Cardiorenal Syndrome: Clinical Outcome Study

Transcription

1 Journal of The Association of Physicians of India Vol. 64 December Original Article Cardiorenal Syndrome: Clinical Outcome Study HR Shah 1, NP Singh 2, NP Aggarwal 3, D Singhania 4, LK Jha 3, A Kumar 5 Abstract Background: Over recent years, the field of medicine has been challenged by the twin epidemic of heart failure and renal insufficiency. The coexistence of the two problems in the same patient, referred to as cardiorenal syndrome (CRS), is defined as disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The mechanisms underlying this interaction are complex and multifactorial in nature. Objective of Study: Identify and classify patients admitted with cardiorenal syndrome into various subtypes and assess clinical outcome at discharge and at three months. Methods: Ours was a longitudinal study of 50 patients admitted in ICU with CRS. They were classified as per RONCO classification (2008) into various subtypes. Outcomes was addressed as favourable for patients stable at discharge and at 3 months follow up, whereas outcome was termed non-favourable for patients who expired or initiated on hemodialysis. Results: Of 50 patients, two-third patients were males (66%), with mean age of males and females being years and years respectively. Majority of the patients had Type-1 CRS (46%) followed by twenty two percent Type-2, twenty six percent type-4 and six percent Type-5. There were no patients with type-3 CRS. At the end of the study, 24 (48%) patients were stable, 12 (24%) required dialysis and 14 (28%) patients had expired. The total non-favourable outcomes (dialysis / death) were higher with subtypes CRS-4 (n-11, 22%) and CRS-1 (n-8, 16%). Anemia, raised serum creatinine, low egfr s, low ejection fraction were significant predictors of non-favourable outcome in our study Conclusion: CRS occurs in all age groups, more commonly in elderlies with a male preponderance. Prevalence of CRS-1 was higher followed by CRS-4. Prognosis was unfavourable in CRS-1, CRS-4 and CRS-5. Sepsis was predominant cause of death in patients with CRS-5 with hundred percent mortality during hospital stay. Risk factors like pre-existing renal impairment, anemia, reduced e GFR and low ejection fraction were significantly associated with worse outcomes. There is need for large scale population / community based studies to chart the prevalence of cardiorenal subtypes and prognosticate each individually Introduction O ver recent years, the field of medicine has been challenged by the twin epidemic of heart failure and renal insufficiency. Editorial Viewpoint Coexistence of heart failure and renal insuffficiency is referred to as cardiorenal syndrome. This study finds elderly male preponderance. Sepsis with CRS-5 was predominant cause of death. Co-existence of the two problems in the same patient, referred to as cardiorenal syndrome (CRS), is defined as disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The mechanisms underlying this interaction are complex and multifactorial in nature. Changes in the renin-angiotensin-aldosterone system (RAAS), the imbalance between nitric oxide (NO) and reactive oxygen species (ROS), the sympathetic nervous system and inflammation are the cardiorenal connectors to develop cardiorenal syndrome. It has been classified in five types by Ronco et al (2008). 1 Acute Cardiorenal Syndrome (Type 1 CRS) is characterised by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Acute heart failure is manifested in form of hypertensive pulmonary edema, acutely decompensated heart failure (ADHF), cardiogenic shock and acute coronary syndrome (ACS). 2 1 DNB Resident, Dept. of Medicine, 2 Director, Meedicine Allied Specialities, 3 Senior Consultant, Dept. of Nephrology, 4 Senior Consultant, Dept. of Cardiology, 5 Research Associate, Dept. of Medicine, Max Super Specialitiy Hospital, Ghaziabad, Uttar Pradesh Received: ; Revised: ; Accepted:

2 42 Journal of The Association of Physicians of India Vol. 64 December Fig. 1: Distribution of study population in different age groups Chronic Cardiorenal syndrome (Type 2 CRS) is characterised by chronic heart failure that leads to progressive decline in GFR and ultimately chronic kidney disease (CKD). Acute Renocardiac Syndrome (type 3 CRS) manifests as acute kidney injury, which can occur as a primary event (e.g. acute glomerulonephritis) or a secondary event (e.g. radiocontrast, exogenous or endogenous nephrotoxins, postsurgical, etc.), followed by cardiac dysfunction as its sequel. Chronic Renocardiac Syndrome (Type 4 CRS) is a condition characterised by increased cardiovascular risk in patients with CKD. Secondary Cardiorenal Syndrome (Type 5) is