“A STUDY ON THE PREVALENCE OF CARDIORENAL

SYNDROME IN TYPE 2 DIABETIC PATIENTS”

Dissertation submitted to

THE TAMILNADU Dr. M.G.R MEDICAL UNIVERSITY

CHENNAI-600 032

In partial fulfilment of the regulations

For the award of the degree of

M.D (GENERAL MEDICINE)

BRANCH-1

Reg. No: 201711260

GOVT. CHENGALPATTU MEDICAL COLLEGE & HOSPITAL, CHENGALPATTU-603001. MAY-2020 CERTIFICATE

This is to certify that the dissertation titled “A STUDY ON THE

PREVALENCE OF CARDIORENAL SYNDROME IN TYPE 2

DIABETIC PATIENTS” is the bonafide original work of Dr. V. VIGNESH in partial fulfilment of the requirements for M.D. Branch-1 (General

Medicine) Examination of the Tamil Nadu Dr. M.G.R. Medical University to be held in May 2020. The period of study was from June 2018 to May 2019.

Prof. Dr. HARIHARAN M.S., MCh., Prof. Dr. R. NARMADHA LAKSHMI, M.D, Dch,

DEAN Professor and HOD,

Chengalpattu Medical College, Department of General Medicine

Chengalpattu Chengalpattu Medical College,

Chengalpattu.

Place:

Date

BONAFIDE CERTIFICATE

This is to certify that dissertation “A STUDY ON THE PREVALENCE

OF CARDIORENAL SYNDROME IN TYPE 2 DIABETIC PATIENTS” is a bonafide work performed by Dr. V. VIGNESH, postgraduate student of

General medicine, Chengalpattu medical college, Chengalpattu, under my guidance and supervision in fulfilment of regulations of The Tamil Nadu Dr.

M.G.R Medical University for the award of M.D. Degree during the Academic period 2017-2020.

Prof. Dr. R. NARMADHA LAKSHMI, M.D, Dch, Professor and HOD, Guide, Department of General Medicine Chengalpattu Medical College, Chengalpattu.

Place:

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DECLARATION

I, Dr. VIGNESH.V, solemnly declare that dissertation titled “A

STUDY ON THE PREVALENCE OF CARDIORENAL SYNDROME

IN TYPE 2 DIABETIC PATIENTS” is a bonafide record of work done by me in the Department of Internal Medicine, Government Chengalpattu

Medical College and Hospital during June 2018 to May 2019 under the guidance of Prof. Dr. R. NARMADHA LAKSHMI , M.D., Dch Professor of General Medicine, Government Chengalpattu Medical College and

Hospital, Chengalpattu. This dissertation is submitted to Tamil Nadu Dr.

M.G.R. Medical University, in partial fulfilment of the University regulations for the award of M.D. Degree (Branch 1) General Medicine- May 2020.

SIGNATURE OF THE CANDIDATE

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ACKNOWLEDGEMENT

I would like to thank our beloved Dean, Govt. Chengalpattu Medical

College and Hospital, Dr. HARIHARAN, M.S, MCh, for permitting me to utilize the hospital facilities for this dissertation.

I extend my sincere thanks to Prof. Dr. R. NARMADHA

LAKSHMI, M.D., Dch Professor and Head of the Department of Medicine, and guide Govt. Chengalpattu Medical College and Hospital for her guidance during the study.

Co-guide DR. S. RAVISHANKAR, M.D., Assistant Professor for his guidance and support throughout the conduct of the study and also during my post graduate course.

I owe my sincere thanks to my Assistant Professor Dr. R.

JAYALAKSHMI, M.D., and Dr. A . SENTHIL KUMARAN, M.D., for her valuable advice and appropriate suggestions.

I am grateful to Dr. S. Ragothaman, M.D., D.M., and Dr. P. Suresh

M.D., D.M., Assistant Professor Department of Cardiology for the guidance and encouragement.

I thank Dr. N. Nagarajan M.D., D.M., Assistant Professor

Department of for the guidance and help provided during the study.

I extend my thanks to family and my senior / Junior postgraduates, who stood by me during my times of need. Their help and support have been invaluable to the study. Finally, I thank all the patients for their extreme patience and cooperation.

PLAGIARISM CERTIFICATE

This is to certify that this dissertation work titled “A STUDY ON THE

PREVALENCE OF CARDIORENAL SYNDROME IN TYPE 2

DIABETIC PATIENTS” of the candidate DR. V. VIGNESH., with registration

Number 201711260 for the award of Degree of M.D in the branch of GENERAL

MEDICINE-BRANCH-I. I personally verified the urkund.com website for the purpose of plagiarism Check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 2% percentage of plagiarism in the dissertation.

Prof. Dr. R. NARMADHA LAKSHMI, M.D, Dch,

Professor and HOD,

Department of General Medicine

Chengalpattu Medical College,

Chengalpattu.

CONTENTS

S. NO. TITLE PAGE NO.

1. INTRODUCTION 1

2. AIM OF THE STUDY 5

3. REVIEW OF LITERATURE 6

4. MATERIALS AND METHODS 41

5. RESULTS AND ANALYSIS 43

6. DISCUSSION 65

7. CONCLUSION 68

8. ABBREVIATIONS 69

9. BIBLIOGRAPHY 70

10. PROFORMA 77

11. MASTER CHART 79

INTRODUCTION

The term cardio renal syndrome has been increasingly used at present.

Diabetes is a most important risk factor for cardiorenal syndrome.

CRS generally defined as pathophysiological disorder of the kidneys and

Heart, whereas acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the other.

Type 1 CRS defined as abrupt worsening of cardiac function (eg acute or decompensated congestive cardiac failure) leading to .

Type 2 CRS reflects a chronic abnormality in cardiac dysfunction (eg chronic congestive failure) lead to progressive chronic .

Type 3 CRS Comprises sudden worsening of renal function (eg acute kidney or ) causing an acute cardiac dysfunction (, , ischemia)

Type 4 CRS is defined as a state of (eg chronic glomerular disease) contributing to decreased cardiac function, left and increased risk of adverse cardiovascular events.

Type 5 CRS nothing but systemic conditions (eg. , ,

Hypertension, , vascultis) causing both cardiac and renal dysfunction.

1

Over all pathogenesis of CRS

 Change in renin angiotensin aldosterone system

 Imbalance between nitric oxide and reactive oxygen species

 Inflammation

 Sympathetic nervous system

Diabetes is an important risk factor for kidney disease and

Biomarkers contribute early diagnosis of CRS & timely therapeutic intervention.

In diabetes, common consequence of inflammation and oxidative related endothelial dysfunction is fibrosis. In heart failure and kidney disease, fibrosis is a common feature. Therefore, fibrosis is not only a marker, it is a primary driver of pathophysiology in several cardiorenal syndrome.

Risk factors for worsening renal function while heart failure:

 Old age

 Comorbidities

 Drugs like leads to renal hypoperfusion

 ACE inhibitors and ARBs for RAAS blockade leading to renal impairment

 Prior

 Previous renal insufficiency.

2

Risk factors regarding LV failure in CKD

 Diabetes

 Hypercholesterolemia

 Age

 Smoking

 Obesity

 Male sex

3

Diagnosis of CRS 1 by renal function test and renal biomarkers for acute kidney injury.

Diagnosis of CRS 2 based on Kidney Disease: Improving Global Outcomes

(KDIGO) / Kidney Disease Outcomes Qualitive Initiative (KDOQI) guidelines: albuminuria and /or GFR <60ml/min/1.73 sq m or a sustained decrease in GFR

>5ml/min/1.73 sq m/yr or >10ml/min/1.73 sq m/5 yrs or sustained increase in albuminuria, along with documented or sustained appearance of CCF before the onset or progression of chronic kidney disease

Diagnosis of cardiorenal syndrome type 3, 4 done by ECHO and cardiac biomarkers.

CRS 5 is identified by both renal and cardiac biomarkers, echo and renal function test, ultrasound.

Treatment mainly target on the primary events of cardiorenal syndrome and glycemic control.

4

AIMS &OBJECTIVES

 To assess the prevalence of cardiorenal syndrome in type 2 diabetic patients.

 To correlate the duration of diabetes and occurrence of cardiorenal

syndrome.

