ASSOCIATION BETWEEN SERUM PROLACTIN LEVELS AND

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A DISSERTATION ON

ASSOCIATION BETWEEN SERUM PROLACTIN LEVELS AND

ADVERSE CARDIOVASCULAR EVENTS IN CHRONIC KIDNEY DISEASE PATIENTS

Submitted to

THE TAMILNADU DR. M. G. R. UNIVERSITY CHENNAI

In partial fulfilment of the regulations for the award of

M. D. DEGREE IN GENERAL MEDICINE BRANCH I

GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE, SALEM

MAY 2020

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DECLARATION BY THE CANDIDATE

I hereby declare that this dissertation titled “ASSOCIATION BETWEEN SERUM PROLACTIN LEVEL AND ADVERSE CARDIOVASCULAR EVENTS IN CHRONIC KIDNEY DISEASE PATIENTS” is a bonafide and genuine research work carried out by me under the guidance of Dr.D. VIJAYARAJU, M.D., Professor, Department of General Medicine, Government Mohan Kumaramangalam Medical College Hospital, Salem, Tamil Nadu, India.

Place : Salem Date :

Signature of the Candidate DR.B.SATHEESH KUMAR

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CERTIFICATE FROM THE GUIDE

This is to certify that this dissertation “ASSOCIATION BETWEEN SERUM PROLACTIN LEVEL AND ADVERSE CARDIOVASCULAR EVENTS IN CHRONIC KIDNEY DISEASE PATIENTS” is a bonafide work done by DR.B.SATHEESH KUMAR in partial fulfillment of the requirement for the degree of M. D. in General Medicine, examination to be held in 2020.

Signature of the Guide Dr. D. VIJAYARAJU, M. D.

Department of General Medicine Govt. Mohan Kumaramangalam

Medical College, Salem

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CERTIFICATE FROM THE HOD

This is to certify that this dissertation titled “ASSOCIATION BETWEEN SERUM PROLACTIN LEVEL AND ADVERSE CARDIOVASCULAR EVENTS IN CHRONIC KIDNEY DISEASE PATIENTS” is a bonafide work done by DR. B. SATHEESH KUMAR under overall guidance and supervision of DR.S.SURESHKANNA M.D., Professor & Head of Department of General Medicine, Government Mohan Kumaramangalam Medical College Hospital, in partial fulfillment of the requirement for the degree of M.D. in General Medicine, examination to be held in 2020.

Seal & Signature of the HOD Dr. S. SURESHKANNA, M. D.

Professor and HOD, Department of General Medicine Government Mohan Kumaramangalam

Medical College, Salem

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CERTIFICATE FROM THE DEAN

This is to certify that this dissertation titled “ASSOCIATION BETWEEN SERUM PROLACTIN LEVEL AND ADVERSE CARDIOVASCULAR EVENTS IN CHRONIC KIDNEY DISEASE PATIENTS” is a bonafide work done by DR.B.SATHEESH KUMAR under overall guidance and supervision of DR.S.SURESHKANNAM.D., Professor

& Head of Department of General Medicine, Government Mohan Kumaramangalam Medical College Hospital, in partial fulfillment of the requirement for the degree of M. D. in General Medicine, examination to be held in 2020.

Seal & Signature of the of the Dean DR.K.THIRUMAL BABU M.D DM

THE DEAN

Government Mohan Kumaramangalam Salem, Tamil Nadu, India

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GOVERNMENT MOHAN KUMARAMANGALAM MEDICAL COLLEGE & HOSPITAL

COPYRIGHT

I hereby declare that THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY, CHENNAI, Tamilnadu, India, shall have the rights to preserve, use and disseminate this dissertation/ thesis in print or electronic format for academic / research purpose.

Signature of the Candidate DR. B.SATHEESH KUMAR

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PLAGIARISM CERTIFICATE

This is to certify that this dissertation work titled

“

ASSOCIATION BETWEEN SERUM PROLACTIN LEVEL AND ADVERSE CARDIOVASCULAR EVENTS IN CHRONIC KIDNEY DISEASE PATIENTS” of the candidate DR.B.SATHEESH KUMAR with registration Number 201711407 for the award of M.D. DEGREE in the branch of

GENERAL MEDICINE. 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 10 percentage of plagiarism in the dissertation.

Guide & Supervisor sign with Seal

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PLAGIARISM RESULT

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ACKNOWLEDGEMENT

I owe my thanks to the dean, Government Mohan Kumaramangalam Medical College and Hospital Prof. Dr.K.THIRUMAL BABU, M.D., D.M, for allowing me to avail the facilities needed for my dissertation work.

I am grateful to Prof. Dr.S.SURESH KANNA.M.D., Head of the Department of Medicine, Government Mohan Kumaramangalam Medical College and Hospital for permitting me to do the study and for his encouragement.

I have great pleasure in expressing my deep sense of gratitude and respect for Prof. Dr. D.VIJAYARAJU, M.D., Dept. of Medicine, Government Mohan Kumaramangalam Medical College and Hospital for approving this study and giving suggestions and guidance in preparing this dissertation.

I am extremely thankful to my unit assistant professors Dr.SUDHASELVI M.D, Dr. KARTHIKEYAN M.D, and Dr.

PALANIVELRAJAN. M.D., Registrar, department of medicine for their valuable guidance and constant encouragement.

I wish to acknowledge all those, including my other postgraduate colleagues and my family who have directly or indirectly helped me to complete this work with great success.

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Finally, I thank the patients who participated in the study with their extreme patience and co-operation without whom this project would have been impossible.

Above all, I thank the Lord Almighty for this kindness and benevolence.

Signature of the Candidate DR. B.SATHEESH KUMAR

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ABBREVATIONS

PRL PROLACTIN

GH GROWTH HORMONE

HPL HUMAN PLACENTAL LACTOGEN

cAMP CYCLIC ADENOSINE MONO PHOSPHATE TRH THYROTROPIN RELEASING HORMONE

kDa KILO DALTON

RIA RADIO IMMUNO ASSAY

IRMA IMMUNO RADIO METRIC ASSAY ICMA CHEMI LUMINO METRIC ASSAY NON – REM

SLEEP NON RAPID EYE MOVEMENT SLEEP REM SLEEP RAPID EYE MOVEMENT SLEEP

PRF PROLACTIN RELEASING FACTORS PrRP PROLACTIN RELEASING PEPTIDE

PRL PROLACTIN

CKD CHRONIC KIDNEY DISEASE

CAHD CORONARY ARTERY HEART DISEASE CIMT CAROTID INTIMA MEDIA THICKNESS CVD CARDIOVASCULAR DISEASE

JAK JANUS KINASE

STAT SIGNAL TRANSDUCER AND ACTIVATOR OF

TRANSCRIPTION

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GFR GLOMERULAR FILTRATION RATE VLDL VERY LOW DENSITY LIPOPROTEIN HDL HIGH DENSITY LIPOPROTEIN

