Protineuria in CKD Patient on Hemodialysis

Proteinuria is a distinguishing feature in primary and secondary forms of chronic glomerulonephritis, which contribute to no more than the 20% of the end-stage kidney disease (ESKD) population. The contribution of non-proteinuric nephropathies to the global ESKD burden is still poorly focused and scarce research efforts are dedicated to the elucidation of risk factors and mechanistic pathways triggering ESKD in these diseases. We abstracted information on proteinuria in the main renal diseases other than glomerulonephritides that may evolve into ESKD. In type 2 diabetes, non-proteinuric diabetic kidney disease (DKD) is more frequent than proteinuric DKD, and risk factors for non-proteinuric forms of DKD now receive increasing attention. Similarly, proteinuria is most often inconspicuous or absent in the most frequent cause of ESKD, i.e. hypertensionrelated chronic kidney disease (CKD), as well as in progressive cystic diseases like autosomal dominant polycystic kidney disease and in pyelonephritis/ tubulo-interstitial diseases. Maintaining a high degree of attention in the care of CKD patients with proteinuria is fundamental to effectively retard progression toward kidney failure. However, substantial research efforts are still needed to develop treatment strategies that may help the vast majority of CKD patients who eventually develop ESKD via mechanistic pathways other than proteinuria.


INTRODUCTION GENERAL INTRODUCTION
In end stage kidney disease (ESKD) patients, mortality due to cardiovascular disease (CVD) is 10 to 30 times higher than in the general population. For example, a 30-year-old dialysis patient has a similar CVD mortality risk to that of an 80-year-old in the general population. This increased risk likely reflects the very high prevalence of CVD, increased prevalence and severity of diabetes, hypertension and left ventricular hypertrophy, and non-traditional risk factors such as chronic volume overload, hyperphosphatemia, anaemia, oxidant stress, and other aspects of the uremic milieu. In this chapter, we focus on epidemiology and management of traditional and non-traditional CVD risk factors, and on ischemic heart disease, heart failure, pericardial effusion, valvular disease, and arrhythmia. T. Daugridas peter.
Chronic kidney disease (CKD) is a worldwide health problem, affecting millions of people (Di Angelantonio et al., 2007). The magnitude of the problem is poorly described by the number of people that will initiate renal replacement therapy (haemodialysis, peritoneal dialysis and renal transplantation), as the incidence of 1-3 per 10,000 per year in the general population may seem small). However, chronic dialysis treatment and transplantation have an enormous impact on the life of individual patients and their families, and renal replacement therapy is very costly (Lysaght, 2002; Dor et al., 2007). The annual worldwide costs are estimated at 70 to 75 billion US dollars to maintain the renal replacement therapy of the roughly 1.1 million worldwide dialysis patients in 2001. In Ghana, renal replacement therapy (mainly haemodialysis and peritoneal dialysis) is available only in two of the teaching hospitals, and the estimated cost of dialysis is GHC 57,600per patient per annum. This amount is rather high for a country with a per capita income of Patients with CKD have a markedly increased incidence of cardiovascular events and cardiovascular disease (CVD) mortality compared with age-matched counterparts in the general population .examined a large Medicare database of 1,091,201 patients to investigate the incidence atherosclerotic vascular disease, congestive heart failure, RRT and death. Individuals with early CKD were much more likely to die than reach renal replacement therapy (RRT), with rates per 100 patient years of 17.7 and 1.6 respectively. This is compared with the rate of 35.7 with atherosclerotic vascular disease and 30.7 with congestive heart failure, illustrating the extreme susceptibility of these individuals to CVD and premature death. These findings were further supported in a study of 27,998 patients with early stages of CKD followed up over 5 years to investigate rate of progression to RRT and mortality. In those individuals with CKD stages 2 and 3, 1.1% and 1.3% required dialysis, while the mortality rate was 19.5% and 24.3% respectively. There is therefore unequivocal evidence that subjects with CKD are among the highest-risk cohorts for cardiovascular events of any studied population. Current cardiovascular risk prediction charts do not adequately incorporate this profound additional risk in calculating 10-year event rates, leading to underestimations and suboptimal primary prevention measures in patients with CKD.
While recent data and consensus have challenged the position of diabetes mellitus as a true coronary heart disease risk equivalent, a growing body of evidence supports this degree of risk in CKD they are to progress to ESRD. Various pathophysiological pathways and explanations have been advanced and suggested to account for this, including endothelial dysfunction, dyslipidaemia, inflammation, left ventricular hypertrophy and cardiac autonomic dysfunction. In this review, we try to understand and further explore the link between CKD and CVD, as well as offering interventional advice where available, while exposing the current lack of RCT-based research and trial evidence in this area Epidemiological research in kidney diseases was long hampered by lack of a common definition of chronic kidney disease (CKD). In 2002 the Kidney Disease Outcome Quality Initiative (K/DOQI) proposed a classification of CKD for diagnosis and risk stratification.
In end stage kidney disease (ESKD) patients, mortality due to cardiovascular disease (CVD) is 10 to 30 times higher than in the general population. For example, a 30-year-old dialysis patient has a similar CVD mortality risk to that of an 80-year-old in the general population. This increased risk likely reflects the very high prevalence of CVD, increased prevalence and severity of diabetes, hypertension and left ventricular hypertrophy, and non-traditional risk factors such as chronic volume overload, hypophosphatemia, anaemia, oxidant stress, and other International Journal of Trend in Scientific Research and Development (IJTSRD) ISSN: 2456-6470 @ IJTSRD | Available Online @ www.ijtsrd.com | Volume -2 | Issue -4 | May-Jun 2018 Page: 2353 aspects of the uremic milieu. In this chapter, we focus on epidemiology and management of traditional and non-traditional CVD risk factors, and on ischemic heart disease, heart failure, pericardial effusion, valvular disease, and arrhythmia.