5

REVIEW OF LITERATURE

CARDIO-RENAL SYNDROME

INTRODUCTION

The global increase in disease of kidneys and heart is associated with a significant impact mainly on morbidity and mortality rates. A disease causing dysfunction of one organ may lead to a dysfunction of another distant organ due to inter-organ crosstalk pathways. Eg, dysfunction of the heart may affect kidneys negatively and vice-versa. Cardiac and renal functions overlaping and both organ shares common vascular risk factors like diabetes and hypertension. Coexistence of heart and kidney dysfunction defined as a“cardio-renal syndrome” (CRS).This umbrella term denotes primary acute or chronic dysfunction of one, i.e. either the heart or the kidneys, which contribute to the acute or chronic dysfunction of other organ. The Acute Dialysis Quality Initiative (ADQI) work group defined and classified the CRS. This group defined CRS as ‘disorders of the heart and kidneys whereby acute or chronic dysfunction of one organ may affect acute or chronic dysfunction of the other organ’.

Epidemiological data shows the rising of incidence of chronic cardiac diseases including hypertension, heart failure and have led to increased prevalence of the CRS.4 Epidemiology of CRS have limited Indian data.

In hospitalized patients Indian study, all age groups having CRS, elderly male patients more commonly involved.2 One more study involving hospitalized

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children, significant risk of mortality seen associated with an increasing incidence of CRS.5

The Acute Decompensated Heart Failure National Registry (ADHERE)6 data shows more than 100,000 patients associated with heart failure (HF) required hospitalization, in that approximately 30% have a diagnosis of chronic kidney disease (CKD) (serum creatinine being greater than 2.0 mg/dl). Over 60% of that patients included in this registry with acute decompensated HF (ADHF) have a stage 3 (GFR<60ml/min per 1.73 m2) or higher stages of Chronic kidney disease.

In “Organ Crosstalk”, complex biological communications and feedback mechanisms occur between the two distant organs for maintaining the normal physiological response of the human body. It is medicated via cellular, molecular, neural and endocrine pathways.

This pathway maintaining homeostasis. But when one organ develops a dysfunction because of disease states, this one lead to initiate and perpetuate structural /functional dysfunction of the another organ also. An, acute and chronic cardiac diseases can directly reflects to the concurrent acute / chronic worsening of the renal function or vice versa. Distant leading to increased mortality and morbidity in Acute Kidney Injury (AKI) due to different mechanisms, which include inflammatory cascades, cell adhesion molecules, up- regulated cytokine and chemokine expressions, neutrophil migration, leukocyte trafficking, caspase-mediated apoptosis, and oxidative stress .Physio-pathological mechanisms, for the simultaneous involvement of both cardiovascular and renal

7

functions, causing the CRS is very complex and not yet been fully understood the pathophysiology. Development of primary cardiac or renal dysfunction, lead to the renin angiotensin aldosterone system (RAAS), pressure sensing baroreceptors, cellular signalling and sympathetic nervous system (SNS) mechanisms dysfunction occur.

Normal Physiology of Cardio-renal Axis

Maintain the hemodynamic balance in the body by heart via systemic circulation and kidney through extracellular fluid volume. The normal cardio-renal axis maintaining the both hemodynamic stability and end-organ perfusion via the following mechanisms by a controlling cardiac output (CO), volume status, and vascular tone in the body. At the times of increased or decreased perfusion pressure, maintenance of GFR is controlled by the RAAS, SNS, local vasodilators such as nitric oxide (NO), adenosine and prostaglandins. If decreased glomerular perfusion resulting from or reduced CO is sense the macula densa and juxtaglomerular apparatus, lead to the stimulation of RAAS, NO, adenosine, and prostaglandin production and prevent major changes in renal function. When renal perfusion pressure decreases, angiotensin II (AII) acts to increases efferent arteriolar resistance so it leads to preserving the intra-glomerular hydrostatic pressure and maintaining eGFR.

8

Classification / Definition /Types of CRS

The term ‘cardio-renal syndrome (CRS)’ used to define the different clinical conditions wherein heart dysfunction and kidney dysfunction overlap. Consensus

Conference conducted by the Acute Dialysis Quality Group7 in 2008 proposed an effective classification of CRS was proposed at (Table 1). CRS is mainly divided into 2 main groups, ‘Cardio Renal’ or ‘Reno Cardiac’ depending on which primary organ (cardiac or renal) is involved. These are again subdivided into the acute or chronic conditions, depend upon the onset of disease and progression.

Type 5 CRS reflects the simultaneous cardio-renal involvement due to acute or chronic systemic disease.

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TABLE I: Classification of CRS

Type 1 Acute Cardio-renal Sudden deterioration of syndrome the cardiac function that leads to a acute kidney injury (AKI)

Type 2 Chronic Cardio-renal Chronic cardiac disorder syndrome leading to the development of progression of chronic kidney disease (CKD) Type 3 Acute Reno-cardiac Abrupt & primarily syndrome worsening the kidney function that initiates the acute cardiac dysfunction Type 4 Chronic Reno-cardiac CKD lead to the syndrome reduction of cardiac function Type 5 Secondary Systemic disorders Cardio-renal either acute or chronic syndrome like Diabetes, Hypertension, sepsis, vasculitis that impair the both cardiac &renal function.

10

TABLE II: NEW CLASSIFICATION OF CRS

CRS CATEGORIES MANIFESTATIONS

Hemodynamic (Acute Chronic) low cardiac output lead to AKI, kidney dysfunction lead to fluid retention. (Acute/Chronic) / / pleuritis due to increased serum urea in the blood. Vascular (Acute /Chronic) Stenosis of Coronary Artery

Atherosclerotic, Thrombotic Stenosis of renal artery

Endothelial Dysfunction Thrombosis of Renal Artery

Neurohormonal(Acute/chronic) Increased serum potassium level/serum Electrolyte, Autonomic, Acid-base calcium level/ serum magnesium level

Increased catecholamine, activation of RAAS, metabolic acidosis

Anemia & or Iron Metabolism Iron deficiency, folate deficiency, infection, Renal tubular injury related Acute or Chronic Nutrient

deficiency, Inflammation Renal

anemia

Mineral metabolism (Mostly due Increased phosphate levels, hypercalcemia, Vitamin D deficiency, to Chronic) increased serum FGF-23. Protein energy wasting (Mostly

because of Chronic)

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PATHOPHYSIOLOGY OF DIFFERENT CARDIO-RENAL SYNDROMES

Type 1 CRS: Acute Cardio-renal Syndrome

Sudden worsening of the cardiac function, leading to an acute kidney injury

(AKI) implies cardiorenal syndrome 1. Acute decompensated heart failure (ADHF) and (ACS) are the common clinical presentation. A risk of acute CRS is very high in the setting of cardiogenic shock and prevent significant deterioration of renal function by early treatment strategy. Acute kidney

Injury is divided into early and late. Early means within 48 hrs and late means within 3-7 days.

Based on congestion is present or not (wet or dry) /perfusion is adequate or limited (warm or cold), ADHF have any four possible hemodynamic profiles. The four clinically determined profiles have shown to be determine the clinical outcomes and may be used for guide the initial heart failure therapy.

Pathogenesis of acute CRS:

1. Renal hypoperfusion occur due to an altered hemodynamis (hypotension) There

are

i. “Cold” pattern -because of reduced effective circulatory fluid volume

(ECFV) (The ‘low flow state’ hypothesis).

ii. “Wet” pattern- systemic or venous congestion is due to a significant increase

in central venous pressure, it also increases the renal venous pressure lead to

the decreasing gradients across the glomerular capillary network resulting in

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reduced GFR. It is also increased by an increased intra-abdominal pressure.

So net renal perfusion pressure finally compromised.

2. Neuro-hormonal Mechanisms:

i. Decreased renal blood flow related to RAAS activation.

ii. Sympathetic activation leads to vasoconstriction. iii. Oxidative Stress lead to the significant increase in circulating reactive

oxygen species (ROS) with increased regulation of pro-inflammatory

mediators.

3. Vasoconstriction and reduction in renal blood flow is due to local release of

adenosine – Recently identified mechanisms.

It is essential to differentiate the acute CRS from renal injury due to hypovolemia.

Stable HF patients usually have hypervolemia mildly at baseline sometimes heart failure become hypovolemic due to overaggressive therapy, severe acute gastroenteritis, or other causes. Although, fluid status of the patients with these two entity is diametrically opposite, it is very difficult to distinguish between this two.

In both clinical conditions, urine electrolytes suggest a pre-renal AKI. History is very important - recent losses of fluids or overuse of diuretic may help to identify the hypovolemia. Analysis of the recent trend in weight is vital in making the right diagnosis. Misdiagnosis of acute CRS as hypovolemia-induced AKI is very dangerous. If volume depletion is erroneously Judged to be the cause of AKI, fluid administration can lead to further worsening of both cardiac and renal function.

