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"Kidneys" 2 (16) 2016

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Next Step in Chronic Kidney Disease Therapy

Authors: Ivanov D.D. - National Medical Academy of Postgraduate Education named after P.L. Shupyk, Department of Nephrology and Renal Replacement Therapy, Kyiv, Ukraine

Categories: Nephrology

Sections: Specialist manual

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Ингибиторы ангиотензинпревращающего фермента/блокаторы рецепторов ангиотензина составляют основу ренопротекторной терапии хронической болезни почек. По мере снижения скорости клубочковой фильтрации увеличивается активность симпатической нервной системы, утрачивается количество функционирующих нефронов, что требует изменения тактики лечения. Снижение риска кардиоваскулярных событий, реализующихся на фоне возрастающей гипертензии, вероятно, диктует необходимость приоритетного назначения симпатолитиков, блокаторов кальциевых каналов и отказа от ингибиторов ангиотензинпревращающего фермента/блокаторов рецепторов ангиотензина. Тактика ­БРИМОНЕЛ — БР(А)И(АПФ)МО(ксонидин)НЕ(биволол)Л(еркани­ди­пин) меняется на МНЕЛД — М(оксонидин)НЕ(биволол)Л(ерканидипин)Д(иуретик), что используется нами на протяжении последних лет. Допускается сочетанное использование торасемида и ксипамида. Отмена ингибитора ангиотензинпревращающего фермента/блокаторов рецепторов ангиотензина требует доказательных данных, которые, возможно, будут получены в исследовании STOP-ACEi.

Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers are the basis of renoprotection therapy in chronic kidney disease. Parallel to decrease of glomerular filtration rate, there is an increase in the activity of the sympathetic nervous system, and the number of functio­ning nephrons reduces, which requires a change of treatment regimen. Reducing the risk of cardiovascular events on the background of increased hypertension probably dictates the need for a priority administration of sympatholytics, calcium channel blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers withdrawal. ARAMONEL formula: ARAMONEL — AR(B)A(CEI)MO(xonidine)NE(bivolol)L(ercandipine) is changed to MNELD — M(oxonidine)NE(bivolol)L(ercandipine)D(iuretic) that is used by us in recent years. Combined use of torsemide and xipamide is allowed. Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers withdrawal requires evidence, which may be obtained in STOP-ACEi trial.


ингибиторы ангиотензинпревращающего фермента, блокаторы рецепторов ангиотензина, блокаторы кальциевых каналов, хроническая болезнь почек, скорость клубочковой фильтрации.

angiotensin-converting enzyme inhibitor, angiotensin receptor blockers, calcium channel blockers, chronic kidney disease, estimated glome­rular filtration rate.

The article was published on p. 10-13


Cardiovascular events are the leading cause of mortality among patients with chronic kidney disease (CKD). ACEI/ARB/DRI consist the base of drug therapy allowing to extend time to renal replacement therapy (KDIGO, 2012 [1]). Drugs of these groups are called renoprotective from the point of view of evidence-based medicine hence they promote extending time of renal replacement therapy start in CKD. The main pharmacological action of these groups of drugs consists in reducing negative effect of angiotensin II.