associated with multiple systemic conditions, either acute or chronic which target both organs simultaneously. Examples include sepsis, systemic lupus erythematosus, amyloidosis and diabetes mellitus. The coexistence of cardiac and renal disease significantly increases mortality, morbidity, complexity and cost of care. The aim of this study was to identify different types of cardiorenal syndrome at our tertiary care hospital, risk factors associated and clinical outcome during hospital stay and at 3 months. Materials and Methods Ours was a longitudinal study. A total of 50 patients, of above Age in years years years years > 80 years years of age admitted with both cardiac and renal dysfunction were evaluated in detail and investigated. Heart failure was classified as per NYHA classification. CKD was staged as per KDOQI guidelines. Special attention was paid to patient with risk factors like hypertension, diabetes, dyslipidemia, coronary artery disease, hypothyroidism, COPD, nephrotoxic drugs ingestion and contrast exposure. Patients were evaluated at the time of discharge and at three months follow up. Outcome was addressed as favourable for patients stable at discharge and 3 months follow up whereas, non-favourable for patients who expired or were initiated on hemodialysis. Investigations included complete hemogram, kidney function tests, cardiac enzymes, pro-bnp, lipid profile, thyroid function test, urine routine and microscopy with culture. Electrocardiograms were done for arrhythmias or ST-T changes. Ultrasound whole abdomen was carried out to evaluate renal parenchymal disease or any other abnormal changes in urinary tract. egfr was calculated using MDRD study equation. Patients were subjected to 2 dimensional echocardiography to assess the ejection fraction at admission and at 3 months follow up. All patients were classified as per RONCO guidelines (2008) into various CRS subtypes and standard treatment was administered per Table 1: Clinical parameters of study subjects Parameters Number of patients Dyspnea 50 NYHA grade 1 1 NYHA grade 2 5 NYHA grade 3 24 NYHA grade 4 20 Pedal edema 35 Chest pain 24 Decrease urine output 22 Nocturia 20 Syncope 5 the management of cardiorenal syndrome. Statistical Analysis A descriptive statistical analysis based on frequency tables of categorical s was performed, using a Pearson`s Chi-square test, to test the significance of the association between qualitative variables. A Student`s t test for independent samples was used to compare means between groups. Statistical data processing was performed using SPSS 20.0 for windows. Differences with a probability of type 1 error less than 5% were considered statistically significant. Results Demographic profile Out of 50 patients, about two-third patients were males (66%). Mean age of males was 64.18±12.95 years and females were ± years. Majority of patients belonged to elderly age group of years as shown in Figure 1. Clinical Parameters of Study Subjects Symptomatology All patients presented with dyspnea (n-50), mainly of NYHA grade 3. Pedal edema was also a common symptom manifesting in 35 subjects. All the other symptoms were given in Table 1. Laboratory Parameters Out of 50 study subjects, 25 patients were known cases of CKD with mean baseline creatinine of 2.63 mg/dl and egfr of ml/

3 Journal of The Association of Physicians of India Vol. 64 December Table 2: Laboratory parameters of study subjects Laboratory parameters No. of patients (n=50) Mean±SD Baseline Creatinine(mg / dl) ±1.36 egfr (ml/min) ±11.67 EF (%) ±13.55 Admission Hemoglobin (gm/ ±2.33 dl) Hb < g/ dl 27 Hb > g/dl 23 Creatinine (mg/dl) ±2.18 e GFR (ml/min) ±17.59 Uric acid (mg/dl) ±1.90 Sodium (meq / l) ±4.50 Potassium (meq/ l) ±1.00 Albumin (gm / dl) ±0.48 EF (%) ±12.8 Discharge Creatinine (mg/dl) ±1.68 e GFR (ml/min) ±12.48 Uric acid (mg / dl) ± months Creatinine mg/dl) ±1.71 e GFR (ml/min) ±15.18 EF (%) ±9.89 Uric acid (mg/dl) ±1.87 6% CRS-1 (n-23) Fig. 2: Prevalence of co-morbidities amongst study population Age in years Table 3: Prevalence of CRS subtypes at discharge and on follow-up at 3 months CRS Outcome at discharge (n) Outcome at 3 months (n) subtype Stable Dialysis Death Total Stable Dialysis Death Total CRS CRS CRS CRS Outcome at discharge (n-50) 16% 32% 52% Stable (n-26) Dialysis (n-16) Death (n-8) years years years > 80 years Outcome at 3 months (n-50) 28% 24% 48% Stable (n-24) Dialysis (n-12) Death (n-14) 26% 46% CRS-2 (n-11) 22% CRS-4 (n-13) CRS-5 (n-3) Fig. 3: Distribution of CRS subtypes at baseline visit min/1.73m 2. Twenty nine subjects had heart failure with reduced ejection fraction (HFrEF) with mean baseline ejection fraction (EF) of 45.34%. Renal, cardiac and