Lack of renal recovery may lead to the invite further fluid administration and this can lead to perpetuate the vicious circle that is already in play. 13

PATHOPHYSIOLOGY OF TYPE 1 CRS

14

TYPE 2 CRS: CHRONIC CARDIO-RENAL SYNDROME

Type 2 cardiorenal syndrome is characterized by a chronic abnormalities of

cardiac function – e.g. congestive heart failure (CHF) can leading to an AKI or

progressive renal dysfunction and CKD. In patients with CHF, 45-63% CKD

observed. There is multiple factor responsible for renal dysfunction in chronic

cardiac condition. Progressive renal hypoperfusion occur due to:

1. Neuro –hormonal activation

2. Hypertension and volume overload due to augmented Na+ reabsorption

3. Progressive atherosclerotic

4. Recurrent oxidative stress

15

PATHOPHYSIOLOGY OF TYPE 2 CRS

16

TYPE 3 CRS: ACUTE RENO -CARDIAC SYNDROME

In acute reno-cardiac syndrome, acute worsening of kidney function is the primary event, it leads to cardiac dysfunction like Acute coronary syndrome, , Acute decompensated heart failure. In this, most common acute cardiac dysfunction syndrome is Acute decompensated heart failure and is defined by a new onset/rapid worsening of previous HF.

Following Factors responsible for the worsening of normal cardiac function or pre-existing underlying cardiac dysfunction in AKI individuals. They are

 Secretion of neurohormones

 AKI related volume overload

 Metabolic acidosis

 Electrolyte disorders particularly hypo / hyperkalemia

 Hyperactivity of SNS

 Medications (NSAID, glitazones).

17

PATHOPHYSIOLOGY OF TYPE 3 CRS

18

TYPE 4 CRS: CHRONIC RENAL- CARDIAC SYNDROME

In chronic reno-cardiac syndrome, any stage of CKD lead to a cardiovascular dysfunction. CKD is a major risk factor for cardiovascular disease

(CVD). Primary CKD lead to a reduction in cardiac function from cardiac remodelling, LV diastolic dysfunction, hypertrophy, and also responsible for an increased risk for cardiovascular events, such as myocardial infarction, HF or stroke. Independent of age and conventional risk factors, CKD is an independent predictor of CVD.10

According to the K/DOQI CKD classification, cardiovascular risk is evident in patients with stages IIIb-IV renal disease and this risk is also seen in patients who underwent renal replacement therapy (RRT) .12 In chronic renal insufficiency cohort (CRIC) study investigators focused on 190 patients presenting with advanced CKD (eGFR<20ml/min/1.73m2) to end –stage renal disease (ESRD)

(receiving PD/HD), and performed serial echocardiographic examinations. In the evaluation period in which patients shifted from advanced CKD to ESRD, the EF decreased from 52.5 to 49.7%. Number of subjects with EF <50 % gradually increase from 29 % in advanced CKD to 48% in ESRD.11,12

In the HEMO study, 1846 chronic hemodialysis patients in that 61.5 % cardiac death is due to an ischemic heart disease .13In a systemic review of 13 studies reported that most of the mortality is due to a cardiovascular death (58 %).14

Accelerated CVD in CKD is because of

19

 Chronic inflammation

 Insulin resistance

 Malnutrition

 Dyslipidemia

 Chronic heart failure/LVH

 Increased fibroblast growth factor 23 levels

20

PATHOPHYSIOLOGY OF TYPE 4 CRS

21

CORONARY ATHEROSCLEROTIC VASCULAR DISEASE

A study done to determine the relationship between CKD and severe in 261 male veterans, results found that an increasing coronary vascular events with decreasing GFR. Patients with CKD significantly have a CAD involving atleast a one coronary artery vessel. Based on serum creatinine, CKD was defined as a eGFR< 60ml/min/1.73 sq.m prior to angiography. CAD was defined as a stenosis of 70% or more on coronary angiography procedure.

TYPE 5 CRS:

It is due to an acute or chronic systemic illness that simultaneously induces cardiac and kidney injury and/or dysfunction. In this subtype Systemic illness is the primary etiology. Some common conditions that lead to combined cardiorenal dysfunction include sepsis, viral infections (HBV, HCV, HIV), amyloidosis,

Systemic lupus erythematous, diabetes mellitus and drugs (cocaine, heroin, chemotherapeutic drugs)

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PATHOPHYSIOLOGY OF TYPE 5 CRS

Numerous drugs act on the heart and kidneys and may cause simultaneous damage. such as

 Metformin

 Radiocontrast agents

 ACE INHIBITORS/ARB

 Aldosterone receptor blocker/AVP receptor blockers

 Diuretics, NSAIDs 23

BIOMARKERS

Depends on the clinical situation, identification of cardiorenal / renocardiac syndrome made. But, the diagnosis is usually confirmed by a various biomarker.

SYNDROMES BIOMARKERS Type 1 CRS Cardiac cTnT, BNP, NT pro-BNP, MPO, MRpro ADM Renal Creatinine, cystatin C, NGAL,KIM- 1,NAG,IL18 Type 2 CRS Cardiac BNP, NT pro-BNP, CRP, ST2

Renal Creatinine, cystatin C, microalbuminuria, CRP, homocysteine, uric acid, urotensin 2,aldosterone Type 3 CRS Cardiac BNP, NT pro-BNP

Renal Creatinine, cystatin C, NGAL,KIM- 1,NAG,IL18 Type 4 CRS Cardiac BNP, NT pro-BNP, CRP

Renal Creatinine, cystatin C, microalbuminuria, homocysteine, uric acid, urotensin 2,aldosterone Type 5 CRS Cardiac BNP, CRP, procalcitonin, ST2

Renal Creatinine, NGAL,KIM-1,NAG,IL18

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MANAGEMENT OF CRS

It requires both pharmacologic and non-pharmacologic treatment, which are

summarized in following table.

DRUGS/NON- DOSE / DRUG SIDE EFFECTS REMARKS FREQUENCY REGIMENS Loop diuretics Start 2.5* chronic Dyselectrolytemia Monitor oral dose followed Arrhythmia clinically (UO, by boluses (q 6-8 Hearing impairment volume status) hrly) or continuous Tinnitus Adjustment of infusion. If Hematological dose UO<1ml/kg/hr, then disorders double as necessary Skin diseases to maximum of 80- Tubulo interstitial 160 mg/hr Dopamine IV 5-15 Tachyarrhythmias Drug mcg/kg/min(systemi Headache, nausea interruption with c vascular resistance Cardiac ischemia MAO-1 increased at dose of Tissue necrosis > 10 mcg/kg/min) Dobutamine IV 2.5- Tachyarrhythmias Drug 20mcgs/kg/min(syst Headache, nausea interruption with emic vascular Hypertension MAO-1 resistance increased Hypotension Contraindicated at dose of <5 Fever with sulphite mcg/kg/min) hypersensitivity allergy

25

Levosimendan IV 6-24mcgs/kg arrhythmias Avoid use of over 10 mins; f/b Headache, nausea vasodilators infusion 0.05-0.2 Hypotension mcgs/kg/min, titrated by response Tolvaptan P.O. start with Hypernatremia Not to be used 15mg/day; increase Hypersensitivity for > 30 to 30mg od to a Hepatotoxicity days(Hepatotoxi max. Of 60mg/day; Nausea and weakness city titration once daily. Fever Monitor rate of anorexia na increase under neurological status Do not use with strong CYP3A inhibitor IV – 2mcgs/kg bolus Hypotension Close optional f/b Hypersensitivity monitoring of continuous infusion Headache, nausea BP at 0.01mcgs/kg/min Creatinine rise Sacubitril/ P.o. start low (49/51 Hyperkalemia Avoid ACE valsartan mg Sacubitril/ Hypotension Inhibitors and valsartan) . double Cough combination dose after two to Dizziness with aliskiren or four weeks as Renal failure other ARB tolerated. Renal For refractory Volume depletion Nephrology replacement condition Hypotension support therpy(UF/IHD/ Hypokalemia

26

SLED/PD) hypophosphatemia Diet fluid and Sodium: < 1.5- Hypotension Individualise salt restriction 2g/day Hyponatremia based on serum Water:< 1.5-2 litre RAAS activation sodium and per day diuretic resistance

DIURETICS

The main aim of therapy in acute CRS is to achieve aggressive diuresis,

typically by using the intravenous diuretics. Most potent class of diuretics are Loop

diuretics and this drug is a first line drugs for this purpose. Other classes of

diuretics as monotherapy are not effective and not recommended but can be

combined with loop diuretics. Correction of volume overload is difficult in the

presence of impaired renal function. Improving the cardiac dysfunction, could

improve the patient outcomes but improving renal function alone is not help to

improve patient outcome. The Following steps in escalation of diuretic therapy in

CRS.

