CARDIORENAL SYNDROME IN PATIENTS WITH

IN KANO.

A DISSERTATION SUBMITTED TO THE NATIONAL

POSTGRADUATE MEDICAL COLLEGE OF NIGERIA IN PARTIAL

FULFILLMENT OF THE REQUIREMENTS FOR THE AWARD OF

FELLOWSHIP OF THE COLLEGE IN INTERNAL MEDICINE

(CARDIOLOGY).

BY

DR MUHAMMAD NAZIR SHEHU

M.B, B.S [B.U.K.] 2002

DEPARTMENT OF MEDICINE

AMINU KANO TEACHING HOSPITAL, KANO.

MAY 2014

i

DECLARATION

I hereby declare that this work is original unless otherwise acknowledged. This work has not been presented to any other College for Fellowship and has not been submitted elsewhere for publication.

Signature------Date------DR MUHAMMAD NAZIR SHEHU May 2014

ii

CERTIFICATION I

SUPERVISORS’ CERTIFICATION This study reported in this Dissertation was done by the candidate under our supervision. We also supervised the writing of the Dissertation.

SUPERVISOR 1. SIGNATURE/DATE:……………………………………………….. Professor SA Isezuo (FMCP) Professor of Medicine and Consultant Physician/Cardiologist, Usman Danfodiyo University Teaching Hospital,Sokoto.

2. SIGNATURE/DATE:……………………………………………….. Professor B. N. Okeahialam, (FWACP). Professor of Medicine and Consultant Physician/Cardiologist, Jos University Teaching Hospital, Jos, Plateau State, Nigeria.

3. SIGNATURE/DATE:------DR M. M. BORODO (FMCP) Associate Professor of Medicine and Consultant Physician/Gastroenterologist, Aminu Kano Teaching Hospital, Kano, Kano State, Nigeria.

iii

CERTIFICATION II

HEAD OF DEPARTMENT’S CERTIFICATION

This is to certify that this work was undertaken by Dr------in the Department of Medicine Aminu Kano Teaching Hospital Kano.

Head of Department’s Name: …………………………………………………………..

Signature and Date ……………………………………………………………………..

iv

DEDICATION

This work is dedicated to my parents, late Alhaji Muhammadu Abua and Hajiya Hasiya

Muhammad, and my grandfather, late Alhaji Shehu Kurfi.

v

ACKNOWLEGDEMENT

All gratitude belongs to the Almighty Allah, who spares my life and made it possible for me to undergo this training. My profound appreciation goes to Professor SA Isezuo, Professor

BN Okeahialam and Dr MM Borodo for their continued thorough supervision and guidance throughout this work.

My gratitude goes to all the doctors and other staff of Medicine Department of AKTH for their encouragement and support during the course of my training and in carrying out this work. I thankfully acknowledge Professor AG Habib, Dr MU Sani, Dr Aliyu Abdu and Dr

Bappa Adamu for their support and contributions to this Dissertation. I extend my special thanks to the Head of Medicine Department Jos University Teaching Hospital, Professor E.

N. Okeke and the entire staff of the department for their contributions.

My thanks go to all the people that assisted me in doing this work, in particular Mallam

Hamisu, Mallam Bashir and Mallam Lawan Na’iya, staff of Health Records Department of

AKTH. Equally appreciated are the staff of Community Medicine Department, Dr AU

Gajida, Dr MU Lawan and Muhammad Usman Jos for assisting me in statistics.

I am especially indebted to my sponsors and employers, Katsina State Government through the Health Services Management Board (HSMB), Katsina. My thanks go to the Board

Chairman, Dr Salisu Banye, the General Manager, Dr Aliyu El-ladan and the Director

Medical Services, Dr Bashir Abdullahi.

I wish to express my sincere gratitude to my wife Hadiza, my children Bashir and Fadimatu, my elder brother Sunusi and the entire extended family members for their support and patience during the period of my residency training.

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TABLE OF CONTENTS

Title page………………………………………………………………… I

Declaration………………………………………………………………. II

Certification I……………………………………………………………. III

Certification II…………………………………………………………… IV

Dedication………………………………………………………………… V

Acknowledgement……………………………………………………….. VI

Table of Contents………………………………………………………… VII

Abbreviations…………………………………………………………….. VIII

List of Tables and Figures…………………………………………………X

Abstract…………………………………………………………………… XI

CHAPTER ONE: INTRODUCTION…………………………………1

CHAPTER TWO: LITERATURE REVIEW------6

CHAPTER THREE: MATERIALS AND METHODOLOGY------35

CHAPTER FOUR: RESULTS………………………………………… 44

CHAPTER FIVE: DISCUSSION…………………………………… 62

LIMITATIONS OF THE STUDY…………………67

CONCLUSION------68

RECOMMENDATIONS………………………… 69

REFERENCES…………………………………………………………… 70

APPENDICES..…………………………………………………………… 88

vii

LIST OF ABBREVIATIONS

ACE-I- Angiotensin converting enzyme inhibitors.

ADHF- Acute decompensated heart failure.

AF- Atrial .

AKI- .

AKTH- Aminu Kano Teaching Hospital.

ARBs- Angiotensin receptor blockers.

ARD- Advanced renal disease.

AST- Aspartate transaminase.

BNP- Brain natriuretic peptide.

BP- Blood pressure.

BUN- Blood urea nitrogen.

CAD- .

CHF- Congestive heart failure.

CK- Creatinine Kinase.

CKD- Chronic .

CK-MB Creatinine Kinase - myocardial band.

CRS- Cardio-renal syndrome.

CVP- Central venous pressure.

DCM- Dilated .

DM- mellitus.

ECG- Electrocardiography

EDTA- Ethylene Diamine Tetrachloroacetic acid eGFR- Estimated glomerular filtration rate.

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GFR- Glomerular filtration rate.

HDL- High density lipoprotein.

HF- Heart failure.

HHD- Hypertensive heart disease

IHD- Ischaemic heart disease.

IL- Interleukin.

JVP- Jugular Venous Pressure.

LDH- Lactate dehydrogenase.

LDLc- Low density lipoprotein cholesterol.

LV- Left ventricle.

LVEF- Left ventricular ejection fraction.

LVH- Left .

NYHA-New York Heart Association.

PND- Paroxysmal nocturnal dyspnoea.

RI- Renal impairment.

SBP- Systolic blood pressure.

SCr- Serum creatinine.

SNS- Sympathetic nervous system.

RAAS- Renin-angiotensin-aldosterone system.

TC- Total Cholesterol.

WBC- White blood cell count.

WRF- Worsening renal function.

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LIST OF TABLES AND FIGURES

Page Table I: Criteria for CRS classification 40 Table II: Baseline clinical characteristics of all 170 patients 45 Table III: Comparison of the clinical characteristics among patients. 46 Table IV: Comparison of the laboratory parameters among patients. 51 Table V: Comparison of electrocardiographic findings among the patients. 53 Table VI: Comparison of echocardiographic findings among patients. 54 Table VII: Comparison of clinical variables among patients with and without CRS 58 Table VIII: Mortality and duration of hospital stay. 59 Table IX: Comparison of deceased and survivors of CRS. 61 Figure 1: Pathophysiology of CRS 13 Figure 2: Heart and kidney interaction 17 Figure 3: Mechanism by which anaemia can cause heart failure and CRS 19 Figure 4: Age group and sex distribution of the participants. 47 Figure 5: Classification of CRS among the group. 48 Figure 6 Types of CRS found among the patients. 49 Figure 7: Aetiology of HF among the study patients. 55 Figure 8: Medication received by the patients. 56 Figure 9 Echocardiographic image of DCM. 91 Figure 10: Echocardiographic image of HHD. 92

Figure 11: Echocardiographic image of rheumatic stenosis. 93

Figure 12: Electrocardiographic tracing of DCM. 94

Figure 13 Electrocardiographic tracing of HHD. 95

Figure 14 Electrocardiographic tracing of acute . 96

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ABSTRACT

Background: The combination of heart failure and renal impairment often defined as cardiorenal syndrome (CRS) has an important prognostic implication among patients with heart failure. It is currently recognized as an independent predictor of morbidity and mortality among the population of patients with heart failure.

Objectives: The main aim of this study was to determine the prevalence, predictors and outcomes of CRS among patients admitted with HF in medical wards of Aminu Kano

Teaching Hospital, Kano, Nigeria.

Methods: The study was cross-sectional in design. Patients aged 18 years and above who satisfied the inclusion criteria were consecutively recruited over a period of 11 months.

Detailed history and physical examination as well as relevant baseline blood chemistry, full blood count, urinalysis, eGFR, electrocardiography, echocardiography and renal ultrasound scan were carried out. Urinary protein creatinine ratio was determined in those with proteinuria. Serum creatinine, urea and electrolytes were measured at presentation and repeated once during heart failure therapy. Heart failure and CRS were defined and classified using appropriate criteria. Data analysis was done using univariate and multivariate analyses.

Results: Of the 170 patients studied, 100 (58.8%) were females and 70 (41.2%) were males.

Mean age of patients was 49.6 ± 18.74 years. One hundred and twenty four (72.9%) patients had CRS, with 54%, 28% and 18% of them having mild, moderate and severe form of CRS respectively. Patients in NYHA class IV HF symptoms were more than 2 times at risk of developing CRS (95% CI=1.008-4.526, RR=2.135, P= 0.048), while those older than 40 years had more than 3 times risk of having CRS (95% CI=1.797-8.582, RR= 3.927, P=0.001).

Patients with CRS had significantly higher mortality rate compared to those without the syndrome (25% vs13% P= 0.031). There was no significant difference in the duration of hospital stay between patients with and those without CRS (17.86±13.11 vs. 15.85±13.46 P= xi

0.378). Serum creatinine of ≥170µmol/L and serum urea of >20mmol/L were the identified predictors of mortality (95% CI, 1.098-6.243 RR= 2.618, p= 0.030 and 95% CI, 1.106-6.757,

RR= 2.734 and p=0.029 respectively).

Conclusion: In conclusion cardio-renal syndrome was frequent in the study heart failure population and was associated with increased mortality. Advanced NYHA class HF symptoms and older age group were the identified predictors of CRS, while high SCr and high serum urea predicted mortality in these patients. CRS assessment is recommended for all patients with HF and studies on its long term outcomes are required.

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CHAPTER ONE

1.0 INTRODUCTION

Cardiorenal syndrome (CRS) has been defined in a variety of ways and continues to be

characterised by ongoing research. The syndrome is defined by some researchers as

“moderate or severe renal dysfunction that develops in a patient with heart failure during

treatment.1 Others describe it as a pathophysiologic disorder of the heart and kidneys

whereby acute or chronic dysfunction of any of the organs may induce acute or chronic

dysfunction of the other. Thus the primary failing organ can be either the heart or the

kidney.2

Heart failure (HF) is defined as a pathophysiological state in which an abnormality of

cardiac function is responsible for failure of the heart to pump blood at a rate

commensurate with metabolic requirements or does so only at an elevated filling

pressure.3

Renal impairment (RI) is frequent in patients with HF and approximately 20% - 40% of

patients hospitalised for acute heart failure syndromes (AHFS) have co morbid renal

impairment (RI).4 Renal dysfunction defined as at least 25% increase in serum creatinine

or values equal or greater than 2mg/dl has for instance been reported to be common in

patients with HF undergoing intensive treatment.5

In an evaluation of data from 1,681 patients aged 65 years and above who were admitted

for acute decompensated HF (ADHF) at 18 hospitals in Connecticut, 21% of patients had

baseline renal failure and 41% had a baseline serum creatinine level >1.5 mg/dl (1 mg/dl

=76.25 µmol/l).6 Similarly, renal dysfunction complicated HF management in 18% of the

11,327 patients admitted to 115 hospitals in the Euro Heart Failure survey program.4

In a study done at Enugu South-Eastern Nigeria, 50% of hospitalised HF patients had

concomitant renal impairment, with GFR as the best predictor of RI.7 Thirty three percent

xiii of all patients admitted with advanced HF at Sagamu South-Western Nigeria had impaired renal function.8 Abnormal renal function was also found in 50% of the 55 patients with hypertensive heart failure admitted at University of Benin Teaching

Hospital Nigeria.9

Cardiovascular disease is now recognised as the leading cause of death in patients with progressive renal disease.10 Co-morbid renal impairment and HF are increasingly recognised as independent risk factors for morbidity and mortality.11 The intersection has important therapeutic and prognostic implications in patients with heart failure.12 Mild renal dysfunction as reflected by an increase in serum creatinine or decreased estimated

GFR has major impact on cardiovascular risk.13 Studies have shown that patients exhibit a

1% increase in mortality for each 1ml/min decrease in creatinine clearance and that in patients with slight reduction in renal function the cardiovascular risk is in the magnitude of that conferred by diabetes mellitus.14,15 The association between renal insufficiency and poor outcome in patients with HF is therefore not merely a marker of advanced cardiac disease but rather it is directly associated with morbidity and mortality independent of standardised measures of HF severity.16 Indeed impaired renal function has for example been identified as a more powerful predictor of mortality in patients with

