Characteristics of cardiorenal syndrome type 2 course against the background of treatment by RAAS inhibitors


ПОД- СЕКЦИЯ 14. Терапия. 

V.I. Kravtsova, graduate student

Kharkov medical academy of postgraduate education

Characteristics of cardiorenal syndrome type 2 course against the background of treatment by RAAS inhibitors

          As you know, anemia can be not just separate nosological unit, but it can also accompany, in most cases, dysfunction of the organism’s systems. Anemia is a frequent attendant of chronic heart failure (CHF), worsening the functional class of this pathology, aggravating the quality of patient’s health and it is an independent factor in mortality and morbidity structure and in hospitalization rate. This pathology is the most frequent in elderly patients with CHF, with diastolic and systolic left ventricular dysfunction, in women in menopause and in people with chronic kidney disease (CKD). According to modern concepts, renogenic anemia is the most frequent complication of chronic kidney insufficiency (CKI) with GFR to 40-60 ml/min (III stage of CKD by NKF-K/DOQI classification). Sometimes anemia can be observed at the early stages of CKD. The origin of anemia in patients with CKD involves not only with the stage of disorder, level of nephrosclerosis but also with the progressing of CKD, presence of diabetes mellitus and concomitant pathology of cardiovascular system. Influence of anemia to the progressing of the both CHF and CKD is a subject to investigation. At the first sight, cardiorenal syndrome (CRS) is a state, when  normal renal function is impair because of heart disorders [1,p. 11-17]. This  conception was recently adopted as definition of CRS [2,p. 957-962]. CRS includes many acute and chronic states, in which primary affected organ can be as heart as kidneys [3,p. 1419-1428]. CRS type 2 is a combination of CHF and CKD. CRS type 2 characterized by disorder of heart function (e.c., chronic congestive heart failure), causing CKD progression. Worsening of renal function against the background of CHF associated with unfavorable prognosis and extension of the term of hospitalization [4,p. 1419-1428]. Prevalence of renal dysfunction under HF is about 24%           [5,p. 671-678]. Even slight GFR reduction significantly increases mortality risk [5,p. 671-678] and consider as marker of vascular disease [6,p. 260-269]. Independent predictors of the renal function worsening are age, hypertension, diabetes mellitus, acute coronary syndrome.

Purpose of the work: to determine he depending between level of anemia and renin-angiotensin-aldosterone system (RAAS) in patients with CRS type 2 during the therapy by RAAS inhibitors iACE spirapril and ARB candesartan.

Clinical characteristic and methods:30 patients with CHF I-IIA and CKD II-III in age from 48 to 74 (average age 68±7,3), 20 female and 10 male (66% female and 34% male) was observed. CHF stage was defined by N.D. Stragesko and V.K. Vasilenko classification (1935) and represents CHF I – 20% and CHF IIA – 80%. CHF’s functional class was defined by NYHA criteria (NYHA, 1964) and was II FC in all patients. Patients was divided into 2 groups: 13 patients get iACE therapy (spirapril) in dose of 6 mg, and 17 patients get ARB therapy (candesartan) in dose of 8 mg (dose was titrated depending on therapeutic effect, level of blood pressure, GFR). Every group was divided more on 2 groups: patients with diagnosis CKD II with CHF IIA and patients with CKD III  with CHF IIA. Patients without clinical manifestation of CRS formed a control group. Research lasted 3 months and patients was examined before and after treatment by RAAS inhibitors. Patients with severe progressive course of diabetes mellitus, heart rhythm impairment, heart defects, toxic nephropathy, oncological diseases and decompensated patients  was excluded from research. Laboratory methods were: clinical blood test, clinical urine test, biochemical blood test with investigation of creatinin and urea rates. In clinical blood test purposely to describe an anemia level standard data was determined and also mean corpuscular volume (MCV) as average erythrocyte quantity was calculated: MCV=Ht/RBC (fl). Mean corpuscular hemoglobin (MCH) was calculated too: MCH=Hb/RBC (pg).

         The assess of the RAAS status serum aldosterone level  was investigated by the set of reagents DRG Aldosterone ELISA (EIA-4128) (USA). Renin activity in serum was determined by the set of reagents DRG Renin ELISA (USA). To determine indicators, blood was getting at the morning time  on an empty stomach in the patient’s supine position. Blood was taken from the cubital vein by silicone needle, by gravity to polyethylene tubes, to renin – to polyethylene tubes with sodium-heparin (Granum, Ukraine). After centrifugation supernatant separated by the sterile needle and posted to tubes “Eppendorf”. Samples was frozen for period no more than 3 months.

Results: before treatment by RAAS inhibitors in patients the RAAS activity a.o. serum level of aldosterone  which increased with CKD progression was noted ( to CKD II ( 124.9±35.7 ) pg/l and for CKD III (159.53±35.1) pg/l for iACE group, i.e. increased in 27.8%; for ARB group - to CKD II this index was (97.6±17.3)pg/l and to CKD III - (148.52±25.4)pg/l, i.e.index increased at 52.2% ). Serum renin activity decreased with the progression of CKD at 26.3% for iACE group and at 25.2% for ARB group. With a view to characteristic of anemia rates of hemoglobin erythrocytes, MCV and MCH was determined, which showed the accretion of normochromiс normocitic anemia in depend of accretion of CKD stage.