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Diagnosis of CRS

Intravenous loop diuretics

Output still inadequate

Increased dosage based on GFR till maximum dose

Output still inadequate

Consider continuous infusion Output still inadequate

Add a thiazide diuretic Output still inadequate

Consider acetazolamide or spironolactone

Output still inadequate

Consider ionotropes

Output still inadequate

Consider ultrafiltration

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In presence of renal insufficiency, the dose of diuretics should be carefully regulated. In contrast, other classes of drugs, the dose of some of the diuretics increased as the eGFR falls.

DIURETIC DOSING IN RENAL INSUFFICIENCY

DRUG CrCl<25ml/min CrCl 25-75ml/min CrCl>75ml/min

Loop diuretic iv

bolus

Furosemide (mg) 160-200 80-160 40-80

Torsemide (mg) 50-100 20-50 10-20

Loop diuretics

Continuous

infusion

Furosemide LD: 40 mg LD: 40 mg LD: 40 mg followed by followed by followed by 20mg/hr for 1hr 10mg/hr for 1hr 10mg/hr for 1hr Inadequate Inadequate Inadequate response: repeat response: repeat response: repeat LD followed by LD followed by LD followed by infusion at infusion at 20mg/hr infusion at 40mg/hr 20mg/hr Torsemide LD: 20 mg LD: 20 mg LD: 20 mg followed by followed by followed by 10mg/hr for 1hr 5mg/hr for 1hr 5mg/hr Inadequate Inadequate response: repeat response: repeat

29

LD followed by LD followed by infusion at infusion at 10mg/hr 20mg/hr Thiazide diuretic

Hydrochlorothiazi 100-200 50-100 25-50

de

(mg)

Chlorothiazide 500-2000 in 1-2 500-2000 in 1-2 500-2000 in 1-2 divided doses divided doses divided doses (mg)

Metolazone(mg) 2.5-20 mg od 2.5-20 mg od 2.5-20 mg od

*LD: Loading dose

For optimize drug delivery another strategyis continuous infusion of loop diuretics. When Compared with bolus therapy, continuous infusion gives a sustained and uniform drug delivery and preventing post-diuretic sodium retention.

The diuretic optimization strategies evaluation (DOSE) trial done in 308 pts admitted with ADHF for compared the efficacy and safety of continuous vs bolus furosemide therapy .15Results found that no difference in symptom control as well as net fluid loss at 72 hrs between the groups. Other studies showed that more diuresis with continuous infusion than with a same dose bolus regimen. However, for routine use of continuous loop diuretic therapy, there is lacking of clinical evidence to support

Loop diuretic plus a thiazide is the most popular combination, although no large scale placebo controlled trials have been performed. Because of low cost and

30

availability Metolazone is used. Metolazone also shown to block sodium reabsorption at the proximal convoluted tubule, which may contribute to its synergistic effects. Chlorothiazide is available in an intravenous formulation. It has a faster onset of action than metolazone.

But, studies have failed to identify any benefit of one over the other. Lower chance of developing metabolic alkalosis is achieved by the combination of loop diuretic with acetazolamide, metabolic alkalosis is a potential side effects of loop diuretics and thiazides. A recent study found that an adding acetazolamide to bumetanide led to significantly increased natriuresis but there is limited data.

ULTRAFILTRATION

In recent years, in CRS subtype 2 ultrafiltration has been increasingly used.

Three randomized trials Ultrafiltration versus Intravenous diuretics for patients hospitalized for ADHF (UNLOAD),Relief for acutely fluid overloaded patients with decompensated congestive heart failure (RAPIDCHF),Cardiorenal rescue study in ADHF (CARESS –HF) have compared diuretic therapy in patients with

ADHF.21-22UF was associated with greater fluid loss than diuretic therapy but no difference in serum creatinine In UNLOAD and RAPIDCHF trial, while in

CARESS-HF weight loss was similar, but there is an increase in serum creatinine and greater adverse effects. Additional trials is going on to see the benefits of UF.

The 2013 ACCF/AHA guidelines for the management of HF stated that “For patients with refractory congestion not responding to medical therapy ultrafiltration may be considered. For the symptomatic management of refractory dyspnea in end

31

stage HF, Peritoneal dialysis is tried with lack of data from large randomized controlled trials.

DIALYSIS:

In case of more advanced AKI, the kidney disease: improving global outcomes

(KDIGO) clinical practice guidelines state that dialysis, not UF alone, should be initiated to treat or prevent life threating signs such as uremic symptoms. Selection of the RRT modality primarily depends on local expertise and availability of staff and equipment for a specific treatment as well as the patients hemodynamic status.

Intermittent and continuous RRT should be implemented as a complementary therapy in patients with AKI or decompensated CKD.

INOTROPES:

For maintain organ perfusion, Inotropes such as dobutamine and milrinone are used in cardiogenic shock patients. Inotropes effects such as increase cardiac output, improve renal blood flow, improve right ventricular output so it lead to a relieve the systemic congestion.

The Renal Optimization Strategies Evaluation (ROSE) trial done in 360 patients with acute HF and renal dysfunction. No significant effect on 72 hours cumulative urine output or renal function as measured by cystatinc levels, when adding dopamine in a low dose (2mcg/kg/min) to diuretic therapy.26

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LEVOSIMENDAN:

It is a calcium sensitizer. It possess a both positive inotropic and vasodilator effects. Some clinical trials and their meta analyses reported the clinical efficacy of livosimendan including improved cardiac performance, rapid symptom relief, reduced hospital stays and better survival in patients with ADHF. Other than cardiac effects, it also increases renal blood flow and GFR. Its adverse effects like hypotension, arrhythmias. It may increase mortality in patients with low systemic

BP.

VASODILATORS:

Although the clinical evidence supporting their use is weak, Vasodilators such as nitroglycerin, sodium nitroprusside and hydralazine are used in patients with acute HF very commonly. Physiologically, arterial dilatation reduces afterload there by help in relieving pulmonary congestion. Reduces the preload venodilatation by increases capacitance. In theory, improving renal perfusion by venodilators such as nitroglycerin can relieve renal venous congestion in patients with acute CRS. But, the use of vasodilators is limited because of hypotension.

CARDIAC RESYNCHRONISATION:

In a study by Van bommel et al,33 patients with HF who eGFR< 60 ml/min/1.73 sq.m demonstrated the decreased response to CRT, defined by a decrease in left ventricular end systolic volume >15% at 6 month follow up, when compared to the normal renal function individual. Worsening of renal function also

33

associated with a poor long term prognosis after CRT. Despite this, a systematic review by Garg et al demonstrated a CRT in patients with CKD shows

Improvement in left ventricular ejection as well as eGFR.

BETA BLOCKERS:

While in acute heart failure, beta blockers are avoided but used in management of chronic heart failure. In a systematic review by Badve et al in a patient with heart failure and CKD, beta blockers use reduced the all risk of CVS mortality. However, increase in and hypotension like adverse effects occur. Caution to be exercised in their use in ADHF because they further reduce forward flow and exacerbate renal dysfunction.

ANGIOTENSIN RECEPTOR ANTAGONISTS:

By causing vasodilatation and increased renal perfusion, ARB increase GFR

However, PROTECT trial36 found that no difference in CVS outcomes compared to placebo in a treatment of the AHF with renal dysfunction.

VASOPRESSIN RECEPTOR ANTAGONISTS:

Tolvaptan, is a selective vasopressin 2 receptor anatagonist whose effect on

CVS actions was described in the efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan-outcomes trial. 37 The study showed no effect on long term mortality or heart failure related morbidity. However, there was an increase in urine output, resulting in improvement as it increased free water clearance.

34

RAAS ANTAGONISM:

It is an integral part of therapy for acute / chronic heart failure and renal failure. Subgroup analysis of clinical trials of RAAS antagonism in HF have demonstrated that the beneficial effects on morbidity are not reduced by concurrent

CKD. The risk of hyperkalemia and worsening renal function is higher in patients with CKD and therefore requires regular monitoring.

Similarly, aldosterone antagonism showed a benefit in CVS outcomes despite a fall in GFR with the same problem of hyperkalemia.

ACE inhibition and ARB are known to worsen renal function, which prompts reluctance to prescribe and early stopping therapy when serum creatinine increases slightly. RAAS blockade should not be discontinued as such patients had decreased mortality despite a decline in GFR. Renal impairment should not be a contraindication to RAAS blockade and treatment should not be withheld. Instead, it should be continued with frequent monitoring and a multidisciplinary management including nephrology specialists.