LDL LOW DENSITY LIPOPROTEIN ESRD END STAGE RENAL DISEASE 1,25[OH2]D3 1,25,DIHYDROXY VITAMIN D3 LH LUTEINIZING HORMONE

IGF INSULIN LIKE GROWH FACTOR

T4 THYROXINE

T3 TRIIODOTHYRONINE

USG ULTRASONOGRAM

PER PER MILLION POPULATION

AP ANTEROPOSTERIOR

EGFR ESTIMATED GLOMERULAR FILTRATION RATE AER ALBUMIN EXCRETION RATE

ACR ALBUMIN : CREATININE RATIO ESRD END STAGE RENAL DISEASE LP(A) LIPOPROTEIN A

AA AMINOACID

DA DOPAMINE

Ca2+ CALCIUM

VIP VASOCTIVE INTESTINAL PEPTIDE

PIF PROLACTIN INHIBITORY FACTORS

GABA GAMMA AMINO BUTYRIC ACID

TCA TRICYCLIC ANTIDEPRESSANTS

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ABSTRACT BACKGROUND:

Chronic kidney disease is defined as progressive loss in renal function over a period of months or years leading to failure of excretory, metabolic, synthetic functions resulting in accumulation of non protein nitrogenous substances and present with various numbers of clinical manifestations.

Prolactin (PRL) is an anterior pituitary hormone. PRL clearance is evidently reduced in CKD patients and its production is also to an extent altered.

Increased level of serum prolactin is in turn associated with essential hypertension, acute component of coronary syndrome, stroke ischemic variety and also in preeclampsia. Elevated levels of serum prolactin which occurs in CKD can also contribute to vascular dearrangements. This might lead to cardiovascular outcomes among CKD patients.

OBJECTIVE:

To study the correlation between serum prolactin level and the adverse cardiovascular events in Chronic Kidney Disease (CKD) patients.

To identify the association between elevated serum prolactin level and carotid intima media thickness (CIMT) in CKD patients

To determine its prognostic outcome

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MATERIALS AND METHODS:

It was a prospective and analytical study of 50 patients admitted in our hospital with CKD and its complications. The study period was from Feb 2018 to Feb 2019 after informed consent patients were evaluated with laboratory investigations, clinical examination.

INCLUSION CRITERIA:

1) Age: 35-65 years 2) Either sex

3) Known CKD Patients with elevated blood urea creatinine and decreased creatinine clearance

4) USG evidence of CKD

(1) Bilateral contracted kidney size <8cm in males and <7cm in females (2) Poor cortico medullary differentiation

(3) Type 2 or type 3 renal parenchymal changes EXCLUSION CRITERIA:

1. Patient refusal

2. Chronic liver disease 3. Seizure disorder

4. Thyroid disease patients 5. Pregnancy

6. Congenital heart disease, RHD, IF Patients on medications - phenothiazines, haloperidol, TCA, reserpine

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RESULT:

In our study among 50 patients with CKD, 28 had raised serum PRL level (about 56% of study population) and among those 28 patients 17 had raised CIMT (about 60.71%). By statistical analysis T test showed a strong correlation for hyperprolactinemia in CKD patients. Chi-square test showed a significant association between hyperprolactinemia and raised CIMT among patients with CKD. By statistical analysis we also found correlation between raised PRL level in CKD patients and T2DM, dyslipidemia and occurrence of CAHD among them.

CONCLUSION:

Serum prolactin levels are raised in patients with CKD. This hyperprolactinemia in CKD patients is associated with increase in the CIMT and occurrence of adverse cardiovascular events among them.

KEYWORDS: Chronic kidney disease, serum prolactin, CIMT.

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1 INTRODUCTION

Chronic kidney disease refers to the irreversible loss of functions of the kidney which develops over period of years classically. At the initial stages it manifests as a biochemical abnormality only and then occurs the loss of excretory and endocrine and metabolic functions of the kidney which leads to manifestation of symptoms and signs of the renal failure.

CKD is one of the chronic disease prevailing in India with approximate prevalence of about 800 per million population (pmp) and the End Stage Renal Disease (ESRD) is about 150-200 pmp.

In India, a study from South India reported a Prevalence of impaired kidney function (eGFR<80 ml/min) to be 8.6 per 1000 after screening 25000 population.

Prolactin is a hormone which is secreted mainly by the anterior pituitary gland and also it is secreted by various tissues in the body. The main action of prolactin is to control breast development and lactation in women. In Male CKD patients, Hyperprolactinemia is associated with sexual dysfunction.

Hyperprolactinemia is associated with loss of libido. Hyperprolactinemia is associated with impaired erection potency.

High prolactin levels may be implicated for this abnormality. This may contribute to gynaecomastia and sexual dysfunction in male CKD patients.

Hyperprolactinemia in female CKD patients leads to mainly galactorrhoea and gonadal disturbances with irregularities of menstrual cycle commonly amenorrhoea.CKD is characterised by elevation of serum prolactin level and

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2 also clearance of prolactin is reduced in CKD and its production is also altered and the biological activity is also increased. Studies conducted recently shows that the prolactins have several biological actions that participate in the atherosclerotic process and endothelial dysfunction. The Carotid Intima Media Thickness (CIMT) is the early marker for atherosclerosis.

Increased serum prolactin level is also associated with essential hypertension, ischemic stroke, and coronary syndrome acute phase and also in preeclampsia.

Prevalence of hyperprolactinemia in CKD varies from 30%to 65%.

Elevated serum prolactin level which occurs in cases of CKD may contribute to the vascular dearrangements in those cases. This might lead to many numbers of adverse cardiovascular outcomes among CKD patients.

This was undertaken as a clinical and biochemical study of association between serum prolactin level and adverse cardiovascular events in chronic kidney disease patients assessed in the department of Internal Medicine at Government Mohan Kumaramangalam Medical College Hospital, Salem.

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AIM OF THE STUDY

1. To study the correlation between serum prolactin level and adverse cardiovascular events in Chronic Kidney Disease (CKD) patients.

2. To identify the association between elevated serum prolactin level and carotid intima media thickness (CIMT) in CKD patients.

3. To determine its prognostic outcome.

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4 REVIEW OF LITERATURE

HISTORY RELATED TO HUMAN KIDNEY

1. In 2^nd century, Charaka explained about the varieties of the prameha or urinary tract infections.

2. Hippocrates diagnosed certain affections of the kidney by means of urine examinations and gave description about renal disease.

3. In the year of 1840 Jacob Henle explained about the urinary casts and it’s a significance.

4. The term UREMIA a feature of CKD was coined by Piorry P.A. in the year of 1847 which is the primary abnormality in renal insufficiency.