Definition: -Structural and functional abnormalities of the kidney for >3 month as manifested by either Kidney damage, with or without deceased GFR as defined by:- Pathologic abnormalities  Marker of kidney damage, including abnormalities in composition of blood in urine or abnormalities in imaging test.   Kidney failure <15 or dialysis Based on this classification increasing knowledge of the epidemiology and significance of chronic kidney disease have evolved. More prevalent hypertension, diabetes mellitus and obesity partly explained the increase. In addition to increasing age, these are all important risk factors for development and progression of CKD. This raises concern about future increased incidence of end stage renal disease (ESRD) and other complications of CKD including increased cardiovascular disease. Persons with CKD are predisposed to three types of CVD, atherosclerosis, arteriosclerosis, and cardiomyopathy when compared with age and gender matched persons with normal kidney function (Wail et al., 2005). In the past cardiovascular death was mainly viewed as the result of accelerated coronary heart disease (CHD). Although CHD is undoubtedly more frequent than in the background population, the importance of the two other, largely unresolved cardiovascular problems, Sudden death and cardiomyopathy (Remppis and Ritz., 2008).  Activation of the sympathetic nervous system Cardio renal syndrome:-Patients with ESRD are well known to suffer a high risk of cardiovascular morbidity and mortality, having more than 10-fold increased risk of cardiac death than age-/gender-matched controls in the general population. Cardiovascular risk is shown to increase even in early stages of CKD. Death due to cardiovascular disease is much more common in patients within all stages of CKD than reaching ESRD needing renal replacement therapy). Multiple explanations may exist for the high cardiovascular risk in CKD patients.
Traditional risk factors for cardiovascular disease, such as hypertension, diabetes mellitus, smoking and dyslipidaemia are risk factors for CKD as well, and highly prevalent in this population . In the course of declining renal function, kidney specific risk factors for cardiovascular disease like accumulation of uremic toxins, inflammation, anaemia, disturbances in calcium and phosphorous balance, lack of active vitamin D and sodium and water retention among others, will contribute to left ventricular hypertrophy (LVH), chronic inflammation, accelerated atherosclerosis, extra vascular calcifications and endothelial dysfunction. CKD patients are also less likely to receive risk-modifying medication and interventions compared to non-CKD patients. Just like cardiovascular disease is prevalent in patients with renal disease, primary heart conditions are commonly associated with renal dysfunction. Reduced renal perfusion, often predisposed by micro vascular and macro vascular disease in the context of the same vascular risk factors associated with cardiovascular disease, may hemodynamically affect kidney function in HF patients. Furthermore, neurohormonal activation, renal venous congestion and adverse effects of pharmacotherapies used in the management of HF, have been suggested as causes for the high prevalence of renal dysfunction in HF patients. Regardless the cause, impaired and worsening, renal function in patients with acute and chronic HF is associated with adverse outcomes and prolonged hospitalization. Even slight decrease in GFR is found to significantly increase mortality risk in patients with chronic HF. Combined heart and kidney dysfunction is common. Primary disorders of either kidney or heart often result in secondary dysfunction or injury to the other organ.
The cardiorenal syndrome (CRS) was earlier used to describe a relatively normal kidney that is dysfunctional because of a diseased heart, with the assumption that in the presence of a healthy heart, the same kidney would perform normally. The more recent recognition of the numerous negative effects of heart disease on kidney function and kidney disease on heart function led to a new definition of the CRS , dividing into 5 different subtypes ofcardiorenal syndrome .The present study included patients with chronic HF and thereby investigates topics related to cardiorenal syndrome type 2. Impaired kidney function in patients with chronic HF is associated with adverse prognosis and even slight decreases in estimated GFR (eGFR) significantly increase mortality risk.
Much of our knowledge on the relationship between HF and renal function originate from selected patient populations in clinical trials or hospitalized patients. There is limited understanding of the pathophysiology of renal dysfunction even in advanced heart failure. Hemodynamic issues as venous congestion and reduced renal perfusion due to powerful vasoconstriction are considered important. However, neurohormonal activation including the RAAS and SNS, oxidative stress, comorbidities and pharmacological heart failure treatment have a role as cardiorenal connectors affecting renal function . The explanation for the impaired prognosis observed in patients with chronic HF and CKD is also incompletely understood. A higher burden of comorbidities, more severe vascular disease and worsened cardiac function may explain part of the alteration.
Furthermore, large randomized trials that have shaped the treatment of chronic HF in the two last decades, have consistently excluded patients with significant renal disease. Lack of evidence based clinical treatment may cause that patients with chronic HF and renal dysfunction are less likely to receive potential life-saving treatment, thereby altering prognosis.   Abnormalities on resting electrocardiography are common in dialysis patients. Among patients who were enrolled in the 4D study (n = 50), 11% had a rhythm other than sinus; three of four patients with an alternative rhythm had atrial fibrillation (Krane et al.,

2009).
Most clinicians have been reluctant to administer prophylactic anticoagulation therapy for chronic AF in dialysis patients. Furthermore, the benefits versus risks from anticoagulation have not been accurately determined in these patients (Genovesi et al., 2009).
Dispersion of the QT interval has emerged as an important predictor of ventricular arrhythmia. The QT dispersion is simply the difference between the shortest and longest QT interval on a standard surface. This is a non-invasive measurement of myocardial repolarization in homogeneity and hence predisposition to re-entry arrhythmias. A QT dispersion above 80 Ms reflects a loss of synchronization in the repolarization process. The QT interval is partially influenced by the concentration of the dialyzable cations calcium, magnesium and potassium and may also be influenced by cardiac filling pressures (Fukuta et al.) To prevent haemodialysis-related myocardial arrhythmias, prolonged dialysis sessions with low ultrafiltration rates, Careful titration of target weight and administration of oxygen during dialysis are recommended. Additionally, beta blockers seem to be an important therapeutic option in high risk patients (Fukuta H et al., 2003).
Hemodialysis patients administered on digitalis therapy have increased risk of arrhythmia. Also duration of hemodialysis, and acetate containing dialysate have close relation with occurrence of arrhythmias among haemodialysis patients. A high calcium phosphate product predialysis may be correlated with increased incidence of ventricular arrhythmias (Antonio et al., 2008). Among patients with diastolic dysfunction, CHF results from impaired ventricular relaxation, which leads to an exaggerated increase in LV end-diastolic pressure for a given increase in LV end diastolic volume. As a result, a relatively small excess of salt and water intake leads rapidly to a large increase LV end diastolic pressure, culminating in the pulmonary edema (Parfrey and Foley, 2005).