hematological parameters recorded at admission, discharge and at three months are demonstrated in Table 2. Prevalence of co-morbidities Among the study population, 39 (78%) patients were hypertensive and 32 (64%) were diabetic. Whereas, 25 (50%) had underlying chronic kidney disease, 24 (48%) patients had CAD and 22 (44%) had Fig. 4: Outcome population at discharge and at 3 month dyslipidemia (Figure 2). Prevalence of Cardiorenal Syndromes (CRS) Subtypes Out of 50 patients enrolled in study, 23 (46%) subjects presented with type 1 CRS, 11 (22%) subjects with type 2 CRS, 13 (26%) subjects with type 4 CRS and 3 (6%) subjects with type 5 CRS. No individual came under the category of type 3 CRS (Figure 3). Outcome and Factors Affecting Outcome Prevalence of CRS Subtypes at Discharge and on Follow-up at 3 months At discharge, mortality rate was 16 % (n-8). Of 42 patients that survived, 21 (50%) belonged to CRS type 1 group, 9 (21%) to CRS type 2 and 12 (28.57%) to group CRS 4 group. Eight patients had expired during the study period. Out of which, 3 patients were in CRS-5 group, two patients each in CRS 1 and 2 and one in CRS -4 group. On follow up at 3 months, total mortality increased to 28% (n-14), as 6 more patients had expired. Three patients, each from CRS-1 and CRS-4 group had expired. Thus, 36 patients survived, of which patients belonging to CRS 1 group were 18 (50%) and 9 (25%) patients each belonged to CRS 2 and CRS 4 group. Summary of outcome were shown in Table 3 and Figure 4. Association of CRS Subtypes with Outcome Study subjects were classified into two groups on the basis of their outcomes as: favourable outcome group including patients

4 44 Journal of The Association of Physicians of India Vol. 64 December 2016 Table 4: Association of CRS subtypes with outcome at discharge and at 3 months Table 5: Association of laboratory parameters with outcome (*Statistical significant ) Variables Favourable Non-favourable p- Baseline creatinine (mg/dl) 1.83± ± * e GFR (ml/min / 1.73m 2 ) 36.09± ± * Admission Hemoglobin (g/dl).75± ± * Creatinine (mg/dl) 2.31± ±2.53 <0.001* egfr (ml/min / 1.73m2) 35.00± ± * Uric acid (mg/dl) 7.49± ± Sodium (meq / l) ± ± Potassium (meq/l) 4.52± ± Albumin (g/dl) 3.32± ± EF (%) 33.07± ± Outcome at discharge Creatinine (mg/dl) 2.28± ± * e GFR (ml/min/1.73m2) 31.21± ± * Uric acid (mg/dl) 6.67± ± Outcome at 3 months Creatinine (mg/dl) 2.2 ± ± * e GFR (ml/min/1.73m2) 33.25± ± * Uric acid (mg/dl) 6.3± ± EF 42.08± ± * Table 6: Association of co-morbidities with outcome CRS Outcome at discharge (n) Outcome at 3 months (n) subtype Favourable Nonfavourable Favourable Nonfavourable CRS CRS CRS CRS Co-morbidities Outcome at discharge (n) Outcome at 3 months (n) Favourable Nonfavourable Favourable Nonfavourable Hypertension 20 (40%) 19(38%) (36%) 14 (28%) Diabetes 14 (28%) 18(36%) (26%) 12(24%) Dyslipidemia 12 (24%) (20%) (20%) 6(12%) Hypothyroidism 6 (12%) 2(4%) (%) 1(2%) COPD 7 (14%) 2(4%) (%) 2(4%) CAD 14 (28%) (20%) (22%) 9(18%) stable at discharge and follow up; non-favourable outcome group including patients who were initiated on dialysis or expired before discharge or within 3 months. The difference between associations of CRS subtypes with outcome is statistically significant for outcome at discharge and for outcome at 3 months (Table 4). Association between Gender and outcome There was no statistically significant association between gender and outcome at discharge (p ). Mean age of patients with favourable outcome (n-26) was 68.8±11.97, and for patients with non-favourable outcome (n-24) was 59.41±17.02). This difference of means was statistically significant (p ). Association of Laboratory Parameters with Outcome The difference between means of baseline creatinine and egfr; haemoglobin; creatinine and egfr at admission, creatinine and egfr at discharge with outcome was statistically significant (Table 5). Association of Co-morbidities with Outcome The association of co-morbidities with outcome were found to be statistically insignificant and the results were shown in Table 6. Discussion Over the past decade with the increase in lifespan and high prevalence of lifestyle disorders like hypertension, diabetes and cardiorenal syndrome has emerged as a significant problem amongst patients. Studies in the West have been conducted to understand the complex relationship between heart and kidneys. However in Indian scenario, cardiorenal syndrome (CRS) remains an uncharted territory. There is a paucity of population or hospital based studies which can reflect upon the magnitude of cardiorenal syndrome in Indian setting, hence this baseline longitudinal study was conducted at our tertiary care hospital. Our study aimed at identifying