5. Frederick Wohler synthesised urea in the year of 1882

6.

Franz Volhard introduced the specific gravity concentration test in the year of 1918 into clinical work.

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5 ANATOMY OF HUMAN KIDNEY

The kidneys are reddish brown in fresh state and situated posteriorly in the peritoneum on both sides of the vertebral column.

Size: Length : 11 cm Breadth : 06 cm AP dimension : 03 cm

The average weight of kidney in men is 150 g and in women it’s about 135 g.

In newborns, there are 12 lobules in the kidney and in adults these are fused and form a smooth surface.

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SURFACE ANATOMY OF HUMAN KIDNEY

ANTERIOR POSTERIOR

Superior poles of both the kidneys are protected by 11^th and 12^th ribs The kidneys extends from T12 to L3 vertebral bodies Right side kidney just below transpyloric plane, 5cm to the right of the midline. Inferior pole is about a finger width superior to the right iliac crest. Left side kidney just above transpyloric plane, 5cm left to the midline.

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STRUCTURE AND FUNCTIONS OF THE NEPHRON

Nephron is the structural unit of the kidney and also

functional unit.

There are 0.8 to 1.5 million nephrons in the kidneys of a healthy adult.

Mechanisms used by the nephrons to process the filtrate includes filtration, reabsorption, secretion and finally excretion.

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The above picture gives an outline about the following in the kidney.

1. Structures in cortex and medulla

2. position of cortical and juxta medullary nephron

3.

major blood vessels

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FUNCTIONS OF THE KIDNEY

The main function of the kidneys is the excretion of waste products derived from metabolism, toxic substances and some drugs.

Kidneys do perform several other important functions which are essential in maintaining normal homeostasis. These are

1. Maintenance of fluid and electrolyte balance 2. Maintenance of acid-base balance.

3. Maintenance of normal BP by means of renin-angiotensin system 4. Endocrine functions.

a. Kidney converts 25(0H)₂ D3 molecule to 1, 25(OH)₂ D3.

b. Erythropoietin production also takes place in kidney.

c. Synthesis of prostaglandins which play an important role in renal auto regulation of blood flow.

5. Ammonia formation which plays an important role in maintaining acid base balance.

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10 CHRONIC KIDNEY DISEASE

Chronic Kidney Disease (CKD) is defined as damage of the kidney for more than a period of 3 months structurally and functionally with or without decreased GFR

Manifestations might include

1. Abnormalities pathologically

2. Abnormalities in composition of blood 3. Abnormality in imaging tests in urine

GFR < 60ml/min/1.73m2 for period of 3 months with or without presence of kidney damage.

Among patients with CKD the stage of disease should be assigned based on the level of kidney function, irrespective of diagnosis according to the KDOQI CKD classification.

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HISTOLOGICAL PROGRESSION OF CKD

On histological examination of biopsy from the CKD patient microscopic view shows

a) Fibrotic cortex b) Sclerotic glomeruli

c) Scattered chronic inflammatory cells infiltrates d) Thickened arteries

e) Dilated tubules filled with casts ( thyroidization appearance)

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ESTIMATED GLOERULAR FILTRATION RATE

EGFR is the best test used to measure the level of kidney function and to determine the stage of kidney disease

GFR is calculated using Cockcroft and Gault formula

Chronic renal failure may be symptomatic or asymptomatic and around 80% of the renal function will be lost before reaching the stage of renal failure. GFR usually would fall to about 40 ml / min even before creatinine or nitrogen levels raise.

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STAGES

OF CHRONIC KIDNEY DISEASE

Chronic Kidney Disease is mainly classified into 5 stages based on the glomerular filtration rate of the patients.

Stage Description GFR ml/min /1.73m² 1 Kidney damage with normal GFR or raised

GFR

> 90

2 Kidney damage with mild or decreased GFR 60-89

3 Moderate decrease in GFR 30-59

4 Severe decrease in GFR 15-29

5 Established Renal Failure <15(or dialysis )

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BASED ON GFR AND ACR CATEGORIES

Green indicates low risk Yellow moderate increased risk Orange high risk Red very high risk

GFR – Glomerumar Filtration Rate AER – Albumin Excretion Rate ACR - Albumin to Creatinine Ratio

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15 AETIOLOGY OF CHRONIC KIDNEY DISEASE

Among the developing countries, Primary glomerulonephritis is the common cause of CRF, whereas diabetic glomerulosclerosis is evolving as the most common cause of CRF in developed countries where life expectancy of diabetics has increased considerably as a result of better diabetic care

Hypertensive and diabetic nephropathy are the foremost underlying causes of both Chronic Renal Disease and ESRD. Important causes of chronic renal failure includes

1.

Primary glomerulonephritis

2.

Secondary glomerulopathy –systemic disease

3.

Interstitial renal disease

4.

Hypertensive renal disease

5.

Obstructive nephropathy

6.

Hereditary / familial renal diseases

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16 PATHOPHYSIOLOGY OF CKD

In CRF patients the number of nephrons goes on diminishing with progression of time. As the stages progress even a single nephron undergoes adaptation and compensatory hypertrophy to maintain the function. At this stage GFR can be maintained to normal limit.

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Clinical Features

Fluid and electrolyte disturbances Volume expansion

Hyponatremia, Hyperkalaemia, Hyperphosphatemia Endocrine - Metabolic disturbances

Secondary hyperparathyroidism Vit. D deficient osteomalacia

Hyperuricemia, Hypertriglyceridemia

Neuromuscular Disturbances

Peripheral neuropathy, Restless leg syndrome, Myoclonus, Seizures, Sleep disorders, Headache, Impaired mentation Cardiovascular and pulmonary complication

Arterial hypertension

Hypertrophic or dilated cardiomyopathy Congestive heart failure

Accelerated atherosclerosis Vascular calcification Dermatologic Disturbances

Pruritus, Fibrosing dermopathy

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HOW TO DIAGNOSE CKD

COMPLICATIONS OF CKD

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APPROACH IN MANAGEMENT OF CKD

Treatment aimed at a specific cause

Look for acute on chronic renal failure and treat

Slowing progression

Management of complications

Preparation of renal replacement therapy

Renal replacement therapy

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MANAGEMENT OF CKD

a) Life style modifications b) Protein restriction c) low salt

d) Strict glycemic control in diabetics (HbA1c < 7%) e) Strict control of hypertension

f) Correction of anemia g) Lipid lowering therapy

h) Control of serum phosphorous, vitamin D, PTH i) Volume overload control

j) Management of hyperkalemia, metabolic acidosis, uremic bleeding if any k) Beta blockers and aspirin for cardio protection

l) ACE inhibitors / angiotensin receptor antagonist for proteinuria m) supplements

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PROLACTIN

Prolactin (PRL) is a poly peptide hormone which contains about 198 amino acid and the molecular weight of PRL is about 22000. It is synthesized in the pituitary gland by the lactotroph cells. These cells are also called as mammotrophs. Among the mass of the pituitary these lactotrophs contribute about 15-20%.

