A STUDY ON ASSOCIATION OF CAROTID INTIMAL MEDIAL THICKNESS AND CARDIOVASCULAR RISK FACTORS IN CHRONIC KIDNEY DISEASE PATIENTS
Dissertation Submitted to
The Tamil Nadu Dr. M.G.R. Medical University
In partial fulfillment of regulations for the award of the degree of
M.D. GENERAL MEDICINE BRANCH – I Reg. No. : 201711160
DEPARTMENT OF GENERAL MEDICINE KILPAUK MEDICAL COLLEGE CHENNAI – 10
THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY CHENNAI
MAY 2020
BONAFIDE CERTIFICATE
This is to certify that the dissertation entitled “A STUDY ON ASSOCIATION OF CAROTID INTIMAL MEDIAL THICKNESS AND CARDIOVASCULAR RISK FACTORS IN CHRONIC KIDNEY DISEASE PATIENTS” is a bonafide work done by Dr. S. RAJESH, Post Graduate student in the Department of General Medicine, Kilpauk Medical College, Chennai - 10, under our guidance and supervision in partial fulfillment of the rules and regulations of The Tamilnadu Dr. M.G.R. Medical University for the award of M.D. Degree Branch I (General Medicine) during the Academic period from 2017 to 2020.
Prof. Dr. P.PARANTHAMAN, M.D, Prof. Dr. K.V. RAJALAKSHMI,M .D, Guide of the Study and Professor and Head of Department Professor of General Medicine, Department of General Medicine Government Royapettah Hospital & Kilpauk Medical College,
Kilpauk Medical College, Chennai - 10 Chennai -14.
Prof. Dr. P.VASANTHAMANI, D.G.O., M.N.A.M.S., D.C.P.S.Y., M.B.A.
DEAN
Kilpauk Medical College, Chennai-10
ACKNOWLEDGEMENT FROM THE GUIDE
This dissertation work done by Dr. S.RAJESH, titled
“A STUDY ON ASSOCIATION OF CAROTID INTIMAL MEDIAL THICKNESS AND CARDIOVASCULAR RISK FACTORS IN CHRONIC KIDNEY DISEASE PATIENTS” was under my supervision for the entire duration of the study and I ensure that the candidate followed the rules of the ethical committee.
Date: Prof. Dr. P. PARANTHAMAN, M.D.
Place: Chennai Guide of the Study and
Professor of General Medicine, Government Royapettah Hospital &
Kilpauk Medical College, Chennai - 10
.
DECLARATION
I, solemnly declare that the dissertation entitled “A STUDY ON ASSOCIATION OF CAROTID INTIMAL MEDIAL THICKNESS AND CARDIOVASCULAR RISK FACTORS IN CHRONIC KIDNEY DISEASE PATIENTS” is done by me at Kilpauk Medical College, Chennai – 10 during the academic year of 2017 to 2020 under the guidance and supervision of Prof. Dr.
P.PARANTHAMAN, M.D., to be submitted to The Tamilnadu Dr.
M.G.R. Medical University towards the partial fulfilment of requirements for the award of M.D. DEGREE IN GENERAL MEDICINE BRANCH – I.
Place: Chennai (Dr.S.RAJESH) Date:
ACKNOWLEDGEMENT
At the outset, I would like to thank my beloved Dean, Prof. Dr. P.VASANTHAMANI, M.D, D.G.O., M.N.A.M.S., D.C.P.S.Y.
M.B.A., for permitting me to utilize the infrastructure and resources needed to conduct this study in Kilpauk Medical College.
I would like to express my sincere gratitude to Prof. Dr. T. ARUNA, M.D Vice Principal, for the timely help and support to this study.
I would like to express my special thanks to Prof. Dr. K.V. RAJALAKSHMI, M.D., Professor & HOD, Department of General Medicine, Kilpauk Medical College for permitting me to conduct this study.
I would like to thank wholeheartedly to my Guide, Prof. Dr. P. PARANTHAMAN, M.D., Professor, Department of General Medicine, Govt. Royapettah Hospital for his valuable guidance and encouragement during this study.
It gives me immense pleasure to express my sincere and deep gratitude to Professors, Prof. Dr. D.VENKATESWARLU, M.D, Prof. Dr. A. SHAIK SULAIMAN MEERAN M.D., Prof. Dr. S. KALAICHELVI, M.D., Prof. R. VENKATRAMAN, M.D., D.M., Prof. Dr. K. GOPINATHAN, M.D., D.N.B., for their constant motivation and critical suggestions.
I am extremely thankful to the Registrar Dr. M.VIJAY USHARAJ M.D., Assistant Professors of my unit Dr. VASANTHAKUMAR, M.D., Dr. P. RAJA, M.D., Dr. T.BALAJI, M.D., and other Assistant Professors for their help and support.
I would always remember with extreme sense of thankfulness, the cooperation and criticism shown by my fellow post graduates colleagues and friends.
I extend my thanks to the Departments of Biochemistry, Cardiology, Radiology for their cooperation and support.
I would like to take this opportunity to show gratitude to my parents Mr. T. SUBRAMANIAN and Mrs. S. MANONMANI, my beloved sister S. SUJATHA and my dear wife Dr. S. NIRMALA, and my friends for their never ending support throughout my life.
I wholeheartedly thank all my study people involved in this study and without them this would not have become a reality.
Finally I thank all of them helped me to finish this study in a successful manner.
PLAGIARISM CERTIFICATE
This is to certify that this dissertation work titled “A STUDY ON ASSOCIATION OF CAROTID INTIMAL MEDIAL THICKNESS AND CARDIOVASCULAR RISK FACTORS IN CHRONIC KIDNEY DISEASE PATIENTS” of the candidate Dr. S. RAJESH with registration number 201711160 for the award of MD in the branch of GENERAL MEDICINE. I personally verified the urkund.com website for the purpose of plagiarism check. I found that uploaded thesis file contains from introduction to conclusion pages and result shows 13 % of plagiarism in the dissertation.
Guide & Supervisor sign with seal
CONTENTS
S.No. TITLE PAGE NO.