Ischemic heart disease :-
Evaluation for coronary artery disease should be performed in dialysis patients with symptoms and/or signs of coronary artery disease, a change in symptoms and signs, including recurrent hypotension, heart failure that is unresponsive to changes in dry weight, and intradialytic hypotension that prevents attaining dry weight (Gill JS et al., 2005).
The K/DOQI guidelines recommend that, at initiation of dialysis, all patients should undergo baseline echocardiography and electrocardiography (K/DOQI, 2005). Anaemia in heart failure:-Chronic heart failure is a syndrome with various pathophysiological consequences. Neuroendocrine, metabolic and immunological changes are identified as HF develops. Anaemia has been recognized by clinicians in HF patients for decades, but has only recent years received attention with systematic research. CKD is a common comorbidity in HF patients with anaemia. The kidneys are essential in the endogenous production of erythropoietin, and renal dysfunction may induce anemia in HF patients creating a vicious circle, termed the "cardio-renalanaemia syndrome". In addition to renal dysfunction, anaemia of chronic disease, iron-deficiency and hem dilution appears to be important aetiologies of anaemia in HF patients). Treatment with ACE and ARB may also contribute to anaemia as these agents may inhibit erythropoiesis. Depending on the definition used and population studied, the prevalence of anaemia in HF patients varies from9 to 69 %).
Anaemia is identified as an independent prognostic factor of mortality in HF patients and haemoglobin levels are related to symptoms and quality of life . Increased myocardial workload due to hemodynamic and neurohormonal changes is a consequence of anaemia, thereby inducing cardiac remodelling and left ventricular hypertrophy (LVH). This may partly explain the impaired prognosis of anaemia in HF patients. Clinical trials investigating specific anaemia treatment with erythropoiesis stimulating agents (ESA) and intravenous iron in HF patients with anaemia have been promising in regard to symptoms and quality of life. Convincing data on mortality are missing and we do not yet know when to start anaemia treatment, treatment goals and who will benefit from treatment. Actually, we don't know if anaemia is a mediator or just a marker of poor prognosis in patients with chronic heart failure.

AIMS OF THE STUDY
The overall aim of the present study is to investigate the association between various risk factors of CVD and different stages of CKD in patients with kidney replacement therapy

The specific objective are:-
To classify the CKD patients into 5 stages according to GFR and albuminuria.  To correlate laboratory findings with CKD classes.  To determine the main cardiovascular risk factors in the patients.  To study the relationship between CKD progression and development of CVD.

Significance:-
 This study is carried out for the CKD in haemodialysis patients .  Identification of CVD risk factors among patients with CKD is potentially useful for raising awareness of the relationship between CKD and CVD.  Encouragement of clinicians to evaluate their CKD patients for CV risk factors, such risk factors may be used in monitoring the progression of the disease and predicting the future events.
 Initiation of treatment for CV risk factors at earlier stages of CKD, which may be effective in reducing CVD events both before and after the onset of kidney failure.

Study design:-
The present study is a cross sectional study, that was conducted from the beginning of March 2016 to the end of august, 2016.

Setting of the study:-
The study was carried out at the Nephrology Department of Dr B. R. A.M. HOSPITAL RAIPUR.

Population of the study:-
Patients from both genders who had CKD on Hemodialysis patient and registered in the Nephrology Department of Dr. B. R. A. M. HOSPITAL RAIPUR. The total number of cases in the department was 50 patients at the end of the study.

Study sample:-
Study sample comprised 50 subjects CKD on HD patients.

The exclusion criteria
 Patients with kidney replacement therapy haemodialysis,  Clinically overt inflammatory disease at the time of investigation.  Clinically significant over hydration or dehydration.  Patients on anti-lipid drugs.

Ethical considerations 1.
Coordination with the Ministry of Health was fulfilled 2. Patient of the participants were given a full explanation about the purpose of the study, assurance about the confidentiality of the information obtained through the questionnaire and blood analysis, and that they have the right to refuse to participate or to drop out in any phase of the study.

Data Collection
Data were collected by both direct and indirect methods.

The direct method
Laboratory investigations including blood sampling after 12-14 hour overnight fasting and the following blood tests were done for patients and controls: Creatinine, urea, , cholesterol, triglycerides, HDL, LDL, , haemoglobin, . Additionally, spot urine samples were tested for ACR. Glomerular filtration rate was estimated in all participating subjects according to the Schwartz formula. , weight, blood pressure were measured for each participant. Body mass index was also calculated for all subjects.

The indirect method
Face to face interview questionnaire was administrated for both patients and controls (Appendix 1), the questionnaire main content included: 1. Personal data.
2. History of the disease (for patients) 3. Physical activity 4. History of CVD in the patients, family

Statistical analyses
Data entry and statistical analyses were performed using SPSS (Statistical Package for Social Sciences) Results were expressed as frequency or Mean ±SD.

Materials
Parameters of clinical study:-50patients (34 males and 16 females with mean age 48.4249years) with CKD and dialyzed 50 long-term HD patients, were included in this one centre study. 50 patients of CKD patients yetdialyzed, the same group of HD patients as in the first study was used and no any healthy subjects were studied. Patients at different stages of CKD were included in a crosssectional study.