STRUCTURE OF PROLACTIN

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PROLACTIN GENE

Prolactin gene is located on chromosome 6 in th humans. Whereas chromosome 17 contains genes related to the Growth hormone and human placental lactogen ( also called as human chorionic somatomammotrophin).

There are many number of factors which are involved in transcription of

prolactin gene. Transcription of prolactin gene is directly supported by estrogen hormone.

PROLACTIN BIOCHEMICAL STRUCTURE

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PROLACTIN HORMONE BIOSYNTHESIS

Despite the evolution from an ancestral hormone common to Growth Hormone (GH) and human placental lactogen [Hpl], PRL shares around 16% of its residues with the GH and 13% with later. The primary translation product of the human prolactin gene is 227 amino acids in length, consisting of around 28 amino acid which is a signal peptide and 199 amino acid hormone with a molecular mass of about 23 kDa.

The Prolactin molecule has 3 disulfide bonds in it. This features in folding of the molecule of prolactin. The Prolactin molecule in turn undergoes many number of post translational modifications. These modifications includes cleavage, polymerization, glycosylation, phosphorylation and finally degradation. Thus the final molecule of Prolactin is variable depending up on the degree of the post translational modifications. Thus different assays used for the prolactin measurement gives various number of results because of this prolactin molecule’s post translational modification.

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COMPARISON OF GH AND PRL AA STRUCTURE

FORMS OF PROLACTIN HORMONE

There are 2 forms of prolactin hormone available to study which includes the following

1. Glycosylated form 2. Phosphorylated form PROLACTIN SYNTHESIS:

The synthesis of prolactin occurs in the following organs and tissues a) Pituitary b) Deciduas c) Myometrium d) Breast e) Lymphocytes f) Leukocytes f) Prostate

AXIS OF PROLACTIN HORMONE

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STRUCTURE OF PITUTARY

PROLACTIN SYNTHESIS AND RELEASE

Following synthesis of prolactin on rough endoplasmic reticulum, PRL hormone is packaged in to secretory granules in the Golgi apparatus and PRL release occurs via exocytosis.

The above illustration diagram depicts about the process and various number of steps involved in the synthesis and release of the prolactin hormone

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26 SITES OF EXTRAPITUTARY PROLACTIN PRODUCTION

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27 PROLACTIN RELEASING PEPTIDE (PrRP)

PrRP a new ligand has been identified by using the arachidonic acid metabolite releasing assay. It contain 2 peptides 31 AA residue (PrRP31) and its amino terminally truncated from (PrRP20) were isolated from bovine hypothalamic extract. PrRP31stimulates the release of PRL in a dose dependent Manner which was verified by carrying out an assay.

Prolactin releasing activity been reported for other peptides including TRH, VIP, PACAP, oxytocin, vasopressin and others. PrRP is the real peptide and cannot mimic release of other pituitary hormones.

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NEUROENDOCRINE REGULATION

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PHYSIOLOGY

PATTERN OF PROLACTIN SECRETION:

Pituitary gland secretes the PRL hormone in a pulsatile manner. The main interval between each pulse of Prolactin hormone secretion is around 8 minutes.

Prolactin secretion & sleep:

Prolactin is secreted in a pulsatile manner 60-90 minutes after the onset of sleep. The amount increases with non – REM sleep. This fall prior to the next REM sleep. PRL level falls to the lower level during non – REM sleep.

The diurnal variation in prolactin secretion is maintained with the occurrence of the sleep.

Prolactin secretion & menstrual cycle^:

During mid – cycle period, PRL seems to be raised. These studies have also shown lower levels during follicular phase compared to luteal phase.

Prolactin secretion & Pregnancy^:

Prolactin levels increase during pregnancy progressively because of estrogen hormone. This stimulates the prolactin hormone production from pituitary.

Prolactin & Lactation^:

Suckling from new born stimulates the release of prolactin hormone from pituitary .Prolactin levels return to baseline over few months gradually.

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30 Prolactin & Thyroid hormones

Thyroid hormones act on the lactotroph cells and decrease the production and release of prolactin subsequently. Serum levels of prolactin hormone are mildly elevated in hypothyroidism.

24hrs VARIATION IN PROLACTIN SECRETION IN ADULTS:

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PROLACTIN SECRETION IN WOMEN

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32 FUNCTIONS OF PROLACTIN

a) Initiation and maintenance of lactation

b) Induce ductal growth and lobular alveolar system c) Synthesis of milk protein like casein and lactalbumin d) Control of osmolality

e) Metabolism of subcutaneous fat, carbohydrate, calcium and vitamin D f) Fetal lung development

g) Steriodogenesis

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FACTORS REGULATING PROLACTIN

INHIBITORY FACTORS:

1. Dopamine

2. Gonadotropin associated peptide 3. Gamma amino butyric acid 4. Somatostatin

5. Bromocriptine, metoclopramide

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RELEASING FACTORS

1. Thyrotropin Releasing Hormone [TRH]

2. Vasoactive Intestinal Peptide [VIP]

3. Peptide histidyl methionine 4. Serotonin

5. Opiod peptides

6. Growth hormone releasing hormone 7. Oxytocin

8. Vasopressin

9. Gonadoropin releasing hormone 10. PrRP

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NORMAL RANGES OF PROLACTIN LEVEL

INDIVIDUAL

NORMAL LEVEL OF PRL Normal menstruating females 2.8 – 29.2 ng/ml

Pregnant women 9.7 – 208.5 ng/ml

Post menopausal women 1.8 – 20.3 ng/ml

Men 2.1 – 17.7 ng/ml

MEASUREMENT OF PROLACTIN

RADIO IMMUNO ASSAY [RIA]: double antibody Assay used to study prolactin level

CHEMILUMINOMETRIC ASSAY[ICMA]

IMMUNO RADIO METRIC ASSAY [IRMA]

BIOASSAY

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36 PATHOLOGICAL STATES IN SECRETION OF PROLACTIN

There are totally 2 states which includes 1. Decreased level – Hypoprolactinemia 2. Increased level – Hyperprolactinemia

HYPOPROLACTINEMIA

It is nothing but the decreased serum levels of prolactin which can occur in the following conditions

a) Sheehan’s syndrome b) Craniopharyngioma c)Idiopathic HYPERPROLACTINEMIA

a) Prolactin secreting tumors b)Acromegaly c)Hypothyroidism d) Chronic renal failure e) Polycystic ovary f) Galactorrhea g) Adrenal insufficiency h) Anorexia nervosa i) Amenorrhea These are the states where prolactin level rises high. Some other conditions are listed in the table

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HYPERPROLACTINEMIA IN CKD:

Elevated levels of serum prolactin is found in the patients of chronic kidney disease .Both the male and female cases with chronic kidney disease have shown to have elevated levels of serum prolactin. The following mechanisms were proposed for this increase in the levels of serum prolactin seen in the patients presented with chronic kidney disease. There is evidence of decrease in the elimination of Prolactin hormone in patients with chronic renal failure. The metabolism of prolactin hormone is reduced in patients with CKD.