NESIRITIDE:

It is a r-BNP approved for the management of ADHF. The recommended administration is 2 mcgs per kg bolus injection followed by continuous infusion at a dose of 0.010mcgs/kg/min. although, nesiritide produces modest improvement in dyspnea, a meta-analysis suggested that it may worsen renal function and hasten death, potentially due to its hypotensive effects. Meanwhile, small studies using

35

low dose nesiritide (0.005 mcgs/kg/min without bolus) in ADHF and cardiac surgery patients have shown increased urine output and preserved renal function.

ARNI:

Neprilysin is an enzyme that contributes to the breakdown of several endogenous vasoactive peptides (natriuretic peptides, bradykinin and adrenomedullin) which counteracts neurohormonal activation leading to vasoconstriction, sodium retention and maladaptive remodeling. Inhibition of neprilysin is a potential therapeutic strategy to delay the development or progression of CVS disease. However, a study of combined inhibition of ACE and

Neprilysin failed due to a high incidence of CVS angioedema. To minimize the risk of this adverse effects a new drug (LCZ696), combining Neprilysin inhibitor prodrug(sacubitril) with an ARB (valsartan) has been developed.

MANAGEMENT OF ANEMIA:

Anemia is highly prevalent in CKD or patients with HF. This results in increased risk of progressive heart failure, CVS events and death. Hence treatment of anemia could impact outcome in patients with HF and CKD.

Anemia management in heart failure is primarily done with intravenous iron treatment, after appropriate investigations. There are studies demonstrating beneficial effects of ferric carboxymaltose on quality of life and functional capacity in patients with HF.

36

Similarly, treatment of anemia in CKD patients using ESAs after correction of iron deficiency also improves cardiac outcomes.

LVAD:

It is an implantable mechanical circulatory support device that has revolutionized the treatment of end stage heart failure. Apart from being used to support patients awaiting heart transplant, there are now offered to patients ineligible for heart transplant as well as destination therapy which can be viewed as an alternative to heart transplant. Renal dysfunction prior to LVAD implantation predicts higher mortality after implantation.

Hence, it is important that patient receives timely referral for LVAD before heart failure worsens and leading to CKD. Renal function usually improves after

LVAD implantation if decreased GFR is due to renal hypoperfusion and most of the recovery tends to occur in the first month after LVAD placement and the improvement is mediated through the reversal of renal hypoperfusion and favourable intrarenal hemodynamics.

MANAGEMENT OF TYPE 3 CRS:

Nephrotoxic medications should be ideally completely avoided and if not possible their dosage should be modified. Renal hypoperfusion should be prevented. Fluid intake should be strictly monitored. Management should depend of

RIFLE criteria. Electrolytes and acid base homeostasis should be maintained.

Patient may require frusemide infusion for adequate output. Patients may need

37

renal replacement therapy. Other methods of dialysis like CRRT or SLED or

CVVH may be considered.

MANAGEMENT OF TYPE 4 CRS:

Strategies to reduce CVS risk in CKD patients have to target both traditional and non-traditional risk factors.

The important traditional risk factors are

 Diabetes

 Hypertension

 Dyslipidemia

 Smoking/ overweight/obesity

The non traditional risk factors include:

 Anemia

 Chronic inflammation

 Secondary hyperthyroidism

 Left ventricular hypertrophy

 Oxidative stress

 RAAS and SNS hyperactivity

 Complications of RRT.

38

Specific treatment is difficult to achieve especially in hemodialysis patients in which clear association between mortality and blood pressure, BMI,

Dyslipidemia and hyperphosphatemia has been demonstrated. There is a clearly established role of secondary anemia correction. However, there are some controversies regarding the benefit of correction of other risk factors. For those hemodialysis patients with secondary hyperparathyroidism, cinacalcet therapy did not significantly reduce the risk of death or major cardiovascular events as per the

EVOLVE study. The SHARP study in CKD patients, demonstrated significant reduction in cardiovascular events, (MI, stroke, or need for coronary artery revascularization), with the use of a combination of ezetimibe plus simvastatin.

Pre dialysis patients should be closely recommended to maintain blood pressure levels below 130/80 mm hg, HbA1c below 7 %, Hb b/n 11 and 12 gm%, C-LDL below 90 mg/dl. Patients should also avoid nephrotoxic drugs and follow a diet with a minimum of 0.6 – 0.8 gm/kg body weight of protein per day.

Management of Type 5 CRS

The management of type 5 CRS will depend on the systemic cause e.g. sepsis, Vasculitis, etc. Which has led to CRS.

39

SUMMARY

Association between renal and cardiac dysfunction has now been studied to some extent and classified. Various pathophysiological mechanisms including hemodynamic and non hemodynamic factors come into play. Awareness about

CRS is important to plan the therapy and maximize the favourable outcome. As per the available data on incidence and prevalence, there is a great increase in CRS also due to an increase in acute & chronic CVD leading to AKI or CKD. Patients with various degrees of cardiovascular involvement due to various pathophysiologic factors.

Heart-Kidney cross talk results in coexistence of various cardiac and renal disorders. Management of CRS is both an art and science, since a lot depends on the clinical assessments of patients along with the use of biomarkers.

In this review, a simplified view of the pathogenesis and therapeutic interventions for the physician while dealing with CRS is presented. Medical treatment options are focused on improving cardiac function, reducing volume overload, managing HF and AKI with CKD. Although management of CRS remains a challenge, increased awareness, early recognition and therapy help to avoid adverse outcomes and improve patient care.

40

MATERIALS AND METHODS

STUDY DESIGN: Cross sectional study

DURATION OF THE STUDY: 1 YEAR

STUDY POPULATION: Patient attending General Medicine OPD and casualty who are all known case of Type 2 DM

SAMPLING METHOD: Convenient sampling method

SAMPLE SIZE: 100

Based on the study done by Michael S Niederman et al, the proportion 55% is taken for sample size calculation. (10)

STUDY PLACE: Govt. Chengalpattu Medical College, Chengalpattu

41

INCLUSION CRITERIA:

 Patients with Type 2 DM

 Both sex

EXCLUSION CRITERIA

 Patient not willing for study

 Patient with Type 1 DM, GDM, Secondary Diabetes

 Patient with Sepsis, Amyloidosis, SLE, Vasculitis

 Patient with Hypertension

 Patient with

 Patient suspected to have non diabetic nephropathy like USG KUB showing

Contracted kidney, Cystic kidney disease

 Patient with other medical illness

42

RESULTS AND ANALYSIS

TABLE: 1 PREVALENCE OF CARDIORENAL SYNDROME IN T2DM

CRS TYPES CRS PRESENT PREVALENCE

CRS 1 3 3%

CRS 2 10 10%

CRS 3 - -

CRS 4 12 12%

CRS 5 7 7%

43

FIGURE 1: PREVALENCE OF CARDIORENAL SYNDROME IN T2DM

PREVALENCE OF CARDIORENAL SYNDROME IN T2DM

12 10 8 PREVALENCE OF CARDIORENAL 6 SYNDROME IN T2DM 4 2 0 CRS 1 CRS 2 CRS 3 CRS 4 CRS 5

The overall prevalence of cardiorenal syndrome in T2DM are 32 %. In that increased prevalence occur in CRS 4 followed by CRS 2.

44

TABLE 2: SEX WISE PREVALENCE OF CARDIORENAL SYNDROME IN

T2DM

SEX MALE FEMALE TOTAL

n 59 41 100

CRS PRESENT 21 11 32

PREVALENCE 36 % 27 %

45

FIGURE 2: SEX WISE PREVALENCE OF CARDIORENAL SYNDROME

IN T2DM

SEX WISE PREVALENCE OF CARDIORENAL SYNDROME IN T2DM

27 MALE FEMALE 36

Among 100 populations of T2DM, Males and Females are 59 and 41 respectively in my study. Males 36 % are more commonly affected than Females population 27 % in my study.