HF, than New York Heart Association (NYHA) class and left ventricular ejection fraction

(LVEF).12

Baseline RI has also been shown to increase both morbidity and mortality risks in patients hospitalized for AHFS.4,17 In a retrospective analysis of data from 1,129 patients, at discharge serum creatinine level >2.5 mg/dL was the most powerful independent multivariate predictor of all-cause readmission.4,18 In a multivariate Cox regression analysis of data from 541 patients, all-cause mortality increased with each quartile of

xiv

Blood urea nitrogen (BUN).4,19 A retrospective review of data from studies of left ventricular dysfunction (SOLVD) trial, showed that when compared to patients having normal renal function and left ventricular systolic dysfunction (LVSD), patient with both renal dysfunction and LVSD were more likely to have more advanced symptoms of HF as measured by NYHA Class.20 In the SOLVD trial, patients with moderate renal insufficiency (creatinine clearance < 60mls/min) experienced greater all cause mortality, pump failure, death and composite end point of death or hospitalisation for worsening

HF.20

In a study of determinants of prognosis among black Africans with hypertensive heart failure, the deceased had significantly higher serum creatinine.21 After multivariate analysis, only serum creatinine had statistically differing values between the deceased and survivors in that study.21 Compromised renal function as demonstrated by low estimated glomerular filtration rate (eGFR), was a strong predictor of mortality in advanced heart failure in a study done in Sagamu, South Western Nigeria.22 In another study at Sagamu on aggravated renal dysfunction (ARD) in patients with heart failure, there was at least three times the risk of death in those with ARD compared to those without ARD and there was more than two times the risk of death in those with GFR <40mls/min.8

The high prevalence of coexistent cardiac and renal dysfunctions is because both target organs are similarly involved in conditions including , diabetes mellitus and atherosclerosis.12,23 These risk factors for cardiac and renal diseases are frequent in

Nigeria. Establishing the prevalence of CRS and its influence on the outcome of HF in a

Nigerian setting would therefore be a useful contribution to the on-going global knowledge on the syndrome.

xv

1.1 JUSTIFICATION FOR THE STUDY

Prognostic factors in patients with heart failure are useful in identifying high-risk individuals who require closer follow-up and more intensive intervention. Heart failure and RI frequently coexist in the same patient, and this combination, often called the “cardiorenal syndrome,” has important therapeutic and prognostic implications.4 The syndrome is now recognised as an independent risk factor for morbidity and mortality.23-28 Moreover, Renal function is an underappreciated prognostic factor in heart failure and RI is commonly viewed as a relative contraindication to some proven efficacious therapies.29 The higher morbidity and mortality found in patients with HF and RI are partly due to reduction in medication and to lower rate of diagnostic and therapeutic procedures.15

In view of the growing incidences of HF and kidney disease,24,25 which are both exceptionally costly to manage and associated with high morbidity and mortality, it is important to understand the magnitude of risks in this patients group. Information on the contribution of renal impairment to outcomes in HF could provide more precise risk stratification and prognostication and, ultimately, enhance the development of optimal therapeutic strategies in these patients.

There are limited data on CRS, particularly in northern part of Nigeria. This study therefore aims at documenting the magnitude, pattern and predictors of CRS as well as its possible peculiarity in an African setting.

1.2 AIMS AND OBJECTIVES

GENERAL OBJECTIVE

xvi

To determine the prevalence and impact of CRS among patients admitted with HF at Aminu

Kano Teaching Hospital (AKTH).

SPECIFIC OBJECTIVES

1. To determine the prevalence of CRS among in-patients admitted with HF.

2. To determine the predictors of CRS among patients admitted with HF.

3. To determine the hospital duration of stay and in-hospital mortality among patients

with CRS hospitalised for HF.

4. To determine the factors that influence mortality in CRS patients hospitalised for HF.

CHAPTER TWO

2.0 LITERATURE REVIEW

The heart and the kidneys share responsibility for maintaining hemodynamic stability and end-organ perfusion. Connections between these organs ensure that subtle physiologic

xvii changes in one system are tempered by compensation in the other through a variety of pathways and mediators. In the setting of underlying heart disease or kidney disease, the capacity of each organ to respond to perturbation caused by the other may become compromised. This has recently led to the characterization of the cardiorenal syndrome

(CRS).30

Impaired renal function has been shown to be associated with significant morbidity and mortality in patients with heart failure and asymptomatic left ventricular systolic dysfunction.23-31 Recently, several studies have reported the association between the development of worsening renal function and poor clinical outcomes in patients admitted to hospital with decompensated heart failure.6,32-34 Primary disorders of either of these organs often result in secondary dysfunction or injury to the other . Acute or chronic heart failure may push the kidneys beyond their ability to maintain glomerular filtration, regulate fluid and electrolytes, and clear metabolic waste. Similarly, acute kidney injury or affects cardiac performance through electrolyte dysequilibration, volume overload, and negative inotropy.30 Such interactions represent the pathophysiological basis of cardiorenal syndrome (CRS).2

Although generally defined as a condition characterized by the initiation and/or progression of renal insufficiency secondary to heart failure 10, the term CRS is also used to describe the negative effects of reduced renal function on the heart and circulation.35

Thus, direct and indirect effects of each organ that is dysfunctional can initiate and perpetuate the combined disorder of the 2 organs through a complex combination of neurohormonal feedback mechanisms. In recognition of this bidirectional nature of cardiac-kidney interactions, categorisation of CRS into 5 different subtypes has been suggested as follows; based upon the organ that initiated the insult as well as the acuity or chronicity of the precipitating event,2,36

xviii

 Type I (Acute CRS) reflects an abrupt worsening of cardiac function (e.g. acute

or decompensated congestive heart failure) leading to acute kidney

injury. Between 27 and 40% of patients hospitalized for acute de-compensated heart

failure (ADHF) appear to develop acute kidney injury (AKI) and fall into this clinical

entity. These patients experience higher mortality and morbidity, and increased length

of hospitalization.

 Type II (Chronic CRS) comprises chronic abnormalities in cardiac function (e.g.,

chronic congestive heart failure) causing progressive chronic kidney disease. This

subtype refers to a more chronic state of kidney disease complicating chronic heart

disease. This syndrome is common and has been reported in up to 63% of patients

hospitalized with congestive heart failure (CHF).36

 Type III (Acute renocardiac syndrome) consists of an abrupt worsening of renal

function (e.g., acute kidney or ) causing acute cardiac

dysfunction (e.g., heart failure, , and ischaemia). This subtype refers to

abnormalities in cardiac function secondary to AKI. The pathophysiological

mechanisms likely go beyond simple volume overload and the recent consensus

definition of AKI may help to investigate this syndrome further.

 Type IV (Chronic renocardiac syndrome) describes a state of chronic kidney disease

(e.g., chronic glomerular disease) contributing to decreased cardiac function, cardiac

hypertrophy, and/or increased risk of adverse cardiovascular events. It refers to

disease or dysfunction of the heart occurring secondary to CKD. There is a graded

and independent association between the severity of CKD and adverse cardiac

outcomes. In a recent meta-analysis,37 an exponential relation between the severity of

xix

renal dysfunction and the risk for all-cause mortality was described with excess

cardiovascular deaths constituting over 50% of overall mortality.37

 Type V (Secondary CRS) reflects a systemic condition causing both cardiac and

renal dysfunction. Although this subtype does not have primary and/or secondary

, it refers to situations where both organs are simultaneously

affected by systemic illnesses either acute or chronic. Examples include ,

systemic lupus erythematosus, diabetes mellitus, , or other chronic

inflammatory conditions.

Despite growing recognition of “cardiorenal syndrome,” no consensus definition of the syndrome has been established.38

2.1 EPIDEMIOLOGY

A meta-analysis of studies evaluating the relationship between renal dysfunction and heart failure revealed that 63% of the study patients had at least mild renal impairment, and 20% had moderate or severe renal dysfunction.39 At least one in four patients hospitalized for acute decompensated heart failure has significant renal dysfunction (eGFR less than 60 mL/min/1.73 m2).2 Approximately 20% - 40% of patients admitted to a hospital for acute HF syndromes (AHFS) have RI, based on clinical history and serum creatinine levels.16 In addition, approximately 25% of patients with chronic heart failure have been found to have reduced GFR40 independent of their level of left ventricular function.40 A prospective cohort study of 754 patients with chronic heart failure found only 17% of patients had an eGFR >

90 ml/min.41 Also 30% of hospitalised patients with HF had a history of chronic RI and 20% had a serum creatinine level >2 mg/dL in an evaluation of 105,388 hospitalisation episodes at

274 hospitals from the Acute Decompensated Heart Failure National Registry (ADHERE).42

Of the overall ADHF patient population, serum creatinine concentrations of more than 2.0

xx mg/dL were evident in 20% of the population, and 9% had serum creatinine concentrations of more than 3.0 mg/dL, while 5% were receiving chronic dialysis at the time of admission.42,43

Serum creatinine values underestimate the burden of renal disease. Sixty percent of patients with ADHF have moderate to severe renal dysfunction. When considering the prevalence of renal dysfunction in the ADHF population using estimated GFR, a powerful predictor of mortality,44 the numbers are even more alarming. According to the National Kidney

Foundation/Kidney Dialysis Outcome Quality Initiative’s GFR classifications45 the majority of patients enrolled in ADHERE had moderate kidney damage. Renal dysfunction was common, with 46.8% of women having severe dysfunction or overt renal failure, and over

60% of men having at least moderate kidney damage.46 Indeed, an analysis of 88,075 registry patients based on estimated GFR, found that more than 95% of patients had at least some degree of renal dysfunction on presentation.47 Patients with renal insufficiency tend to be male, older, are more often diabetic, and are more likely to have myocardial ischemia and a history of myocardial infarction than are patients with normal renal function.48

Concomitant renal impairment and heart failure had been found in some African studies. In a study of chronic heart failure at Yaounde General Hospital Cameroon, Renal dysfunction, defined as creatinine clearance <60 ml/min, was present in a quarter (24,3%) of the 140 study patients.49 Approximately 11.8% of the heart failure patients demonstrated signs of renal impairment in a South African study on anaemia and renal dysfunction in patient with

DCM.50 In the Soweto study, 141 (20%) had an estimated glomerular filtration rate indicative of moderate to severe renal dysfunction.51

Nigerian studies of hypertension and cardiac failure revealed that RI is common in patients with cardiac failure.52,53 Renal impairment was found in 32.9% of patients in a clinical study on advanced heart failure at Sagamu, South-Western Nigeria.22 In a study of poor prognostic factors among HF patients done at Kano North-Western Nigeria, renal impairment was

xxi found in 11% of the patients.54 About eight percent of the total patients admitted with HF in a

Nigerian Teaching Hospital had chronic renal failure which was the cause of HF in them.55 In general the prevalence of RI in patients admitted with HF in some of these studies ranges from 7% to 50%. However, issues on sample size, definition of RI in HF and the parameters used for the diagnosis of RI might be responsible for the observed variations in the prevalence of RI in those studies.

2.2 AETIOLOGY

The aetiology of RI in patients with HF is complex, and probably multifactorial. There may be interplay of several factors in the same patient. These factors can be summarised as follows:

● Intrinsic renal disease including: renal , nephron loss (glomerulonephritis, , diabetes mellitus, and hypertension) and resistance.

● Inadequate renal perfusion: (inadequate preload), inadequate cardiac output

(excessive vasoconstriction), hypotension (with normal or low cardiac output, as in vasodilatory shock and cardiogenic shock respectively) and abnormally high central venous pressure.

 Drug-induced (NSAIDs, cyclosporine, tacrolimus, ACE inhibitors, ARBs, etc).

2.3 PATHOPHYSIOLOGY

Although not directly applicable to the cardiorenal syndrome, the potential of an association between renal dysfunction and cardiac dysfunction is supported by a study of the effects of renal transplantation on left ventricular systolic function. The study evaluated the effects of kidney or kidney/pancreas transplantation in 138 patients with end-stage renal disease

(ESRD), left ventricular ejection fraction (LVEF) of 40% or less, and diagnosed heart failure.56At mean 6.6 months post transplantation, mean LVEF had increased from 32% at baseline to 47%, and to 52% at mean 12.5 month follow-up. The vast majority of patients

xxii

(>86%) had an improvement in LVEF of more than 5%. At long-term follow-up (mean, 36.8 months), 73% of patients were in New York Heart Association (NYHA) class I.56 At baseline, 58% were NYHA class IV.56 Why such dramatic improvements should occur in patients following kidney transplantation is unclear from the study, but the investigators hypothesised that the reduction in uremic toxins resulting from the improved kidney function reduced cardiac stress.56

The pathophysiology of heart failure and renal insufficiency can be linked to intrinsic renal disease, haemodynamic abnormalities, exogenous factors, humoral and immune mediated damage.