1 INTRODUCTION 1
2 AIMS AND OBJECTIVES 9
3 REVIEW OF LITERATURE 10
4 MATERIALS AND METHODS 38
5 RESULTS & ANALYSIS 43
6 DISCUSSION 73
7 CONCLUSION 77
8 BIBILIOGRAPHY 78
9 ANNEXURE
1
INTRODUCTION
Chronic Kidney Disease (CKD) is a very serious complication equated with very early death and quality of life is decreased in such patients. Because of this there could be huge increase in health care expenditures.1,2,3 The overall prevalence of renal stage disease in the end stage may continue to rise globally. Moreover if we see the current patterns the number of patients with early CKD (Chronic kidney disease) from which end stage renal disease may develop in the future may emerge leading to the present status of increasing number of end- stage renal disease by a factor of 30 to 60.4,5 The overt disease morbidity of chronic kidney disease (CKD) in our country cannot be determined accurately. The approximate number of overall cases of CKD ranges from about eight hundred per million population and the new cases among the end-stage renal disease (ESRD) is about one hundred fifty to two hundred per million population.6 More over early CKD (Chronic kidney disease) will not progress to later stage which is end-stage renal disease in all patients. But there are instances where many will probably die of conditions associated with them. So many patients with CKD (Chronic Kidney Disease) have cardiovascular disease and die
2
prematurely from this condition instead of surviving long enough to face dialysis or transplantation.7,8
Different surveys showed that the risk factor for certain cardiovascular disease may increase much earlier in chronic kidney disease and in cases of renal dysfunction also, even at higher glomerular filtration rates.1,9 More over people with chronic kidney disease may have a tendency of excess traditional risk factors for cardiovascular disease such as hypertension, diabetes, and hyperlipidemias.7 Renal disease also endangers the environment which promotes cardiovascular injury in a ways which is more or less specific to end-stage renal disease. Vascular calcification can happen with dyregulation of calcium and phosphorus leading to anemia and hyperhomocysteinemia among the usually liable individuals of end-stage renal disease.10,11,12
Most of the evidence shows that the nature of the vascular disease associated with end-stage renal disease may evolve over in patients with progressive renal impairment and it may co-relate with standard risk factors like diabetes, dyslipidemia and hypertension. Hence, this study mainly concentrates on the relation of carotid intimal thickness in different stages of chronic kidney disease. Atherosclerosis as it says, is a severe form which is often asymptomatic, as it involves a direct
3
identification of vessel wall which is necessary to detect affected individuals at an early stage. However, it is been suggested by the IAP (International Atherosclerosis Project) that it is a process which occurs simultaneously in the carotid, cerebral and coronary arteries.11
Carotid artery IMT (Intimal medial thickness) is well-established index of systemic artherosclerosis which co-relate well with the incidence of coronary heart disease as well as stroke.12,13 The same index correlates well with uremic population as well as non-uremic population.14 It is shown that carotid artery intimal medial thickness acts an independent predictor of mortality of cardiovascular risk factor among patients who are undergoing hemodialysis.15,16 The measurement of CMIT (carotid artery intimal medial thickness) of the common carotid artery by B-Mode ultrasound was significantly found to have suitable noninvasive method to visualize the arterial walls and to determine the early stages of the process of atherosclerosis.17-20 Carotid artery intimal medial thickness when it is measured is very helpful in making the correct decision as to which is the best method of treatement, either surgical or medical in patients with carotid artery stenosis and it is also helpful in assessing the effects of medical therapies of atherosclerosis.19
4
CKD is characterized by a gradual decrease in glomerular filtration rate and past evidence of population of nephron.20 The course is substantially one of the most progressive and leading to the loss of nephron function indicating a end-stage renal disease. Kidney failure is the most vital aspect of the spectrum, which indirectly represent a minority of the entire population being affected by kidney disease.
There is always a time gap between the initial onset of disease and development of end-stage renal disease which may considerably vary not only with similar disease processes but also at different disease stages. The long progressive nature of the patients with chronic kidney disease and the ensuing end-stage renal disease is making it a substantial additional burden on entire health resources since all other modalities of procedures are expensive. There are various factors for kidney injury which may lead to the final common pathway of end-stage renal disease and this syndrome is characterized by metabolic disorders such as hypertension, anemia, renal bone disease , malnutrition, neuropathy and quality of life being impaired and reduced expectancy of life. There are much increased evidence acquired in the past decades where there are much adverse outcomes of chronic kidney disease such as renal failure,
5
cardiovascular disease and premature death which can be easily prevented by delay in detection of chronic kidney diseases.
Initial stages of chronic kidney disease can be evaluated through laboratory investigations tests alone. Treating the earlier stages of chronic kidney disease and initiating the treatment of cardiovascular risk factors at early stage of chronic kidney disease should be very effective in reducing the rate of progression to end-stage renal disease.
Among patients with chronic kidney disease, the atherosclerotic cardiovascular disease may be leading cause for disease burden and death. The carotid artery intimal medial thickness has been involved as a marker for diagnosing early atherosclerosis. The overall increased incidence of cardiovascular disease are the consequences of a high prevalence of both traditional risk factors, uremia-related “new factors”
such as hyperhomocysteinemia, and infections like herpes virus and Chlamydia pneumoniae and additional oxidative stress can very well lead to increase in atherosclerotic risk among the patients. With respect to National Health and Nutrition Examination Survey (NHANES), the overall prevalence of chronic kidney disease among the Unites states of America population is fifteen percentages. It becomes apparent that the severity of chronic kidney disease along with the cardiovascular
6
disorder in any large population make is very vulnerable combination for both patients and healthcare systems.
On an average fifty percent of patients with end stage renal disease will die from a cardiovascular incidence where it is indicative of a cardiovascular mortality that is thirty times higher among patients undergoing dialysis and five hundred times higher in the age group of twenty five to thirty four year old end stage renal disease patients than in individuals from the general population of the same age and race.
There are many previous studies suggesting that CMIT i.e., carotid artery intimal medial thickness can be used as a marker for atherosclerosis cardiovascular disease. Non invasive assessment of intima medial thickness of carotid arteries by high resolution B – mode ultrasonography is widely used in observational studies and trials as an intermediate or proxy measure of generalised atherosclerosis. Increased intima medial thickness of carotid arteries has been associated with unfavourable levels of established cardiovascular risk factors, prevalent cardiovascular disease and atherosclerosis elsewhere in the arterial system.