and classifying patients with cardiorenal syndromes and assessing their clinical outcome at discharge and at follow up after three months. The purpose of the study also included association of various co-morbid conditions on outcome of patients under different CRS subtypes. In the following, we discuss the demography, distribution of CRS sub-types, outcomes associated with each type and major risk factors (previous renal insufficiency, anemia, reduced egfr and low ejection fraction) significantly affecting the clinical outcome. In our study, there was male preponderance (M:F-2:1) which could be due to increase in the number of acute coronary events and other risk factors like hypertension, diabetes and dyslipidemia in men, now diagnosed even at younger age groups, whereas women usually

5 Journal of The Association of Physicians of India Vol. 64 December develop such illnesses to a lesser extent mostly at later stages in life after menopause. More than half of our study population was in elderly age group i.e. above sixty years. Structural abnormalities with fibrosis and calcification of the heart and central arteries, along with autonomic dysfunction, underlie reduced cardiac performance leading to cardiac decompensation and heart failure (HF). HF is characterized by the heart s inability to maintain an adequate cardiac output and may be the result of systolic or diastolic dysfunction or reduced compliance. The effects of decrease egfr per se interact with the effects of aging in cardiovascular end-organ damage and in the genesis of heart failure (HF) and cardiorenal syndrome (CRS). Almost half of the patients had non-favourable outcome. One fourth of the patient subset expired during the study. Prevalence of non-favourable outcomes was significantly higher in CRS-4 and CRS-1 with maximum deaths and dialysis requiring population occurring within these two groups. This could be due to devastating presentations of patients in CRS-1 with acute coronary syndromes, acute decompensated heart failure or cardiogenic shock leading to AKI associated with increased cardiovascular mortality, prolonged hospitalisation, increased readmissions and accelerated progression to CKD stages 4-5. This was previously purported in a single centred based study on acute cardiorenal syndrome wherein AKI during hospitalization occurred four times more frequently in Acute Decompensated Heart Failure (ADHF) patients than in ACS patients, and patients with ACS had increased in-hospital mortality. 5 Co-existing renal insufficiency is one of the strongest independent risk factors and predictors of mortality. 6 Our study reported half of the population with haemoglobin less than g/dl. The term Cardiorenal Anemia Syndrome (CRAS), coined by Silverberg et al defined as a condition induced by dysfunction of either organ exacerbating dysfunction of either organ. Anemia causes increase in oxidative stress and lack of oxygen supply to heart leading to compensatory increase in heart rate and stroke volume which activates RAAS and SNS causing renal vasoconstriction and fluid retention. 9 In a previous study, it was established that the prevalence of anemia was high amongst patients with cardio-renal syndrome, present in almost one-third of CRS patients. However, it was not associated with increased mortality, as raised serum creatinine and low ejection fraction were other variables also contributing to adverse outcome. 3 Similar trend was observed in our study. Three-fourth population in our study had significant LV dysfunction with ejection fraction less than forty percent at admission. All these patients had non-favourable outcome at follow up. This association was notable, adding to the evidence that patients with heart failure (HF) have poor outcomes in terms of rapid deterioration of renal function with increase in morbidity and mortality. This is due to a complex interplay of various factors such as imbalance of failing heart (low cardiac output and hypotension), neuro-hormonal system activation, sympathetic over activity, nitric oxide (NO) reactive oxygen species (ROS) and inflammatory cascade. These form a vicious cycle and cause further worsening of heart and kidneys. Risk factors contributing towards worsening renal function during heart failure include old age, comorbidities, drugs like diuretics causing renal hypoperfusion, ACE (angiotensin converting enzyme) inhibitors and ARBs (angiotensin receptor blockers) for RAAS (renin-angiotensin-aldosterone system) blockade leading to renal impairment, prior myocardial infarction and previous renal insufficiency. On similar grounds in a past experience it was determined that patients with CHF, renal dysfunction is common, deteriorates over a relatively short period of time, is unlikely to recover substantially and augurs a poor prognosis. A noteworthy contribution by CHARM STUDY investigators also concluded that decreased renal function had been found as an independent risk factor for poor cardiovascular outcomes in patients with chronic heart failure with markedly reduced left ventricular ejection fraction. 