-INTRINSIC RENAL DISEASE: Atherosclerosis, renal vascular disease, diabetes, and hypertension are significant precursors of both renal dysfunction and HF.57,58 As a result, intrinsic renal disease frequently coexists with HF.59

-HAEMODYNAMIC ABNORMALITIES AND EXOGENOUS FACTORS: Diminished renal perfusion is frequently a consequence of the haemodynamic changes associated with

HF and its treatment. Severe pump failure leads to low cardiac output and hypotension

(carcinogenic shock). Neurohormonal activation produces both fluid retention, which increases central venous pressure, and vasoconstriction, which leads to increased after load and diminish cardiac output. Diuresis can cause hypovolaemia and reduced preload, while the use of intravenous vasodilators can lead to hypotension. In addition, agents such as nonsteroidal anti-inflammatory drugs (NSAIDs), cyclosporine, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) can decrease renal perfusion.60-63 The resultant diminution in renal blood flow/GFR can lead to RI even in the absence of intrinsic renal disease. Angiotensin II–induced vasoconstriction of the efferent glomerular arteriole helps to preserve GFR in patients with HF and RI.64 Neurohormonal blockade with ACE inhibitors and/or ARBs impedes this vasoconstriction, reducing

xxiii glomerular capillary pressure and, hence, reduced GFR, leading to an acute, small increase in serum creatinine level.65,66 Although initially worrisome, especially given the mortality risk associated with similar acute increases in serum creatinine level in patients with HF,67-69 the resultant decrease in glomerular hyperfiltration seems to be renoprotective over the long term, and supports continuation of these therapies in the absence of .70-73

Because patients who are volume-depleted may be especially sensitive to this efferent arteriolar vasodilation,73,74 restoring and maintaining a normal volume status before and throughout therapy with a neurohormonal blocking agent may help alleviate the initial acute decline in renal function.

Figure 1 Pathophysiologic link between cardiac and renal failure. ACEI-angiotensin converting enzyme inhibitor; ARB-angiotensin receptor blocker; BP-blood pressure; BUN- blood (serum) urea nitrogen; CAD-coronary artery disease; CO- cardiac output; CVP-central venous pressure; DM-diabetes mellitus; GFR-glomerular filtration rate; HF-heart failure; HTN- hypertension; LV -left ventricular; LVEF-LV ejection fraction; LVH-LV hypertrophy; Na-sodium; NSAIDs-nonsteroidal anti-inflammatory drugs; SCr -serum creatinine; SVR- systemic vascular resistance.17

xxiv

High central venous pressure is another cause of renal dysfunction that is often overlooked.

While it is true that decreased forward flow as a result of decreased cardiac output in ADHF can cause acute deterioration in kidney function, there are several reasons why this mechanism fails to completely explain the development of the CRS. First, altered haemodynamics alone is inadequate to explain the mechanism of kidney injury in ADHF as redundant feedback mechanisms exist to prevent it. Second, the CRS has been observed in patients with diastolic dysfunction who have normal left ventricular systolic function.41 In the

ADHERE registry, acute kidney injury occurred at similar rates in patients with both systolic and diastolic dysfunction.75 And finally, subgroup analysis of the ESCAPE trial showed evidence that poor forward flow alone was insufficient to explain worsening kidney function.76 In this trial, an improved cardiac index was not associated with improved renal outcomes, but increased CVP and atrial pressures were associated with decreased kidney function.76 In the ELEGANT study,77 it was established that increasing venous pressure above 19 cm of water produced significant reductions in GFR, sodium excretion, and fractional excretion of sodium, which resolved completely when venous pressure was restored to basal levels.77

Urine flow decreased when renal venous pressures were increased to 20 mmHg. This also led to a drop in glomerular perfusion pressure, and a reduction in GFR.77 It is hypothesized that increased venous pressure distends the venules surrounding the distal nephron. This leads to compression of the tubule, increased tubular fluid pressure, and back leak of filtrate into the interstitium. An increased interstitial pressure then results in venous congestion and interstitial hypoxia.78 Furthermore, as hydrostatic pressure within the Bowman’s capsule increases, glomerular filtration fails and the RAAS is activated and the SNS is triggered.79

Studies in human subjects have also demonstrated that increased central venous and right atrial pressure are associated with worsening kidney function as well as increased mortality.80

xxv

Damman and colleagues have demonstrated that increased venous pressure is an independent determinant of glomerular filtration in patients with heart failure.81 In this study the lowest glomerular filtration rate was observed in patients with lowest renal blood flow and highest right atrial pressures.

HUMORALLY AND IMMUNE MEDIATED DAMAGE:

Research into the pathophysiology of the cardiorenal syndrome has not fully established the key mechanism operative in this syndrome, but experimental evidence does provide a more compelling argument linking renal dysfunction to cardiac dysfunction by indicating a connection between neurohormonal activation and cardiac and renal dysfunctions. The neurohormonal and sympathetic nervous system (SNS) maladaptations that occur with cardiac dysfunction also occur during periods of suboptimal renal function.82 Renal dysfunction induces inappropriate activation of the renin-angiotensin-aldosterone system

(RAAS), causing vasoconstriction and fluid and sodium retention. The RAAS, in turn, activates the nicotinamide adenine dinucleotide phosphate–oxidase pathway, resulting in the excess formation of reactive oxygen species (ROS).82 Excessive ROS production results in a nitric oxide (NO)—ROS imbalance that decreases antioxidants and NO, increases oxidative stress on both organs, and, ultimately, activates proinflammatory cytokines such as interleukin (IL)-1, IL-6, C reactive protein, and tumour necrosis factor-α, which may have negative effects on inotropy and may cause cardiac remodelling and worsen atherosclerosis.82,83

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are released in response to stretch of the cardiac chambers, and play a role in regulation of extra cellular fluid volume

(ECFV) by inducing sodium and water loss. They are elevated in both heart failure and reduced kidney function. Although they are an ideal therapeutic target, their role in the pathophysiology of CRS is not known. Erythropoietin is purported to decrease apoptosis in

xxvi renal cells and cardiac myocytes by decreasing oxidative stress.84 Small trials have revealed that heart failure patients who received erythropoietin had improved kidney function,85 but their place in the treatment of CRS cannot be confirmed without long-term studies.

Antidiuretic hormone (ADH) levels are elevated in HF due to non osmotic stimuli from baroreceptor stimulation.86 Antagonism of ADH would seem to have a role in the CRS, but studies of vasopressin receptor 2 antagonists did not result in improvement in kidney function.87

There is direct evidence to demonstrate that HF is associated with tubulointerstitial damage.

A recent study by Damman and colleagues showed that congestive heart failure is associated with increased markers of tubulointerstitial damage such as N-acetyl-beta-D-glucosaminidase

(NAG), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase associated lipocalin

(NGAL).88 Other studies have also demonstrated renal tubular and interstitial damage as well.89

Finally, SNS activity increases, a phenomenon associated with vasoconstriction, cardiomyocyte necrosis, and increased myocardial inotropy, chronotropy, and hypertrophy.67,90 Such a neurohormonal milieu is evident in patients identified with the cardiorenal syndrome. A recent analysis of 48 patients with ADHF and renal dysfunction described a unique neurohormonal profile that included elevated plasma renin activity, elevated concentrations of angiotensin II and aldosterone, and decreased levels of natriuretic peptides,66 including BNP, which counteracts and inhibits maladaptive effects of various neurohormones.66,91

There was a correlation between RI and circulating levels of neurohormones in patients with

HF. Activation of renin- angiotensin-aldosterone system (RAAS) leads to renal hypoxia, vasoconstriction, intraglomerular hypertension, glomerulosclerosis, tubulointerstitial fibrosis, and proteinuria. 57 Similarly, sympathetic nervous system activation causes proliferation of

xxvii smooth muscle cells and adventitial fibroblasts in the vascular wall of intrarenal blood vessels.92 Cytokines are also released by the activated inflammatory cells. Cytokines may stimulate renin secretion as a component of the systemic stress response, and tubulointerstitial inflammation may have effects on adaptive responses of glomerular haemodynamics to impaired renal function.93

In summary, it appears that regardless of whether decreased perfusion occurs as a result of hypoperfusion or venous congestion, the consequent processes resulting in kidney injury are the same. RAAS activation results in increased angiotensin II which stimulates nicotinamide adenine dinucleotide hydrogen (NADH) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-oxidases. The resulting NADPH/NADH suppresses superoxide dismutase, and increases reactive oxygen species. This results in the well known cascade of hypoxic ischemic injury, inflammation, apoptosis and cell death.

In addition to the adverse affects of HF on renal function, RI adversely affects cardiac function, producing a vicious cycle in which RI impairs cardiac performance, which then leads to further impairment of renal function. As a result, RI is a major determinant of the progression of HF, congestion, and recurrent decompensation and hospitalisation (see figure

2).94,95

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Figure 2: In cardio-renal syndromes, there are two important aspects: the first is the sequence of organ involvement and the second is the bi-directionality of signalling leading to a vicious cycle. Another important aspect is the time frame in which the derangements occur (chronic or acute). In all cases, there are moments in which prevention is possible, in others mitigation of the insult is potentially feasible, in others, therapeutic strategies must be implemented. At different times, a crucial role is played by imaging techniques and biomarkers enabling the clinician to make an early diagnosis, establish illness severity, and to potentially predict outcomes. This flowchart describes a series of conditions indicating that patients may move from one type to another of cardio-renal syndromes.36 THE CAUSATIVE ROLE OF ANAEMIA IN CRS

The interaction between chronic heart failure, chronic kidney insufficiency and anaemia, form a vicious cycle, termed the cardio-renal anaemia syndrome. The interaction between these three conditions causes deterioration of the cardiac and renal functions and worsens anaemia. Each of the three can cause or be caused by the others.96

Tissue hypoxia due to anaemia, leads to peripheral vasodilatation and decreased vascular resistance, which in turn reduces blood pressure. The sympathetic system is activated and this causes , increased stroke volume and peripheral vasoconstriction in order to maintain adequate blood pressure.97 However, increased sympathetic activity also causes renal vasoconstriction, resulting in renal blood flow and glomerular filtration rate (GFR) reduction, leading consequently to renal ischaemia.97 The reduced renal blood flow activates the renin angiotensin aldosterone system (RAAS) and antidiuretic hormone, causing further renal vasoconstriction, as well as salt and water retention. The renal insufficiency thus

xxix produced may also cause anaemia through reduced erythropoietin production and bone marrow suppression.98 The fluid retention mentioned above, causes plasma volume expansion which leads to LV dilatation and stress on an already stressed myocardium. The consequent

LV hypertrophy leads to necrosis and apoptosis of myocardial cells, myocardial fibrosis and cardiomyopathy resulting in CHF. Additionally, elevated level of renin, angiotensin and aldosterone causes damage of cardiac cells directly, exacerbating the damage already done.97,98 The level of tumour-necrosis factor α (TNFα) is increased in CHF and there is evidence that cardiac cells produce this cytokine in response to injury, which damage the heart further.99 This increased production of cytokines has also been implicated in the development of chronic disease anaemia and may also worsen anaemia in CKD and CHF patients, thus forming a vicious cycle of disease progression (Figure 3).100

Figure 3.The mechanism by which anaemia can cause heart failure and renal failure.79

2.4 DIAGNOSIS: Cardiorenal syndrome should be suspected in patients with long-standing

HF who experience an episode of decompensation despite adequate therapy for chronic HF including chronic high-dose diuretic therapy.12

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The following groups of patients have been identified to have the highest risk of developing

CRS:

 Patients with previous heart failure hospitalisation.

 A history of worsening renal function with previous ADHF episode.

 A history of transient dialysis.

 Marked functional tricuspid or mitral regurgitation.

