Impact of Acute Kidney Injury in Patients with Acute Decompensated Heart Failure: Cardiorenal Syndrome.

Introduction: Cardiorenal syndrome (CRS) is a complex interdependent relationship between the heart and kidneys, prevalent in hospitalized patients with acute decompensated heart failure (ADHF). The main aim of this study is to evaluate cardiac and renal function, treatment factors, and outcomes because of mortality and persistent renal dysfunction in acute decompensated heart failure (cardiorenal syndrome type 1) patients. Methods: We studied 100 patients hospitalized with ADHF and acute kidney injury (AKI). Patients were evaluated clinically, biochemically, ultrasonographically


Introduction
A cute decompensated heart failure (ADHF) carries high mortality and its prevalence is increasing in India.1 It is a prevalent condition in hospitalized patients with acute decompensated heart failure (ADHF) and is associated with increased morbidity, mortality, and healthcare costs. 2 Cardiorenal syndrome (CRS) is a complex and interdependent relationship between the heart and kidneys, in which dysfunction of one organ contributes to the dysfunction of the other.There are five types of CRS, and in this study, we focus on CRS type 1, which is characterized by acute kidney injury (AKI) occurring as a result of ADHF.AKI in ADHF is associated with an increased risk of short-and longterm all-cause and cardiovascular mortality, increased length of stay, readmission rates, and healthcare costs.The pathophysiological mechanisms leading to AKI in ADHF are complex and involve alterations in cardiac output, systemic hemodynamics, and compromised kidney perfusion, as well as increased systemic venous hypertension. 3n the ADHF setting, worsening renal function (WRF) is a prevalent condition, affecting 10% to 40% of patients.4 The definition of WRF commonly used in clinical practice is an absolute increase in serum creatinine value by > 0.3 mg/dL.5A meta-analysis of 23 cohort, registry, and randomized controlled studies found that ADHF patients with WRF had an almost two-fold higher rate of all-cause mortality than those without WRF. 7anaging CRS type 1 presents several challenges, including comorbidities, diuretic resistance, and the use of diuretics associated with "pseudo-AKI."There have been recent advances in the understanding of CRS type 1, including the emergence of newer markers of kidney injury, but their role in prognostic outcomes is not clear.AKI in patients with acute decompensated heart failure is a serious complication that contributes to worse clinical outcomes and increased mortality rates.Timely recognition, aggressive management, and a multidisciplinary approach are essential to improve patient outcomes in this complex cardiorenal syndrome. 8he aim of this study is to the evaluation of cardiac and renal function, treatment factors, and outcomes because of mortality and persistent renal dysfunction in acute decompensated heart failure (cardiorenal syndrome type 1) patients.

Material and Methods
We enrolled one hundred patients in this prospective observational study with acute decompensated heart failure patients who were selected from admitted to the tertiary cardiac care hospital during the period of 12 months from May 2017 to May 2018.Patients were diagnosed with heart failure based on a combination of symptomatology and associated echocardiographic evaluation.

Inclusion Criteria:
Inclusion criteria included all patients admitted with cardiac failure with LVEF ≤ 40% of any etiology with a duration of hospital stay of more than 24 hours with acute kidney injury.Acute kidney injury was diagnosed using the RIFLE criteria proposed by the acute dialysis quality initiative group, with worsening of renal failure defined by an increase in the absolute serum creatinine value by >0.3 mg/dL. 5Cardiorenal syndrome-I was defined as a quick decline in cardiac function that results in an acute decrease in renal function.ADHF was defined as either new-onset HF or decompensation of chronic HF with symptoms enough to warrant hospitalization leading to decreases in glomerular filtration.Patients with documented chronic kidney disease including renal artery stenosis.

Enclusion Criteria:
The exclusion criteria of the study were patients with first-time detected chronic kidney disease as evidenced by smaller kidney size.Patients with diabetic nephropathy (proteinuria >300mg/24 hrs).Patients with a history of Non-steroidal anti-inflammatory drugs (NSAID) abuse.Patients not satisfying the above criteria (hospital stay <24 hrs).Patients with terminal illnesses/life expectancy less than one year.
Indonesian J Cardiol Vol.44, Issue II April -June 2023  Creatinine clearance was estimated using the Cockroft-Gault formula.Echocardiography was done for all these patients.Both 2D and color Doppler echocardiography were done by a single experienced cardiologist.Left ventricular systolic performance was quantified as the LV ejection fraction.The operational definition of systolic dysfunction for study purposes is an ejection fraction of less than 40%.The left ventricular diastolic performance was quantified by Doppler and graded from I to III. 9

Follow up:
All 100 of the study's participants were monitored until discharge, and a follow-up is scheduled for 3 months to one year to find out persistent renal dysfunction and predictors of mortality at one year.In-hospital outcome and mortality was recorded.Follow-up details regarding functional improvement, readmission, worsening symptoms, and death were carefully recorded.Information about deceased patients was obtained.
Written informed consent was taken from patients or their relatives before the procedure.The study protocol was approved by the institutional ethics committee (UNMICRC/CARDIO/2016/11).

