Резюме
Лісовий В.М., Андон’єва Н.М., Дубовик М.Я. Особливості корекції анемії у пацієнтів з діабетичною нефропатією на перитонеальному діалізі.
Метою роботи було дослідження ефективності, безпеки та переносимості еритропоетинів, які використовувалися для корекції анемії у пацієнтів з діабетичною нефропатією в термінальній стадії хронічної хвороби нирок на замісній нирковій терапії методом перитонеального діалізу. Сімнадцяти хворим на протязі 48 тижнів призначалась антианемічна терапія еритропоетинами: в фазі корекції – еритропоетин-бета до досягнення цільового рівня гемоглобіну, в фазі підтримуючої терапії – метоксіполіетіленгліколь епоетін бета – активатор рецепторів еритропоетина подовженої дії. Початковий рівень гемоглобіну склав 67-98 г/л (в средньому 84,1±4,67 г/л). Одержаний рівень гемоглобіну на кінець дослідження склав 108,5±2,4 г/л, рівень гематокриту - 34,8±2,6%. Дослідження показало, що використання еритропоетинів у пацієнтів з діабетичною нефропатією дозволяють ефективно і безпечно корегувати анемічний синдром.
Ключові слова: хронічна хвороба нирок, анемія, діабетична нефропатія, перитонеальний діаліз, еритропоетини.
Резюме
Лесовой В.Н., Андоньева Н.М., Дубовик М.Я. Особенности коррекции анемии у пациентов с диабетической нефропатией на перитонеальном диализе.
Целью работы было исследование эффективности, безопасности и переносимости эритропоэтинов, применяемых для коррекции анемии у пациентов с диабетической нефропатией в терминальной стадии хронической болезни почек на заместительной почечной терапии методом перитонеального диализа. Семнадцати больным на протяжении 48 недель назначалась антианемическая терапия эритропоэтинами: в фазе коррекции - эритропоэтин-бета до достижения целевого уровня гемоглобина, в фазе поддерживающей терапии – метоксиполиэтиленгликоль эпоэтин бета – активатор рецепторов эритропоэтина длительного действия. Исходный уровень гемоглобина составил 67-98 г/л (в среднем 84,1±4,67 г/л). Полученный уровень гемоглобина к концу исследования составил 108,5±2,4 г/л, уровень гематокрита – 34,8±2,6%. Исследование показало, что применение эритропоэтинов у пациентов с диабетической нефропатией позволяют эффективно и безопасно коррегировать анемический синдром.
Ключевые слова: хроническая болезнь почек, анемия, диабетическая нефропатия, перитонеальный диализ, эритропоэтины.
Summary
Lesovoy V. N., Andonieva N.M., Dubovik M.Ya. Features of anemia correction in patients with diabetic nephropathy on peritoneal dialysis.
Research of efficiency, safety and shipping ot erythropoetins, applied to correction of anemia at patients with diabetic nephropathy in end-stage renal disease receiving replaceable renal therapy by a method peritoneal dialysis was the wprk purpose. Seventeen patients during 12 months were administered with antianemia erythropoetin therapy: in the correction phase erythropoietin beta for achieving target hemoglobin levels in a phase of maintenance therapy - long-acting erythropoietin. Initial hemoglobin level was 67-98 g/l (mean 84,1±4,67 g/l). The average hemoglobin level at the end of the research was 108,5±2,4 g/l, the mean hematocrit - 34,8±2,6%. Results from the research showed that the use of erythropoetin in patients with diabetic nephropathy on peritoneal dialysis can effectively and safely treat anemic syndrome.
Key words: chronic kidney disease, anemia, diabetic nephropathy, peritoneal dialysis, erythropoietin.