 Patients with severe diastolic dysfunction (regardless of the ejection fraction),

secondary pulmonary hypertension and right ventricular dysfunction.12

A careful history should identify factors that may be responsible for exacerbating disease and

HF-related renal dysfunction, such as infection, use of nephrotoxic agents, or risk factors for renal artery stenosis.12

Laboratory data:

One of the cornerstones of CRS therapy is the early identification of worsening kidney function. This can be accomplished with the use of biomarkers that become detectable before the traditional tests for kidney function, including glomerular filtration rate or serum creatinine. 36 Biomarkers such as NGAL, NAG, and KIM-1 have been associated with tubulointerstitial damage and have been used to identify acute kidney injury. Serum cystatin

C is elevated earlier than creatinine. Furthermore, while cystatin C in the serum is a marker of reduced glomerular filtration, urinary cystatin C is a marker of tubular dysfunction. Other biomarkers that have been proven useful include BNP, IL-18, and Fatty Acid Binding Protein

(FABP).36

Individual biomarkers of renal injury

Neutrophil gelatinase-associated lipocalin

xxxi

Neutrophil gelatinase-associated lipocalin (NGAL) seems to be one of the earliest kidney markers of ischaemic or nephrotoxic injury in animal models and is detected in the blood and urine of humans soon after AKI.36 In a recent study, a single measurement of urinary NGAL was able to predict those with subsequent AKI, with a sensitivity and specificity of 90 and

99%, respectively. Neutrophil gelatinase-associated lipocalin could be used as an earlier marker of impending worsening renal function during the treatment of ADHF.36

Cystatin C

Cystatin C appears to be a better predictor of glomerular function than serum creatinine in patients with CKD. In AKI, urinary excretion of cystatin C has been shown to predict the requirement for renal replacement therapy (RRT) earlier than creatinine.101

Kidney injury molecule-1

Kidney injury molecule-1 (KIM-1) is a protein detectable in the urine after ischaemic or nephrotoxic insults to proximal tubular cells.102 Urinary KIM-1 seems to be highly specific for ischaemic AKI and not for pre-renal azotemia, CKD, or contrast induced nephropathy.102

N-acetyl-β-(D)glucosaminidase

N-acetyl-β-(D) glucosaminidase is a lysosomal brush border enzyme found in proximal tubular cells.103 N-acetyl-β-(D) glucosaminidase has been shown to function as a marker of kidney injury, reflecting particularly the degree of tubular damage. It is not only found in elevated urinary concentrations in AKI and CKD, but also in diabetic patients, patients with essential hypertension, and HF.104

Interleukin-18

Interleukin-18 (IL-18) is a pro-inflammatory cytokine detected in the urine after acute ischaemic proximal tubular damage. It displays good sensitivity and specificity for ischaemic

AKI, with increased levels 48 h prior to the increase in serum creatinine.105,106

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Of the biomarkers presented above, NGAL (urine and plasma) and Cystatin C are most likely to be integrated into clinical practice in the near future.36,101 However clinical trials will be needed to see if earlier identification of AKI and the use of specific treatment algorithms based on these markers will improve prognosis.36

Thus detection of these biomarkers might be used to diagnose CRS at an earlier time point, facilitate targeted therapy for CRS by modifying pharmacologic therapy, and monitor progression of disease. Nevertheless, a high index of suspicion for identifying patients with

CRS is needed as testing for biomarkers at this time is expensive. Thus answers to the following questions may guide the possible clinical usefulness of these biomarkers by physicians; (i) Can biomarkers be used to (early) identify and classify CRS? (ii) Can biomarkers be used to risk-stratify patients with regard to reversibility? (iii) Can biomarkers be used as targets for treatment? (iv) Can biomarkers be used to monitor the effects of treatment? (v) Can imaging of the heart and kidneys be combined effectively with biomarkers across the spectrum of diagnosis and treatment of CRS? 36

The baseline investigations include urea, electrolyte and creatinine, estimated glomerular filtration rate (eGFR) and full blood count.

Urinalysis, including microscopic analysis for urine eosinophils (seen in allergic interstitial or renal atheroembolism) should be done. When renal failure is secondary to hypoperfusion (pre-renal), the fractional excretion of sodium is characteristically <1.107

Acute tubular necrosis may be diagnosed on the basis of an increase in urinary sodium

(fractional excretion of sodium >1), reduction in urine nitrogen concentration and typical urinary sediment findings.107

Renal ultrasound with Doppler imaging of renal arteries, and assessment of renal resistivity indices, should be performed to assess renal size, renal artery stenosis, or obstruction and to characterize structural renal disease.

xxxiii

If suspicion for renal artery stenosis is high, one can consider magnetic resonance imaging with angiography, although this is increasingly difficult in patients with systolic HF due to the presence of devices.

Renal biopsy: In patients in whom the cause of acute renal failure is unclear even after a thorough history, physical examination, and laboratory and clinical investigations are performed, renal biopsy may provide definitive diagnostic information that is helpful in guiding therapy or prognosis.12

2.5 TREATMENT

HF with co morbid RI can be difficult to manage because both cardiac and renal functions are exquisitely dependent on circulating volume.57

The approach to the management of cardiorenal syndrome include:12 withdrawal of the offending agents, optimizing heart failure therapy, normalisation of volume status while avoiding overdiuresis and attendant renal dysfunction and implementation of evidence-based pharmacologic and device therapy to improve patient outcomes.

WITHDRAWAL OF THE OFFENDING AGENTS

The first approach is to consider discontinuation of drugs that contribute to RI, such as aspirin and other NSAIDs. ACE inhibitors and ARBs should be discontinued in patients with renovascular disease who develop a significant increase in their serum creatinine level, and these agents may need to be temporarily reduced or discontinued in patients who have excessive vasodilation.46 However, given their long-term beneficial effects in both HF and

RI, therapy with an ACE inhibitor or ARB should be continued or reinstituted whenever possible.108,109

OPTIMIZE HEART FAILURE THERAPY

While therapy for ADHF often focuses on volume removal, careful review of the patient’s

HF therapy addressing the adequacy of vasodilator therapy, blood pressure control, or the

xxxiv potential for additional adjuvant therapy (digoxin, nitrates, cardiac resynchronization therapy) is important. Addressing factors that can provide additional symptom relief (paracentesis, thoracocentesis) or optimize cardiac function (revascularization, correction of valve disease) should be considered early in the hospitalization.

Neurohormonal Blockade

This involves blockage of RAAS using ACE inhibitors, ARB, direct renin inhibitors or aldosterone antagonist. While most of these medications cause an acute drop in GFR through the dilatory effect on the efferent arteriole, they have long-term reno- and cardioprotective effects. Therefore, patients who are prone to develop CRS yet able to tolerate a small reduction in GFR, up to 30% from the baseline, may benefit from these agents.30 As RAAS has been implicated in oxidative damage, its interruption through ACE inhibition or angiotensin blockade may prevent the development of CRS.30

Similar to RAAS blockade, beta blockers through their effect on the SNS may have a role in the long-term prevention of adverse cardiac events and in remodelling. However in CRS, their role is limited by the altered haemodynamics. Unless the underlying aetiology of ADHF is myocardial infarction, beta blockers are often held until the patients are haemodynamically stable.30

DIURETICS

Volume overload is a frequent component of both HF and RI and a major cause of clinical symptomatology. Consequently, play an important role in the treatment of both conditions. 107 Their symptomatic benefit in patients with HF has led to almost universal clinical acceptance, even though their efficacy and safety have never been evaluated in large scale, randomized clinical trials.107

Use of diuretics involves a delicate balance. The dose must be sufficient to achieve effective relief of fluid overload and its ensuing symptoms without stimulating adverse physiologic

xxxv effects. Excessive diuresis produces hypovolaemia and extracellular fluid contraction, leading to hypotension, reduced cardiac output, diminished GFR, and further impairment of renal function.107 In case of diuretic resistance; several studies suggest that a continuous infusion of diuretics is more effective than are intermittent boluses.110-115

ULTRAFILTRATION

When diuretic resistance persists, ultra filtration should be considered. In patients with moderate- to-severe HF, ultra-filtration has been shown to improve symptoms, haemodynamics, urine output, and diuretic responsiveness.116,117 Moreover, unlike loop diuretics, ultra-filtration produces less long-term neurohormonal activation.116-119

In two trials of ultrafiltration in patients with ADHF, the “Relief for Acutely Fluid

Overloaded Patients with Decompensated Congestive Heart Failure (RAPIDCHF)” and “Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute

Decompensated Congestive Heart Failure (UNLOAD),” there was marked weight loss and relief of heart failure symptoms,120,121 but no improvement of kidney function.

Nevertheless, published case reports have shown improved kidney function with ultrafiltration.122

INOTROPES

Inotropes augment contractility and are an essential component of the treatment of low-output

HF manifested by cardiogenic shock. They improve short-term haemodynamics but increase the risk of adverse events and mortality.123 Patients hospitalized for ADHF who received milrinone or dobutamine had significantly increased in-hospital mortality compared with those who received nitroglycerin or after adjusting for differences in baseline covariates and propensity score in an analysis of data from the ADHERE registry.123

Levosimendan, a phosphodiesterase inhibitor, has been studied in CRS. In one study, levosimendan resulted in improved GFR when compared to dobutamine.124 However, another

xxxvi study of levosimendan and dobutamine did not show any benefit.125 Currently, the role of inotropic agents in CRS remains unknown.30

VASODILATORS

Vasodilators (e.g. Nitrates and Nesiritide) decrease preload and after load, reducing ventricular work, increasing stroke volume, and augmenting cardiac output. They are indicated in patients with AHFS who have signs of congestion and hypoperfusion with adequate blood pressure.126

Nitrates effectively relieve pulmonary congestion, and their use, in combination with a low- dose diuretic, has proved to be more efficacious than high-dose diuretic therapy alone in patients with AHFS.108

Nesiritide is a recombinant form of Human B-type natriuretic peptide (hBNP).It is a counter regulatory hormone produced by the ventricles in response to pressure and volume load. In patients with HF, hBNP produces balanced vasodilation, improves cardiac output, and inhibits activity of the RAAS, sympathetic nervous system, and endothelin system.127-129

In an evaluation of few cohorts of patients with HF who underwent cardiac catheterization, nesiritide exerted a renal vasodilatory effect, which maintained renal blood flow despite a significant decrease in renal perfusion pressure.130 However a meta-analysis demonstrated poorer renal outcomes with nesiritide.121

Adenosine Antagonist.

Adenosine is generated locally in the macula densa in response to diuretics that block sodium and chloride absorption, resulting in afferent arteriolar constriction and decreased

GFR. Antagonizing adenosine might have a role in preserving kidney function in CRS. To this extent, KW-3902, an adenosine A1-receptor antagonist, was found to improve kidney function and decrease diuretic resistance in patients with ADHF and CRS.131

xxxvii

Vasopressin Antagonists.

By making use of their aquaretic properties, vasopressin (V2 receptor) antagonists have been used in severe heart failure. However, clinical trials such as the “Efficacy of Vasopressin

Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST)” trial showed no benefit of tolvaptan, a vasopressin antagonist, on all cause mortality or the combined end point of cardiovascular mortality or hospitalization for ADHF.132 Kidney function remained stable throughout this trial, and the use of vasopressin antagonists in the CRS conundrum may be limited to those patients complicated by hyponatraemia. Although other studies showed there was some renal benefit,133 the cost of these medications would prohibit them from being used routinely.

LEFT VENTRICULAR ASSIST DEVICES

In selected patients with refractory low output syndrome and RI, expeditious placement of a left ventricular assist device may restore clinical stability and reversal of renal dysfunction.134

A ventricular assist device (VAD) is a mechanical circulatory device that is used to partially or completely replace the function of a failing heart. Some VADs are intended for short term use, typically for patients recovering from heart attacks or heart surgery, while others are intended for long term use (months to years and in some cases for life).135 Long term VADs are normally used to keep patients alive with a good quality of life while they wait for a heart transplantation (known as a "bridge to transplantation").135 The pumps used in VADs can be divided into two main categories - pulsatile pumps, that mimic the natural pulsing action of the heart, and continuous flow pumps. Pulsatile VADs use positive displacement pumps.

Continuous flow VADs normally use either centrifugal pumps or an axial flow pump.135

ALGORITHM FOR CARDIORENAL SYNDROME MANAGEMENT

xxxviii

Although there are no agreed guidelines for managing patients with cardio-renal and/or reno- cardiac syndromes, a specific treatment strategy should be targeted to the specific type of

CRS as described below:36

ACUTE CARDIO-RENAL SYNDROME (TYPE 1): Vasodilators and loop diuretics are widely recommended in cases of ADHF and in CRS type 1. Vasopressin receptor 2 antagonists can improve hyponatraemia, but without any clear survival benefit.36 If congestion coincides with low blood pressure, or in cardiogenic shock, inotropic agents should be considered. Extracorporeal ultrafiltration may be useful in ADHF associated with diuretic resistance. If systemic hypotension persists, then norepineprine may be considered, along with elective ventilation and/or intra-aortic balloon pumping. Depending upon pre- existing co-morbidity and the underlying aetiology, left ventricular assist devices as a bridge to transplantation or cardiac surgery may be appropriate. It should be mentioned that over- treatment with loop diuretics, ACE-I, and/or spironolactone may induce AKI.

CHRONIC CARDIO-RENAL SYNDROME (TYPE 2)

Therapy of CHF with concomitant renal impairment is still not evidence-based, as these patients are generally excluded from CHF trials.136 Typically, these patients are hypervolaemic, and more intensive diuretic treatment is needed. Thiazide diuretics may be less effective, and loop diuretics are preferred. To improve natriuresis, loop diuretic infusions are more potent, and combinations with amiloride, aldosterone antagonists, or metolazone may be considered,136, as increasing doses of loop diuretics are associated with worse outcomes.36 In refractory cases, renal replacement therapy may be required.36

Angiotensin converting enzyme inhibitor and ARB initiation may cause deterioration in renal function, which is frequently transient and reversible. Patients with CKD or renal artery stenosis are at a higher risk, and careful monitoring is recommended.36

ACUTE RENO-CARDIAC SYNDROME (TYPE 3)

xxxix

Type 3 CRS has only recently been recognized as a clinical entity, hence there is little known about the treatment of this complication. As typical clinical scenario would include AKI following contrast exposure, or following cardiovascular surgery (CSA-AKI), prevention likely affords a better chance to improve outcome than treating established disease.36

CHRONIC RENO-CARDIAC SYNDROME (TYPE 4)

Angiotensin converting enzyme inhibitors and beta-blockers are cardio protective in CKD patients. Besides preventing hypervolaemia and a positive sodium balance, the other key management strategies include correcting anaemia and minimizing vascular calcification.