Individuals with lesser degrees of renal dysfunction are also predisposed to cardiovascular events. Several recent reports from
7
prospective population based studies suggest that mild-to-moderate renal insufficiency predicts cardiovascular morbidity and mortality.
Indeed,patients with CKD are more likely to die of CVD than to develop renal failure.In patients with CKD there is a high prevalence of traditional CVD risk factors,such as advanced age, diabetes, and hypertension. Some studies, however, indicate that the relationships between estimated glomerular filtration rate (eGFR) and CVD morbidity, and mortality are independent of these characteristics.These observations have led to the suggestion that “nontraditional” risk factors such as inflammation, abnormal calcium and phosphorous metabolism, anemia, hyperparathyroidism, hypoalbuminemia, and albuminuria may contribute to the risk of CVD in CKD patients.
8
JUSTIFICATION
• Previous cross-sectional studies in cohorts without CKD have demonstrated associations between carotid IMT and both cardiovascular risk factors and the presence of CVD
• Several large observational studies have also shown that carotid IMT is a predictor of coronary heart disease events that remains significant after adjustment for traditional risk factors.
• The relationship between IMT and risk for cardiovascular events in the context of a dominant risk factor such as CKD has been examined in only a few studies.
9
AIM & OBJECTIVES AIM
The aim of the study is to find the association of carotid intimal medial thickness in patients for cardiovascular disease in chronic kidney patients.
OBJECTIVES
1. To study the prevalence of cardiovascular risk factors in patients with CKD.
2. To study the relation of carotid intimal thickness in different stages of CKD
3. Association of carotid intimal medial thickness and risk factors for cardio vascular disease in patients with CKD
10
REVIEW OF LITERATURE
Chronic kidney disease (CKD), often leading to a gradual and irreparable loss of renal function, CKD is common enough to be considered a world wide public health threat. It is associated with a series of complications, such as infections, reduction in protein synthesis, impaired wound healing, cardiac insufficiency and increased rates of hospitalization in hemodialysis patients2
There is high prevalence of chronic kidney disease (CKD) and it seems to be gradually increasing.CKD patients should introduce appropriate measures to hinder the progression of kidney function deterioration as well as to avoid the development or progression of CKD-related diseases. The current guiding principle for the management of the CKD recommend dietary and lifestyle modifications, though they have largely been based on general population studies.20
Cardiovascular manifestations in patients with chronic kidney infection (CKD) is normal and has significant impact in terms of both physical suffering and economic burden. CKD is characterized by the damage to kidney and function of kidney, which is independent of the kind of kidney infection. Among people with constant kidney infection,
11
the stages are characterized by the degree of kidney function, and CKD stage 3 includes those with a stable, or step by step declining, estimated glomerular filtration rate of 30 to 60 mL/min/1.73 m.
Recognition of kidney illness has expanded lately, mostly because of the widespread presentation of reporting of GFR, and halfway because of the aging population which has an expanding predominance of hypertension and diabetes – conditions in which minor kidney sickness is exceptionally normal, and minor kidney disease is very common, clinically kidney diseace is often recognized too late to save the function of kidney.
When patients suffer from end stage kidney illness (CKD type 5) and enter dialysis programs, they have an alarmingly high pace of cardiovascular disease with those in the most youthful age scope of <25 years having equitable cardiovascular death rates to 75-to 85-year-olds in the general population. Hence there is an increasing interest in the cardiovascular disease status of patients with initial stage kidney manifestations so that efforts can be done to prevent cardiovascular disease to occur in future.
Chronic kidney disease is associated with an increased risk of adverse cardiovascular disease outcomes. In patients with kidney failure
12
on dialysis, mortality due to CVD is 10 – 30 times that in the general population . Individuals with lesser degrees of renal dysfunction are also predisposed to cardiovascular events. Several recent reports from prospective population based studies suggest that mild-to-moderate renal insufficiency predicts cardiovascular morbidity and mortality. In patients with CKD there is a high prevalence of traditional CVD risk factors,such as advanced age, diabetes, and hypertension. Some studies, however, indicate that the relationships between estimated glomerular filtration rate (eGFR) and CVD morbidity, and mortality are independent of these characteristics.These observations have led to the suggestion that “nontraditional” risk factors such as inflammation, abnormal calcium and phosphorous metabolism, anemia, hyperparathyroidism, hypoalbuminemia, and albuminuria may contribute to the risk of CVD in CKD patients.
Most patients with chronic kidney disease actually do not suffer from symptoms of uremia, nor do they have mortality from kidney disease. Most of patients with chronic kidney disease die from cardiovascular disease, even before their kidney needs a replacement therapy.
13
Thus this study was conducted to study the prevalence of cardiovascular risk factors in patients with CKD. To study the relation of carotid intimal thickness in different stages of CKD and to find the association of carotid intimal medial thickness and risk factors for cardiovascular disease in patients with CKD.
Anatomy of Kidney21,22,23
Kidney is located at about the T12 to L3 vertebrae, but the right is positioned little lower due to minor displacement by the liver. Upper portions of the kidneys is protected by eleventh and twelfth ribs. Kidney are about 11–14 cm in length, 4 cm in thickness and 6 cm wide , it is covered by a fibrous capsule which is composed of irregular, dense connective tissue. This capsule is protected by a shock-absorbing layer of fat tissue, which is called the renal fat pad, which in turn is surrounded by a hard renal fascia. The fascia and the peritoneum adhere the kidney to the posterior abdominal wall in a retroperitoneal position.
14
The kidney has the outer area called the renal cortex and an inner area called the medulla. The renal columns have the connective tissue that extends down from the cortex through the medulla to divide the renal pyramids and renal papillae. The papillae are bundles of collecting ducts that transfer urine from nephrons to the calyces for the excretion. The renal columns also divide the kidney into six to eight lobes and provide the protective framework for the renal vessels that enter and exit the cortex.