Statistical analysis:
Using SPSS 26.0 software (IBM, Inc., Chicago, IL, USA), the categorical variables were expressed as frequencies (percentages), and the continuous variables were expressed as the mean ± standard deviation.The Chi-square test and independent t-test were used for categorical variables Univariate and multivariate analysis models were used to find out the predictors of persistent renal dysfunction at follow-up.A P-value <0.05 was considered statistically significant.

Results:
A total of 100 patients with acute decompensated heart failure and acute kidney injury were included in this study.The mean age of the patients was 62.60± 12.26.years.Most of the patients (75%) were in the age group of 50-75 years.The majority of the patients were males, constituting 72% of the total population, while females constituted 28%.
The baseline characteristics of the study population are mentioned in Table 1.The most common symptom in the patients with cardiorenal syndrome was dyspnea, which was present in 92% of the patients.Decreased urine output was the second most common symptom, present in 82% of the patients, followed by chest pain, which was present in 57% of the patients.In most of the patients, this was the first time they had these complaints, while 25% of the patients had a history of similar complaints in the past.Most of the patients were on NYHA class III (64%) followed by NYHA class IV (23%) and class II (13%).
The most common etiology of presentation in the patients was acute myocardial infarction, which was present in 47% of the patients.Among patients with myocardial infarction (MI), 27% had anterior wall MI, while 20% had inferior wall MI.Dilated cardiomyopathy was the next most common presentation, which was present in 46% of the patients.28% had non-ischemic and 18% of patients had old acute coronary syndrome with ischemic cardiomyopathy as a cause of presentation, while 7% of patients had valvular heart disease as an etiology.
29% of patients had a history of previous myocardial infarction.35% of patients had a history of type 2 diabetes mellitus, while 69% of patients had a history of hypertension.25% of patients (all males) were smokers, 14% of patients were chronic alcoholics, 6% of patients had a history of thyroid disease, 3% had pre-existing atrial fibrillation (AF) and 2% of patients had a family history of cardiomyopathy.According to the previous medication history of all patients, 61% of Patients had a history of diuretic use, 39% had a history of ACE inhibitor use, 50% were on beta blockers, 26% were on antiplatelets, 24% were on statins, 11% on sodiumglucose cotransporter-2 inhibitors and 26% were using aldosterone inhibitors.
In terms of laboratory investigations, the mean hemoglobin value was 11.13±2.18g/dL.The mean serum creatinine level was 2.03± 0.94 mg/dL, the mean eGFR was 41.63 ±18.99 mL/hr, the mean SGPT was 228.21± 597.89U/L.The mean total WBC count was 12886.70±5368.78/mm3, and the average platelet count was 1.08±1.17lacs/ml.SGPT with a mean of 228.21 ± 597.89 U/L, and SGOT with a mean of 250.29 ± 867.82 U/L.The mean serum bilirubin level was 2.06 ±1.36 mg/dl, and the mean alkaline phosphatase level was 85.83 ± 32.61 U/L.Chest X-ray showed changes of pulmonary congestion in 97 patients while 3 patients had normal chest X-ray.Echocardiography showed severe LV dysfunction (LVEF <35%) in 90 patients while 10 had LVEF >35%.USG KUB showed that the mean right kidney size was 10.2±1.32 cm, the mean left kidney size was 10.1 ± 1.32 cm, and the mean cortico-medullary differentiation was 3.24± 0.62 mm.
Revascularisation was performed in 34% of the total population, 37% had inotrope infusion, 24% of patients needed renal replacement therapy, 19% had required intra-aortic balloon pump (IABP) for hemodynamic support and 10% of patients had invasive mechanical ventilation.Out of them, 13% had in-hospital mortality.
In According to these variables, NYHA class IV, lowering of systolic blood pressure and MAP, anemia, maximum creatinine, and urea, and lowering in eGFR and LVEF had significant effects on patients with acute decompensated heart failure and acute kidney injury in mortality.However, the variables such as BMI, total count, platelets, potassium, SGOT, alkaline phosphatase, and S. Bilirubin did not show any significant difference between the expired and discharged patients or alive and expired patients (table 2).All expired patients need inotrope infusion and most of them also need renal replacement therapy (92.3%).Half of them (53.84%)required IABP for hemodynamic support and invasive mechanical ventilation.
According to binary logistic regression model  3).
We assessed a discharged total of 87 patients for predictors of persistent renal dysfunction at more than 3 months follow-up (table 4).After discharge 26(29.89%)patients had renal dysfunction.Out of 26 patients, 30.76% had NYHA class IV, MAP also decreased significantly (P 0.02) in 30.76% of patients, and lower hemoglobin (<12%) was significantly seen in 42.3% of patients (P 0.02).Renal dysfunction and factors associated with it were responsible for the rehospitalization of patients after discharge.Maximum creatinine and urea don't show a significant difference between renal dysfunction and normal renal function patients (P 0.06, 0.24) at more than 3 months to oneyear follow-up.Revascularisation was needed in 26.92% out of 26 patients, 65.38% population needed inotrope infusion, 42.30% population needed renal replacement therapy, and 23.07%needed IABP for hemodynamic support.11.53% of patients need invasive mechanical ventilation support.
In terms of patient outcome and predictors of mortality at one year (N=87 patients) as post-index hospitalization (table 6).Out of 87 living patients 25 (28.74%)patients had died at 3 months to one-year outcome.Out of 87 living patients 12 patients had revascularisation out of them 1 patient had died (P 0.29) other 12 patients had renal replacement therapy HHF-hypertensive heart failure, AF-Atrial fibrillation, *P value <0.05 shows statistically significant.
Indonesian J Cardiol Vol.44, Issue II April -June 2023 for persistent renal dysfunction out of them 10 patients died (P <0.0001), 26 patients had persistent renal dysfunction for more than 3 months out of them 12 patients were died (P 0.01).27 patients had recurrent HHF (>2 admissions) out of them 12 patients died and a new onset of AF was seen in 5 patients out of 2 patients were died within 12 months post index hospitalisation.In summary, lowering in MAP and systolic blood pressure, anemia, eGFR value and LVEF, maximum creatinine, and maximum level of urea were independent predictors of in-hospital mortality.NYHA class-IV, anemia, and lower mean arterial pressure were independent predictors of persistent renal dysfunction at 3 months to one-year outcome.Persistent renal dysfunction, renal replacement therapy for treating persistent renal dysfunction, and recurrent HHF (more than 2 admissions) post-hospitalization index within 12 months were predictors of mortality (25%) at one year.