Some recent evidences are arising that production of PRL is increased in patients with chronic disease of kidney. So overall there is a disordered regulation of PRL synthesis and disordered elimination in patients with chronic disease of the kidney. But in turn exact mechanism behind tis elevation in serum prolactin levels in patients with chronic disease of kidney is yet to be identified by the studies. Transplantation of kidney for patients with chronic kidney disease gets back the levels of prolactin to normal in these CKD patients. Whatever the alterations which are responsible for the impairment of PRL regulation in cases presented with uremia, these are reversed by means of successful renal transplantation.

The rise in serum PRL levels which is seen in patients with chronic kidney disease is one of the major causative factor for the incidence of hypogonadism, decrease in libido and dysfunction of sexual functions among male CKD patients. In female CKD patients, the rise in serum prolactin levels lead to menstrual irregularities, decreased libido, and orgasmic dysfunction.

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38

MULTISYSTEM INVOLVEMENT IN CKD

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39 RISK FACTORS FOR CARDIOVASCULAR DISEASE IN CKD:

There are numerous number of risk factors listed for the cardiovascular disease which occurs in a CKD patient further can be classified into

1. Traditional risk factors 2. Uremia related risk factors TRADITIONAL RISK FACTORS

a) Age b) Male sex c) Hypertension d) Smoking e) Diabetes f) Dyslipidemia h) Left ventricular hypertrophy UREMIA RELATED RISK FACTORS

a) Uremic toxins b) Adipokine imbalance c) Insulin resistance e) Protein energy wasting f) Subclinical hypothyroidism

g) Sympathetic activation h) Uremic bone disease i) Volume overload j) Genetics / epigenetics

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40 PATHOPHYSIOLOGICAL INTERACTION OF KIDNEY AND

HEART IN CKD

Increased risk of disease of cardiovascular system in individuals with CKD is because prevalence of risk factors (traditional), such as hypertension and diabetes are high. The Associations of function of kidney and albuminuria with cardiovascular risk are somehow independent of those traditional risk factors. Thus, nontraditional mechanisms which are specific to the kidney make plays contributions to the cardiovascular disease. Evaluation of these mechanisms could possibly reveal ways to decrease the cardiovascular risk in individuals with chronic kidney disease. There are many research studies but the main therapeutic way, those leading to specific therapies for CKD is yet to be discovered.

For development of CKD, hypertension contributes to be a risk factor. The cause and effect association can be in opposite direction also. In the early phases CKD can cause hypertension, which is more likely to increase the risk of cardiovascular disease in affected patients.

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41

There are multiple number of factors and enzymes in the patho-physiological interaction of cardiovascular and renal system in CKD patients resulting in cardiovascular mortality which is explained above in a flowchart manner.

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42 Expression of the endothelial enzyme nitric-oxide synthase is also down regulated in CKD patients, which implies possible mechanism for the dysfunction of the coronary endothelium in the early stages of chronic kidney disease.

Dyslipidaemia and inflammation low grade variety are also caused by CKD. In many cases with impaired function of kidney and albuminuria, lipid profiles turned atherogenic, owing to the defective function of HDL cholesterol and excessive oxidation of the LDL cholesterol. Mechanisms of the increase in the systemic inflammation in CKD are unclear, but increase in the production of inflammatory mediators were attributed to the raised amount of oxidative stress and accumulation of proteins which are post synthetically modified and some amount of toxins that are cleared by means of normal renal function.

Bioavailability of molecule nitric oxide, which is involved in the contraction of vascular smooth-muscle and growth, Aggregation of platelets, and adhesion of leucocytes to the endothelium, were decreased. Activity of enzyme renalase is lowered in patients with chronic kidney disease. Renalase enzyme is produced by the organ kidney and inactivates the catecholamines. All these vasoactive factors were involved in endothelial function. Albuminuria is taken as a sign of and as a contributor to, impaired function of endothelium.

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43

Atherosclerosis and the valvular heart disease are seen in patients with kidney failure, but they can occur in those with early stages of chronic kidney disease also. The key modulators in this section have not been evaluated in the intervention trials, but might include calcification inhibitors for example fetuin- A and Gla matrix protein, promotors (hyperphosphatemia), and calcium and phosphate complex, leptin and also parathyroid hormone.

(66)

44

CAROTID ARTERY

Common carotid artery arises from the aorta directly on the left side and on the right side as branch of the brachiocephalic trunk.

These in turn divides into external and internal branches at the level of thyroid cartilage and near to C4 vertebra.

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45

STRUCTURE OF ARTERY AND VEIN

There are three layers in the human arteries which include 1. Tunica externa / Tunica adventitia 2. Tunica media

3. Tunica intima

CAROTID INTIMA MEDIA THICKNESS (CIMT) IN CKD PATIENTS Many number of factors contribute to the atherosclerotic disease of cardio vascular system. Few of them include hypertension and hyperlipidemia and insulin resistance. Among these insulin resistance is seen among some patients. Increase in the carotid intima media thickness (CIMT) because of the

(68)

46 calcification and atherosclerotic change which occurs in CKD patients lies as the important predictor for the cardiovascular morbidity and mortality in CKD cases.

Measurement of CIMT of the CCA by means of ultra-sonogram in B- mode been found to be one of the suitable method to visualize the arterial walls noninvasively and to monitor the atherosclerotic process in early stages.

Measurement of CIMT also helps in decision making clinically as the best method of treatment, either surgical or medical in those cases with stenosis of carotid artery and is useful to assess the effects of medical therapies in atherosclerosis.

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47

CIMT can be used with no adverse effects repeatedly for detection of the atherosclerotic changes in CKD patients for the evaluation of cardiovascular risk. It allows one to observe the arterial wall and also the actual site of atherosclerotic change and the main factor is it is not calcification of the plaque dependent.

Calcification probably affects the media of the arteries, atherosclerotic plaques, myocardium, and also heart valves. This calcification causes stiffness of arteries and consequently increase in the pulse pressure. In patients with CKD, calcification of coronary vasculature is very common. This calcification of coronary arteries predicts the risk of adverse cardiovascular events among patients with chronic kidney disease.