Optimum renal replacement therapy is required as well.36

SECONDARY CARDIO-RENAL SYNDROME

A core concept is that treatment of the primary illness (diabetes mellitus, amyloidosis, sepsis, rhabdomyolysis, haemorrhagic shock, etc.) in general improves both heart and kidney function.36

PREVENTION OF CARDIO-RENAL SYNDROMES

The rationale for the prevention of CRS is based on the concept that once the syndrome begins it is difficult to interrupt, not completely reversible in all cases, and associated with serious adverse outcomes. Prevention can be approached using CRS classification system.36

ACUTE CARDIO-RENAL SYNDROME (TYPE 1)

The most important preventive approach in patients with de novo HF consists of the basic preventive strategies of the American Heart Association/American College of Cardiology for

Stage A and B HF. These call for blood pressure control, use of drugs that block the renin– angiotensin–aldosterone system, beta-adrenergic blockers (BB), coronary artery disease risk factor modification, and compliance with dietary and drug treatments. As venous congestion seems to be an important haemodynamic factor driving worsening renal function (WRF)137 in

xl

ADHF, future studies should evaluate whether a CVP-tailored therapy might prevent WRF in those patients.138

CHRONIC CARDIO-RENAL SYNDROME (TYPE 2)

In this setting, therapies that improve the natural history of chronic HF include angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), BB, aldosterone receptor blockers, combination of nitrates and hydralazine, and cardiac re-synchronization therapy.108

ACUTE RENO-CARDIAC SYNDROME (TYPE 3)

The clinical problem in many cases is sodium and water retention. Avoidance of hypervolaemia should help prevent cardiac decompensation. In addition, uraemic changes, hyperkalaemia, and mediators of inflammation can have adverse cardiac consequences.36

CHRONIC RENO-CARDIAC SYNDROME (TYPE 4)

Type 4 CRS is a common syndrome since it involves the progression of CKD, often due to diabetes mellitus and hypertension, with accelerated calcific atherosclerosis, progressive

LVH, and the development of diastolic and systolic dysfunction.138 The core prevention concept beyond attention to usual risk factor modification is that the reduction in the rate of progression of CKD may lead to reduced rates of type 4 CRS.

SECONDARY CARDIO-RENAL SYNDROME (TYPE 5)

Early diagnosis, prompt and adequate treatment of the primary illness protects the two organs affectation.

2.6 PROGNOSIS

Cardiac and renal diseases are common and frequently coexist to significantly increase mortality, morbidity, and the complexity and cost of care.36 The prognosis of patients with the cardiorenal syndrome is poor. Multiple clinical trials and registries have confirmed that renal dysfunction either on presentation or that worsens during hospitalisation, confers a poor

xli prognosis and substantially increases the risk of in-hospital, intermediate, and long-term death.28,95,139, Two of the 3 non-invasive measures found to predict in-hospital mortality drawn from an ADHERE analysis were for example related to kidney function: baseline blood urea nitrogen (BUN) level, systolic blood pressure (BP), and serum creatinine concentration.140 Patients with a BUN less than 43 mg/dL had a crude in-hospital mortality rate of 2.8% versus 8.4% among those above the cut off point. The risk of death was compounded with cumulative risk factors; patients with an elevated BUN and systolic BP of less than 115 mm Hg had an in-hospital death rate of 15.3% versus 5.6% among those with an elevated BUN and higher BP. In patients with an elevated BUN, systolic BP less than 115 mmHg, and serum creatinine concentrations 2.75 mg/dL or greater, the death rate escalated to

19.8% versus 13.2% among those with better kidney function.140

Patients with renal insufficiency had significantly longer hospital stays (10.3vs8.2days, respectively=0.003) and a 59% higher rate of readmission within 30 days of discharge (27% vs 17%, respectively; P=0.016).141

In a retrospective analysis of data from 1,129 patients, a discharge serum creatinine level

>2.5 mg/dL was the most powerful independent multivariate predictor of all-cause readmission.142 In a multivariate Cox regression analysis of data from 541 patients, all-cause mortality increased with each quartile of blood urea nitrogen (BUN), with an adjusted mortality relative risk of 2.3 for patients in the highest compared with the lowest quartile.19

In a meta analysis of 80,098 hospitalized and nonhospitalized patients, an eGFR < 53 ml/min was associated with a 51% 1-year mortality compared to a 38% 1-year mortality for an eGFR

< 90 ml/min.30 Preserved kidney function with an eGFR > 90 ml/min was associated with a

24% 1-year mortality.30 Acute kidney injury complicate one-third of congestive heart failure admissions, resulting in a threefold increase in length of stay, a greater likelihood for hospital readmission, and a 22% higher mortality rate.30 Those poor outcomes occurred with increase

xlii in serum creatinine of as little as 0.33 mg/dl, regardless of its presence at admission or its development during the course of heart failure treatment.30

In an analysis of data from 433 patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE), both baseline serum creatinine and BUN levels were significant independent predictors of 6-month mortality.18

Similarly, worsening renal function during hospitalisation for AHFS also signifies a significantly poorer prognosis.6 Data from 1,002 patients admitted to academic medical centres for ADHF showed approximately 72% of patients had a serum creatinine increase

>0.1 mg/dL during their hospitalization, and even this small increase was associated with worse outcomes.32 The mortality risk associated with acute serum creatinine elevation in 412 patients hospitalized for ADHF was evaluated.142 Adjusted 6-month mortality were 0.8 for a

>0.1-mg/dL increase, 1.15 for a >0.2-mg/dL increase, 1.61 for a >0.3-mg/dL increase, 1.83 for a >0.4-mg/dL increase, and 2.86 for a >0.5-mg/dL increase in serum creatinine.142

In the Prospective Outcomes Study in Heart failure (POSH), the median length of stay during the index hospitalization was 10 days for the whole group of 299 patients. Patients with worsening renal function (WRF) remained in hospital 4 days longer than those without

WRF.34

2.7 RISK FACTORS OF CRS

In a study to determine the incidence and predictors at admission of worsening renal function

(WRF), a history of HF, pharmacologically treated diabetes mellitus, admission creatinine, and elevated systolic BP (>160 mm Hg) were the factors most strongly associated with

WRF.33 In POSH study referred to above, a multivariable analysis revealed that admission serum creatinine, , pulmonary oedema and insulin treated diabetes were independently associated with WRF.34 Study done on DCM in South Africa revealed that patients with an estimated GFR <60 mL/ min/1.73 m2 were significantly older, had

xliii significantly greater mean serum creatinine, potassium and uric acid concentrations relative to those with a higher estimated GFR (≥60 mL/min/1.73 m2).50 After a multivariate analysis, eGFR <60mL/min was significantly commoner among older age group.50

Other predictors of CRS are co morbid conditions (e.g. severe hypertension, anaemia), impaired left ventricular ejection fraction (LVEF), history of MI and NYHA functional class.143 In particular, the presence of underlying intrinsic kidney disease is one of the strongest risk factors, as it determines the “reserve” available for the kidneys to respond to the insult posed by ADHF and the aggressive diuresis and natriuresis needed during treatment of ADHF.1

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CHAPTER THREE

3.0 METHODOLOGY

3.1 BACKGROUND OF THE STUDY AREA The study was conducted at Aminu Kano Teaching Hospital [AKTH], Kano, Nigeria which has a bed capacity of 500. The hospital was established in 1988 and is situated in the North

Western part of Nigeria. It has several clinical departments including Medicine, Surgery,

Pediatrics, Obstetrics and Gynecology with the full support of well equipped laboratories and a functional intensive care unit (ICU). It has a cardiac diagnostic center with echocardiography and electrocardiographic services. The medical wards have a total bed capacity of 78, with an average daily admission of 10 patients. The hospital serves as a referral center for Kano state and surrounding states including Jigawa, Katsina, Zamfara,

Bauchi, Gombe and Yobe, as well as the neighboring Niger Republic.

3.2 STUDY DESIGN- The study is a cross-sectional in design.

3.3 STUDY POPULATION- This was made up of patients hospitalised at AKTH with heart failure and who satisfied the inclusion criteria.

3.4 INCLUSION CRITERIA

 Age of 18 years and above.

 Patients admitted for the first time with diagnosis of HF (diagnosed using

Framingham criteria).

3.5 EXCLUSION CRITERIA

 Patients who were on maintenance dialysis before admission.

 Patients with polycystic kidney disease or sickle cell disease.

 Patients who denied consent to participate in the study.

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3.6 SAMPLE SIZE DETERMINATION

Minimum sample size was calculated using the formula-N=Z2PQ/d2 144 applying the precision value of 5% and prevalence of CRS of 11% as obtained from previous local study.54

N=Z2PQ/d2 where

N=Minimum sample size

Z= Constant at 95% confidence interval (i e 1.96)

P=Best estimate of prevalence of HF in literature expressed as a fraction of

100 (in this case11%= 0.11).

Q= (alternative probability) 1.0-P (0.89) d=absolute precision limit required (5%) 0.05

Thus N= (1.96)2 (0.11)0.89/ (0.05)2 =150.44 This was rounded up to 170, to cater for an estimated attrition rate of 10%. 3.7 SAMPLING TECHNIQUE

Patients who satisfied the inclusion criteria were recruited consecutively until the required sample size was achieved.

3.8 STUDY PROTOCOL

Patients suspected to have HF were interviewed using a standard Proforma to obtain demographic data, clinical history, general and cardiovascular examinations including anthropometric measurements. Drugs used during admission were recorded.

The patients had the following investigations: serum creatinine [SCr], urea and electrolytes

[U/E/], complete blood count, blood glucose, serum uric acid, lipid profile, urinalysis, electrocardiogram (ECG), and echocardiography. Urinary protein-creatinine ratio was determined to estimate 24 urine protein excretions in those who had proteinuria on urinalysis.

Renal ultrasound scan was done on all the patients. Glomerular filtration rate (GFR) was estimated using the Cockcroft–Gault equation which has been validated worldwide and in

Nigerian patients as representative of the real determined GFR145-147. Serum creatinine [SCr],

xlvi urea and electrolytes [U/E] were repeated once during the treatment at day seven or at discharge.

Heart failure was diagnosed according to the Framingham criteria.148 These consist of the major and minor criteria for HF. The major criteria included orthopnoea, paroxysmal nocturnal dyspnoea, raised jugular venous pressure, , third heart sound with or without gallop rhythm and pulmonary rales while the minor criteria included dyspnoea on exertion, dry cough, pedal oedema, tachycardia, tender hepatomegaly and ascites. A minimum of two major criteria or one major plus two or more minor criteria were required to make a diagnosis of HF provided they were not attributable to causes other than HF.148

Renal impairment in HF (CRS) was diagnosed by estimated glomerular filtration rate (eGFR)

<60 mls/min/1.73m2.7,12,27,149

Severity of clinical symptoms was assessed by New York Heart Association (NYHA) functional class as follows:143

Class I----Dyspnoea during intense activity.

Class II----Dyspnoea during ordinary activity.

Class III----Dyspnoea during less than ordinary activity but comfortable at rest.

Class IV----Dyspnoea at rest with inability to carry on any physical activity without discomfort.

3.9 Procedures

Blood pressure measurement was taken on the left and right arm using a standard mercury sphygmomanometer (Accoson Germany). The arm with the highest blood pressure reading was recorded. Using appropriate cuff size for the patient, the systolic blood pressure was recorded at phase I Korotkoff sound while the diastolic blood pressure was recorded at phase

xlvii

V Korotkoff sound. Height was measured with a stadiometer. Measurements were done in a standing position on a flat surface and recorded in metres with patients not wearing shoes or headgear. Weight was recorded in kilograms using weight-based scale (Avery Nigeria limited) on a firm horizontal surface with patients wearing light clothing.

Twelve lead surface ECG recording was done on all recruited patients by the investigator using Schiller Cardiovit AT-102 ECG machine (Switzerland). All recordings were done 5 – 8 hours post-prandial with stylet control set at 10mm/mV and paper speed at 25mm/sec. Four cardiac cycles were recorded per lead and a long lead II taken to serve as rhythm strip.

Transthoracic echocardiography was performed by the author on all patients using ALOKA

SSD-4000 machine (Japan). Two dimensional guided M-mode echocardiography was performed on each subject in the left lateral decubitus position. Subjects were examined using standard parasternal, and apical views. The left ventricular measurements taken included interventricular septal thickness in end-diastole (IVSDd), posterior wall thickness in end- diastole (PWTd), left ventricular internal diameter in end-diastole (LVIDd) and left ventricular internal diameter in end-systole (LVIDs). Left ventricular systolic function was calculated by Teichholz’s formula.150 All measurements were done according to the recommendation of the American Society of Echocardiography (ASE) methods of leading- edge to leading-edge convention with simultaneous ECG recording.22 Left ventricular internal diameter and interventricular septal and posterior wall thickness were measured at end diastole and end systole. The aortic root was measured at end diastole and the left atrium was measured at end-ventricular systole, including the thickness of the posterior wall of the aorta. Continuous-wave Doppler was used to interrogate the valves when there was suspicion of any valvular lesion. Tissue Doppler imaging was used to differentiate normal from pseudo- normal left ventricular filling in diastolic dysfunction.