Renal Hilum
The renal hilum is the portal for the entry and exit of the renal vessel , nerves, lymphatics, and ureters. Major and minor calyxes in the kidney form from the renal pelvis. The smooth muscle in the renal pelvis transfers the urine via peristalsis into the ureter. Descending aorta forms the renal arteries, However the renal veins return cleansed blood directly to the inferior vena cava.
15 Nephrons and Vessels
The renal artery first bifurcates into segmental arteries, and then it branches to form interlobar arteries that pass through the renal columns to reach the cortex .The interlobar arteries, branch out into arcuate arteries, cortical radiate arteries, and into afferent arterioles.
16
17
Nephrons are the “functional units” of the kidney; they purify the blood . The afferent arterioles makes a tuft of high-pressure capillaries which is about 200 µm in diameter, which is called glomerulus.
Remaining part of the nephron consists of a tubule whose proximal end cover the glomerulus, which is Bowman’s capsule. The glomerulus and Bowman’s capsule together form the renal corpuscle. These glomerular capillaries purify the blood. After the blood passes from the renal corpuscle, the capillaries forms a second arteriole, the efferent arteriole. Capillary network forms the peritubular capillaries and vasa recta, surrounding the more distal portions of the nephron tubule, before returning to the venous system.
Function of the Kidney,24,25
The major function of the kidneys is to maintain homeostasis.
That means kidneys manage fluid levels, electrolyte balance and other factors which are helpful to maintain the internal environment of the body consistent and comfortable.
Excretion of waste
The kidneys excrete various type of waste products in the urine. Two major compounds that kidneys remove are as follows:
18
• Uric acid, which is the end product of nucleic acids breakdown
• Urea, which is from the breakdown of proteins Reabsorption of nutrients
The kidneys absorbs the nutrients from the blood and transport them into the circulation.
This reabsorption helps to maintain the homeostasis.
Reabsorbed products include:
• Glucose
• Bicarbonate
• Sodium
• Water
• Amino acids
• Phosphate
• Chloride,
Maintaining pH
The kidneys manage the pH through two processes:
19
• Reabsorbing the bicarbonate from urine: Bicarbonate neutralize acids.
• Excreting hydrogen Osmolality regulation
Osmolality is the body's electrolyte-water balance.
the main cause of electrolyte imbalance.If osmolality increases in the blood plasma, the hypothalamus in the brain activates via pituitary gland, which in turn, releases antidiuretic hormone (ADH).
When the SADH hormone is released, kidney does the following:-
• Increase the urine concentration
• Increase the water reabsorption
• Reopening portions of the collecting duct Regulating blood pressure
Kidneys regulate blood pressure in the arteries by causing changes in the extracellular fluid.
20 Secretion of important compounds
• Erythropoietin
• Renin
• Calcitriol
21 CHRONIC KIDNEY DISEASE26,27
Chronic kidney disease (CKD) refers to a gradual and irreversible loss of renal function. Prevalence of CKD in the United States is found to be 14.5% among adults (9).Similar prevalence rate has been found in Europe, Australia and Asia (9-11).CKD is defined as a circumstances of kidney damage and/or decreased glomerular filtration that lasts for at least 3 months (8). Due to unnoticed rising trend of increasing body weight, hypertension and insulin resistance among the people, there is also a similar trend seen in CKD prevalence (12). CKD can be divided into 5 stages, depending on the kidney damage, i.e., albuminuria, and failure of kidney function as evaluated by glomerular filtration rate (GFR). CKD is mainly characterized by a continuous course of deterioration renal function gradually leading to stage 5 CKD, also known as ESRD that is end-stage renal disease, which requires renal replacement therapy (RRT). at present, two major kinds of replacement therapy are clinically present, that is dialysis and kidney transplantation.
Dialysis is in addition available as hemodialysis (HD, entailing extracorporeal filtration of blood) and peritoneal dialysis (PD, which utilises the peritoneal membrane as a filter).
22 Definition of chronic kidney disease
Structural or functional abnormalities of the kidney, for > 3 months, with or without decreased golmerular filteration rate, manifest by either pathological abnormalities; or
Raised markers of kidney damage, including abnormality in the composition of the blood or urine, or in imaging test. Other criteria of CKD is GFR < 60 ml / min / 1.73 m2 for > 3 months, with or without kidney damage.
Risk factors for CKD
• Diabetes
Diabetes is the leading cause of kidney failure. Dietary modification, lifestyle modification and compliance to treatment can help manage diabetes and prevent complications.
• Hypertension
High blood pressure is the second leading cause of kidney disease. Hypertension can be a cause and the symptom of kidney manifestation. Keeping the blood pressure under control can help prevent kidney disease, or help keep it from getting worse.
23
• Family History
Family history of kidney manifestation is an important risk factor for the occurrence of CKD in future.
• Age
Age of the individual above 60 years itself is a risk factor for kidney disease; as over time, the kidneys lose some function naturally.
• Ethnicity
African Americans, Americans and Asian-Americans are more likely to have kidney disease. It can be due to higher rates of diabetes and high blood pressure, which are the two leading causes of kidney failure.
• Proteinuria
• Dyslipidemia
• Hyperuricemia
• Obesity
24
• Cigarette smoking
• Alcohol
Various other causes of kidney failure are:
•
development of many cysts in the kidneys.
•
kidneys.
•
• Autoimmune diseases – lupus or
•
Symptoms of CKD28
Chronic kidney disease is a slow and gradual progressive disease.
Signs and symptoms in CKD is usually seen only in the advanced stage when the condition has become serious, because even if one kidney stops functioning, the other can carry out normal functions.
25
The most common signs and symptoms of CKD are as follows-
•
• Haematuria
• Dark colour urine
• Disoriented
• Decreased urine output
• Swollen feet, hands, and ankles and finally face if edema is severe
• Tiredness
• High blood pressure
•
• Itchy skin
• Loss of appetite
• More frequent urination, especially at night
• Cramps
• Nausea
26
• Pain on the side or mid to lower back
• Shortness of breath
• Protein in urine
• Unexplained
Complications of chronic kidney disease
Anaemia- Anemia in chronic kidney disease begins when the GFR falls below 30-35% of normal level. Anemia is of normochromic and normocytic type.This is basically brought about by diminished generation of erythropoietin by the falling kidney,various other components add to sickness which are inhibitors of erythropoiesis, smaller RBC life expectancy, platelet destruction, diminished iron inatke, and secondary hyperparathyroidism. Anemia is a sole indicator of mortality and has additionally been related with increase morbidity in CKD. Anemia treatment improves the quality of life, cognitive and sexual function, reversal of ST-T changes on EC.