Discussion
This prospective observational study provides valuable insights into the demographic and clinical characteristics of ADHF patients with AKI, including the high prevalence of comorbidities such as coronary artery disease, hypertension, and diabetes mellitus.This highlights the importance of identifying and addressing risk factors and comorbidities in the management of CRS type 1.The study underscores the significant impact of AKI on the outcomes of ADHF patients, including increased mortality and persistent renal dysfunction.
The results are consistent with previous studies that have shown the high prevalence and negative impact of renal dysfunction on heart failure outcomes.Yang et al and Shai et al have demonstrated a significant association between worsening renal function and poor outcomes in heart failure patients. 10,11Mullen et al have also highlighted the importance of cardiorenal syndrome in decompensated heart failure. 12n our study population, the most common age group was 50 to 75 years.In general, most of the studies have shown that the incidence of AKI is higher with increasing age.Most of the patients in our group were males; this is consistent with most of the studies where the male population predominates (72%).A similar finding was observed in the Indian College of Cardiology National Heart Failure Registry. 1 The most common symptom in acute decompensated heart failure is dyspnoea (92%), which is also the most common presentation in our study.Among dyspnoea, 41 % of patients had NYHA class-IV dyspnoea, while 29 % had NYHA class-III dyspnoea.All patients had B/L crepitations of variable degrees on lung auscultation.The second most common symptom in our study was decreased urinary output.It occurred in a total of 82% of patients during indexed admission.The decreased urine output is also considered to be a criteria for diagnosing acute kidney injury.
Acute decompensated heart failure (ADHF) carries high mortality and its prevalence is increasing in India.Our study reported 25% mortality in patients with acute decompensated heart failure and acute kidney injury in AMI.Similar results were noted in a study by Hsing-Shan Tsai et al which showed mortality rates of 30% among patients of MI with AKI.11This finding shows AKI as an important prognostic marker in cases of AMI as its presence increases mortality of AMI by 2 to 3 times.The present study reported 13% mortality during hospitalization.Acute worsening of renal function during hospitalization for ADHF is a strong and consistent independent predictor of adverse outcomes. 12hang et al. analyzed the one-year survival and renal function recovery of acute kidney injury patients with chronic heart failure.Our study also emphasizes the importance of renal function in determining immediate short-term and long-term outcomes in patients with heart failure. 13n our study, we found that parameters like Low hemoglobin, baseline creatinine, and urea levels, baseline eGFR, maximum levels of urea and creatinine, and lower LVEF have shown a consistent relationship with mortality during hospitalization.This effect continued for 3 months as well as 6 months of mortality.Mean hemoglobin levels were 11.13 gm/dl at presentation and 9.65 gm/dl in mortality group.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.14In our study anemia was significantly associated with increased mortality.It is consistent with other studies showing that anemia is frequently linked to poor outcomes in people with CRS-1. 1,15tudies have shown the benefits of multidisciplinary Indonesian J Cardiol Vol.44, Issue II April -June 2023 care, including optimal medical therapy, fluid management, and renal replacement therapy when necessary, in improving outcomes in these patients which was also seen in our study as improving renal function did improve the prognosis in our patients. 16,17onarow et al reported that BUN, SBP, and creatinine levels were the three variables most predictive of in-hospital mortality in the Acute Decompensated Heart Failure National Registry (ADHERE).18Our study had significantly higher values of serum Creatinine and Blood Urea in the Mortality group as compared to the survivor group at all points of follow-up.
In our study, the statistically significant lower EF values occurred in the mortality group as compared to the survivor group.Jepth Curtis et al have shown that mortality linearly decreases as LVEF increases to 45%. 19any other studies have shown low EF and association of worse outcomes. 1,19,20Indian College of Cardiology National Heart Failure registry data suggests higher serum creatinine levels and poor LVEF contributed to 30-day mortality and rehospitalization in ADHF. 1 Our study's findings are highly consistent with the studies conducted in this setting.
On 3 months of follow persistent renal dysfunction occurred in 23 patients.At the end of the 6-month follow up total of 16 patients had persistent worsening of Renal function.Zhang et al studied AKI in heart failure with a one-year follow-up.He found a total of 35% of patients had non-recovery of renal function.Different rates in our studies could be due to smaller numbers of patients with CRS-1 in this study (n=60). 13hese findings support the need for early detection and management of AKI in ADHF patients, including the use of appropriate diuretic strategies to avoid worsening renal function.Overall, the study provides useful information on the clinical characteristics of patients with acute decompensated heart failure and acute kidney injury, but further research is needed to explore the optimal management strategies for this population.
The study underscores the significant impact of AKI on the outcomes of ADHF patients, including increased mortality and persistent renal dysfunction.The findings emphasize the importance of identifying risk factors and addressing comorbidities to improve the management of CRS type 1.This study's results are limited by several important factors.First and foremost is the sample size.For a disease that has a very high prevalence, it may be essentially difficult to conclude a small group of the population, especially considering the nature of the study center.Population behavior is to seek health care only when the functional limitation becomes severe enough to disturb day-to-day activities.This study was a single-center experience study.The second factor is the patients received treatment from different physicians and the treatment protocol was individualized.So, the outcome difference would have had some impact due to these factors.