Chemicals and reagents
Chemicals and reagents used in this study are shown in Table 3.9.1.

Equipment
The main equipment that were used are listed in Table  3

Sampling and processing:-
Blood samples were collected from patients and controls who agreed to participate in the study after overnight 12-14 hr . Five ml blood were obtained from each subject and divided into EDTA tube (1.0 ml) and vacationer plain tube (4.0 ml). Vacationer plain tubes were left for short time to allow blood to clot, then clear serum samples were obtained by centrifugation at 4000 rpm for 10 minutes. A spot sample of morning urine in the fasting state was collected from each subject. Urine albumin, urine creatinine and CBC were done in the same day of collection. Serum samples were stored at -20 ºC until the time of performing the analysis. All biochemical analyses were done in the laboratory of the Dr. B.R.A.M.HOSPITAL RAIPUR.

Blood Pressure: -
Blood pressure was measured by trained personnel using a mercury sphygmomanometer and a stethoscope. Measurements were taken from the left upper arm after subjects had been sitting for >5 min in accordance with the recommendations of the American Heart Association (Kirkendall et al., 1967). Duplicate measurements were taken with a 5 minute rest interval between measurements and the mean value was recorded to the nearest 2.0 mmHg

URINALYSIS:-
Early morning urine was collected in plastic containers from the respondents and urine protein was determined using the dip-stick qualitative method (CYBOW™ DFI Co Ltd, Gimhae-City, Republic of Korea).

Principle
The test is based on the protein error of indicators principle. When pH is held constant by a buffer indicator, dyes release H+ ions because of the protein present and change colour from yellow to blue-green.

SAMPLE
COLLECTION AND PREPARATION :-Venous blood samples were collected after an overnight fast (12 -16 hours). About 7 mls of venous blood were collected and, 5 ml dispensed into vacutainer® plain tubes. After clotting, it was then centrifuged at 500 g for 15 min. The serum was stored at -80°C until assayed. The remaining 2 ml were dispensed into tubes containing 2.5 µg of potassium ethylenediaminetetraacetic acid (K2 EDTA) as an anticoagulant.

Cholesterol  Principle
The present method utilizes a phenol substitute (4aminoantipyrine (4-AAP) that performs like phenol but without being corrosive. The intensity of the red colour produced is directly proportional to the total cholesterol in the sample when read at 500 nm. Triglycerides in the sample are hydrolysed by lipase to glycerol and fatty acids. The glycerol is then phosphorylated by ATP to glycerol-3-phosphate (G3P) and ADP in a reaction catalysed by glycerol kinas. G3P is then converted to dihydroxyacetone phosphate (DAP) and hydrogen peroxide by glycerophosphate oxidise (GPO). The hydrogen peroxide then reacts with 4-aminoantipyrine (4-AAP) and 3, 5-dichloro-2-hydroxybenzen (3,5-DHBS) in a reaction catalyzed by peroxidise to yield a red coloured quinoneimine dye. The intensity of the colour produced is directly proportional to the concentration of triglycerides in the sample.

HDL-Cholesterol  Principle
The method employed herein is in a two reagent format. The first reagent contains anti human βlipoprotein antibody which bind to lipoproteins (LDL, VLDL and chylomicrones) other than HDL. The second reagent contains enzymes which then selectively react with the cholesterol present in the HDL particles. Consequently only HDL cholesterol is subject to cholesterol measurement. The primary reading is done at 600 nm and the secondary at 700 nm.

Urea Nitrogen (BUN)
Determination of urea nitrogen in serum is widely used as a screening test for renal function. When used in conjunction with the determination of creatinine in serum, it is helpful in the differential diagnosis of the three types of azotemia; pre-renal, renal and postrenal.

 Principle
The present procedure is based on a modification of the method of Talked and Schubert (1965). Urea is hydrolyzed in the presence of water and urease to produce ammonia and carbon dioxide. The liberated ammonia reacts with α-ketoglutarate in the presence of NADH to yield glutamate. An equimolar quantity of NADH undergoes oxidation during the reaction catalyzed by Glutamate dehydrogenase (GLDH) resulting in a decrease in absorbance (340 nm) that is directly proportional to the urea nitrogen concentration in the sample.

Creatinine
Creatinine measurements are used in the assessment of renal dysfunction. Elevated creatinine levels are found in renal diseases and insufficiency with decreased glomerular filtration (uraemia or azotemia if severe); urinary tract obstruction; reduced renal blood flow including congestive heart failure, shock and dehydration.

 Principle
This method is based on a modification of the kinetic procedure which is fast, simple and avoids interferences incorporating a surfactant and other ingredients to minimize protein and carbohydrate interferences. Creatinine reacts with picric acid in alkaline conditions to form a colour complex (yelloworange) which absorbs at 510 nm. The rate of formation of colour is proportional to the creatinine in the sample.(Fabiny and Ertingshausen, 1971)

Biological Activities
Human parathyroid hormone (hPTH) is a major physiological regulator of phosphocalcic metabolism. hPTH increases serum calcium concentration by its actions on kidney (enhancing tubular Ca2+ reabsorption and phosphate excretion) and bone (Stimulating osteoclastic activity and bone (stimulating osteoclastic activity and bone resorption). It indirectly affects intestinal absorption of Ca2+ by stimulating renal 1α-hydroxylation of 25 hydroxyvitamin D. The release of PTH is controlled in a negative feedback loop by the serum concentration of Ca2+. PTH is synthesized in the chief cells of the parathyroid glands and secreted as an 84 amino acid moleule called " intact PTH " which is the main bioactive product. This molecule is degraded by proteolytic cleavage between amino acids 33-37 at peripheral site to form biologically active amino terminal fragments which are cleared only by glomerular filtration, while the bioactive intact PTH and amino-terminal fragments are also metabolically degraded in the liver and other tissues. Thus the measurement of intact PTH correlates best with the hormone production and biological activity. horse radish peroxidase (HRP) are added. After an incubation allowing for the information of a sandwich: coated PAbs-human PTH-Mab -HRP the microtitre plate is washed to remove unbound enzyme labeled antibody. Bound enzyme-labeled anti body is measured through a chromogenic reaction. The chromogenic solution tetramethyl benzydine (TMB) is added and incubated. The reaction is stopped with the addition of stop solution and the microtitre plate is then read at the appropriate wavelength.

