagnosis GFR in study and control groups has no differ (44.9 Ѓ} 21.3 vs 41.2 Ѓ} 14.6 ml/min, P =0.47), but following graft function depression rate was lower in group which received treatment in comparison with control group: -0.47 Ѓ} 0.6 ml/min/month и -1.31Ѓ} 1.6 ml/min/month (p = 0.02). Therefore 3-year survivability of graft was 21.3% vs 64.8% in patients receiving treatment (Р=0,01). CONCLUSION. Our study showed that transplantation glomerulopathy as the most often variant of chronic humoral rejection is characterized by unfavorable prognosis regardless of its morphological case and process activity at diagnosis. Combined treatment including plasmapheresis, human intravenous immunoglobulin and rituximab makes it possible to delaythe progression of chronic rejection at least in some patients with chronic humoral rejection revealed in late period after renal allotransplantation.

антитело-опосредованное отторжениетрансплантационная гломерулопатияплазмаферезвнутривенный человеческий иммуноглобулинритуксимабantibody-mediated rejectiontransplant glomerulopathyplasmapheresishuman intravenous immunoglobulinrituximabReferencesColvin RB et al. Diagnostic Pathology: Kidney Diseases. Amirsys; Salt Lake City: 2011Colvin RB et al. Diagnostic Pathology: Kidney Diseases. Amirsys; Salt Lake City: 2011Colvin RB, Nickeleit V. Heptinstall’s Pathology of the Kidney. Jennette JC, Olson JL, Schwartz MM, Silva FG editors. Vol. 2. Lippincott-Raven; Philadelphia: 2006. Р.1347-1490Colvin RB, Nickeleit V. Heptinstall’s Pathology of the Kidney. Jennette JC, Olson JL, Schwartz MM, Silva FG editors. Vol. 2. Lippincott-Raven; Philadelphia: 2006. Р.1347-1490Racusen LC, Colvin RB, Solez K et al. Antibody-mediated rejection criteria – an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003; 3: 708–714Racusen LC, Colvin RB, Solez K et al. Antibody-mediated rejection criteria – an addition to the Banff 97 classification of renal allograft rejection. Am J Transplant 2003; 3: 708–714Sis B, Mengel M, Haas M et al. Banff ‘09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant 2010;10(3):464-471Sis B, Mengel M, Haas M et al. Banff ‘09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant 2010;10(3):464-471Gloor J, Cosio F, Lager DJ et al. The spectrum of antibodymediated renal allograft injury: Implications for treatment. Am J Transplant 2008; 8: 1367–1373Gloor J, Cosio F, Lager DJ et al. The spectrum of antibodymediated renal allograft injury: Implications for treatment. Am J Transplant 2008; 8: 1367–1373Sis B, Campbell PM, Mueller T et al Transplant glomerulopathy, late antibody-mediated rejection and the ABCD tetrad in kidney allograft biopsies for cause. Am J Transplant 2007 Jul;7(7):1743-1752Sis B, Campbell PM, Mueller T et al Transplant glomerulopathy, late antibody-mediated rejection and the ABCD tetrad in kidney allograft biopsies for cause. Am J Transplant 2007 Jul;7(7):1743-1752Jordan SC, Quartel AW, Czer LS et al. Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation 1998 Sep 27;66(6):800-805Jordan SC, Quartel AW, Czer LS et al. Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action. Transplantation 1998 Sep 27;66(6):800-805Everly MJ, Everly JJ, Arend LJ et al. Reducing De Novo Donor-Specific Antibody Levels during Acute Rejection Diminishes Renal Allograft Loss. American Journal of Transplantation 2009; 9(5): 1063–1071Everly MJ, Everly JJ, Arend LJ et al. Reducing De Novo Donor-Specific Antibody Levels during Acute Rejection Diminishes Renal Allograft Loss. American Journal of Transplantation 2009; 9(5): 1063–1071Montgomery RA, Zachary AA, Racusen LC et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 2000 Sep 27;70(6):887-895Montgomery RA, Zachary AA, Racusen LC et al. Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients. Transplantation 2000 Sep 27;70(6):887-895Rocha PN, Butterly DW, Greenberg A et al. Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. Transplantation 2003; 75: 1490–1495Rocha PN, Butterly DW, Greenberg A et al. Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection. Transplantation 2003; 75: 1490–1495Smith RN, Malik F, Goes N et al Partial therapeutic response to Rituximab for the treatment of chronic alloantibody mediated rejection of kidney allografts. Transpl Immunol 2012;27(2-3):107-113. doi: 10.1016/j.trim.2012.08.005. Epub 2012 Aug 30Smith RN, Malik F, Goes N et al Partial therapeutic response to Rituximab for the treatment of chronic alloantibody mediated rejection of kidney allografts. Transpl Immunol 2012;27(2-3):107-113. doi: 10.1016/j.trim.2012.08.005. Epub 2012 Aug 30Billing H, Rieger S, Susal C et al. IVIG and rituximab for treatment of chronic antibody-mediated rejection: a prospective study in paediatric renal transplantation with a 2-year follow-up. Transpl Int 2012; 25: 1165Billing H, Rieger S, Susal C