Conclusion
The most common presenting complaint in patients with acute decompensated heart failure and acute kidney injury was dyspnea on exertion, followed by decreased urine output.Managing cardiorenal syndrome remains complex.In this population, impaired renal function is associated with increasing mortality and morbidity.CRS-1 is linked to a 25% increased risk of mortality.Lowering in MAP and systolic blood, eGFR value, severe LVEF, anemia, high maximal serum creatinine, and urea level were independently associated with worse mortality outcomes.

Table 1 .
Demographic and clinical details of total population.

Table 2 .
Results of multivariate analysis of confounding variables using the backward.model.

table 2 )
However -hospital mortality and outcome measures in expired and discharged patients (

Table 3 .
Regression analysis to predictors of mortality.

Table 5 .
Logistic regressions for predictors of persistent renal dysfunction at more than 3months to one-year.

Table 6 .
Predictors of mortality at 1 year.
Indonesian J Cardiol Vol.44, Issue II April -June 2023 OPTIMIZE-HF Investigators and Hospitals.Influence of a performance-improvement initiative on quality of care for patients hospitalized with heart failure: results of the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF).Arch Intern Med.2007 Jul 23;167(14):1493-502. 19.Curtis JP, Sokol SI, Wang Y, et al.The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure.J Am Coll Cardiol.2003 Aug 20;42(4):736-42.20.Toma M, Ezekowitz JA, Bakal JA, et al.The relationship between left ventricular ejection fraction and mortality in patients with acute heart failure: insights from the ASCEND-HF Trial.Eur J Heart Fail.2014 Mar;16(3):334-41. .