46

TABLE 3: AGE WISE PREVALENCE OF CARDIORENAL SYNDROME

IN T2DM

AGE 41-50 YR 51-60 YR >60 YR

n 38 35 27

CRS TOTAL 7 8 17

PREVALENCE 18 % 23 % 63 %

CRS 1 2 1 -

CRS 2 2 2 6

CRS 3 - - -

CRS 4 2 3 7

CRS 5 1 2 4

47

FIGURE 3: AGE WISE PREVALENCE OF CARDIORENAL SYNDROME

IN T2DM

AGE WISE PREVALENCE OF CARDIORENAL SYNDROME IN T2DM

63

AGE WISE PREVALENCE OF CARDIORENAL SYNDROME IN 23 T2DM 18

41-50 Yrs 51-60 Yrs >60

Mean age: 54.5 years

Among 100 populations, 63 % of cardiorenal syndrome’s are more than 60

48

TABLE 4: DURATION OF DIABETES WISE PREVALENCE OF

CARDIORENAL SYNDROME IN T2DM

DURATION <5 YR 5-10 YR >10 YR

OF DIABETES

n 30 41 29

CRS TOTAL 4 13 15

PREVALENCE 13 % 32 % 52 %

CRS 1 1 2 -

CRS 2 1 4 5

CRS 3 - - -

CRS 4 2 4 6

CRS 5 - 3 4

49

FIGURE 4: DURATION OF DIABETES WISE PREVALENCE OF

CARDIORENAL SYNDROME IN T2DM

DURATION OF DIABETES WISE PREVALENCE OF CARDIORENAL SYNDROME IN T2DM

60%

50%

40% DURATION OF DIABETES WISE 30% PREVALENCE OF CARDIORENAL SYNDROME IN T2DM 20%

10%

0% <5 yr 5-10 yr >10yr

Mean duration of diabetes: 7.5 Years

Among 100 populations in my study, 52 % of cardio renal syndrome’s are more than 10-year duration of diabetes individual.

50

TABLE 5: URINE SPOT PCR IN DM WITH HEART FAILURE

URINE SPOT PCR DM WITH HEART FAILURE

POSITIVE 13

NEGATIVE 37

Among 100 diabetic populations, 50 patients presented with heart failure in that 13 of DM with Heart Failure Positive for urine spot PCR.

51

TABLE 6: eGFR IN DM WITH HEART FAILURE

eGFR DM WITH HEART

FAILURE

<60 ml/min/1.73sq.m 17

>or =60 ml/min/1.73sq.m 33

Among 100 populations ,17 of DM with heart failure are < 60 ml/min/1.73sq.m.

52

TABLE 7: ULTRASOUND IN DM WITH HEART FAILURE

USG FINDING DM WITH CHRONIC

REGARDING DKD HEART FAILURE

PRESENT 5

ABSENT 38

Among 100 populations, 5 of DM with chronic heart failure – USG finding regarding DKD present.

53

TABLE 8: NYHA STAGES IN DM WITH ACUTE/CHRONIC HEART

FAILURE

STAGES CRS PRESENT PREVALENCE n

I 0 0 6

II 2 25 % 8

III 6 40 % 15

IV 9 43 % 21

54

FIGURE 5: NYHA STAGES IN DM WITH ACUTE/CHRONIC HEART

FAILURE

NYHA STAGES IN DM WITH ACUTE/CHRONIC HEART FAILURE 50% 45% 40% 35% 30% NYHA STAGES IN DM WITH 25% ACUTE/CHRONIC HEART 20% FAILURE 15% 10% 5% 0% Stage 1 Stage 2 Stage 3 Stage 4

Among 50 population of diabetes with heart failure, 25 % / 40 % / 43 % of

Cardiorenal syndrome are NYHA Stage II/III/IV respectively. Most of the CRS present in NYHA IV in my study.

55

TABLE 9: EJECTION FRACTION IN DM WITH HEART FAILURE

EF % n CRS PREVALENCE

PRESENT

45-54(Mild) 10 2 20 %

30-44(Moderate) 16 6 38 %

<30(Severe) 24 9 38 %

TOTAL 50 17

56

FIGURE 6: EJECTION FRACTION IN DM WITH HEART FAILURE

EJECTION FRACTION IN DM WITH HEART FAILURE 40%

35%

30%

25%

20% EJECTION FRACTION IN DM WITH HEART FAILURE 15%

10%

5%

0% 45-54% 30-44% <30%

In DM with Heart Failure population, 38 % have moderate/ severe left ventricle systolic dysfunction. Moderate/severe left ventricular Dysfunction more prone for cardiorenal syndrome.

57

TABLE 10: DURATION OF CKD RESPONSIBLE FOR HEART DISEASE

DURATION OF CKD CRS 4

<3 YR 4

3-6YR 5

>6YR 3

58

FIGURE 7: DURATION OF CKD RESPONSIBLE FOR HEART DISEASE

DURATION OF CKD RESPONSIBLE FOR HEART DISEASE 6

5

4

DURATION OF CKD 3 RESPONSIBLE FOR HEART DISEASE 2

1

0 <3 YR 3-6YR >6YR

More number of cardiorenal syndrome 4 is observed in 3-6 yr duration of diabetes.

59

TABLE 11: SYSTOLIC DYSFUNCTION IN CRS 4

STAGES OF SYSTOLIC

CKD DYSFUNCTION

III -

IV 2

V 3

60

FIGURE 8: SYSTOLIC DYSFUNCTION IN CRS 4

SYSTOLIC DYSFUNCTION IN CRS 4 3.5

3

2.5

2 SYSTOLIC DYSFUNCTION IN CRS 1.5 4

1

0.5

0 CKD III CKD IV CKD V

In cardiorenal syndrome 4, systolic dysfunction more commonly occurs in

End stage renal disease.

61

TABLE 12: DIASTOLIC DYSFUNCTION IN CRS 4

STAGES OF CKD DIASTOLIC DYSFUNCTION

III 4

IV 2

V 1

62

FIGURE 9: DIASTOLIC DYSFUNCTION IN CRS 4

DIASTOLIC DYSFUNCTION IN CRS 4 4.5

4

3.5

3

2.5 DIASTOLIC DYSFUNCTION IN 2 CRS 4 1.5

1

0.5

0 CKD III CKD IV CKD V

In cardiorenal syndrome 4,most of the diastolic dysfunction occur in early stages of CKD

63

TABLE 13: EF % GRADING IN CRS 4

GRADING OF EF% CKD III CKD IV CKD V

HFrEF

NORMAL >OR=55 - - -

MILD 45-54 - 1 -

MODERATE 30-44 - 1 1

SEVERE <30 - - 2

64

DISCUSSION

Over the past decades with the increase in life span, Life style disorders such as Diabetes Mellitus, Hypertension, Cardiorenal syndrome Prevalence increases.

This life style disorders emerged as a significant problem among patients. West countries conducted a study to understand a relation between Heart and Kidneys. In

India study about cardiorenal syndrome is less. In India some study conducted about cardiorenal syndrome for prognosis purpose like CARDIORENAL

SYNDROME: CLINICAL OUTCOME STUDY, CARDIORENAL SYNDROME

TYPE 4: A STUDY OF CARDIOVASCULAR DISEASE IN CKD.

Our study aimed at identify and classify cardiorenal syndrome in T2DM.

Overall prevalence is 32 % of cardiorenal syndrome in T2DM at tertiary care centre. In our study, 50 diabetic patients present with acute/chronic heart failure and another 50 diabetic patients present with chronic kidney disease. By past and clinical history Cardiorenal syndrome categories. Majority of the patients in T2DM had CRS 4 – 12%, followed by ten percent CRS – 2, seven percent CRS -5 and three percent CRS – 1.

There were no patients with type – 3 CRS in T2DM. More commonly occur in elderly people with male preponderance in this study. Long duration of diabetes is an important risk factor responsible for cardiorenal syndrome in Type 2 diabetes mellitus is identified in this study.

In CARDIORENAL SYNDROME: CLINICAL OUTCOME STUDY, CRS increases with co morbidities with Hypertension, Diabetes, coronary artery disease, 65

Chronic kidney disease, dyslipidemia. CRS more commonly occur in elderlies with a male preponderance. In this study CRS 1 is followed by CRS 4.our study shows increased prevalence of CRS 4 is followed by CRS 2 in Diabetic population.

Another study CARDIORENAL SYNDROME TYPE 2: A STRONG

PROGNOSTIC FACTOR OF SURVIVAL results is CRS more commonly in aged, diabetes, hypertension, clinically dyspnoeic at NYHA stage III or IV,lower EF patients.our study shows moderate/ severe LVSD and clinically @ NYHA III and

IV responsible for cardiorenal syndrome either 1,2 or 5 subtypes.

Cardiorenal syndrome 4 in Diabetics significantly prevalence high, most common cardiac abnormality in our study is diastolic dysfunction rather than systolic dysfunction. most of the diastolic dysfunction occur in early stages of

CKD.

But systolic dysfunction more common in End stage renal disease.

Diabetes and uncontrolled Hypertension were the major risk factors responsible CRS. It has been suggested an interplay of diabetes mellitus and /or hypertension mediated and cardiac failure associated kidney injury with a related and mutually perpetuating pathophysiology, this was demonstrated by the model of

Kishimto et al.

66

LIMITATIONS:

Other than diabetes, Hypertension / Dyslipidemia is also responsible for cardiorenal syndrome. hypertension and dyslipidemia not included in my study.