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Two millilitres of venous blood was obtained from each patient. This was placed in Ethylene

Diamine Tetrachloroacetic acid [EDTA] bottle for the purpose of haemoglobin estimation and White blood cell count. Ten millilitres of venous blood was taken after (8-12 hours) overnight fast for the purpose of doing fasting plasma glucose (FPG) , Lipids profiles[TC;

LDL; HDL; TGL;]. serum U/E/Cr were measured using auto analyser Cobas integra 400 plus

(Germany). All samples were analysed in the central laboratory of AKTH.

3.10.1 DEFINITION OF TERMS

Classification of cardiorenal syndrome12

 Mild: HF+ eGFR 30–59 mL/min/1.73m2.

 Moderate: HF+ eGFR 15–29 mL/min/1.73 m2.

 Severe: HF + eGFR <15 mL/min/1.73 m2 or dialysis.

Table I: Criteria for classification of CRS into various types:36

Syndrome Type I Type II Type III Type IV Type V

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Definition AHF/ADHF/ACS CHF/CHD AKI CKD Systemic leading to kidney leading to leading to leading to disease injury or kidney injury heart the heart leading to dysfunction and/or disease disease, the heart dysfunction and/or injury or and kidney dysfunction dysfunction injury or dysfunct. Primary AHF, ADHF, CHF, LV AKI CKD Systemic events ACS or remodelling or disease cardiogenic shock cardiomyopathy (sepsis, amyloidosis etc) Secondary AKI CKD AHF, ACS CHD (LV AHF, ACS, events remodelling, CHD, AKI shock dysfunction) and CKD. AHF, ACS Key: AHF= Acute heart failure, ADHF= Acute decompensated heart failure, ACS= , AKI= Acute kidney injury, CHF= Chronic heart failure, CHD= Chronic heart disease, CKD= Chronic kidney disease, LV= Left ventricle.

Dyslipidaemia: Total Cholesterol > 200 mg/dL (5.2 mmol/L), LDL ≥ 100 mg/dl (2.6

mmol/L), or HDL (< 40 mg/dl in males and < 50 md/dl in females) TG >

1.7mmol/l.151

Diabetes: Diabetes was diagnosed based on history of diabetes, need for antidiabetic agents,

or a fasting blood sugar greater than or equal to 7 mmol/l or 126 mg/dl in the

presence of symptoms or FBS ≥7mmol/l present in at least two occasions in the

absence of symptoms .151

Hypertension: Patient was diagnosed to be hypertensive if he had history of hypertension,

being on anti-hypertensive medications or blood pressure greater than or equal

140 mm Hg systolic or 90 mm Hg or more diastolic on at least 2 occasions.152

Hypertensive heart disease

In patients with systemic hypertension, the diagnosis of hypertensive heart disease

was based on the presence of clinical, ECG and echocardiographic features of long

l

standing hypertension that cannot be explained by any alternative condition. The

clinical features included displaced heaving apex, an S4 heart sound, loud A2, grade II

or more hypertensive retinopathy.150 The ECG definition of HHD was based on the

presence of left ventricular hypertrophy which was defined using the Sokolow-Lyon

voltage criteria (sum of the amplitude of S wave in V1 and R wave in V5 or V6

>3.5mV),153 evidence of left (broad P wave in lead II and

prominent negative deflection in VI) and conduction abnormalities (left anterior

fascicular block and left ).154 Echocardiographic abnormalities

included concentric or eccentric left ventricular hypertrophy (LVH), increased left

ventricular mass index, increased left ventricular or left atrial size and volumes, and

diastolic or systolic left ventricular dysfunctions.150

Ischemic heart disease was diagnosed if the subject had either positive history of typical

or acute myocardial infarction, and/or typical ECG abnormalities of acute

myocardial infarction or myocardial ischemia, plus ventricular regional wall motion

abnormalities on 2D echocardiography. These ECG abnormalities were hyperacute T-

wave, convex type of ST-segment elevation, inverted T-wave, prominent Q-wave,

poor R-wave or QS-wave (for STEMI) and planer type or down sloping of ST-

segment depression, T-wave inversion for non ST-segment myocardial infarction

(NSTEMI).154 The echocardiographic abnormalities included: hypokinesia (reduced

movement) akinesia (absent movement), dyskinesia (movement in the wrong

direction, e.g. outward movement of the left ventricular free wall during systole) and

aneurysm (out-pouching of all layers of the wall).155,156

Diastolic dysfunction: A patient was considered to have diastolic dysfunction if there was

evidence of abnormal left ventricular relaxation. This was assessed by using Doppler

li

echocardiography of transmitral flow pattern: E/A ratio, E’, E/E’ ratio, E-wave

deceleration time (DT) and isovolumic relaxation time (IVRT).157

Three abnormal patterns were recognised in diastolic dysfunction:

 Impaired relaxation pattern- there is reduced E/A ratio (< 1), prolonged E-

wave DT >240ms, and prolonged IVRT >90ms.

 Pseudo normal pattern- E:A ratio 1-1.5, E-wave DT 160-200ms, IVRT

<90MS, E’ <7cm/s and E/E’ ratio >15.

 Restrictive pattern-Increased E/A ratio >1.5, short E-wave DT <160ms, and

IVRT <70ms

Systolic Dysfunction: Systolic dysfunction was defined as left ventricular ejection fraction

(LVEF) of <45% .158

Arrhythmia: This was diagnosed using appropriate ECG criteria and included among others,

atrial fibrillation, flutter, bradyarrhythmias, supraventricular tachycardia, ventricular

tachycardia or fibrillation.158

Anaemia: Anaemia was defined based on haemoglobin level as 10.0-10.9g/dl (Mild

anaemia), 7-9.9g/dl (moderate anaemia) and <7g/dl (severe anaemia).159

3.10.2 DATA ANALYSIS

All data generated were collated, checked and analysed using computer based statistical package for social sciences [SPSS] version 16.0. Quantitative variables were described using mean and standard deviation. Qualitative variables were presented as percentages, bar chart and pie chart. The student t-test and the non parametric χ2 or fisher’s exact test were used to test for significant among the non categorical and categorical variables respectively. Multiple regression analyses were used to determine the predictors for CRS and mortality. A P value of less than 0.05 was considered significant.

3.10.3 ETHICAL CONSIDERATION

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Approval for the study was obtained from the Ethical Committee of AKTH and informed consent was obtained from each patient. The provision of the HELSINKI declaration was respected.

CHAPTER FOUR 4.0 RESULTS 4.1 Baseline clinical characteristics of patients

A total of 170 patients who satisfied the inclusion criteria were studied over the period of eleven months (November 2010-September 2011). They consisted of 70 (41.2%) males and

100 (58.8%) females giving male to female ratio of 1:1.4 (Table II). The mean age of the patients was 49.6 ± 18.7 (range 18-90 years) (Table II). Figure 4 shows the sex and age distribution of the study population. The most frequent age group was that of 55-64years.

Compared to the group without CRS, those with CRS were significantly older (53.2±18.1 vs.

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39.6±17.1 p <0.0001), had higher frequency of hypertension (66.9% vs. 39.1% p=0.001) and diabetes (16.1% vs. 4.3% p= 0.043) (see Table III).

Table II: Baseline characteristics of all 170 patients

Variables n(%)

Age(years) 49.6 ±18.74

Gender Male 70(41.2) Female 100(58.8)

Hypertension 101(59.4)

Diabetes 22(12.9) Atrial fibrillation 38(22.4) Clinical aetiology of HF HHD 77(45.3) DCM 39(22.9) PPCM 25(14.7) RHD 15(8.8) IHD 6(3.5) Co-pulmonale 8(4.7)

SBP(mm Hg) 122.0±37.1

DBP(mm Hg) 80.6±24.4

MAP(mm Hg) 93.9±25.8

Hb(mg/dl) 11.4±2.4

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Serum urea(mmol/l) 13.6±8.0

Serum creatinine(µmol/l) 277.5±419.4 e GFR(ml/min) 45.6±31.2

Serum uric acid(mmol/l) 503.6±248.4

TC(mmol/l) 4.0±1.2

LDL(mmol/l) 2.3±0.96

HDL(mmol/l) 1.0±0.5 TG(mmol/l) 1.1±0.6 37.51±16.4 LVEF(%)

HHD= Hypertensive heart disease DCM= , PPCM= Peripartum cardiomyopathy, RHD= Rheumatic heart disease, IHD= Ischaemic heart disease, SBP= Systolic blood pressure, DBP= Diastolic blood pressure, MAP= Mean arterial pressure, Hb= Haemoglobin, eGFR= Estimated glomerular filtration rate, TC= Total cholesterol, LDL= Low density lipoprotein cholesterol, HDL= High density lipoprotein cholesterol, TG= Triglyceride, LVEF= Left ventricular ejection fraction. Table III: Comparison of the clinical characteristics among the patients.

Variables Total CRS present CRS absent P value n=170(%) n=124(%) n=46(%)

Gender - Male 70(41.2) 53(42.7) 17(37.0) 0.496 Female 100(58.8) 71(57.3) 29(63.0)

Age(years) 49.55±18.74 53.22±18.05 39.65±17.05 <0.0001

Hypertension 101(59.4) 83(66.9) 18(39.1) 0.001

Diabetes 22(12.9) 20(16.1) 2(4.3) 0.043

PND 162(95.3) 119(96.0) 43(93.5) 0.448

Orthopnoea 161(94.7) 119(96.0) 42(91.3) 0.255

JVP 136(80.0) 101(81.5) 35(76.1) 0.437

Cardiomegaly 158(92.9) 116(93.5) 42(91.3) 0.612

S3 151(88.8) 110(88.7) 41(89.1) 0.938

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Key: PND=Paroxysmal nocturnal dyspnoea, JVP=Jugular venous pressure, S3= Third heart sound.

Figure 4: Age group and sex distribution of the participants.

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4.2 Prevalence of CRS

One hundred and twenty four (72.9%) of the study patients had CRS (Table III). Figure 5 shows that 67 (54%), 35 (28%) and 22 (18%) of the CRS group had mild, moderate and severe grades respectively. Majority of the CRS patients, 103 (83%) had type I CRS, 16

(13%) had type II CRS while the remaining 5 (4%) had type IV CRS (Figure 6). No study patient had type III and V CRS.

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Figure 5: Classification of CRS among the group. Mild: HF+ eGFR 30–59 mL/min/1.73m2,

Moderate: HF+ eGFR 15–29 mL/min/1.73 m2, Severe: HF + eGFR <15 mL/min/1.73 m2 or dialysis.

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Figure 6: Types of CRS found among the patients.

4.3 Laboratory parameters of patients

Compared with the group without CRS, the CRS group had significantly higher mean level of serum urea (15.4mmol/L vs. 8.7mmol/L p=<0.0001) uric acid (550.2mmol/L vs.

lix

377.8mmol/L, p= <0.0001) and creatinine (348.1 µmol/L vs. 87.1 µmol/L, p=<0.0001) while the mean eGFR was significantly lower in CRS group (30.9 ml/min vs. 85.1 ml/min, p<0.0001) (see Table IV). The mean serum levels of other measured variables were not significantly different among the two groups.

Proteinuria was found among 129 (75.9%) of the study population. One hundred patients

(77.5%) with proteinuria had CRS, compared to 29 (22.5%) of those without CRS and the difference was statistically significant (p= 0.017). Among patients with proteinuria, 24 hours protein excretion was <1g in 89 (69%) and within a range of 1-3.49g in 33 (25.6%) while 7

(5.4%) had nephrotic range proteinuria (3.5- 9.6g/day).

Of the 124 patients with CRS, 103 (83.1%) had normal renal ultrasounds scan, 18 (14.5%) had kidneys with bipolar length of less than 8 cm bilaterally (shrunken kidneys) with loss of corticomedullary differentiation and 3 (2.4%) had bilateral . All the 46 patients without CRS had normal renal ultrasound scan findings.

Table IV: Comparison of the laboratory parameters among patients with and without CRS.

Variables CRS present CRS absent P value Mean ± SD Mean ± SD

Hb(mg/dL) 11.393±2.52 11.572±2.24 0.672

Na(mmol/L) 133.74±6.43 132.91±6.42 0.456

TC(mmol/L) 3.98±1.25 3.98±0.97 0.972

LDL(mmol/L) 2.28±1.04 2.34±0.73 0.721

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TG(mmol/L) 1.16±0.63 0.99±0.28 0.065

HDL(mmol/L) 1.00±0.59 0.98±0.37 0.779

UA(mmol/L) 550.21±258 377.85±162 <0.0001

eGFR(ml/min) 30.94±15.91 85.16±27.57 <0.0001

Urea(mmol/L) 15.43±8.28 8.71±4.29 <0.0001

SCr(µmol/L) 348.16±472.17 87.16±20.01 <0.0001 Key: Hb= haemoglobin, Na=Sodium, TC= Total cholesterol, LDL=Low density lipoprotein,

TG= Triglyceride, HDL=High density lipoprotein, UA = Uric acid, e-GFR=Estimated glomerular filtration rate, SCr= Serum creatinine.