Chronic kidney Disease per se is now taken as an independent risk factor for occurrence of adverse cardiovascular events and increased CIMT.

(70)

48 The following factors contributes for this increase in the risk of increased CIMT among those patients with CKD

1. Oxidative stress 2. Inflammation

3. Vascular calcification 3. Advanced glycation end products

In addition to the above several retention of uremic solutes may have properties of proatherogeneity. Finally healthy kidneys produce substances which inhibits CVD and thermogenesis, like enzyme renalase, a soluble monoamine oxidase which regulates the cardiac function and blood pressure of an individual. In end stages of CKD, very low plasma concentrations of this inhibitor of the nervous system (sympathetic) contributes to the sympathetic over activity.

NORMAL CIMT INCREASED CIMT

The normal CIMT which is evaluated by means of using B mode USG in an adult is around 0.74 mm with deviation of about 0.14 mm.

Increase in CIMT measures 1 mm or above or presence of plaque in CCA is considered abnormal. Coronary Artery Disease which is characterized by the critical stenosis of the coronary arteries is highly prevalent in the

Chronic Kidney Disease patients which can be diagnosed by means of the increase in the Carotid Intima Media Thickness (CIMT).

(71)

49 HYPERPROLACTINEMIA IN CKD PATIENTS & RISK OF

INCREASE IN CIMT

Chronic kidney disease is linked with inflammatory states in a chronic manner. This state of chronic inflammation leads these patients to the increase in risk of atherosclerosis and CAHD. Recent conducted studies states that Prolactin plays a role in the process of atherosclerosis. Hyperprolactinemia is mostly seen in patients presenting with essential hypertension.

Hyperprolactinemia manifests in patients in the acute phase of coronary syndrome. During the episodes of ischemic stroke also hyperprolactinemia manifests. Increased serum levels of prolactin are found in men with erectile dysfunction. This increase in serum prolactin level helps in predicting the increased cardiovascular risk among them. Increased serum levels of prolactin hormone found in patients with preeclampsia and they play a role in the failure of heart that accompanies cardiomyopathy (post-partum). In some recent studies receptors for Prolactin were found to be present in atherosclerotic plaques and these receptors were found to be mostly situated in the macrophages at sites of highly prominent inflammation.

(72)

50 So Hyperprolactinemia in patients with CKD may be a factor of contribution for the enhanced inflammation seen in patients of CKD.

Hyperprolactinemia in CKD patients contributes to the dysfunction of endothelium. Hyperprolactinemia in CKD may contribute to increase in the probability of atherogenesis .It may be a contributing factor for vascular derangements seen in CKD patients. Hyperprolactinemia may be a factor of causation for the increase in CIMT and adverse cardio vascular outcome in patients with CKD.

(73)

51

MATERIALS AND METHODOLOGY

The study was conducted in 50 patients with chronic kidney disease. All the patients were on Conservative line of management.

The study was conducted in patients admitted in Govt. Mohan Kumaramangalam Medical college Hospital, Salem from February 2018 to February 2019.

The patients who fulfill the criteria for being diagnosed as CKD and who were on Conservative line of treatment were taken in to this study. The patients were evaluated with B-mode ultrasonography for CIMT measurement, ECG and ECHO for presence of Coronary Artery Heart Disease and fasting serum prolactin level was measured in them to assess the presence of hyperprolactinemia.

INCLUSION CRITERIA:

Patients presented with established Chronic Kidney Disease Symptoms of uraemia for 3 months or more than that.

Elevated levels of blood urea, serum creatinine and decrease in Ultrasound evidence for Chronic Kidney Disease:

Bilateral contracted kidney – size less than 8 cm in case of male and less than 7cm in case of females.

Poor cortico medullary differentiation Type II or III Renal Parenchymal changes.

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52 EXCLUSION CRITERIA

a) Patient refusal

b) Patients with Chronic liver disease, seizure disorder, thyroid disorder patients c) Patients with Congenital, Rheumatic and Ishcemic Heart disease

d) Pregnancy

e) Patients on drugs like Phenothiazines, Haloperidol, Tricyclic antidepressants, Opiod or cocaine abuse, ACE inhibitors and Reserpine

In detail clinical history and examination were collected in all diagnosed CKD patients. And also Height and weight and Blood pressure of all those patients were recorded.

The following investigations were performed in the cases

Complete Blood Count Peripheral Smear Study Erythrocyte sedimentation rate Blood Urea Nitrogen Serum Creatinine

Lipid profile

Urine analysis Electrocardiogram

Echocardiogram USG abdomen and pelvis

Fasting serum prolactin level CIMT

After selecting the appropriate patients, about 5 ml of blood is collected as sample in non – heparinized bottle and sent for serum prolactin measurement and calculation.

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53

The Quantitative determination of Serum Prolactin level was done by means of Fully Automated Bidirectional Interfaced Chemo Luminescent Immune Assay.

Reference range of serum PRL :

INDIVIDUAL NORMAL LEVEL - PRL Normal menstruating females 2.8 – 29.2 ng/ml

Pregnant women

9.7 – 208.5 ng/ml

Post-menopausal women 1.8 – 20.3 ng/ml

Men 2.1 – 17.7 ng/ml

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54

RESULTS AND OBSERVATIONS

A total of 50 Patients with Chronic Kidney Disease who were on conservative line of treatment were studied.

Among 50 patients 34 patients were male patients and 16 patients were female patients.

Particulars f Respondents (n=50) Percantaage (100 %)

Male 34 68.0

Female 16 32.0

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55

AGE DISTRIBUTION

The patients of chronic kidney disease, in my study were between 35 years to 65 years. Among 50 patients with chronic kidney disease , 7 patients were between 35 - 40 years of age , 13 patients were in the age group of 41-50 years, 20 patients were in the age group of 51-60 years , 10 patients were 61 years and above.

Particulars Respondents (n=50) Percentage (100%)

35 to 40 yrs 7 14

41 to 50 yrs 13 26

51 to 60 yrs 20 40

61 to 65 yrs 10 20

(78)

56

OBSERVATION REGARDING CHRONIC KIDNEY DISEASE IN THIS STUDY

The duration of Chronic Kidney Disease in this study varied from 2 to 8 years.

The creatinine clearance varied from 1.32-32.96.Among the 50 CKD patients 30 had creatinine clearance <15 ml/min, 19 patients had creatinine clearance 15-30 ml/min, 1 patient had creatinine clearance in the range of 30- 60ml/min.

Creatinine

clearance ml/min

CKD Stage Number of .Respondents

Percentage

30-60 III 1 2

15-30 IV 19 38

<15 V 30 60

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57

BLOOD UREA LEVEL DISTRIBUTION

Among the 50 patients with CKD Blood urea values varied from 60 mg/dl to 199 mg/dl.