Prognosis and risk of admission in the hospital not assessed.

67

CONCLUSION:

Now a days cardio renal syndrome is recognised as an emerging entity in patients with diabetics having both cardiac and renal dysfunctions. Our study concluded that CRS in Diabetes more common in elderly individual with a male predominant. Long duration of Diabetes is important risk factor for Cardio renal syndrome is identified in our study. Prevalence of CRS 4 is higher followed by

CRS 2. Low EF is also an important risk factor for CRS. Diastolic dysfunction is more common in early stage of CKD. Systolic dysfunction occurs in late stage of

CKD.

So in diabetic patients with chronic heart failure, more attention was given to the Elderly with low ejection fraction individual. Routine Renal function test is important to detect early diagnosis of CKD and aggressive treatment of Heart failure needed. In CKD due to diabetic, early screening by Echo is important to detect cardiovascular disease.

68

ABBREVATION:

CRS: Cardio Renal Syndrome.

DM: Diabetes Mellitus.

HF: Heart Failure.

ADHF: Acute Decompensated Heart Failure.

NYHA: New York Heart Association.

EF: Ejection Fraction.

RAAS: Renin Angiotensin Aldosterone System.

CKD: Chronic Kidney Disease.

AKI: Acute Kidney Injury. eGFR: estimated Glomerular Filtration Rate.

69

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heart failure. Circulation 2006; 113:671.

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PROFORMA

 Name:

 Age /sex:

 IP no :

 Date of admission:

 Address for communication:

 Duration of Type 2 DM :

 Family H/O Diabetes :

 H/O Cardiovascular disease :

 H/O Chronic Kidney Disease :

 Weight : Height: BP: PR:

 GENERAL EXAMINATION:

 CVS:

 RS:

 ABDOMEN:

 CNS:

77

 Investigations :

Urine Routine:

RFT :

Urea Creatinine

URINE SPOT PCR :

Protein Creatinine Ratio

GFR :

USG KUB :

ECG:

ECHO :

78

MASTER CHART

URINE R/E PREVIOUS RFT RFT URIN DURATI AGE/ FAMILY DURATION NYHA E TYPES S.NO NAME ON OF ECHO eGFR USG SEX H/O DM OF HF STAGES SPOT eGFR OF CRS T2DM Album Urea Cr ml/mi Urea Cr Sugar PCR ml/min/ in mg% mg% n/1.73 mg% mg% 2 1.73m m2

H.F 1 Shanmugam 67/M 17yr + IV 40% + +++ +ve 40 1.1 67 60 2 33 Normal CRS 5 N.Diagosed Acute MI 2 Selvaraj.R 43/M 3yr + II 35% - + -ve 30 0.8 106 39 1.5 51 Normal CRS 1 with HF

3 Mohan 48/M 1yr - 1yr I 47% - + -ve 32 0.8 103 30 0.7 120 N -

CMD 4 Radhakrishnanan 49/M 6yr + 5yr IV 49% + ++ +ve 35 1.2 64 31 1.3 59 CRS 2 Altered

5 Srinivasan 69/M 7yr + 2yr III 31% - + -ve 42 0.7 112 40 0.6 134 N -

CMD 6 Selvam 62/M 11yr - 2yr IV 33% + ++ +ve 39 1.6 44 40 2.1 32 CRS 2 Lost

7 Kumaravel 55/M 11yr - 5yr II 42% - ++ -ve 36 0.9 88 38 1 78 N -

8 Perumal 45/M 4yr + 1yr IV 35% - + -ve 41 0.9 91 45 1.1 72 N -

79

Acute MI 9 Subramani 54/M 7yr - IV 29% ++ ++ +ve 31 0.7 118 42 1.9 37 Normal CRS 1 with HF

10 Kotti 56/M 10yr + 4yr IV 28% - + -ve 30 0.7 117 30 0.8 100 N -

H.F 11 Gajendran 49/M 8yr + III 40% + ++ +ve 45 1.2 64 90 3 22 Altered CRS 5 N.Diagosed

12 Santhanam 51/M 7yr - 3yr I 29% - + -ve 30 0.8 102 32 0.9 89 N -

13 Lokesh 46/M 3yr + 1yr III 26% - + -ve 42 0.9 91 40 1 80 N -

CMD 14 Jayabal 55/M 4yr + 1yr IV 27% + + +ve 61 2.1 33 79 2.6 26 CRS 2 Lost H.F 15 Shanmugam 55/M 9yr - III 50% - + -ve 36 0.9 88 49 1.9 37 Normal CRS 5 N.Diagosed

16 Jayasekar 70/M 9yr - 2yr IV 46% - + -ve 35 0.9 83 32 0.7 111 N -

17 Vijayakumar 41/M 2yr + 1yr II 28% - + -ve 40 0.9 93 42 1.0 82 N -

18 Arunagiri 69/M 9yr + 2yr II 29% + ++ +ve 40 1.4 50 43 1.7 40 Normal CRS 2

19 Kasi 55/M 8yr - 4yr III 38% - + -ve 38 1.0 78 40 1.2 63 N -

80

20 Ranganathan 49/M 1yr - 1yr I 26% - + -ve 42 1.0 79 45 1.0 79 N -

21 Lakshmanan 58/M 6yr - 2yr IV 26% - + -ve 38 0.9 87 32 0.8 99 N -

22 Srinivasan 45/M 7yr + 2yr III 40% - + -ve 38 0.8 105 38 0.7 122 N -

23 Moorthy 72/M 15yr + 4yr IV 29% - ++ -ve 39 1.5 46 44 1.9 35 Normal CRS 2

24 Kumaravel 60/M 15yr - 5yr IV 33% - + -ve 40 1.0 76 40 1.2 62 N -

25 Bala 55/M 4yr + 1yr II 50% - Trace -ve 35 0.8 100 31 1.0 78 N -

26 Selvaraj.S 48/M 11yr - 5yr I 49% - + -ve 39 0.7 120 37 1.1 71 N -

27 Sekar 53/M 15yr + 4yr III 29% - + -ve 42 0.8 101 49 0.7 118 N -

28 Mahadevan 75/M 14yr - 3yr III 28% + +++ +ve 31 1.1 65 35 1.2 59 Normal CRS 2

29 Nagappan 43/M 11yr + 3yr IV 28% - + -ve 49 0.7 123 60 0.9 92 N -

30 Vadivelu 52/M 3yr - 1yr IV 27% - Trace -ve 40 0.8 102 46 0.7 118 N -

31 Vijayakumar 63/M 20yr + 4yr III 26% + ++ +ve 30 1.2 61 40 1.6 114 Normal CRS 2

81

32 Bommi 65/F 9yr + 3yr IV 28% - + -ve 37 1.2 45 39 1.7 30 Normal CRS 2

33 Vijayalakshmi 44/F 8yr - 2yr II 28% - + -ve 36 0.8 78 38 0.9 68 N -

34 Umamaheshwari 42/F 1yr + 1yr III 42% - Trace -ve 36 0.9 69 35 0.7 92 N -

35 Shantha 54/F 12yr - 4yr I 48% - ++ -ve 40 0.7 87 39 0.8 75 N -

36 Muniyammal 57/F 4yr + 2yr IV 29% - + -ve 42 0.7 86 45 0.7 86 N -

37 Kuppu 49/F 7yr - 2yr II 53% - + -ve 40 0.7 89 41 0.8 76 N -

38 Kaliyammal 65/F 18yr - 4yr III 41% - +++ -ve 31 0.8 72 40 0.9 63 N -

Acute MI 39 Gnanmmal 48/F 8yr + III 32% ++ +++ +ve 40 0.9 67 60 2.0 27 Normal CRS 1 with HF

40 Anjalidevi 59/F 9yr - 4yr IV 26% - + -ve 40 0.7 86 38 0.8 73 N -

41 Seshammal 50/F 3yr + 1yr II 50% - + -ve 38 0.6 106 41 0.9 66 N -

CMD 42 Amudha 50/F 15yr + 2yr IV 40% + + +ve 46 1.5 38 70 2.2 24 CRS 2 Altered

82

43 Ranjithammal 45/F 10yr - 3yr IV 34% - ++ -ve 45 0.6 105 48 0.8 75 N -

44 Rajammal 52/F 9yr + 2yr IV 27% - + -ve 38 0.8 76 41 0.9 66 N -

45 Muthammal 50/F 1yr - 1yr I 51% - Trace -ve 40 0.9 69 50 1.0 61 N -

46 Sokkammal 42/F 10yr + 3yr III 29% - ++ -ve 38 0.8 75 38 0.9 65 N -

47 Kuppammal 53/F 2yr + 1yr IV 35% - + -ve 40 0.8 73 37 0.6 102 N -

CMD 48 Vijaya 61/F 6yr - 5yr III 29% + ++ +ve 50 2.0 26 65 2.9 17 CRS 2 Lost

49 Govindhammal 51/F 4yr - 1yr III 26% - + -ve 42 0.8 77 36 0.9 67 N -

H.F.N. 50 Shanthi 62/F 18yr + IV 27% + +++ +ve 35 0.8 73 41 1.6 33 Normal CRS 5 Diagnosed