LIPOPROTEIN
Chronic renal failure patients are found to have elevated plasma lipoprotein level .It has been associated with a frequency distribution of apolipoprotein . It has been found that elevated lipoprotein level in the
27
chronic kidney disease patients is because of genetic variation.
Therefore, it can be stated that kidneys have an important role in lipoprotein metabolism. Thus it is indicated that increase liver production or decrease lipoprotein catabolism can be a causative factor in the rising incidence of atherosclerotic disease found in chronic kidney disease and hemodialysis patients. Subtle structural changes such as thickening of arterial intimamedia complex thickness (IMT) occur early in the atherosclerotic disease process. Noninvasive tool for early assessment of atherosclerosis B-mode ultrasonography.Superficia vascular districts, such as the carotid or femoral artery can also been evaluated using the technquie.
Hyperphosphatemia and hyperparathyroidism
One of the earliest indication of impaired renal function is hyperparathyroidism . It is found in patients with a glomerular filtration rate of 60 ml/min. Parathormone is biggest uremic toxin that leads to bone disease, pruritus, metastatic calcification, encephalopathy, anemia, sexual dysfunction, peripheral neuropathy and hyperlipidemia.
Management of chronic renal failure is mainly depend on control of serum phosphate levels. Rate of progression of renaldisease is mainly depend on precipitation of calcium phosphate in renal tissue, which
28
starts quite early,it is closely related to hyperphosphatemia and calcium phosphate product. Thus leading the important role in vascular calcification, calciphylaxis, CVD and death.
MALNUTRITION
The frequency of hypoalbuminemia is more among patients beginning dialysis, it is of multifactorial origin, and is linked with poor outcome. Hypoalbuminemia is a state of chronic inflammation rather than of nutrition in itself. Intake of protein begin to reduce when the glomerular filtration rate falls below 50 ml/min. Further reduction in renal function causes reduced appetite, thus increasing the risk of malnutrition.
29 Stages of CKD
Chronic kidney disease progress can be assessed by changes in the GFR rate -
Stage 1 - GFR rate is normal. nevertheless, evidence of kidney disease has been detected.
Stage 2 - GFR rate is lower than 90 ml, and evidence of kidney disease has been detected.
Stage 3 - GFR rate is lower than 60 ml, regardless of whether evidence of kidney disease has been detected.
Stage 4 - GRF rate is lower than 30 ml, regardless of whether evidence of kidney disease has been detected.
Stage 5 - GFR rate is lower than 15 ml. Renal failure has occurred.
30 Formula to determine GFR
31
Intervention to reduce risk of CKD progression
32
Relation of carotid intimal thickness in different stages of CKD
Cardiovascular disease and accelerated atherosclerosis and have been documented for many years as chief causes of morbidity and mortality in patients of end-stage renal disease .Measurement of carotid intimal thickness, is increasingly used to assess atherosclerosis, and to monitor the progression and the effects of treatment. Intima-media complex, which comprises of endothelial cells, smooth muscle and connective tissue is the place of lipid deposition in plaque formation.
The mean and maximum carotid intimal thickness in healthy adults was found to be 0.67 and 0.70 mm respectively.
Assessment of the carotid intimal thickness is a sound, safe, and non-invasive method of diagnosing subclinical atherosclerosis. Many cross-sectional studies in cohorts without chronic kidney disease have established associations between carotid intimal thickness and both cardiovascular risk factors and the presence of cardio vascular disease. It is also found that carotid intimal thickness is a predictor of coronary heart disease manifestations.
Carotid Intimal Thickness
Carotid ultrasound is an ongoing imaging apparatus, it is a promptly accessible, economical, quick, safe, and non intrusive analytic
33
methodology, that is ending up progressively well known to use by doctors. This procedure, which serves both as an early detector and a subsequent instrument, gives data about common carotid (CCA), bifurcation, internal and external carotid arteries. Meta analysis done regarding carotid ultrasound from 2010 to 2012 showed that carotid intimal thickness can be effectively utilized as a marker of atherosclerosis development in the setting of various risk factors, or as a predictor of cardiovascular (CV) and stroke events in daily clinical practice . For evaluating carotid arteries fundamental frequency of at least 7 to maximum 15 MHz linear phased array probes are used to evaluate carotid arteries defining of the peak values and the means of Intima-media thickness (IMT) of carotid arteries is an important part of the study and vary based on age, gender, and ethnicity. intimal thickness is measured as the distance between two echogenic lines, divided by echo lucent gap in the wall of the artery though, the intima and media are, technically, identical by ultrasound. It is suitable to measure thickness 3 times in the anterior, posterior and lateral plans which include total of 18 measurements. Automated measurement, instead of manual measurements, make measurements faster and more accurate. Based on some various studies, CIMT values can be defined as follows:
34
• CIMT over the 75th percentile of mean for the age, gender and ethnicity or absolute thickness more than 1.0 mm are considered an abnormal findings,
• Individuals with IMT in less than the 50th percentile are classified in the low risk group.
• For screening for Heart Attack Prevention and Education Task Force, the 75th-percentile threshold is considered an abnormal result.
All the more generally, the most distant mass of the CCA, explicitly near the carotid bifurcation, is used for the estimation of the IMT. Be that as it may, it could be assessed in far and near walls of the both CCA and ICA segments. In light of the simple access to the CCA, estimation is a lot simpler and the outcomes are progressively reproducible. As of late, there has been a more prominent enthusiasm for considering the ICA, in light of the fact that it appears that there is a higher relationship between discoveries in the ICA and CAD just as cardiovascular and stroke events.If the quartile is discrepant between the right and left carotid supply arteries, we may apply the higher quartile.
For the most part, the thickness of intima-media in the bifurcation of the carotid is higher than ICA or CCA. Normally, carotid plaques were
35
characterized as local IMT of 1.5 mm. (go between 1.2 – 1.9 mm in various investigations) or as a central thickening of more prominent than 50% of the surrounding area.