УДК 616.61-008.64 612.339.1

Kharkiv National Medical University,

4 Lenin Avenue, Kharkiv,61022,Ukraine

проспект Ленина, 4, Харьков, 61022,Украина 

Харьковский национальный медицинский университет

dubovik-m-j@mail.ru

 Introduction. Anemia is most early and frequent complication of chronic kidney disease (CKD), and usually develops in the decrease of glomerular filtration rate (GFR) to 60-40 ml / min., although it can also occur in the early stages of renal disease. According to Astor B.et al. approximately half of patients with chronic kidney disease suffer from anemia [3, 6], which prevalence and severity in Ukraine significantly exceed that in developed countries. [1] Thus, according to ESAM more than half of the patients in Western Europe (53%) achieved the target hemoglobin level (more than 110 g / l), and in Ukraine, according to the register with CKD, there are no more than 20% of the patients, including NAM [1, 4]. In addition, there are a large number of patients with unacceptably low hemoglobin values ​​(less than 70 or even 60 g / l). [6] DM is a major cause of renal anemia. According to the results of epidemiological research NHANES III (National Health and Nutrition Examination Survey), which was conducted in the U.S., reduction of hemoglobin level in patients with CKD III-IV stages on the background of diabetes was observed two times more often than in patients with appropriately impaired renal function with other pathology [7]. According to the WHO, the criterion for diagnosis of anemia is a decrease of hemoglobin level:  women - <120 g / l  and men - <130 g / l [2]. However, in clinical practice, anemia is often diagnosed only when the hemoglobin level falls significantly below these thresholds [3]. If you use these criteria, anemia affects about one in four patients with diabetes of the first or second type (about 23%) [9-11]. In this case, a greater reduction of hemoglobin (<110 g / l) occurs in about 7-8% of patients [11]

According to the Ishimura F. et al., anemia has an adverse effect on the progression of diabetic complications, increases the risk of heart disease and increases mortality [4, 9]. It should be noted that patients with chronic kidney disease and anemia have higher rates of hospitalization, cardiovascular diseases, cognitive impairments in comparison with patients with renal disease, which flows without anemia [5, 7]. It is found that the mortality in patients on dialysis with hemoglobin <80 g / l is two times higher than with hemoglobin 100-110 g / l. Since anemia in diabetes develops in predialysis stage of DN and, along with hypertension and dyslipidemia, catalyzes the progression of cardiac disease, the correction of renal anemia should be started at the predialysis stage [3, 6].

The etiology of anemia in diabetes has many factors, is specified with different causes, such as inflammation, poor absorption of iron and vitamins, autoimmune disorders, medication, or the presence of chronic disease, but a leading role in its development is insufficient production of erythropoietin [2,4].

In healthy adults, more than 2 million red blood cells per second, or 138 million every minute are synthesized. [4] Central role in the regulation of erythropoiesis is erythropoietin (EPO) - renal hormone, which is a glycoprotein consisting of 165 amino acids belonging to the superfamily of cytokines. The normal levels of erythropoietin in serum is in the range 0.01-0.03 iu / ml, and during hypoxia and anemia may increase by 100-1000 times [10,11].

According to Bosman D. et. al., erythropoietin deficiency is the cause of normochromic, normocytic anemia, which often occurs in patients with diabetic nephropathy even before the decline of renal function [7].При диабетической нефропатии анемия развивается раньше и чаще и протекает тяжелее, чем у больных с заболеваниями почек другой природы.Например, по данным эпидемиологического исследования NHANES III (National Health and Nutrition Examination Survey), проводившегося в США, частота анемии у больных ХБП III–IV стадий и СД была в 2 раза выше, чем у больных с сопоставимым нарушением функции почек, не Сходные критерии использованы в Европейских рекомендациях по лечению анемии у больных ХБП (гемоглобин < 115 г/л у женщин и < 135 г/л у мужчин в возрасте менее 70 лет и < 120 г/л у мужчин в возрасте Если использовать эти критерии, то анемией страдает примерно каждый четвертый больной СД 1 или 2 типа (около 23%) [9–11].Более выраженное снижение уровня гемоглобина (< 110 г/л) наблюдается примерно у 7–8% пациентов.Сходные критерии использованы в Европейских рекомендациях по лечению анемии у больных ХБП (гемоглобин < 115 г/л у женщин и < 135 г/л у мужчин в возрасте менее 70 лет и < 120 г/л у мужчин в возрасте старше 70 лет) [8].

Most of the times for the treatment of renal anemia artificially synthesized erythropoietin beta is used. It is prescribed to patients subcutaneously at a dose of 20 iu / kg 3 times a week. The preparation of a new class of stimulating erythropoiesis (SSE) of III generation is methoxy epoetin beta - activator of continuous erythropoietin receptor. Due to the increase of the partial ejection period the drug can be used one time per month.

In addition, the successful correction of anemia with erythropoietin requires monitoring iron status in the body: ferritin level of 200-500 mg / l, transferrin saturation 20-40%, amount of hypochromic red blood cells <2.5% [8, 9].

The aim of the research was investigation of the efficacy, safety and tolerability of erythropoietin in patients with anemia against a background of diabetic nephropathy, who are on a continuous ambulatory peritoneal dialysis (CAPD).