83

RFT URINE R/E PREVIOUS ECHO ECHO FAMIL CARDIA DURATIO Urine AGE/ Y DURATION CKD C BIO Types of S.No NAME N OF Spot USG SEX H/O OF CKD Stages MARKE CSR T2DM PCR DM eGFR RS Urea Cr ml/min/ Alb Sugar D.D S.D D.D S.D mg% mg% 1.73sqm

51 Dhamotharan 42/M 1Year + 3Month 60 2.0 37 III Trace + - K.Echoes ↑ - EF58% - EF58% Negative -

52 Ramachandhiran 61/M 6Year + 2Year 45 2.0 34 III Trace + + K.Size ↑ - EF61% Grade I EF60% Positive CRS 4

53 Egamabaram 70/M 12Year - 2Year 49 2.4 27 IV + ++ + K.Size ↑ - EF62% - EF62% Negative -

54 Sivalingam 46/M 6Year - 1Year 42 1.7 44 III Trace + - K.Echoes ↑ - EF57% - EF57% Negative -

CMD altered 55 Kumaravel 65/M 12Year + 5Year 110 4.2 14 V ++ ++ + - EF62% - EF29% Positive CRS 4 K.Size ↑

56 Sundaramoorthy 54/M 4Year - 1Year 71 2.5 27 IV + + + K.Echoes ↑ - EF58% - EF61% Negative -

57 Godhandan 48/M 2Year - 4Month 40 1.3 59 III Trace + - K.Echoes ↑ - EF57% - EF66% Negative -

K.Echoes ↑ 58 Kanniyappan 42/M 2Year - 1Year 123 5.0 13 V + ++ + - EF68% Grade I EF59% Positive CRS 4 Mild K.Size ↑

59 Venugopal 58/M 3Year + 1year 43 1.3 57 III + + + K.Echoes ↑ - EF65% - EF58% Negative -

60 Govindharaj 49/M 7Year - 2Year 49 1.8 40 III + + + K.Size ↑ - EF60% - EF62% Negative -

61 Ganesan 69/M 8Year + 3Year 98 3.0 21 IV + + + K.Size ↑ - EF70% - EF41% Positive CRS 4

62 Ezhumalai 61/M 8Year + 3Year 47 4.4 14 V ++ + + K.Size ↑ - EF61% - EF57% Negative -

84

CMD altered 63 Francis 43/M 4Year + 2Year 70 3.0 23 IV + + + - EF60% - EF60% Negative - K.Echoes ↑ Newly CMD altered 64 Vadivel 55/M 12Year - 79 2.6 26 IV Trace ++ + - EF57% - EF40% Positive CRS 5 diagnosed K.Echoes ↑

65 Muthu 51/M 11Year - 1Year 61 1.5 49 III + +++ + K.Echoes ↑ - EF62% - EF61% Negative -

66 Shankar 41/M 6Year + 3Year 60 1.5 52 III Trace + - K.Size ↑ - EF60% - EF59% Negative -

67 Palani 59/M 7Year - 4Year 46 2.0 34 III + + + K.Size ↑ - EF62% Grade I EF55% Positive CRS 4

68 Kaliyamoorthy 59/M 13Year - 2Year 49 2.1 32 III + ++ + K.Echoes ↑ - EF56% - EF55% Negative -

69 Chellappan 47/M 4Year + 1Month 51 1.8 41 III + ++ + K.Echoes ↑ - EF64% - EF62% Negative -

Newly CMD Lost 70 Shankar 68/M 15Year + 60 2.4 27 IV + ++ + - EF60% - EF31% Positive CRS 5 diagnosed K.Size ↑

71 Mani 59/M 11Year - 1Year 52 1.4 52 III + + + K.Size ↑ - EF60% - EF65% Negative -

CMD altered 72 Murugadass 72/M 13Year - 8Year 150 4.6 13 V ++ ++ + - EF65% - EF27% Positive CRS 4 K.Size ↑

73 vetrimaran 53/M 7Year - 1Year 40 1.7 42 III Trace + - K.Size ↑ - EF57% - EF67% Negative -

74 Sundhar 66/M 7Year - 5Year 81 4.6 13 V ++ ++ + CMD altered - EF59% - EF59% Negative -

75 Suresh krishna 54/M 9Year + 2Year 56 1.3 58 III Trace ++ - K.Size ↑ - EF64% - EF58% Negative -

76 Atlee 45/M 1Year + 2Month 50 1.9 39 III Trace + - K.Echoes ↑ - EF62% - EF60% Negative -

K.Size ↑ 77 sasikumar 70/M 11Year + 6Year 35 1.7 40 III Trace + + - EF61% Grade I EF66% Positive CRS 4 K.Echoes ↑

78 Sarath 57/M 7Year - 3Month 71 2.6 26 IV + + + K.Echoes ↑ - EF60% - EF61% Negative -

85

79 Valarmarthy 41/F 2Year - 1Month 45 1.3 45 III Trace + - Normal - EF60% - EF55% Negative -

80 Chandra 68/F 13Year + 1Year 59 1.6 32 III + ++ + Normal - EF59% - EF67% Negative -

81 Soroja 49/F 3Year + 1Year 51 2.2 24 IV ++ + + K.Echoes ↑ - EF59% Grade I EF61% Positive CRS 4

K.Size ↑ 82 Devika 55/F 9Year - 2Year 71 2.3 22 IV + + + - EF62% Grade I EF60% Positive CRS 4 K.Echoes ↑

83 Rani 48/F 2Year - 1Year 50 1.6 34 III Trace + - K.Echoes ↑ - EF58% - EF59% Negative -

84 Niramila 67/F 14Year - 3Year 61 2.1 23 IV + ++ + K.Size ↑ - EF59% - EF58% Negative -

85 Kanniyamal 65/F 14Year + 5Year 60 2.0 25 IV + + + K.Size ↑ - EF60% - EF47% Positive CRS 4

86 Anijalatchi 58/F 8Year + 2Year 65 2.4 21 IV + + + K.Size ↑ - EF65% - EF60% Negative -

87 Malliga 49/F 2Year + 5Month 42 1.5 37 III Trace + + K.Size ↑ - EF67% - EF61% Negative -

88 Rajeshwari 45/F 3Year + 7Month 70 2.2 24 IV Trace + - K.Echoes ↑ - EF61% - EF67% Negative -

89 Mala 56/F 7Year + 1Year 57 1.4 39 III + ++ + K.Echoes ↑ - EF65% - EF59% Negative -

90 Jaya 41/F 4Year - 1Year 50 1.5 38 III Trace + - Normal - EF63% - EF58% Negative -

K. Size ↑ CMD 91 Subiradevi 58/F 11Year + 3Year 49 1.6 33 III Trace + + - EF59% Grade I EF59% Positive CRS 4 Altered

92 Malliga 52/F 6Year + 2Year 70 1.6 34 III + + + K.Echoes ↑ - EF62% - EF55% Negative -

93 Laxshmi 46/F 7Year - 1Year 62 1.7 32 III + + + K.Echoes ↑ - EF61% - EF59% Negative -

94 kannammal 63/F 11Year + 3Year 60 2.4 20 IV + +++ + CMD altered - EF59% - EF61% Negative -

86

Newly 95 Maheshwari 56/F 8Year - 40 1.5 36 III Trace + + K.Echoes↑ - EF57% - EF41% Positive CRS 5 diagnosed

96 Jeeva 54/F 8Year - 5 Month 40 1.7 31 III Trace ++ - Normal - EF61% - EF62% Negative -

97 Rani 47/F 3Year - 1Year 80 2.1 25 IV + + + K.Size ↑ - EF61% - EF62% Negative -

98 Dhatchanini 55/F 7Year - 9Month 86 2.5 20 IV + + + Normal - EF60% - EF60% Negative -

99 pravathy 48/F 6Year + 1Year 40 1.6 34 III + + + K.Echoes ↑ - EF61% - EF61% Negative -

K.Size ↑ CMD 100 Sivagami 70/F 14Year - 9Year 99 3.5 13 V ++ +++ + - EF59% - EF35% Positive CRS 4 lost

87