4.4 ECG and echocardiographic findings

Left ventricular hypertrophy was the most frequent ECG finding and recorded in a total of

125 patients. It was significantly higher among the CRS group (p=0.002) (Table V). was present in 10 of the study population all of whom had CRS. Left atrial enlargement and AF were the next most prevalent ECG findings and the observed differences of these variables (AF and left atrial enlargement) were not statistically significant among CRS group compared to those without CRS (Table V).

Table VI shows echocardiographic findings among patients. The CRS group had significantly larger aortic diameter, thicker septum, thicker posterior wall and higher left ventricular mass

lxi index (LVMI). A total of 49 (28.8%) patients had LVH (high LVMI) by echocardiography.

There was no significant difference in the prevalence of LVH by echocardiography between patients with CRS and those without CRS (32.3% vs. 19.6% p= 0.105). Though the mean EF was higher in the CRS group the difference was not statistically significant. No significant differences were found in the measures of transmitral valve flow and other measures of diastolic dysfunction among the two groups.

Table V: Comparison of electrocardiographic findings among the CRS and non CRS-patients.

Variables Total patients CRS present CRS absent P value n=170(%) n=124(%) n=46(%)

LVH 125(73.5) 99(79.8) 26(56.5) 0.002

AF 38(22.4) 31(25.0) 7(15.2) 0.174

LAD 31(18.2) 25(20.2) 6(13.0) 0.276

LBB B 10(5.9) 10(8.1) 0(0.0) 0.038

RAE 2(1.2) 2(1.6) 0(0.0) 0.531

LAE 75(44.1) 54(43.5) 21(45.7) 0.806

PVC 25(14.7) 20(16.1) 5(10.9) 0.39 Key: AF= Atrial fibrillation, LAD= , LBBB=Left bundle branch block, RAE=, LAE= Left atrial enlargement, PVC=premature ventricular contraction, LVH= Left ventricular hypertrophy.

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Table VI: Comparison of echocardiographic findings among the CRS and non-CRS groups. Variables Total patients CRS present CRS absent P value n=170 Mean ± SD Mean ± SD

AO(cm) 3.0±0.49 3.1±0.46 2.9±0.53 0.018

LA(cm) 4.6±0.91 4.6±0.92 4.7±0.89 0.456

RVID(cm) 3.3±0.68 3.3±0.72 3.3±0.5 7 0.593

IVSD(cm) 0.93±0.35 0.98±0.35 0.8±0.29 0.002

LVIDd(cm) 5.9±1.22 5.9±1.12 6.1±1.24 0.589

LVIDs(CM) 4.8±1.32 4.8±1.33 4.8±1.34 0.845

PWTD(CM) 0.89±0.29 0.93±0.31 0.81±0.25 0.026

LVMI(g/m2 ) 105.42±19.32 125.66±35.23 92.36±25.63 0.002

EF(%) 37.51±16.4 38.44±16.32 35.00±16.53 0.225

FS(%) 20.92±10.72 21.5±10.87 19.4±10.27 0.259

E -Velocity(m/s) 0.83±0.34 0.85±0.35 0.77±0.30 0.18

E- wave DT 175.4±79.2 172±80.2 184.2±76.9 0.384

A-Velocity(m/s) 0.54±0.35 0.56±0.36 0.49±0.32 0.238

IVRT 73.7±23.0 73.4±23.8 34.7±21.1 0.736

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E/A 1.40±0.98 1.45±1.01 1.28±0.89 0.322 Key: AO= Aorta, LA = Left atrium, RVIDd= right ventricular internal diameter in diastole, IVSd =

Interventricular septal wall thickness in diastole, PWTd = Posterior wall thickness in diastole, LVMI=

Left

ventricular mass index, LVIDd = Left ventricular internal diameter in diastole, LVIDs= Left ventricular

internal diameter in systole, FS =Fractional shortening, EF = Ejection fraction, E-Velocity= Early filling

velocity, A-Velocity= Late filling velocity. E-wave DT= E- wave deceleration time, IVRT= Isovolumic

relaxation time

4.5 Aetiology of HF among patients

Figure 7 shows the aetiology of heart failure among the study participants. The most common aetiology was hypertensive heart disease found in 52.4% CRS and 26.1% of non CRS group.

Non CRS group had higher frequency of DCM (28.3% vs 21.0%), PPCM (26.1% vs10.5%), rheumatic heart disease (10.9% vs 8.1%) and ischaemic heart disease (4.3% vs 3.2%).

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Figure 7: Aetiology of HF among the study patients. Key: HHD= Hypertensive heart disease, DCM= Dilated cardiomyopathy, PPCM= peripartum cardiomyopathy, RHD= Rheumatic heart disease, C.pulm= Cor-pulmonale, IHD= Ischaemic heart disease, CRS= Cardiorenal syndrome.

4.6 Medications received by the patients

Figure 8 shows the various types of medication received by the patients. Frusemide, aldactone, ACE-I/ARBs, digoxin and aspirin were the most frequently prescribed drugs.

Frusemide, ACE-I/ARBs and digoxin were more frequently prescribed among the CRS group, while the non CRS patients had higher rate of aldactone and aspirin prescription. The least prescribed drug was hydralazine received by 3.2% of CRS patients.

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Figure 8: Medication received by the patients. Key: BB= β blockers, ACG=Anticoagulants.

4.7 Predictors of CRS

Table VII shows the distribution of clinical variables among the patients. Compared to those without CRS those with CRS had higher prevalence of SBP >160mmHg (16% vs. 4% p=

0.043) and were more likely to have low DBP <60mm Hg (16.9% vs. 6.5% p= 0.048). The

SBP level of 160 mm Hg was achieved after testing for the various SBP levels ranging from the minimal SBP of 60 mm Hg. After gradual testing of several DBP levels, the DBP level of

<60 mm Hg was found to be associated with CRS. There was no significant association found between CRS and various levels of the mean arterial pressure (MAP) tested and the

lxvi mean MAP was not statistically significant among the group with CRS and those without the

CRS (see table VII). Other parameters significantly higher among the CRS group compared to those without CRS were diabetes mellitus (16% vs. 4% p=0.043) and NYHA IV (54.0% vs. 34.8% p=0.026). Patients aged above 40 years were significantly higher in number among the CRS group compared to the group without (84% vs 52%. P= <0.0001). No significant differences were found between the two groups in the frequency of anaemia, AF and LVEF

<45%.

However, on multivariate analysis only age >40 years (95% CI=1.797-8.582, RR= 3.927,

P=0.001) and NYHA IV (95% CI=1.008-4.526, RR=2.135, P= 0.048) were found to be the independent predictors of CRS, while diabetes, DBP and SBP were not.

Table VII: Comparison of clinical variables among patients with and without cardiorenal syndrome. Variables CRS present CRS absent n=124(%) n=46(%) P - value

Age(>40years) 104(84) 24(52) <0.0001

SBP>160mmHg 20(16) 2 (4) 0.043 DBP <60mmHg 21(16.9) 3(6.5) 0.048 MAP ±SD 94.7±28.6 92.0±17.6 0.603

Diabetes 20(16) 2(4) 0.043

NYHA IV 67(54.0) 16(34.8) 0.026

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AF 31(25) 7(15) 0.077

Anaemia 72(58) 26(57) 0.886

LVEF(<45%) 87(70) 35(76) 0.339 Key: SBP>160=Systolic blood pressure more than 160mmHg, DBP <60mm Hg= Diastolic blood pressure <60 mm Hg, MAP= mean arterial pressure, NYHA IV=New York Heart Association class IV, AF=Atrial fibrillation, LVEF=Left ventricular ejection fraction.

4.8 Mortality and duration of hospital stay

Table VIII shows the outcomes (death and duration of hospital stay) among patients. Of the

170 patients, 37 (21.8%) died. Although no autopsy was done, clinically recognisable causes of death were 20 patients died of cardiogenic shock; 5 patients died from uraemic ; 5 patients died from pulmonary oedema; 3 patients died from sepsis and 4 patients had sudden death likely from or . The mean length of hospital stay for all patients was 17.32 ± 13.2days. The CRS group had significantly higher mortality rate compared to those without CRS (P= 0.031). The difference in the duration of hospital stay was not statistically significant between the group with CRS and those without CRS (P= 0.378).

Table VIII: Mortality and duration of hospital stay. Variables Total patients CRS present CRS absent P-value n=170(%) n=124(%) n=46(%)

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Death 37(21.8) 31(25) 6(13) 0.031

Duration of stay(Days) 17.32±13.20 17.86±13.11 15.85±13.46 0.378

4.9 Factors that influence mortality

Table IX shows the comparison of clinical and laboratory parameters among the deceased and the survivors of CRS. While the deceased had significantly higher proportion of patients with SCr of ≥170µmol/l, urea of >20mmol/l, e GFR of <53ml/min and NYHA class IV (P=

0.001, 0.001, 0.045 and 0.009 respectively), the survivors had higher proportion of patients with SBP >160mmHg (p=0.001). Those significant levels of SCr, urea, e GFR and SBP used in the calculations above were obtained after testing for various levels of those parameters.

There was no association found between the mortality and different DBP and MAP levels.

Also no association found between mortality and the mean levels of DBP (see table IX) and

MAP (92.2±24.8 vs. 94.5±26.2 p= 0.672). On multivariate analysis, only SCr >170µmol/l

(95% CI, 1.098-6.243 RR= 2.618, p= 0.030) and urea of >20mmol/l (95% CI, 1.106-6.757,

RR= 2.734 and p=0.029) were the predictors of mortality among the CRS patients. Systolic blood pressure >160 mm Hg and eGFR <53 ml/min were found to have no effect on mortality or survival after the multivariate analysis.

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Table IX: Comparison of Deceased and Survivors of CRS. Variables Deceased Survivors P-value

n=31(%) n=93(%)

NYHA class IV (%) 21(67.7) 46 (49.5) 0.009

AF 8(25.8) 23(24.7) 0.905

DM 5(16.1) 15(16.1) 1

SBP>160 mmHg 2(6.5) 19(25.3) 0.001

DBP 79.2±20.5 81.1±25.9 0.713

LVEF<45% 22(71) 65(69.9) 0.91

Anaemia 19(61) 53(57) 0.177

SCr>170 µmol/l 21(67.7) 42(45.0) 0.001

Urea>20mmol/l 12(38.7) 18(19.4) 0.001 eGFR<53mil/min 31(100) 82(88.1) 0.045 Key: HF= Heart failure, SBP>160=Systolic blood pressure more than 160mmHg, NYHA IV=New York Heart Association class IV, AF=Atrial fibrillation, DM=Diabetes mellitus, LVEF=Left ventricular ejection fraction, e-GFR=Estimated glomerular filtration rate, SCr= Serum creatinine.

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CHAPTER 5 DISCUSSION This study determined the prevalence, predictors and outcomes of cardio-renal syndrome among patients admitted in heart failure in a tertiary hospital. The syndrome was common among the study population with a prevalence of 72.9%. The prevalence rate obtained in the current study is higher than what was reported in some of the local studies, on the prevalence of renal impairment in patients with HF. 7, 8, 9,49,54,55 In general the prevalence of renal impairment in patients admitted with heart failure in those studies ranged from 7%- 50%. The differed findings may be due to differences in the study design and the study population.

Some of the previous studies that reported low prevalence rate (<30%) for instance studied only one type of CRS (type 4) or used SCr alone to define renal impairment.54,55 Furthermore some were retrospective in design, with SCr measured only once at admission considered.54,55

This would have probably led to the exclusion of patients that might have developed CRS during admission. Others had small sample sizes (<100 patients) that might have led to underestimation of CRS prevalence as their major limitation.7,8,9 There are however, some previous studies that have recorded high CRS prevalence.41,44,47,160 In one study, 60% of patients with ADHF had moderate CRS.44 Indeed when eGFR was used in defining renal dysfunction the number was even higher with >95% of patients in ADHERE registry having at least some renal dysfunction on presentation.47

In an analysis of data from Efficacy and safety of nebivolol in elderly heart failure patients, only 9.9% of patients had normal renal function as defined by eGFR ≥90 mL/min.160 A total of 48.1%, 38.9% and 3.1% of patients had mild (eGFR 60–89), moderate (eGFR 30–59), and

lxxi severely reduced kidney function (eGFR <30) respectively.160 In another study only 17% of patients had creatinine clearances >90 mL/min in a study of renal insufficiency and HF.41

The high prevalence of CRS in the current study may not be unconnected with the late presentation of patients with severe form of HF as well as close monitoring of patients for

CRS during admission.