Changes in RAAS activity and anemia in patients with CRS type 2.


aldosterone, pg/l

renin activity, mcg/g*l

hemoglobin, g/l

red blood cells

MCV, fl

MCH, pg




124.9 ±35.7

2.35 ±0.5

122 ±22.1

4.2 ±1.2

58.3 ±21.5

28.3 ±2.2












30.3 ±1.8









27.9 ±2.5










50.3± 15.2


30.2 ±2.1





159.53± 35.1

1.73± 0.4




25.3± 1.6




2.83± 0.3








23.4± 1.5




148.52± 25.4

2.23± 0.4



41.6± 14.3















       Table 1

Analyzing the data from table 1( tab.1) hemoglobin rate decreased by 14.7% for iACE group. and by 16.9% for ARB group before treatment to CKD III as compared with CKD II.  MCV decreased by 27.9% and 13.3% for iACE and ARB groups accordingly. Decline MCH by progression of CKD was noted at 10.6% for iACE group and 6.4% for ARB group. I.e. progression of anemia against the background of increasing of RAAS activity in patients with CHF II A with CKD II - III before treatment by RAAS inhibitors was observed. After three months of therapy reduction trend of RAAS activity was shown: decline of the serum aldosterone rate in iACE by 37.7% to the patients with CHF II A with CKD II and by 40.6% to the patients with CHF II A with CKD III. But serum renin activity in first group increased by 24.6% and 63.5%% was observed. For ARB group reduction of serum aldosterone rate by 36.1% and 39.5% to CKD II and CKD II receptively was observed. but serum renin activity reduced to 19.4% in patients with CKD II and increaseв to 7.6% in patients with CKD III. Indexes of  hemoglobin and erythrocytes increased in patients with CKD II as in iACE group ( to 19.6% and 9.5% resp. ) as in ARB group ( to 5.1% and 14.3% resp. ). However. in patients with CHF II A with CKD III these indexes reduce for iACE group (Hb increase insignificantly to 1.9% erythrocytes decrease to 12.5% ). and for ARB group ) both indicators reduced to 8.2% and 13.3% ). MCV and MCH rates have a similar situation: in patients with CKD II these indexes increased during the therapy by RAAS inhibitors. and in patients with CKD III the progression of anemia was observed and passing if from normochromic normocitic to hypochromic microcitic as evidenced MCV reduction to 42±14.5 till 40±12.6 fl (N from 39 to 97 fl) and MCH reduction from 25.3±1.6 to 23.4±1.5 pg(N from 26.5 to 33.5 pg) for iACE group. and MCV from  41.6±14.3 to 39.2±11.7(fl) and MCH from 26.1±2 to 24.5±1.8 (pg) for ARB group.

         Discussion: RAAS hyperactivation results to licking of renal glomeruli which results to evolution of glomerulosclerosis and to progression of anemia. reduction in BP’s control. aggravation of arterial hypertension. RAAS’s blockade affects the endothelial function. remodeling of the vessels and the myocard. defeat of target organs. slows the progression of nephropathy. induce regress of kidney’s impairment. and reduce the microalbuminuria. Sartrans selectively block the binding of angiotensin II with its AT1 - receptors which realize their negative effects. then iACE. iACE have so called “escape” effect in connection with appearance of alternative pathways of synthesis of  the angiotensin II by means of himase. catepsin. tissue plasminogen activator. Proteinuria is not just the index of the CKD progression. but also a factor of anemia worsening which in turn burden the course of CRS. So administration of iACE and ARB is recommended for CKD even without hypertension.

         Conclusion: our research shows that during the therapy by RAAS inhibitors the decrease of RAAS activity was observed. Nevertheless with the progression of CKD in CRS anemia worsening too. CKD III characterized by reduction of hemoglobin and erythrocyte rates. MCV and MCH indexes as in iACE as in ARB groups.


  1. Bongartz LG. Cramer MJ. Doevendans PA. Joles JA. Braam B. The severe cardiorenal syndrome: ‘guyton revisited.’ Eur Heart J 2005;26:11-17.
  2. Ronco C. House AA. Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone wrong Intensive Care Med 2008;34:957-962.
  3. Berl T. Henrich W. Kidney-heart interactions: epidemiology. pathogenesis. and treatment Clin J Am Soc Nephrol 2006;1:8-18.
  4. McCullough PA. Contrast induced nephropathy J Am Coll Cardiol 2008;51:1419-1428.
  5. Hillege HL. Nitsch D. Pfeffer MA. et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure Circulation 2006;113:671-678.
  6. Bhatia RS. Tu JV. Lee DS. et al. Outcome of heart failure with preserved ejection fraction in a population-based study N Engl J Med 2006;355:260-269.