et al. IVIG and rituximab for treatment of chronic antibody-mediated rejection: a prospective study in paediatric renal transplantation with a 2-year follow-up. Transpl Int 2012; 25: 1165Fehr T1, Rusi B, Fischer A et al. Rituximab and intravenous immunoglobulin treatment of chronic antibodymediated kidney allograft rejection. Transplantation 2009 Jun 27;87(12):1837-1841Fehr T1, Rusi B, Fischer A et al. Rituximab and intravenous immunoglobulin treatment of chronic antibodymediated kidney allograft rejection. Transplantation 2009 Jun 27;87(12):1837-1841Rostaing L, Guilbeau-Frugier C, Fort M et al. Treatment of symptomatic transplant glomerulopathy with rituximab. Transpl Int 2009; 22: 906Rostaing L, Guilbeau-Frugier C, Fort M et al. Treatment of symptomatic transplant glomerulopathy with rituximab. Transpl Int 2009; 22: 906Bachelet T, Nodimar C, Taupin J-L. Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody-mediated rejection: a pilot study. Clin Transpl 2015; 29 (5): 439–446Bachelet T, Nodimar C, Taupin J-L. Intravenous immunoglobulins and rituximab therapy for severe transplant glomerulopathy in chronic antibody-mediated rejection: a pilot study. Clin Transpl 2015; 29 (5): 439–446Gloor JM, Sethi S, Stegall MD et al. Transplant glomerulopathy: subclinical incidence and association with alloantibody. Am J Transplant 2007; 7: 2124Gloor JM, Sethi S, Stegall MD et al. Transplant glomerulopathy: subclinical incidence and association with alloantibody. Am J Transplant 2007; 7: 2124Kieran N, Wang X, Perkins J et al Combination of Peritubular C4d and Transplant Glomerulopathy Predicts Late Renal Allograft Failure. J Am Soc Nephrol 2009 October; 20(10): 2260–2268Kieran N, Wang X, Perkins J et al Combination of Peritubular C4d and Transplant Glomerulopathy Predicts Late Renal Allograft Failure. J Am Soc Nephrol 2009 October; 20(10): 2260–2268Haririan A, Kiangkitiwan B, Kukuruga D et al. The impact of c4d pattern and donor-specific antibody on graft survival in recipients requiring indication renal allograft biopsy. Am J Transplant 2009; 9: 2758Haririan A, Kiangkitiwan B, Kukuruga D et al. The impact of c4d pattern and donor-specific antibody on graft survival in recipients requiring indication renal allograft biopsy. Am J Transplant 2009; 9: 2758Kedainis RL, Koch MJ, Brennan DC et al. Focal C4d+ in renal allografts is associated with the presence of donor-specific antibodies and decreased allograft survival. Am J Transplant 2009; 9: 812–819Kedainis RL, Koch MJ, Brennan DC et al. Focal C4d+ in renal allografts is associated with the presence of donor-specific antibodies and decreased allograft survival. Am J Transplant 2009; 9: 812–819Kayler LK, Kiss L, Sharma V et al. Acute renal allograft rejection: diagnostic significance of focal peritubular capillary C4d. Transplantation 2008;85(6):813-820Kayler LK, Kiss L, Sharma V et al. Acute renal allograft rejection: diagnostic significance of focal peritubular capillary C4d. Transplantation 2008;85(6):813-820Hong YA, Kim HG, Choi SR et al. Effec tiveness of rituximab and intravenous immunoglobulin therapy in renal transplant recipients with chronic active antibody-mediated rejection. Transplant Proc 2012;44:182-184Hong YA, Kim HG, Choi SR et al. Effec tiveness of rituximab and intravenous immunoglobulin therapy in renal transplant recipients with chronic active antibody-mediated rejection. Transplant Proc 2012;44:182-184An GH, Yun J, Hong YA. The effect of combination therapy with rituximab and intravenous immunoglobulin on the progression of chronic antibody mediated rejection in renal transplant recipients. J Immunol Res 2014;2014:828732. doi: 10.1155/2014/828732. Epub 2014 Jan 29An GH, Yun J, Hong YA. The effect of combination therapy with rituximab and intravenous immunoglobulin on the progression of chronic antibody mediated rejection in renal transplant recipients. J Immunol Res 2014;2014:828732. doi: 10.1155/2014/828732. Epub 2014 Jan 29Zarkhin V, Lovelace PA, Li L et al. Phenotypic evaluation of B-cell subsets after rituximab for treatment of acute renal allograft rejection in pediatric recipients. Transplantation 2011;91(9):1010–1018Zarkhin V, Lovelace PA, Li L et al. Phenotypic evaluation of B-cell subsets after rituximab for treatment of acute renal allograft rejection in pediatric recipients. Transplantation 2011;91(9):1010–1018Lefaucheur C, Nochy D, Andrade J et al. Comparison of Combination Plasmapheresis/IVIg/Anti-CD20 Versus HighDose IVIg in the Treatment of Antibody-Mediated Rejection. Am J Transplant 2009; 9 (5): 1099-1107Lefaucheur C, Nochy D, Andrade J et al. Comparison of Combination Plasmapheresis/IVIg/Anti-CD20 Versus HighDose IVIg in the Treatment of Antibody-Mediated Rejection. Am J Transplant 2009; 9 (5): 1099-1107

The authors declare that there are no conflicts of interest present.