As of late, 3D strategies award plaque volume estimation over a particular fragment of the artery. Gray scaling of the blood vessel wall and plaque is another ability of the carotid ultrasound. Moreover, lumen width, blood stream speed, and sheer stress are giving more data about the patient ailment. Every one of these information could be acquired in a similar session without extra damage to the patient.
CIMT and cardiovascular risk factors
Most of the major cardiovascular risk factors affect carotid artery wall. In view of the consequence of an investigation on316 Framingham offspring cohort population, CCA-IMT and ICA-IMT had comparative hazard elements aside from absolute cholesterol which was not associated to CCA-IMT. This investigation uncovered that consistently CCA-IMT expanded by 0.007 mm and ICA-IMT expanded by 0.037mm, and age was the most grounded indicator of the both CCA- IMT and ICA-IMT. After age, sexual orientation demonstrated a solid relationship with CIMT. What's more, HDL cholesterol, smoking, hypertension and diabetes had a huge connection to the IMT's of both
36
CCA and ICA. In another investigation on Multi-Ethnic Study of Atherosclerosis (MESA) populace, it has been demonstrated that CIMT and all the more explicitly ICA-IMT have significant reverse correlation with both HDL cholesterol level and number of particles
CIMT and early detection of atherosclerosis
Early location of atherosclerosis is currently a significant point in medicine. It has not yet been resolved that screening for subclinical atherosclerosis diminishes the rate of future cardiovascular occasions, however as per the present rules that suggest populace based screening techniques, for example, Framingham Risk Score (FRS) and Systematic Coronary Risk Evaluation (SCORE)10, more aggressive preventive interventions can be considered for high risk patients. By and large, contrasted with early location, we may expect that determination of atherosclerosis in the propelled stages would prompt to higher costs and less therapeutic benefits.
The workplace based FRS or SCORE have restricted worth, and most of patients with intense myocardial localized necrosis have low to to intermediate scores. In an endeavor to upgrade prescient intensity of FRS, numerous non-conventional hazard elements were presented.
Among them, coronary conduit calcium score, CIMT and highly
37
sensitive C-receptive protein showed progressively satisfactory results.
The ongoing American College of Cardiology Foundation–American Heart Association rules give carotid intima–media thickness a level IIa proposal for cardiovascular hazard assessment. Their rules prescribed performing CIMT examines in populaces with FRS of 10–20 % without known CAD, cerebrovascular disease,fringe vein malady, cerebrovascular sickness, peripheral artery disease or abdominal aortic disease..
Inspite of a huge positive connection among's CAC and CCA- IMT, CIMT is a less sensitive test than CACS for the identification of subclinical atherosclerosis. Based on an ad meta-analysis study demonstrating the sensitivity, specificity and diagnostic Odds ratio of CCA-IMT for CAD to be as 68%, 61.5% and 3.2, in order, 15 whereas, these parameters for ICA-IMT were measured as 79%, 74.4% and 7.9, respectively. Likewise, the examination demonstrated that there was no noteworthy distinction between analytic Odds proportion of CIMT and carotid plaque for conclusion of CAD. To clarify specificity value of CIMT for CAD, it was proposed that thickening in carotid arteries happens earlier than in coronary arteries in the process of the atherosclerosis.
38
METHODOLOGY
STUDY DESIGN Single centre
Non randomized Cross Sectional Study DURATION OF STUDY
One year (March 2018-February 2019) PLACE OF STUDY
The study was conducted in the in patients inthe Department of Internal Medicine and Department of NephrologyGovernment Royapettah Hospital, Chennai.
STUDY POPULATION
Study conducted among the patients of four medical units and the Nephrology department of Government Royapettah Hospital.
TARGET POPULATION
Chronic kidney disease patients admitting in medical wards were the target population.
39 SELECTION OF PATIENTS
Inclusion Criteria
A) The patients who fulfilled the criteria for CKD and who were on conservative management were taken into the study.
Criteria for chronic kidney disease:
1. Presence of objective kidney damage for at least three months.
Kidney damage being defined as pathologic abnormalities ormarkers of damage including abnormalities in blood or urine tests orimaging studies. Imaging study is usually an ultra sonogram abdomenshowing.
a. Bilateral contracted kidneys, or;
b. Poor corticomedullary differentiation or;
c. Type II or type III Renal parenchymal changes or;
d. More than one of the above.
and
2. Glomerular filtration rate (GFR) less than 60ml/min/1.73m2for at least three months with or without kidney damage.
40
B) CKD patients getting treated at Nephrology department and Department of Internal Medicine, Government Royapettah Hospital, with stage 2, 3, and 4.
C) Patient age greater than 18 years.
Exclusion Criteria
A) Patient having diagnosed as ARF.
B) History of carotid surgery.
C) Patient of age less than18 years.
D) Patient having previous history of ischemic heart disease, myocardial infarction and stroke
E) CKD stage 1 & 5
F) Patients with nephrotic syndrome G) Patients on statins
SAMPLE SIZE
Sample size was determined based on Study
Prevalence and risk factors for cardiovascular disease among chronic kidney disease patients: results from the Chinese cohort study of chronic kidney disease (C-STRIDE)
41 Authored by
Jun Yuan et al Published in
risk was 9.8%
Description:
• The confidence level is estimated at 95%
• with a z value of 1.96
• The confidence interval or margin of error is estimated at +/- 5
• Assuming p% =9.8% and q%=90.2%
n = p% x q% x [z/e%] ² n= 9.8x 90.2x [1.96/5]² n= 135.8
Expected loss ratio = 10%
Final minimum sample size adjusted to losses = 150
42 SAMPLING PROCEDURE
Convenience sampling procedure INSTRUMENT
1. Questionnaire Pretested Semi structured question regarding history
2. Routine reports from hospital during admission
3. Investigations: Patients who were included in the study were asked for the history of diabetes mellitus, hypertension, smoking, intake of alcohol and hyperlipidemia. Pulse rate and blood pressure were taken. Height and weight were measured for body mass index calculation. The information wereentered based on the proforma prepared.
Patients were subjected to carotid Doppler for measuring carotid intimal medial thickness. If any patient’s carotid initmal medial thickness is greater than 0.89mm then we hadrefered the patient to Cardiology Department, GRH for further evaluation and management.