As CKD progresses, the role of hyperactivity of sympathetic nervous system increases. Its role consists in compensation of the decrease of glomerular filtration rate (GFR) arising from the decrease in the number of functioning nephrons. Increased activity of sympathetic nervous system is accompanied by an increase in blood pressure and cardiovascular risks. This requires administration of combination antihypertensive therapy accounting the effects of combination drug treatment on sympathetic neural function and its relationship with blood pressure control [2]. Sympatholytic agents, calcium channel blockers, beta-blockers and diuretics are added as adjunct the-rapy to ACEI/ARB/DRI. While the choice of ACEI/ARB is determined by elimination route kidney/liver depending on the level of GFR, preference for molecules of other classes is evidence-based. 
Standard therapeutic approach presented in the table 1. 
In clinical nephrology, clonidine was supplanted by moxonidine and lercanіdipine which mediates its action through low-voltage receptors and does not affect glomerular blood flow, and nebivolol which reduces central aortic pressure. Namely, these drugs have become the drugs of choice. Thus, in practical nephrology we began to use the following formula: 
ARAMONEL — AR(B)A(CEI)MO(xonidine)
NE(bivolol)L(ercandipine) [3].
However, as renal function decreases or low functional renal reserve is observed, requirement for ACEI/ARB/DRI in combination or alone as basic agents loses its relevance. In recent years, nephrologists have been increasingly using an approach of refusal from ACEI/ARB/DRI if glomerular filtration rate is less than 30 mL/min (CKD 4–5 stages). This is due to the fact that the renal substrate for renoprotection disappears. Thus, formula changes to the following one: MNELD — M(oxonidine)NE(bivolol)L(ercandipine)D(iuretic), Where diuretic is usually presented by loop diuretic, namely torasemide, furosemide or xipamide.
In order to develop the evidence on the basis of accumulated experience, in 2016 Multicentre randomized controlled trial of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker withdrawal in advanced renal disease: the STOP-ACEi trial starts in UK [4]. The aim of the trial is to confirm preliminary findings which suggest that withdrawal of ACEi/ARB treatment can stabilize or even improve renal function in patients with advanced progressive CKD (stages 4–5).
The approach of refusal from ACEI/ARB/DRI in low functional renal reserve was stated in Guidelines of Expert Committee of the All-Russian Scientific Society of Cardiology and the Russian Scientific Society of Nephrology yet in 2009 [5] and being carried out in this country. In our practice, for the past 3 years we have been as well refusing from the use of ACEI/ARB/DRI if eGFR is less than 30 mL/min (CKD 4–5). Our data show no increase in mortality from cardiovascular causes in these patients, and some increase in time to dialysis. However, it is extremely important to use individual approach to assign optimal doses of moxonidine, nebivolol, lercandipine and diuretic. Dosing of all drugs except for moxonidine may take into account the genetic code of CYP metabolism and have different therapeutic range. Probably only moxonidine may be used at the maximum dose when required.
Two more questions need to be clarified in the presented material. The first is associated with the reduction of excreting function of the kidneys with the decline in renal functional reserve. Regarding this, recommendations to increase fluid intake and intravenous administration of a significant number of solutions for the purpose of detoxification often become unacceptable. This practice likely leads to artificial dilution of creatinine, creating the illusion of a therapeutic effect. Need to remind that blood samples for creatinine may be held no sooner than 4 hours after intravenous infusion. 
It is getting more effective from the diuretics, using higher dosages and more practical — a combination of two. With progressive decrease in GFR is better to use loop diuretics such as torasemide, and xipamide. Their dosage is need to be increased in CKD 4–5, accounting for torasemide to 200 mg per day and xipamide 80 mg/day. Important is the possibility of their combined use, as they have a slightly different implementation mechanism of diuretic effect. Note that combination of furosemide and torasemide is inappropriate due to single target in a renal tubule.
In addition, to maintain a stable diuretic effect almost always a one free day in a week is required, and at the maximal doses better to use diuretic every other day. The only exception is the presence of chronic heart failure, where mainly due to the increase in brain natriuretic peptide we can achieve a diuretic effect with prolonged continuous use of loop diuretics.
The second issue is the feasibility of replacing lercanidipine by amlodipine which is stronger in the antihypertensive effect. Our considerations are based on our own practice are following. Based on evidence there are apparent advantages in patient survival when using lercanidipine [6], its replacement with amlodipine is possible if the possibilities of rationally assigned combinations of drugs are exhausted, or to increase compliance in the fixed combination, for example, triple or polypill. 
Thus, the modern practice is changing paradigms and dogmas of clinical Nephrology. Calling for dialogue on the subject, we hope, that evidence obtained will probably allow for review of common approach of using ACEI/ARB/DRI as the basic initial therapy for CKD and use of individualized therapy depending on the stage of CKD. This way, a solution for the main goal of reducing cardiovascular mortality will possibly be found.
Conflict of interest: the data presented in part with Prof Guido Grassi (Italy) in submission as letter to Editor in Cardiovascular Research, 4.04.2016.


1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease // Kidney inter. — 2013. — 3. — 1-150.

2. Grassi G. Sympathetic overdrive in hypertension: clinical and therapeutic relevance // The e-journal of the ESC Council for Cardiology Practice. — 24 Nov 2015. — Vol. 13, № 36.

3. Ivanov D. // Почки. Нирки. Kidneys. — 2016. — 1(16). — Р. 16.

4. Bhandari S. et al. // Nephrol. Dial. Transplant. — 2016. — 31(2). — 255-261.

5. http://www.health-medix.com/articles/misteztvo/2009-03-24/7-14.pdf

6. Ortiz M., Calcino G. Inferred mortality differences between dihydropypiridine antihypertensives // Hypertension. — 2009. — 53. — 1116.

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