Materials and methods. The study was conducted at the Department of Nephrology and peritoneal dialysis in V. I. Shapoval Kharkiv Regional Clinical Center of Urology and Nephrology. Seventeen patients (10 men and 7 women) aged from 23 to 55 years (mean 38,3 ± 3,7 years) with CKD V stage as a consequence of diabetic nephropathy, who were on CAPD, mean 44 ± 5, 8 months (from 6 to 84 months) took part in the research. Adequacy of peritoneal dialysis (PD) was measured with KT / V, which was 1.9-2.7.

Patients underwent correction of anemia with erythropoietin in the background of basic iron therapy and vitamins B. Erythropoietin-beta was injected subcutaneously at a dose of 18-30 iu / kg 3 times per week to achieve the target hemoglobin level (110-120g / l). If the increase of hemoglobin was 10-25 g / l for 1 month of treatment, the dose remained the same, if the increase of hemoglobin for the last month was less than 10 g / l, the dose was increased by 25%, if the hemoglobin increase for the last month was more than 25 g / l, in this case the dose was reduced by 25%. Later in the phase of maintenance therapy a long-acting erythropoietin at a dose of 75-100 mg one time a month was prescribed, which was less burdensome for patients and medical staff. If the hemoglobin level exceeded 120 g / l, the dose of erythropoietin was reduced by 50%.

With the development of secondary iron deficiency and reduction of sensitivity to erythropoietin intravenous iron injection at a dose of 100 mg one time a month was added.

Examination of the patients included a determination of the level of hemoglobin, hematocrit, glycosylated hemoglobin, serum iron, ferritin, transferrin. To eliminate the causes of resistance to erythropoietin the level of serum PTH, serum albumin, indicators of dialysis adequacy, the presence of latent infections and bleeding were determined. Monitoring of blood pressure, ECG dynamics were conducted sistematically.

Determination of hemoglobin, hematocrit, red blood cells in the correction phase was conducted one time every 2 weeks and one time per month in the maintaining phase. Serum ferritin, transferrin saturation were monitored monthly in patients who did not receive iron intravenously, and at least once every 3 months, who did get iron.

Duration of supervision lasted for 48 weeks.

Evaluation of the effectiveness of erythropoietin therapy was based on time frame for achieving the target level of hemoglobin, hematocrit, timing of the disappearance of clinical signs of anemia (weakness, muscle adynamia, dizziness, etc.).

The resulting survey data were processed using the program Statistica 6.0. The difference between groups was considered statistically significant at p <0.05.

Results and discussion. Hemoglobin level at the beginning ranged from 67 to 98 g / l (mean 84,1 ± 4,67 g / l). Hematocrit level was 24,2 ± 2,71%.

As a result of treatment by the end of 15 weeks hemoglobin rose to 108,5 ± 2,4, and hematocrit up to 34,8 ± 2,6%. In order to get effective correction with erythropoietin iron content in the body was controlled. In our supervision, 3 (17%) patients had a decrease in serum iron, 5 (29%) have low levels of ferritin, which required the use of iron supplements to normalize these indicators.

The results of treatment are presented in the table.

Table

Results of erythropoietin in patients with diabetic nephropathy on peritoneal dialysis
 

Three (17%) patients had increased blood pressure to 170/100 mm Hg, and therefore the dose of erythropoietin was reduced to 18 IU / kg and enhanced antihypertensive therapy. In the remaining 14 patients (82%) BP indicators were 138 ± 14/84 ± 9 mm Hg and have not changed much by the end of the research. Variations of the levels of parathyroid hormone and albumin from 462 ± 42,2  to 513± 40,6 and from 36,6 ± 0,7 to 40,1 ± 1,5, respectively, were minor and did not influence the resistance of erythropoietin.

The main clinical symptoms of anemia were fatigue, tachycardia, shortness of breath, dizziness. On the background of correction of erythropoietin in 12 patients (71%) decreased fatigue, shortness of breath - in 4 (23%), dizziness - in 6 (35%), tachycardia disappeared - in 5 (29%), 3 (18%) patients had normal sleep.