Urine sample for urine protein and blood samples for hemoglobin, hematocrit, urea, creatinine, fasting blood sugar, lipid profile were collected and subjected to biochemical tests.
43
RESULTS
Table 1: Distribution of study participants according to their age (N=150)
Sl.No. Age Frequency Percentage
1 20-30 yrs 10 6.8
2 31-40 yrs 18 12.0
3 41-50 yrs 42 28.0
4 51-60 yrs 44 29.1
5 61-70 yrs 30 20.1
6 > 70 yrs 6 4
Mean=57.14±13.03 Total 150 100
44
Graph 1: Distribution of study participants according to their age (N=150)
Majority of Patients in our study was in age group 51-60 years (29.1%) and 41-50 years (28.0%), followed by 61-70 years (20.1%), 31-40 years (12%) and 20-30 years (6.8%). Mean age of patient was 57 years.
6.80%
12.00%
28.00% 29.10%
20.10%
4.00%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
20-30 yrs 31-40 yrs 41-50 yrs 51-60 yrs 61-70 yrs > 70 yrs
Percentage
Age in years
45
Table 2: Distribution of study participants according to their gender (N=150)
Sl.No Gender Frequency Percentage
1 Male 97 64.6
2 Female 53 35.3
Total 150 100.0
Graph 2: Distribution of study participants according to their gender (N=150)
Male preponderance was observed in our study with 65% patients being males.
65%
35%
Male Female
46
Table 3: Distribution of study participants according to their type of education (N=150)
Sl.No. Type of education
Frequency Percentage
1 Illiterate 24 16
2 Primary level 28 18.67
3 Middle level 32 21.33
4 Higher
secondary school
44 29.33
5 Graduate 22 14.67
Total 150 100
47
Graph 3: Distribution of study participants according to their type of education (N=150)
Majority of the patients (29.33%) have studied till higher secondary level, followed by 21% till middle school level, 18% till primary level of education, 16% of them were illiterates and only 14%
of the patients were graduates.
16.00% 18.67% 21.33%
29.33%
14.67%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
Illiterate Primary level Middle level Higher secondary
school
Graduate
Percentage
Type of education
48
Table 4: Distribution of study participants according to their type of occupation (N=150)
Sl.No. Type of occupation Frequency Percentage
1 Unemployed 21 14.0
2 Unskilled 46 30.66
3 Semi-skilled 25 16.67
4 Skilled worker 30 20
5 Semi-profession 16 10.67
6 Profession 12 8.0
Total 150 100
49
Graph 4: Distribution of study participants according to their type of occupation (N=150)
Majority of the study participants (31%) are engaged in unskilled type of work. Around 14% of them are unemployed followed by 17%
engaged in semi-skilled type of work, 11% are semi-professionals and 8% of them are professionals.
14%
31%
17%
20.00%
11%
8%
0%
5%
10%
15%
20%
25%
30%
35%
Percentage
Type of occupation
50
Table 5: Distribution of study participants according to their presence of Hyperlipidemia (N=150)
Sl.No. Hyperlipidemia Frequency Percentage
1 Yes 116 77.33
2 No 34 22.67
Total 150 100.0
51
Graph 5: Distribution of study participants according to their hyperlipidemia status (N=150)
Dyslipoproteinemia was present among 78% of the study participants.
78%
22%
Yes No
52
Table 6: Distribution of study participants according to their status of alcohol intake (N=150)
Sl.No. Alcoholic status
Frequency Percentage
1 Present 84 56
2 Absent 66 44
Total 150 100.0
53
Graph 6: Distribution of study participants according to their status of alcohol (N=150)
Around 56% of the study participants were seem to be alcoholic.
56%
44%
Present Absent
54
Table 7: Distribution of study participants according to their status of smoking (N=150)
Sl.No. Smoking Frequency Percentage
1 Present 90 60
2 Absent 60 40
Total 150 100.0
55
Graph 7: Distribution of study participants according to their status of smoking (N=150)
Around 60% of the study participants were smokers.
60%
40%
Present Absent
56
Table 8: Distribution of study participants according to their past history of diabetes mellitus and hypertension (N=150)
Sl.No. Past history of DM/HTN
Frequency Percentage
1 Present 81 54
2 Absent 69 46
Total 150 100.0
57
Graph 8: Distribution of study participants according to their past history of diabetes mellitus and hypertension (N=150)
Diabetes or hypertension was present among 54% of the study participants.
54%
46% Present
Absent
58
Table 9: Distribution of study participants according to their family history of cardiovascular disease (N=150)
Sl.No. F/H CVD Frequency Percentage
1 Present 40 26.67
2 Absent 110 73.33
Total 150 100.0
59
Graph 9: Distribution of study participants according to family history of cardiovascular disease (N=150)
Family history of cardiovascular disease was present among 27% of the study participants.
27%
73%
Present Absent
60
Table 10: Distribution of study participants according to their levels of Blood pressure (N=150)
Sl.No. Blood Pressure Frequency Percentage
1 120/80 71 47.33
2 > 140/80 69 46
3 > 160 10 6.67
Total 150 100.0
61
Graph 10: Distribution of study participants according to their levels of Blood pressure (N=150)
Around 47% participants had normal blood pressure levels around 120/80 mm of Hg followed by 46% of the participants with >140/80 mm of Hg and 6.67% with >160 mm of Hg.
47% 46.00%
6.67%
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
120/80 > 140/80 > 160
Percentage
Blood presssure levels
62
Table 11: Distribution of patients according to their duration of disease (N=150)
Sl.No. Duration Frequency Percentage
1 1-5 yrs 32 21.3
2 6-10 yrs 58 38.67
3 11-15 yrs 39 26
4 16-20 yrs 21 14
Mean
=16.13±2.62
Total 150 100
63
Graph 11: Distribution of patients according to their duration of disease (N=150)
Majority of Patients in our study are having duration of CKD for 6-10 yrs (38%), 11-15 yrs (26%) and 1-5 years (21%), and 16-20 years (14%). Mean duration of CKD among patients were 16 years.