Calculated measurements :-
Glomerular filtration rate was calculated by MDRD fomula: GFR (ml/min/1.73m2)  Albumin/creatinine ratio ACR (mg/g) = Microalbumin in urine (mg/L) x1000 /creatinine in urine (mg/dl) x10 the urine creatinine value is multiply by 10 to convert mg/dL to mg/L, then divide the urine albumin value by the urine creatinine value to arrive at the ratio, then multiply by 1000 to express the value as (mg albumin/g creatinine).  Low density lipoprotein was calculated by Friedewald equation: LDL (mg/dl) = cholesterol -(HDL + triglycerides)

Biochemical analysis
Serum urea, creatinine, albumin, cholesterol, triglycerides, HDL, urine albumin, and urine creatinine were analyzed manually using Stat Fax-1904 plus spectrophotometer. Two levels of lyophilized multi-control sera ; normal and abnormal levels were analyzed with each run. The concentration of LDL was calculated from the results of a profile including total cholesterol, HDL and triglycerides using the Friedewald equation (LDL = cholesterol -(HDL + triglycerides/5)) (Kaplan and Szabo, 1983). Biomedical,. Complete blood count was measured using Cell-DYN 1800 cell counter,

The Kidneys 4.Location and structure
The kidneys lie against the dorsal body wall beneath the parietal peritoneum in superior lumbar region where they receive some protection from the lower part of the rib cage. The right kidney is positioned slightly lower than the left kidney. Each kidney (about 12.5 cm long, 7.5 cm wide and 2.5 cm thick) has a medial indentation (the hilus) in which there is two renal arteries, renal vein, and ureter. A fibrous renal capsule encloses each kidney.
The kidney has three regions, outer granulated layer called renal cortex, renal medulla that consists of cone shaped tissue masses called medullary pyramids, and renal pelvis which is a central space or cavity that is continuous with the ureter (Marieb, 2003).
LOCATION-the kidney occupy the epigastria, hypochondric, lumber , umbilical region. Vertically they extend from the upper border of 12 th thorasicvertibra to the centre of body of 3 rd lumber vertebra. The right kidney is slightly lower than the left and the left kidney is a little nearer to the median plane than right.
The trans pyloric plane passes through the upper part of the hilus of the right kidney, and through the lower part of the hilus of the left kidney.

SHAPE SIZE WEIGHT
-each kidney is about 11 cm long , 6 cm broad and 3 cm thick. The left kidney is a littlie longer and narrower than the right kidney .on an average the kidney weight 150gm in male and 135gm in female . the kidney is raddish brown in colour.
International Every nephon is associated with two capillary beds: The glomerulus and the peritubular capillary bed. The glomerulus is both fed and drained by arterioles. The afferent arteriole is the feeder vessel, and the efferent arteriole receives blood that has passed through the glomerulus. The efferent arterioles then breaks up to form the peritubular capillary bed, which closely clings to the whole length of the tubule. The peritubular capillaries then drain into an interlobular vein that leaves the cortex (Marieb, 2003).

FUNCTIONS OF THE KIDNEYS:-
The kidneys play an important role in the maintenance of normal body function. The basic function of the kidneys has to do with the formation of urine through complex filtration, reabsorption and secretion mechanisms. In addition, the kidneys also excrete urea and uric acid which are the end products of protein and nucleic acid metabolism.
The kidneys regulate fluid, electrolyte and acid base balance of the body and create a steady environment for the metabolic processes of tissues and cells. This function is essential for life and it is realized by balancing solute and water transport, excreting metabolic waste products, conserving nutrients, and regulating acid-base balance in the body.
Additionally, the kidney also produces three important hormones; erythropoietin which stimulates the production of red blood cells, renin which regulates blood pressure and calcitriol (the active form of vitamin D) which helps in regulation of plasma calcium levels.

Principles of renal pathophysiology:-
Renal injury can be characterized as either acute or chronic. Each has a distinctive clinical expression.

Acute kidney injury
Acute renal failure (ARF) is defined as ″a rapid decline in renal filtration function″. This condition is usually marked by a rise in serum creatinine concentration or azotemia (a rise in blood urea nitrogen concentration) immediately after a kidney injury.
Emergency dialysis may be needed until the situation resolves and the kidneys begin functioning again (Agraharkar, 2007). Acute renal insufficiency typically presents with the symptoms of volume overload secondary to impaired urine formation or excretion (Glassock, 1987).
The consequent retention of sodium and therefore of water can cause an expansion of the intravascular spaces and extravasation of fluid into the interstitial space throughout the body. The resulting volume expansion can therefore present as peripheral edema, pulmonary edema, or congestive heart failure. In acute renal failure both academia (resulting from failure to excrete or buffer the endogenous metabolic production of acids) and hyperkalemia (resulting from the lack of excretion of dietary potassium) can result in cardiac arrhythmias and sudden death. Acute uraemia has a particularly inhibitory effect on platelet function resulting in increase in the bleeding tendency (Kissane and Schreiner, 1990).