Blood Urea[mg/dl] Number of.Patients Percentage (100%)

60-80 12 24

80-100 12 24

100-120 11 22

120-140 4 8

>140 11 22

(80)

58

SERUM CREATININE VALUES

Among the CKD patients serum creatinine values varied between 2.0 mg/dl to 16.2 mg/dl.

Sr. Creatinine level No. of .Patients Percentage

<5 23 46

5-10 18 36

10-15 7 14

15-20 2 4

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59

SYSTEMIC HYPERTENSION

JNC 7 classification

CATEGORY SYSTOLIC BLOOD

PRESSURE mmHg

DIASTOLIC BLOOD PRESSURE mmHg

Normal <120 <80

Prehypertension 120-139 80-89

Stage I 140-159 90-99

Stage II >160 >100

In the 50 chronic kidney disease patients studied all of them were found to be patients of systemic hypertension.

Particulars Number of respondents (n=50) Percentage (100%)

Present 50 100.0

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60

TYPE 2 DIABETES MELLITUS

Among the 50 CKD patients studied 19 patients were found to be present with T2 Diabetes mellitus.

Particulars No. of respondents (n=50) Percentage (100%)

Absent 31 62.0

Present 19 38.0

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61

DYSLIPIDEMIAS

Among the 50 CKD patients Dyslipidemias were detected in 25 patients.

Particulars respondents (n=50) ercentage (100%)

Absent 25 50

Present 25 50

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62 USG EVIDENCE FOR CHRONIC KIDNEY DISEASE

Ultrasound features of following were taken as evidence for chronic kidney disease

A] Bilateral contracted kidneys: Size < 8cm in male & < 7 cm in female.

B] Poor corticomedullary differentiation.

C] Type II or III Renal parenchymal changes.

All 50 patients in the study had evidence of CKD in USG Abdomen

Particulars Respondents (n=50) Percentage (100 %)

Present 50 100.0

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63

ECG EVIDENCE FOR PRESENCE OF CAHD

Among the 50 patients who were part of this study 18 patients were found to have evidence of coronary artery heart disease in ECG.

Particulars Number of respondents (n=50)

Percentage (100%)

Absent 31 62.0

Present 19 38.0

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64

ECHO EVIDENCE FOR CAHD

The following features on ECHO by M – Mode and 2 – D Echo were taken as indicative of CAHD:

A] Abnormal systolic wall motion.

B] Systolic wall thickening

C] Segmental wall motion abnormalities D] Ejection fraction < 55%

Among the 50 patients who were part of this study 18 patients had echocardiographic evidence of coronary artery heart disease.

Particulars No. of respondents (n=50)

Absent 31 62.0

Present 19 38.0

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65

SERUM PROLACTIN

Serum prolactin level was measured for the 50 patients with chronic kidney disease using fully Automated Bidirectionally Interfaced Chemi luminescent Immuno Assay [C.L.I.A].

Among the 50 CKD patients 28 patients had raised serum prolactin levels.

Positive 28 56.0

Negative 22 44.0

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66

CIMT

CIMT was measured for the 50 patients with chronic kidney disease using B mode ultrasonography.

Among the 50 CKD patients 18 patients had increased CIMT.

Positive 18 36.0

Negative 32 64.0

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67

DESCRIPTIVE STATISTICS

Upon summarizing the study of 50 CKD patients following data could be obtained.

Item Min. Max. Mean S.D

Age 35 65 52.66 9.09947

Symptom Duration 2 10 5.84 2.01382

Urea 60 199 108.72 34.0102

Creatinine 2 16 6.736 3.8466

Creatinine Clearance ml /mm 1.32 32.96 12.949 7.8150 Serum Prolactin (ng / ml) 4.32 76.80 25.119 17.1080

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68

SIGNIFICANCE OF ASSOCIATION BETWEEN SERUM PROLACTIN LEVELS AND AGE DISTRIBUTION OF PATIENTS WITH CKD CHI-SQUARE TEST, SERUM PRL (ng/ml) - AGE

Age Positive Negative Total Statistical inference (n=28) (100%) (n=22) (100%) (n=50) (100%)

35 to40 yrs 4 14.2% 3 13.6% 7 14.0% X²=1.3188 .7246>0.05 Not Significant 41 to 50 yrs 6 21.4% 7 31.8% 13 26.0%

51 to 60 yrs 13 46.4% 7 31.8% 20 40.0%

61 to 65 yrs

5 17.8% 5 22.7% 10 20.0%

From statistical analysis serum prolactin levels did not show any significant association with age of the CKD patients.

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69 SIGNIFICANCE OF ASSOCIATION BETWEEN SEX OF THE CKD

PATIENTS AND SERUM PROLACTIN LEVELS

CHI – SQUARE TEST, SERUM PROLACTIN (ng / ml) - SEX

Sex Positive Negative Total Statistical inference (n=28) (100%) (n=22) (100%) (n=50) (100%)

Male 17 60.7% 17 77.27% 46 68.0% X²=.1.5524 .2127>0.05 Not Significant

Female 11 39.3% 5 22.72% 4 32.0%

From the statistical analysis of above data there is no significant association between serum prolactin levels and sex of the CKD

patients.

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70 SIGNIFICANCE OF ASSOCIATION BETWEEN CKD PATIENTS WITH SYSTEMIC HYPERTENSION AND INCREASED SERUM

PROLACTIN LEVELS

CHI – SQUARE TEST, SERUM PROLACTIN (ng / ml) - SHT

SHT Positive Negative Total

Statistical inference (n=28) (100%) (n=22) (100%) (n=50) (100%)

Present 28 56% 22 44.0% 50 100% -

No statistically significant association could be found between the CKD patients with systemic hypertension and increased serum prolactin levels.

(93)

71 SIGNIFICANCE OF ASSOCIATION BETWEEN DIABETIC PATIENTS WITH CHRONIC KIDNEY DISEASE AND INCREASED

SERUM PROLACTIN LEVELS

CHI – SQUARE TEST, SERUM PROLACTIN (ng / ml) - T2DM

T2 DM Positive Negative Total

Statistical inference (n=28) (100%) (n=22) (100%) (n=50) (100%)

Absent 14 50% 17 77.27% 31 62.0%

2=3.8895 .0485 >0.05

Significant Present 14 50% 5 22.72% 19 38.0%

Statistically significant association could be established between the chronic kidney disease patients with T2 diabetes mellitus and increased serum prolactin levels.