In the phase of correction target Hb level was achieved at 15 weeks in 15 patients (88.2%) with diabetic nephropathy: at 8 week 4 patients (23%), after 12 weeks a further 9 patients (53%) reached it,  and 2 patients (12 %) – at 15 weeks. Average increase of hemoglobin was 12,2 ± 3,8 g / l. In 2 (12%) patients with baseline Hb 65-68 g / l use of erythropoietin did not produce the expected clinical effect. One of them was diagnosed with resistance to these drugs. The second one progressed hypertension, and therefore the therapy with erythropoietic stimulants was discontinued. The other patients were undergoing the treatment well, side effects were not noted.

In the phase of maintaining therapy (33 weeks) conversion to a long-acting erythropoietin with a more convenient mode of injection was held. 9 patients (53%) received the drug at a dose of 100 mg 1 time a month, 6 (35%) - in a dose of 75 mg 1 time per month. And in 2 patients after 22 and 24 weeks of the research hemoglobin level reached at an average 134,2 ± 2,6 g / l, and therefore the treatment was discontinued. And only after 4-6 weeks with hemoglobin 109,4 ± 3,1 g / l  erythropoietin therapy was resumed at a dose of  75 mg 1 time per month.

The average dose of beta-erythropoietin in correction phase was 6040 ± 1846 IU per week, in the phase of maintaining therapy the mean dose of long-acting erythropoiesis stimulator was 96 ± 34 mg per month, which corresponded to the results of similar studies [7, 11].

The observation showed that the use of erythropoietin in patients with diabetes not only eliminates the anemic syndrome and enables to avoid blood transfusions, but also reduces the morbidity and mortality due to the prevention of cardiovascular and infectious complications, improves quality of life, improves cognitive functions, sexual activity and helps to maintain disability in patients on dialysis, that undoubtedly has important medical and social importance.

Conclusions:

1. The study showed that the correction of anemia with erythropoietin is effective and safe in patients with diabetes treated with renal replacement therapy with peritoneal dialysis. 88.2% of patients reached target Hb level at 15 weeks of observation, which led to a decrease of clinical symptoms of anemia and quality of patients’ life.

2. It was noted that iron deficiency is refractory to the action of erythropoietin, and stimulants of erythropoiesis requires constant monitoring of blood pressure.

Литература
 Гланц С. Медико-биологическая статистика / С. Гланц. - М: Практика, 2008. – 459 с.
 Дедов И.И. Сахарный диабет и артериальная гипертензия / И.И. Дедов, М.В. Шестакова. – М.: МИА, 2006. – С. 99-110.
Добронравов В.А. Анемия и хроническая болезнь почек / В.А. Добронравов, А.В. Смирнов // Анемия. – 2005. - № 2. – С. 2-8.
Прогностическое значение ранней коррекции анемии у больных хронической почечной недостаточностью / Л.Ю. Милованова, А.Ю. Николаева, Т.А. Козлова [и др.] // Нефрология и диализ. – 2009. - № 6 (1). – С. 54.
Шутов Е.В. Лечение анемии метоксиполиэтилен-гликоль-эпоэтином бета у больных, получающих гемодиализ / Е.В.Шутов, С.В. Лашутин, И.Г. Коломийцева, Е.В. Шувалов // Клиническая нефрология. - 2011. – Т. 2. – С. 14.
Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994) / B. Astor, P. Muntner, A. Levin [et al.]// Arch. Intern. Med. – 2002. – Vol. 162. - P. 1401-1408.
Anemia with erythropoietin deficiencyoccurs early in diabetic nephropathy / D. Bosman, A. Winkler, J. Marsden [et al.] // Diabetes Care. - 2001. - 24. – Р. 495-499.
Duranay M. Parvovirus B 19 infection and unresponsiveness to erytropoietin therapy in haemodialysis patients / M. Duranay, M. Bali, M. Sahin // Nephrol. Dial. Transplant. – 1998. - Vol. 13. – Р. 779-780.
9. Diabetes mellitus increases the severity of anemia in non-dialyzed patients with renal failure / F. Ishimura, Y. Nishizawa, S. Okuno [et al.] // J. Nephrol. - 1998. - Vol. 11. – Р. 83-86.
10. Thomas M. Anaemia in diabetes: is there a rationale to TREAT? / Thomas M., Cooper M., Rossing K., Parving H. // Diabetologia. – 2006. - Vol. 49, Iss. 6. – P. 1151-1157.
11. Thomas M. Anemia with impaired erythropoietin response in diabetic patients / M. Thomas, M. Cooper, C. Tsalamandris [et al.] // Arch. Intern. Med. - 2005. - Vol. 165. - Р. 466-469.