Chronic kidney disease
In chronic renal failure the metabolic consequences of uraemia are slowly progressive in nature. Chronic acidosis can affect myocardial contractility; contribute to central nervous system toxicity. Water and salt intake persistently exceeds excretory capacity, edema formation occurs. Chronic sodium retention can manifest as persistent arterial hypertension. Kidney also fails to convert 25-hydroxyvitamin D to the metabolically active 1, 25-dihydroxyvitamin D, resulting in the defective absorption of calcium from the intestinal tract; secondary hypocalcemia induces secondary hyperparathyroidism with concomitant demineralization and resorption of bone. Depression of red cell production is the consequence of decreased renal production of the hormone erythropoietin.
Increased red blood cell destruction resulting from uremic toxins as well as the mechanical damage to red cell observed in a variety of glomerular disease. Finally, patients with chronic kidney failure had depressed cellular immunity and humoral immunity (Kissane and Schreiner, 1990).

CHRONIC KIDNEY DISEASE Definition of CKD:-
The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) in the USA defines CKD as ″kidney damage for ≥ 3 months, as confirmed by kidney biopsy or markers of kidney damage, with or without a decrease in GFR or GFR < 60 mL/min/1.73 m2 for ≥ 3 months, with or without kidney damage″.
Kidney damage is ascertained by either kidney biopsy or markers of kidney damage, such as urine abnormalities (proteinuria), blood abnormalities or abnormalities on imaging studies (NKF, 2002). Glomerular filtration rate:provides an excellent measure of the filtering capacity of the kidneys. A low or decreasing GFR is a good index of CKD. Since the total kidney GFR is equal to the sum of the filtration rates in each of the functioning nephrons, the total GFR can be used as an index of functioning renal mass (Rose, 1984) Proteinuria :-Normal urinary protein excretion in an adult is less than 100 mg/24 h. Higher levels of excretion (more than 200 mg/24 h) suggest that glomerular pathology allows the passage of macromolecules such as albumin, which are not normally filtered. Excretion rates tend to increase on standing, during exertion, or with fever. Pressor agents such as angiotensin and norepinephrine tend to increase proteinuria.
In health, proteinuria results from tubular protein excretion, particularly Tamm-Horsfall protein.
Albumin is the pre-dominant protein filtered by the glomerulus, and therefore it is the most consistent marker of glomerular pathology. In health, albumin contributes little to urinary proteinuria (around 12 mg/24 h), as proteins crossing the GBM are mainly reabsorbed and degraded via receptor-mediated endocytosis. This process shows a preference for cationic proteins and only a limited capacity for albumin, resulting in even minor glomerular abnormalities raising albuminuria. Microalbuminuria refers to albumin excretion in the range of 30 to 300 mg/24 h (20 to 200 µg/min). This equates to a urinary albumin-creatinine ratio (ACR) of 17 to 250 mg/g for menand 25 to 355 mg/g for women. not only defines the presence of CKD but also has important implications for diagnosis of the type of kidney disease and is associated with a worse prognosis for both kidney disease progression and the development of CVD (Sarnak et al., 2003).
Twenty-four hour or other timed collections were the traditional way to measure urine albumin excretion (UAE) but measuring urine albumin/creatinine ratio (ACR) in a spot collection of morning urine in the fasting state is currently recommended as a simple, quick and comparatively accurate way of determining albuminuria Albuminuria is defined as an ″ACR of 30 mg/g or higher″, with microalbuminuria defined as an ″ACR of 30 to 300 mg/g″, and macroalbuminuria defined as an ″ACR over 300 mg/g″ (Coresh et al., 2007).

Classification of CKD
Chronic kidney disease has been classified into various stages for the purpose of prevention, early identification of renal damage and institution of preventive measures for progression of the primary damage and appropriate guidelines for instituting management for prevention of complications in severe CKD (Vijayakumar et al., 2007).
National kidney foundation classified CKD into 5 stages according to the level of GFR (Table 2.3). For stages 1 and 2, kidney damage was assessed by spot albumin-to-creatinine ratio (NKF, 2002).

Cardiovascular disease in CKD patients:-
Arterial vascular disease and cardiomyopathy are the primary types of CVD. In CKD, it is useful to consider two subtypes of arterial vascular disease, namely atherosclerosis and arteriosclerosis or large vessel remodelling (Sarnak et al., 2003).

Epidemiology of CVD in CKD:-
Cardiovascular disease is frequently associated with CKD, and CKD appears to be a risk factor for CVD. The National Kidney Foundation, American Heart Association, and the Seventh Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure have classified the presence of chronic kidney disease as a cardiovascular risk factor (Shlipak et al., 2005).
National Kidney Foundation Task Force on Cardiovascular Disease in Chronic Renal Disease issued a report which showed that there was a high prevalence of CVD in CKD and that mortality due to CVD was 10 to 30 times higher in dialysis patients than in the general population. The task force recommended that patients with CKD be considered in the "highest risk group" for subsequent CVD events (Levey et al., 1998).
Cardiovascular disease accounts for approximately half of deaths in ESRD. The incidence of myocardial infarction and stroke in the dialysis population is 5 to 15 fold higher in ESRD. This increased risk is only partially explained by a high prevalence of atherosclerotic cardiovascular disease (ASCVD) and traditional ASCVD risk factors at the initiation of dialysis (Longenecker et al., 2002).
It was recognized that earlier stages of CKD also are a risk factor for CVD mortality. The risk for death from CVD was 1.8 times greater for persons with an estimated GFR of less than 70 mL/min per 1.73 m2 than for those with a GFR of 90 mL/min per 1.73 m2 or more after adjustment for age, race, sex, systolic blood pressure (SBP), serum total cholesterol level, BMI, diabetes, family history of CVD, physical inactivity, and level of education

Figure-showing Stages of hypertension
Hypertension is one of the most common traditional cardiovascular risk factors that is highly prevalent in CKD (Sarnak et al., 2003). Chronic kidney disease associated hypertension develops by a large variety of pathophysiological mechanisms. While fluid overload and activation of the renin-angiotensin system have long been recognized as crucial pathophysiological pathways, sympathetic hyperactivation, endothelial dysfunction and chronic hyperparathyroidism have more recently been identified as important factors contributing to CKD-associated hypertension (Hadtstein and Schaefer, 2008).
The prevalence of CKD-associated hypertension varies between 30 % and 100 % depending on the target population, cause of renal disease, and level of renal function (Blankestijn, 2005).
Obesity and physical inactivity:weight Body mass index (BMI) Body mass index is defined as a measurement of the relative percentages of fat and muscle mass in the human body, in which weight in kilograms is divided by height in squared meters and the result is used as an index of obesity (World Health Organization, WHO, 2000). Also, it is well-known that patients with impaired renal function exhibit significant alterations in lipoprotein metabolism. Although lipid abnormalities were originally considered as complications of ESRD, these changes can be present in early stages of CKD and may actively participate in the pathogenesis of serious complications such as ACVD (Tsimihodimos  et al., 2008).