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72 SIGNIFICANCE OF ASSOCIATION BETWEEN DYSLIPIDEMIA IN CKD PATIENTS AND INCREASED SERUM PROLACTIN LEVELS

CHI – SQUARE TEST, SERUM PROLACTIN (ng / ml) – DLM

DLM Hyperprolctinemia Positive

Hyperprolactinemia

Negative Total Statistical inference (n=28) (100%) (n=22) (100%) (n=50) (100%)

Absent 11 39.28% 15 68.18% 26 52.0% X²=4.1214 .0.0423>0.05 Significant

Present 17 60.71% 7 31.81% 24 48.0%

Statistically significant association could be drawn between dyslipidemia in CKD patients and raised serum PRL levels.

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73

SIGNIFICANCE OF ASSOCIATION BETWEEN CHRONIC KIDNEY DISEASE AND INCREASED SERUM PROLACTIN LEVELS

T- TEST, SERUM PROLACTIN – Chronic Kidney Disease

Hyperprolactinemia Mean S.D Statistical inference Positive (n=28) 37.3582 12.7716 T=9.7535

Df=48 .0001<0.05 Significant Negative (n=22) 9.5418 4.391

According to Statistical analysis of data using T – Test there is a significant association between increased serum prolactin levels and presence of Chronic Kidney Disease.

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74 SIGNIFICANCE OF ASSOCIATION BETWEEN SERUM PROLACTIN LEVELS AND CORONARY ARTERY HEART DISEASE USING ECG

CHI – SQUARE TEST, SERUM PROLACTIN (ng / ml) – ECG FOR CAHD EVIDENCE

ECG Positive Negative Total Statistical inference (n=28) (100%) (n=22) (100%) (n=50) (100%)

Absent 10 35.71% 21 95.5% 31 62.0% X²=18.662 .000<0.05 Significant Present 18 64.28% 1 4.5% 19 38.0%

According to the statistical analysis there was a significant association between increased serum prolactin levels and ECG evidence of CAHD

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75

ECHO EVIDENCE FOR CAHD

CHI – SQUARE TEST, SERUM PROLACTIN (ng / ml) – ECHO FOR CAHD EVIDENCE

ECHO Positive Negative Total Statistical inference (n=28) (100%) (n=22) (100%) (n=50) (100%)

Absent 10 35.71% 21 95.5% 31 62.0% X²=18.662 .000<0.05 Significant Present 18 64.28% 1 4.5% 19 38.0%

According to the statistical analysis there was a significant association between increased serum levels of prolactin and ECHO evidence of CAHD.

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76

SIGNIFICANCE OF ASSOCIATION BETWEEN SERUM PROLACTIN LEVELS AND INCREASED CIMT IN CKD PATIENTS

CHI – SQUARE TEST, SERUM PROLACTIN (ng / ml) – CIMT

CIMT Positive Negative Total Statistical inference (n=28) (100%) (n=22) (100%) (n=50) (100%)

Absent 11 39.2% 21 95.5% 32 64.0% X²=16.870 Df=1 .000<0.05 Significant

Present 17 60.7% 1 4.5% 18 36.0%

According to the statistical analysis there was a significant association between increased serum prolactin levels and increased CIMT in CKD patients.

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77

DISCUSSION

Hyperprolactinemia in Chronic Kidney Disease patients

The kidneys play very important role in regulating endocrine system in the body. The kidneys themselves produce certain number of hormones.

Hormones like erythropoietin and calcitriol are some of the examples⁷⁶. Kidneys also play an important role to certain extent in the metabolism of some hormones. Kidneys also play an important role in the degradation of certain hormones like for example insulin and cortisol.

In chronic kidney disease patients, pertaining to various endocrine systems in the body various abnormalities are noted. There are alterations in mechanisms of signal feedback of various hormones in the human body. In addition alteration of production of the hormone also occurs. In addition there occurs changes also in transport, protein binding and metabolism of hormones.

In addition elimination of various hormones also gets altered in patients with CKD.

In addition to the above, patients with chronic kidney disease also suffer from the various other number of conditions. These include mainly the following Protein energy malnutrition (PEM), a state of chronic inflammation, multiple intake of drugs, and presence of metabolic acidosis and then most importantly there occurs disturbance in the hypothalamic – pituitary – gonadal axis in patients with CKD⁷⁷.

(100)

78 One of the major abnormality of endocrine system detected in patients with chronic kidney disease is increase in the serum prolactin levels. Several studies regarding this have shown that serum prolactin levels remain elevated in patients with chronic kidney disease .This increase in the serum PRL occurs in both male and female patients with chronic kidney disease and the prevalence is about 30 % to 65%^3,8. Due to the reduced clearance by the kidneys this occurs ⁸. There is alteration in the dopaminergic activity in patients with chronic kidney disease. There is increased production of the prolactin hormone^9,10. This also takes part in the increased prolactin levels which is seen in this group of CKD patients.

In our study, we studied 50 patients presented with chronic kidney disease .In our study all patients were on conservative line of management.

Many studies have been conducted so far to establish the correlation regarding the levels of serum prolactin levels in CKD patients and many studies were conducted to find out the involvement of cardiovascular system in CKD cases.

A Similar study of evaluating the serum prolactin levels in chronic failure of the renal system patients, CRF patients on haemodialysis and transplant recipients was conducted by “R Peces & S Casado et all⁷²”. In this study R Peces & S Casasdo et all⁷² conducted serum prolactin estimation in total of twelve patients of chronic kidney disease who were on conservative line of treatment and thirty patients of chronic kidney disease who were on haemodialysis basis and nineteen patients of chronic kidney disease who were post transplant recipients with a functioning kidney.

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79 At the end of their study authors have shown that base point levels of serum prolactin remain elevated in patients with chronic kidney disease. This increase in the serum levels of hormone PRL was demonstrated in both CKD patients who were on conservative line of treatment and in CKD patients who were on haemodialysis routine. In their study these authors also demonstrated that the elevated serum PRL hormone level showed a delay in response to stimulation with produced by the TRH. . In this study R Peces & S Casado et al also have shown that Serum prolactin levels remain normal in those CKD patients who have received a successful transplant with functioning kidney. In this study authors have established that the increase in the serum prolactin hormone levels due to the decrease in renal catabolism and impaired regulation of hypothalamic – pituitary axis.

As with other studies in our study also serum prolactin level was found to be elevated in 56 % of CKD patients. Remaining 44 % had normal serum prolactin levels.

A similar study of evaluating things about hyperprolactinemia and impaired response by the pituitary to the suppression and the stimulation in the patients with chronic kidney disease was conducted by “V.S.Lim, S.C.Kathpalia and L. Frohaman¹”. Here the authors analyzed the reversibility of abnormalities those mentioned above with the management by the mode of renal transplantation. In this study authors have found out the increase in basal serum prolactin levels in patients with chronic kidney disease. In this study authors also have demonstrated that PRL hormone showed lack of

ASSOCIATION BETWEEN SERUM PROLACTIN LEVELS AND

A DISSERTATION ON