21.30%
38.67%
26.00%
14.00%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
40.00%
45.00%
1-5 yrs 6-10 yrs 11-15 yrs 16-20 yrs
Percentage
Duration of COPD
64
Table 12: Distribution of study participants according to their pack years (N=150)
Sl.No. Pack Years Frequency Percentage
1 11-14 yrs 35 23.3
2 15-18 yrs 42 28
3 19-22 yrs 47 31.3
4 Nil 26 17.3
Mean=17.54±2.97 Total 150 100
65
Graph 12: Distribution of study participants according to their pack years (N=150)
Majority of Patients in our study are having pack years between 19-20 yrs (31%), followed by 15-18 years (28%), and 11-14 years (23%).
Mean pack years of patient was 17 years.
23.30%
28.00%
31.30%
17.30%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
11-14 yrs 15-18 yrs 19-22 yrs Nil
Percentage
Pack Years
66
Table 13: Distribution of study participants according to their BMI (N=150)
Sl.No. BMI Frequency Percentage
1 15 – 20 35 23.3
2 21 – 25 42 28
3 26 – 30 47 31.3
4 > 30 26 17.3
Mean=22.65±2.8 Total 150 100
67
Graph 13: Distribution of study participants according to their BMI (N=150)
Majority of Patients in our study are having BMI between 26-30 yrs (31%), followed by 21-25 years (28%), and 15-20 years (23%).
Mean BMI of the patient was 22.
23.30%
28.00%
31.30%
17.30%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
15-20 21-25 26-30 >30
Percentage
BMI
68
Table 14: Distribution of study participants according to their diagnosis (N=150)
Sl.No. Diagnosis Frequency Percentage
1 DIABETES 22 14.6%
2 CGN 24 16%
3 HYPERTENSION 64 42.67%
4 CIN (Contrast-induced nephropathy)
20 13.33%
5 OBSTRUCTIVE UROPATHY(OU)
9 6%
6 SOLITARY KIDNEY 6 4%
7 ANALGESIC
NEPHROPATHY
5 3.33%
Total 150 100%
69
Graph 14: Distribution of study participants according to their diagnosis (N=150)
Hypertension was the leading cause for Chronic Kidney disease in 42.67% cases. Diabetes (14.6%) was second leading cause of chronic kidney disease. CIN accounted for (13.3%) cases of CKD.
14.60% 16%
42.67%
13.33%
6% 4% 3.33%
0.00%
5.00%
10.00%
15.00%
20.00%
25.00%
30.00%
35.00%
40.00%
45.00%
Percentage
Diagnosis
70
Table 15: Association of risk factors of cardiovascular disease with carotid artery intimal medial thickness (N=150)
Sl.No. Variable CMIT <0.89 (n=54)
CMIT
>0.89 (n=96)
p value
1 Age
21-30 31-40 41-50 51-60 61-70
>70
3 7 20 10 12 2
7 12 22 34 18 3
0.192
2 Gender
Male Female
35 19
62 34
0.97 3 H/O Hyperlipidemia
Present Absent
34 20
82 14
0.001 4 H/O Alcohol
Present Absent
17 37
67 29
<0.001
5 H/O Smoking
Present Absent
20 34
70 26
<0.001 6 Pack Years
11-14 15-18 19-22 Nil
10 15 12 17
25 27 35 9
0.005
7 Past H/O DM/HTN
Present Absent
20 34
61 35
0.001 8 F/H Cardiovascular
disease
Present Absent
12 42
28 68
0.355 9 Duration of disease
1-5yrs 6-10 yrs 11-15 yrs 16-20 yrs
14 20 13 7
18 38 26 14
<0.001
71
From the above table we infer that significant association of cardiovascular risk factors such as hyperlipideamia, alcohol, smoking, pack years and past history of diabetes and hypertension were seen with CIMT.
Table 16: Univariate correlation of lab parameters of
cardiovascular disease with carotid artery intimal medial thickness (CIMT) (N=150)
Parameter Mean±SD
r
(Correlation Coefficient)
p value Serum Creatinine 1.36±0.21
mg/dL
0.61 <0.001 Serum Urea 24.48±4.98
mg/dL
0.37 <0.001 Serum Calcium 7.86±2.18
mg/dL
0.18 0.128 Serum Total
Cholesterol
293.54±49.74 mg/dL
0.23 0.018 Serum Triglyceride 163.95±104.39
mg/dL
0.38 <0.001
Serum HDL 37.28±7.66
mg/dL
0.19 0.06
SerumLDL 113.64±47.89 mg/dL
0.23 0.02
Serum VLDL 26.56±7.98 mg/dL
0.08 0.40
Serum Albumin 3.36±0.21 mg/dL
0.13 0.28
Hemoglobin 12.97±1.44g/dL 0.02 0.30
Serum Phosphorus 4.76±0.13 mg/dL
0.57 <0.001
72
Univariate correlation analysis between CIMT and study parameters of creatinine, urea, calcium, serum total cholesterol levels, serum triglyceride levels, serum HDL levels, LDL, VLDL, albumin, hemoglobin and phosphorus were performed in CKD patients, significant correlation (P <0.05) of CIMT was found with creatinine, urea ,serum total cholesterol, serum triglyceride and phosphorus levels.
73
DISCUSSION
In our study a total of one hundred and fifty patients were studied for CIMT (carotid artery intimal- medial thickness) in association with cardiovascular risk factors. The study was carried out during a period of one year. Mean age of the patients were 57.14±13.03 years.Majority of Patients in our study was in age group 51-60 years (29.1%) and 41-50 years (28.0%), followed by 61-70 years (20.1%), 31-40 years (12%) and 20-30 years (6.8%).
In the current study the mean carotid artery intimal medial thickness in chronic kidney disease patients was 0.86 ± 0.21 which is comparable with other studies done by Shoji et al 29 who studied carotid artery intimal medial thickness in one hundred and ten predialysis patients with 0.88± 9 0.03 mm. The present study showed strong association between CIMT and history of hyperlipidemia (p=<0.001) similar results were obtained in a study by Brzosko et al 34(P = 0.02).
In the current study, out of the 150 patients, 16% of the patients were illiterate and 18% had primary education. Similar findings were seen in several studies.30,31,32