Classification of BMI
The most common quantitative lipid abnormalities in predialysis CKD patients are hypertriglyceridemia, increased concentrations of triglyceride-rich lipoprotein remnants, reduced high density lipoprotein (HDL) levels as well as increased concentrations of lipoprotein (Vaziri and Moradi , 2006). Urinary albumin excretion between 30 and 300 mg/day, or 30-300 mg/g is defined as microalbuminuria, any urinary albumin value below these limits is considered as normal UAE, whereas any value above them reflects the presence of macroalbuminuria or clinical proteinuria (American Diabetes Association, 2004; Kidney Disease Outcomes Quality Initiative, 2004).
It has long been noted that subclinical elevations of UAE are related to higher risk of subsequent development of clinical nephropathy in patients with diabetes mellitus, and that increased UAE was associated with higher risk for CV events and mortality in both diabetic and non-diabetic individuals (Mogensen, 1984; Stehouwer et al., 1992).
Prolonged protein loss leads to hypoalbuminemia, hyperlipidemia and coagulation abnormalities following hyperfibrogenemia, increase in Factor III and Von Willebrand factor. Microalbuminuria occurring in early diabetic nephropathy is a marker of vascular endothelial dysfunction (Amaresan, 2005).
Anaemia:-Anemia is simply a hemoglobin level lower than the normal range for a particular age and sex of the patient. Anaemia is defined as a low red blood cell count.

The normal range for Hb and RBC:-
Since the red blood cells contain haemoglobin, we simply measure its concentration. The kidney being the main source of erythropoietin, anaemia is apparently an integral part of advancing renal failure. Anaemia exerts an independent effect on CVD in CKD. For every 1g/dl drop in mean haemoglobin , the risk of cardiac failure increases by 25% and risk of death increases by 14% ( Metivier, 2000).
Depression of red cell production is the consequence of decreased renal production of the hormone erythropoietin. Increased red blood cell destruction resulting from uremic toxins as well as the mechanical damage to red cell observed in a variety of glomerular disease (Kissane, 1990) The pathophysiology of CVD induced by anaemia- Calcium/phosphorus metabolism:-In humans with CKD, there appears to be a relationship between disorders of mineral metabolism (abnormal levels of serum calcium and phosphorus), abnormal bone (renal osteodystrophy), and vascular calcification (Moe and Chen, 2004).
Progressive nephron loss is associated with phosphate retention and hypocalcaemia early in the disease, but then can develop hypocalcaemia when given calcium or vitamin D. This triggers increased parathyroid hormone (PTH) activity.
The secondary hyperparathyroidism along with hyperphosphatemia and increased calcium phosphate ion product are identified as independent cardiovascular risk factors (Brancaccio et al., 2002).
Secondary hyperparathyroidism results in impaired calcitrol synthesis, increased skeletal resistance to PTH, increased parathyroid cell hyperplasia, and decreased expression of calcium sensing receptors. These end in decreased cardiac contraction, LVH and valvular calcification.

Characteristics of the study population
The present study is a cross sectional study, that included 50 patient of CKD among haemodialysis.

Socio-demographic characteristics of the study population
The distribution of the study population by gender showed that males represented 34 (68%) and of the females represented 16 (32%) of the patients.  Obstructive uropathy 5.7% Graph showing:-Etiology factor of CKD patient   All the participants were tested for the function of the kidney. Glomerular filtration rate was determined from serum creatinine and subjects height according to Schwartz formula . Albumin/creatinine ratio was determined from spot urine sample to indicate the damage of the kidney and used as a marker of CVD event. Glomerular filtration rate and ACR were used in defining and classifying CKD.

Chronic kidney disease-specific CVD risk factors
The participants were investigated for some of CVD risk factors that are considered specific to CKD such as anaemia, and albuminuria.   had normal ACR while other patients had abnormal ACR 43 albuminuria. The results showed that the patients enrolled in this study could be classified into stages of CKD stage 1, 2, 3 where stage was not present. Stage 4 rare incidence, followed by stage 5, The increased presentation of stage 5 in the study population is due to initiation of haemodialysis dialysis for many of stage 5 patients and in some cases death of the patients before reaching stage 5. Absence of stage 1,2 ,3,these stages referred and hospitalized in the Nephrology Department of DR. B.R.A.H. RAIPUR. since the disease in such early stages is asymptomatic and criteria of kidney impairment is very mild especially in stage 1. Unfortunately no data regarding the prevalence of CKD and CKD stages is available in our populations to compare the study findings.