11 Many studies have reproduced in detail the complex connections and associations involving heart renal dysfunction and its impact on the patient outcome. Our study was a preliminary attempt to prognosticate the umbrella term cardiorenal syndrome and its subtypes individually in Indian scenario. Limitations in Study Sample size was small which resulted in certain known statistically significant relationships to come out to be insignificant. Cystatin C could not be evaluated due to unavailability of test at our centre. CKD staging was applied as per older classification based on e GFR as albuminuria was not quantified in our study Only ejection fraction (EF%) from various echocardiographic parameters was evaluated at admission and follow up to judge the outcome, thereby patients with HFpEF (diastolic heart failure) could be underdiagnosed. Treatment details in form of drugs administered/ therapeutic interventions/ devices were not taken into account that can alter the outcome Follow up at 6 months or

6 46 Journal of The Association of Physicians of India Vol. 64 December year could derive better understanding and more confident analysis of the natural history and dynamic course of various CRS sub-types Conclusions Cardiorenal syndrome is nowadays being recognised as a common entity in patients having both cardiac and renal dysfunction, thereby being classified in either of CRS sub-types on the basis of etiology. Our study concluded that CRS can occur in all age groups, more commonly in elderlies with a male preponderance. Prevalence of CRS-1 was higher followed by CRS-4. CRS -2 had a slightly better outcome may be by chance as patients were steady after 3 months; whereas non-favourable outcome were significantly higher in CRS-1, CRS-4 and CRS-5. Sepsis was predominant cause of death in patients with CRS-5 with hundred percent mortality during hospital stay. Risk factors like pre-existing renal impairment, anemia, reduced e GFR and low ejection fraction were significantly associated with worse outcomes across all CRS sub-types. There is scope for large scale population /community based studies to chart the prevalence of cardiorenal subtypes and prognosticate each individually. Follow-up studies should be undertaken to understand the natural history of cardiorenal syndrome with time and perceive the dynamicity of each subtypes during the course. Suitable disease models for mechanistic oriented investigations are needed to provide further impact on management of cardiorenal syndrome and lay down better standard of care for patients. References 1. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R. Cardiorenal syndrome. Journal of the American College of Cardiology 2008; 19: Forman DE, Butler J, Wang Y, Abraham WT, O Connor CM, Gottlieb SS et al. Incidence, predictors at admission, and impact of worsening renal function among patients hospitalized with heart failure. J Am Coll Cardiol 2004; 43: Silva RP, Barbosa PH, Kimura OS, Sobrinho CR, Sousa Neto JD, Silva FA et al. Prevalance of anemia and its association with cardiorenal syndrome. International Journal of Cardiology 2007; 120: Santoro A. Heart failure and cardiorenal syndrome in elderly. J Nephrol 2012; 25: Eren Z, Ozveren O, Buvukoner E, Kaspar E, Degertekin M, Kantarci G. A Single- Centre Study of Acute Cardiorenal Syndrome: Incidence, Risk Factors and Consequences. Cardiorenal Medicine 2012; 2: Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardio 2000; 20: Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: Smith GL, Lichtman JH, Bracken MB, Shlipak MG, Phillips CO, DiCapua P et al. Renal impairment and outcomes in heart failure: systematic review and meta-analysis. J Am Coll Cardiol 2006; 47: Silverberg DS, Wexler D, Blum M. The correction of anemia in severe resistant heart failure with erythropoietin and intravenous iron prevents the progression of both the heart and the renal failure and markedly reduces hospitalization. Clinical Nephrology 2002; 58: De Silva R, Nikitin NP, Witte KK, Rigby AS, Goode K, Bhandari S et al. Incidence of renal dysfunction over 6 months in patients with chronic heart failure due to left ventricular systolic dysfunction: Contributing factors and relationship to prognosis. Eur Heart J 2006; 27: Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation 2006; 113:671.