The high prevalence of renal insufficiency in patients with heart failure may be partly because patients with renal dysfunction tend to be older and have higher prevalence of co- morbidities such as hypertension and diabetes that cause both intrinsic renal disease and heart failure.47 The presence of these diseases, especially hypertension, disrupt renal blood flow auto regulation, making the kidney more susceptible to develop renal dysfunction during treatment for heart failure. In patients with a history of hypertension, the renal auto regulatory curve shifts to the right such that decrease in mean arterial pressure results in decreased intraglomerular pressure and GFR at blood pressures that would not affect renal function in normal subjects.10 The decrease in the mean arterial pressure may be as a consequence of decreased forward flow, vasodilator medications, or diuretics.10

The patients in the current study were relatively young with mean age of 49 .6 ± 18.7 years.

This observation is similar to the results of previous studies done on heart failure patients in the study centre and another study among HF patients from Sagamu, South-Western Nigeria with mean ages of 46.9 ± 17.9 and 51.4 ± 15.6 respectively.8,54 These findings are however in contrast to the higher mean ages reported from the United States of America (USA) (61 ±

18 years) and Europe (71.3 ± 12.7 years).161 The age difference may be in part due to earlier occurrence of some of the causes of heart failure especially peripartum cardiomyopathy and rheumatic heart disease in the Nigerian population.54,162

In the current study population, the CRS group was significantly older than those without

CRS. This finding was similar to some previous reports.51 163 A South African study revealed

lxxii that, DCM patients with renal impairment (<60ml/min) were significantly older than those without renal impairment.50 The older age group had higher prevalence of atherosclerosis, which has been identified as an important risk factor for CRS.138,149 The preponderance of females in the current study agrees with earlier studies done in Nigeria.164,165 It however contrasts the findings of other studies.22,54 The differed findings may be due to higher prevalence of peripartum cardiomyopathy which is exclusively a female disease and was the third leading cause of HF in the current study.

The predictors of CRS among patients with heart failure in the current study were NYHA class IV and age >40years. A study on prognostic implication of renal insufficiency among patients with left ventricular dysfunction revealed that advanced NYHA class III-IV was associated with CRS among patients with heart failure.20 In their cohort, McAlister et al found that 39% of patients in NYHA class IV and 31% of patients in NYHA III symptoms of heart failure were associated with at least moderate form of renal dysfunction.28

The major mechanisms involved in the pathogenesis of CRS including under perfusion from reduced cardiac output and venous congestion are more pronounced in patients with advanced heart failure defined as NYHA class III-IV.20 The decrease forward flow reduces renal perfusion pressure leading to renal dysfunction. On the other hand, the increase venous congestion causes impairment of tubular function and glomerular filtration. These 2 mechanisms (reduced forward flow and venous congestion) also cause neurohormonal activation that affect renal blood flow and glomerular autoregulation.30

In-hospital mortality was significantly higher among patients with CRS compared to those without. Registries and clinical trials have consistently confirmed that renal dysfunction is associated with substantial increase in the risk of in-hospital, intermediate and long term death.28 ,94,139 Risk ratios for death during hospitalization, complications, and length of stay

>10 days increased sevenfold, twofold, and threefold, respectively, in those who developed

lxxiii

CRS compared with those who did not.166 In the Study of Left Ventricular Dysfunction

(SOLVD), moderate degrees of renal insufficiency were independently associated with an increased risk for all-cause mortality in patients with heart failure.167 Even after adjustment for all other prognostic factors, survival was significantly associated with renal function in patients with either systolic or diastolic dysfunction.163 The mortality rate of 25% among

CRS patients in this study was rather lower than what was recorded by other studies.22,167, 168

A Nigerian study on advanced heart failure with aggravated renal dysfunction recorded a total mortality rate of 72.2% over 36 months study period.8 Other studies recorded a mortality rate of 47-72.2%.167,168 While the Nigerian study recruited patients with advanced heart failure, other studies had larger samples (755 and 1004 patients) and longer study period which may explain the higher mortality recorded in these studies.

There was no difference in duration of hospital stay among patients with or without CRS. A study on aggravated renal dysfunction among patients with HF in Nigeria also observed no significant difference in the duration of hospital admission among patients with and without aggravated renal dysfunction.8 However in the United State of America, acute kidney injury was estimated to result in a threefold increase in length of hospital stay and a 22% higher mortality rate among HF patients over the age of 65 years.30 Other studies also reported longer hospital stay >10 days (4 days longer) among HF patients with renal dysfunction compared to those with no renal dysfunction.34, 141

Renal dysfunction, in the absence of heart failure, carries a poor prognosis. It is not surprising, therefore, that the concomitant presence of the 2 diseases had poorer outcomes.76

However it has been speculated that the higher mortality observed in CRS may be attributable, at least in part, to more advanced heart failure, excess co-morbidities, and/or therapeutic nihilism in patients with concomitant renal insufficiency (who are less likely to receive proven efficacious therapies for either the index condition or the co-morbidities). It

lxxiv has also been speculated that patients with renal insufficiency are at higher risk for drug toxicities and do not obtain the same benefits from medications shown to be efficacious in the healthier patients enrolled in trials.163

The only variables that predicted mortality in this study were SCr ≥170µmol/L and serum urea of >20mmol/L. Measures of renal dysfunction have been found to be more powerful predictors of mortality than measures of LV dysfunction (LVEF and NYHA) in patients with

CRS.12,140 In a Nigerian study, serum creatinine was found to correlate with mortality in heart failure.8 In an African multicentre study, only serum creatinine had statistically differing values between the deceased and survivors of heart failure.21 In a study of risk stratification for in-hospital mortality in ADHF, of the 39 variables evaluated serum urea level of

≥15.35mmol/L at admission was identified as the best single discriminator between hospital survivors and non survivors.140 In the Enhanced Feedback for Effective Cardiac Treatment

Study, increasing serum urea level was significant and independent predictor of both 30 days and 1 year mortality.169

Increasing SCr and urea were identified as significant and independent predictors of mortality or re-hospitalisation in the Outcomes of a Prospective Trial of Intravenous Milrinone for

Exacerbation of Chronic Heart Failure study.170 Similarly, in a retrospective review of 1004 consecutive patients hospitalized for heart failure at 11 geographically diverse hospitals, worsening renal function was associated with a 7.5-fold increase in the adjusted risk of in- hospital mortality.171 Renal dysfunction causes further congestion and activation of neurohormonal system which are the factors that have been associated with adverse outcomes in patients with heart failure.140

LIMITATIONS

lxxv

 In some of the patients, it was difficult to identify the primary failing organ (between

the heart and kidneys) and this might have influenced the CRS classification into its

subtypes.

 Other population of HF patients especially those attending outpatients’ clinic were not

included and this might have affected the prevalence of CRS.

CONCLUSIONS

1. The prevalence of CRS was high among patients with heart failure.

2. NYHA class IV and age >40 years were the identified independent predictors of

CRS. Mortality rate was significantly higher among patients with the syndrome than

those without.

lxxvi

3. Measures of the renal function, SCr >170µmol/L and urea of >20mmol/L were

identified as the predictors of mortality.

RECOMMENDATIONS

Based on the findings in this study the followings are recommended.

1) Renal function should be routinely determined and monitored in patient with heart

failure. This will help in identifying patients with CRS that may be potentially

associated with poor outcome.

2) Further studies with long term follow up period and larger sample size are

recommended to determine the long term influence of CRS on the outcome of HF.

lxxvii

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APPENDIX ONE QUESTIONNAIRE CARDIORENAL SYNDROME AMONG PATIENTS ADMITTED WITH HEART

FAILURE IN MEDICAL WARDS OF AMINU KANO TEACHING HOSPITAL.

1. Personal Biodata: Serial No: Age (years) Sex: [M] [F] Ethnic group: Marital status: [S ] [M ] ------Occupation ------2. History Yes No Yes NO Orthopnoea [ ] [ ] PND [ ] [ ] Dyspnoea on exertion [ ] [ ] NYHA Class ------2.Other medical conditions Diabetes [ ] [ ] Smoking [ ] [ ] If yes, duration of DM ------If yes, number of pack year ------Depression [ ] [ ] Hypertension [ ] [ ] Renal disease [ ] [ ] If yes, duration of HTN ------Ischaemic heart disease [ ] [ ] HIV test positive [ ] [ ] [ ] Unknown 3. Risk factors of CRS [ ] [ ] If yes specify------4. Physical findings Height ------cm Weight ------kg BMI ------Kg/m2 Pedal oedema [ ] [ ] Third Heart sound [ ] [ ] Tachycardia [ ] [ ] Tender hepatomegaly [ ] [ ] Blood pressure------Raised JVP [ ] [ ] Pulmonary rales [ ] [ ] Cardiomegaly [ ] [ ] 4. Labs findings PARA VALUE PARAMETER VALUE

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METER Serum Uric acid TC (mmol/l) mmol/L LDH U/L LDL (mmol/l) Na (mmol/l) TG (mmol/l) Glucose (mmol/l) HDL (mmol/l) Hb g/dl CK U/L Total WBC x 109 /L CK-MB U/L PARAMETER VALUE PARAMETER VALUE Cr (µmol/l) Cr (umol/l)

Urea (µmol/l) Urea (mmol/l)

eGFR ------ECG  Arrhythmia : Yes No If yes, specify……………………………………………….  Ischaemic Heart disease [ ]Yes No[ ]

 Left ventricular hypertrophy [ ]Yes No[ ]

 Other ECG Findings ------.Echocardiography: 1. Regional Wall motion abnormalities Yes/No if yes Segment involved……………… 2. Regional wall motion index ……………………………………. 3. Intra-Cardiac Thrombus ………. Yes/No if yes, location of thrombus …………………… 4. ……….. Yes/No 5. Systolic Dysfunction …….. Yes/No, Ejection fraction ……………………… 6. Diastolic Dysfunction Yes/No, if yes stage……………………………… LA (mm) ……………… Aorta (mm) ……………… LVIDd (mm) ……………….. LVIDs (mm) ………… LVPWd (mm) ……… LVPWs (mm) …………… IVSTd (mm) ………… IVSTs (mm) …………. LVMI ………….. MV E wave velocity (cm/s) …………. MV A wave velocity (cm/s) …………… E/A ratio …………….. E – Wave DT (ms) ………… e’ velocity (cm/s) ………… E/e’ ……………………

Medications on admission: Yes No Nitrates (IV) [ ] [ ] Frusemide [ ] [ ] Dopamine [ ] [ ] Dobutamine [ ] [ ] ACE-I/ARB [ ] [ ] Frusemide (oral) [ ] [ ] Beta blockers [ ] [ ] Digoxin [ ] [ ]

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Hydralazine [ ] [ ] Yes No Nitrates (oral) [ ] [ ] Spironolactone [ ] [ ] [ ] [ ] Aspirin [ ] [ ] Anticoagulants [ ] [ ] OUTCOMES: Hospital length of stay: ------days Death during admission No [ ] Yes [ ]

APPENDIX TWO Echocardiographic images of different causes of HF.

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Figure 9 (A and B): Dilated cardiomyopathy (DCM) in one of study patient- apical 4 chambers view showing a large apical thrombus (9A) and parasternal long axis view with M- mode (9B) showing thin walled and dilated hypokinetic left ventricle. There is mild (<3mm) pericardial effusion.

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FIGURE 10 : Echocardiographic features of one of the patient with hypertensive heart disease with M-mode showing thickened left ventricular posterior wall and septum. .

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Figure 11: 2D and M-mode showing rheumatic mitral valve stenosis in one of the study patient, with heavly calcified mitral valve, thickened and fibrotic subvalvular apparatus. M- mode shows decrease E-F slope and both anterior and posterior mitral valve leaflets moving anterior due to fusion of commisures.

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Figure 12- Electrocardiographic tracing of one of the study female patient with dilated cardiomyopathy showing low limb leads voltage and poor R- wave progression over the chest leads.

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Figure 13- ECG tracing of a study patient with hypertensive heart disease (HHD) showing left ventricular hypertrophy (LVH) with .

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Figure 14- ECG features in one of the patients with acute myocardial infarction showing ST- segment elevation and T- wave inversion over the anterior, lateral and inferior leads with loss of R-wave over the affected leads.

APPENDIX THREE

CONSENT FORM

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I am Dr Muhammad Nazir Shehu, a resident doctor with the department of medicine Aminu Kano Teaching Hospital Kano conducting a study on cardiorenal syndrome among patients admitted with heart failure in medical wards Aminu Kano Teaching Hospital.

I will be very grateful if you will agree to participate in the project as a participant. All that is required of you is that you will be administered a questionnaire then you will be examined and blood sample will be taken for analysis. This procedure will be repeated during admission.

Kindly sign in the space below If you are willing to participate. Participation is entirely voluntary and refusal to participate will not affect you in any way.

Those who are found to have cardiovascular risk factors and other co-mobidities will be referred to a specialist for proper evaluation and treatment.

Information obtained in this study will be treated with utmost confidentiality.

Thank you.

Name of client…………………………………..

Sign/thumbprint……………………..

Date………………………………….

Name of researcher......

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Date......

Name of witness......

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Date......

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