Hypertension
The present study showed that there is association between hypertension and CKD. Forty seven percent of patients had a history of hypertension and were given the anti-hypertensive drugs. The means of systolic and diastolic blood pressure were significantly higher in patients as compared to controls. The relationship between hypertension and progression of CKD was clear within stages of CKD since the frequency of hypertensive patients gradually increased through stages 2, 3 and 5.
The results are in agreement with those of other authors who found an association between hypertension and CKD and showed that hypertension was frequent in all stages of CKD Database estimated the prevalence of hypertension among Adult with CKD as being closer to 50% and demonstrated that renal function in hypertensive adult with CKD deteriorated significantly more rapidly than in normotensive adult, and raises the possibility that improved blood pressure control may be one method of slowing the progression of CKD in this population (Mitsnefes et al., 2003).
In another study that was carried out on CKD adult patients not receiving renal replacement therapy showed that 76% of patients had history of hypertension. Locatelli et al. (2003) found out that hypertension plays a major role in determining cardiac damage at all stages of CKD, including the dialytic phase. (Wheeler et al., 2003)

Physical inactivity, obesity and family history of CVD
Half of the patients of the present study were physically inactive. Frequency of physical inactivity among patients was two-fold higher as compared to controls. With respect to CKD stages the results showed that all cases in stage 2 were active, inactivity was increased in stages 3 and 4, and in stage 5 all cases were inactive. This indicates a positive correlation between physical inactivity and CKD progression. (2005) stated that low physical activity is a predictor of cardiovascular mortality in persons with chronic kidney disease. In the present study BMI was used as an indicator for obesity.
The results showed that the frequency of underweight among patients was higher than controls. Overweight and obesity were not encountered in the study population. Chronic kidney disease stages in the study revealed that the frequency of underweight increased as GFR declined through stages 2, 4 and 5. Our results are in accordance with the study of Litwin et al. (2005) who showed that patients with CKD were lighter and had lower BMI than controls. The variation in the results may be because we studied the presence of obesity in our study population who are already suffering from CKD and not CKD as a sequel to obesity. In studying family history of CVD as a risk factor of CVD in the study population, the results indicated that there was no difference between patients and controls since they had nearly equal percentages of subjects with family history of CVD. This observation indicates that there is a genetic factor in causing CVD.

Dyslipidaemia
In the general population, high plasma concentrations of LDL cholesterol, low concentrations of HDL cholesterol, and to some extent high total triglyceride concentrations are associated with increased atherosclerotic CVD risk (Wilson et al., 1998). There seems to be a gradual shift to the uremic lipid profile as kidney function deteriorates (Kronenberg et al.,  2002).
Uremic lipid profile shows dyslipidaemia with elevated cholesterol, triglyceride and decreased HDL. Our study showed significant increase in total cholesterol, triglycerides and LDL in the patients as compared to the controls. The results also revealed significantly lower level of HDL in the patients. A gradual shift to the uremic lipid profile as CKD progresses was evident in CKD stages of the present study (gradual increase of cholesterol, triglycerides, LDL, and decrease in the levels of HDL). This finding is in agreement with other studies that assessed the association between CKD and some CVD risk factors including dyslipidemia. Studies conducted on older patients in different stages of CKD found that the CKD patients had high prevalence of dyslipidemia 6.5 Chronic kidney disease specific CVD risk factors:-

Albuminuria
Elevation of albuminuria is related to higher risk of subsequent development of clinical nephropathy and that increased albuminuria is associated with higher risk for CVD events (Mogensen, 1984).
More than one method can be used to determine urine albumin execration (KDOQI, 2004). In the present study ACR in spot morning urine samples was used to measure albuminuria.
The results showed that there was association between CKD and increased level of ACR with significant difference between patients and controls. Macroalbuminuria (ACR> 300 mg/g) was predominant in the patients followed by microalbuminuria (ACR= 30-300 mg/g), while few patients (8.3%) had normal albuminuria (ACR<30 mg/g). Albuminuria showed irregularity between stages of CKD, i.e. ACR levels fluctuated between stages.
This irregularity can be attributed to the cause of the renal disease, since albuminuria varies according to the cause of the renal disease (Sarnak et al., 2003).
Our findings are congruent with other studies, which suggested that albuminuria is a common feature in CKD and is related to the underlying glomerular or interstitial damage reported that albuminuria was frequent even in early stages of CKD.

Anaemia
Anaemia has been shown to be significantly associated with LVH in both dialysis patients and patients with early CKD, suggesting that anaemia is primarily implicated in the development of LVH in CKD (Silverberg et al., 1998 and Levin et al.,  1999).
Anaemia is a potentially modifiable risk factor; its treatment seems to have a more beneficial effect on LVH regression if it is given as early as possible during the course of CKD and before patients have reached ESRD In the present study, the majority of patients were anaemic and the mean values of haemoglobin 9.51 showed significant decrease in patients as compared to controls. The results showed continuous decrease of haemoglobin in stages 3, 4 and 5, which indicate an association between anaemia and CKD progression in the study population. (Locatelli et al., 2003)
Hypertension was considered when blood pressure was more than 140/90 mmHg. All patients were categorised into hypertensive and normotensive group according to blood pressure. Findings of 2D-echo were compared among hypertensive and normotensive ESRD patients albuminuria, the majority of the patients 86% (43) had albuminuria and normal14%(7)patient.

Recommendations:-
 Patients with CKD should be classified into stages according to the NKF-KDOQI and routinely tested for GFR and ACR levels to observe the progression of the disease.  Regular evaluation of CVD risk factors in CKD patients is needed for early diagnosis of these risk factors.  Aggressive management of CVD risk factors, especially modifiable risk factors such as: hypertension, anaemia, dyslipidemia, and physical inactivity in early stages, is important in controlling the disease progression and may reduce the CVD events.  Increase attention to CVD events, even at early stages of CKD, not only by nephrologists, but more importantly by cardiologists and the general medical community.  Encourage the general physician for early referral of the patients with primary kidney deterioration to the nephrology centers will enable early prevention of CVD.
 Increase awareness of CKD and its complications and methods of control and prevention, on the level of public community, is important in reducing its adverse consequences.  Further studies are needed to investigate other emerging cardiovascular risk factors, such as homocysteinaemia, High sensitivity C-reactive protein, lipoprotein (a), and oxidative stress. ultrasonographic measurements such as the measurement of increased intima-media thickness (IMT) of large arteries, is important as early marker and sensitive predictor of CVD events in CKD patients.  Regular reporting and documentation on the incidence and prevalence of CKD, in our community.