CHAPTER ONE

INTRODUCTION AND LITERATURE REVIEW
1.1. Introduction:
End stage renal disease (ESRD) is a major health problem and each year the number of patients is increasing. Chronic renal failure (CRF) is the final common pathway of a number of kidney diseases. The choices for a patient who reaches the point where renal function is insufficient to sustain life are: chronic dialysis treatments, renal transplantation, or death. With renal failure of any cause, there are many physiologic derangements. Homeostasis of water and minerals (sodium, potassium, chloride, calcium, phosphorus, magnesium, sulfate), and excretion of the daily metabolic load of fixed hydrogen ions is no longer possible. Toxic end-products of nitrogen metabolism (urea, creatinine, uric acid, among others) accumulate in blood and tissue. Finally, the kidneys are no longer able to function as endocrine organs in the production of erythropoietin and 1, 25-dihydroxycholecalciferol (calcitriol). If the disease becomes irreversible, patients must always be hemodialyzed. Renal replacement treatment (RRT) techniques include dialysis, haemofiltration and combination of the two and transplantation. Dialysis is used in cases of acute renal failure until renal function improves. It may also be used to prepare patients for transplantation and to maintain them until the transplant functions adequately. Dialysis procedures remove nitrogenous end-products of catabolism and begin the correction of the salt, water, and acid-base derangements associated with renal failure. Dialysis is an imperfect treatment for the myriad abnormalities that occur in renal failure, as it does not correct the endocrine functions of the kidney. The measurement of delivered dose of renal replacement treatment (RRT) can be described by various terms: efficiency, intensity, frequency, and clinical efficacy. For the quantification of the dialysis dose two parameters are most commonly used namely the normalized dose of dialysis (Kt/V value) and the urea reduction rate (URR). Numerous studies have demonstrated a correlation between the delivered dose of hemodialysis and patient mortality and morbidity and the normalized dose of dialysis (Kt/V) as an index of dialysis efficacy. Values of <1.0 have been associated with higher rates of morbidity and mortality than values >1.0. Recent data suggest that values of (Kt/V) greater than 1.2 or 1.3 is ideal. Lowrie EG, Zhu X and Lew NL (1998) examined the effect of dialysis dose on mortality. He found that with an increase in average URR over time, URR may have become less important as a predictor of mortality (3). Eknoyan G and Levin N (2002) reported

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that a minimum Kt/V of 1.2 thrice weekly is indicated as standard. (5) Brause M, Nuemann A, Schumacher T, Grabensee B and Heering, found that higher Kt/V values (0.8 versus 0.53) were correlated with improved uremic control and acidbase balance. Investigators from the Cleveland Clinic found that a mean Kt/V of (1.0) was associated with increased survival. (41)

1.2. Literature Review: 1.2.1. The Kidneys Structure and Function:
The kidneys are a paired organ system located in the retroperitoneal space. Each kidney weighs about 150 grams and is bean shaped with central hilus on the medial side, where vessels, lymphatic, and renal pelvis join.(7) The kidneys are each composed of about one million nephrons, the major functions of which are to remove from the plasma various metabolic waste products, and to maintain the volume and composition of extracellular fluid (ECF). This is achieved by production of a large volume of glomerular filtrate, which is then subjected to selective reabsorption as it passes down the tubules. The main purpose of this system is to excrete the required quantities of waste products while conserving water and electrolytes. (8) The kidneys receive 20% of cardiac output passing through the glomeruli, where around 20% of the plasma volume (550 ml/min; 800 liters/day) is filtered off giving glomerular filtration rate (GFR) of 120 ml/min (180 liters/day). The process of filtration is aided by the high pressure in the glomerular capillaries which is due to their position between two arterioles. The capillary walls consist of vascular endothelium having cytoplasmic fenestrations allowing direct contact between the content of the capillary and the glomerular basement membrane. Outside the basement membrane is the layer of visceral epithelial cells (podocytes), which make contact with the basement membrane by cytoplasmic processes (pedicels). The factors which regulate passage across the glomerular capillary wall include the pressure differences across the wall, the sieving effect of the slit pores and the negative charge of the basement membrane which retards the passage of negatively charged macromolecules, especially proteins. (8) Each glomerulus is composed of several lobules with the capillary loops lie at the periphery, while the core is made up of mesangial cells. The mesangial cells have a number of functions, including a structural supportive role; they also contain actomyosin and may regulate blood flow through the glomeruli. They have phagocytic properties and are responsible for maintenance of the basement membrane. (8)

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Reabsorption in the proximal convoluted tubule is both active and passive. The epithelial cells have brush border consisting of fine microvilli which increases the cellular absorptive area. The driving force of sodium reabsorption leads to passive reabsorption of urea, chloride and water, down concentration, electrical and osmotic gradients, respectively. Most of the filtered glucose and amino acids and much of the potassium, bicarbonate and phosphate are also actively reabsorbed. (8) Thereafter the thin descending and thin ascending limbs of the loop of Henle allow equilibration between the tubular lumen and interstitium. This maintains the hypertonicity of the interstitium which is essential to the mechanism of urine concentration. The next segment of the nephron is the thick ascending limb of the loop of Henle which continues the reabsorptive function of the proximal tubule. (8) In the distal convoluted tubule, active sodium reabsorption takes place influenced by aldosterone and in exchange there is secretion of hydrogen ions and potassium. Final adjustment of water balance occurs both in the distal tubule and collecting tubule. In states of water depletion, antidiuretic hormone (ADH) acts on these parts of the tubule to make them permeable to water which is then reabsorbed into the hypertonic interstitium down an osmotic gradient, leading to the production of a low volume, concentrated urine. Thus, tubular function each day reduces the 180 liters of glomerular filtrate to around 1.5 liters of urine which enables waste products to be excreted in a high concentrated form. (8) In addition to their homeostatic and excretory roles, the kidneys also have hormonal and metabolic functions. Specialized cells in the juxtaglomerular apparatus secrete rennin, an enzyme which converts plasma angiotensinogen to angiotensin I. Angiotensin converting enzyme then converts angiotensin I to angiotensin II which raises blood pressure by means of its vasoconstrictor effect and stimulation of aldosterone secretion by adrenal cortex. (8) The kidneys secrete erythropoietin which stimulates erythropoiesis. Deficiency of erythropoietin is the main cause of the severe anaemia which is characteristic of advanced chronic renal failure. (8) One of the most important metabolic functions of the kidneys is the hydroxylation of vitamin D. The proximal tubules contain the enzyme 1α hydroxylase which is necessary to convert 25-hydroxyvitamin D3 (25(OH) D3) to 1, 25-dihydroxyvitamin D3 (1, 25(OH)2 D3), the active form of vitamin D3, whose main effect is to increase calcium absorption from the intestine. The deficiency of 1, 25(OH)2 D3 which occurs in chronic renal failure and has important role in the production of renal osteodystrophy. (8)

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1.2.2. Urea:
Urea constitutes nearly the half non protein nitrogenous substance (NPN) in the blood. It's synthesized in the liver from Co2 and ammonia that rises from deamination of ammonia of amino acid in the reaction of urea cycle. Which is major excretory product of protein metabolism and carried in the blood to kidney, where is readily filtered from plasma by glomerulus, most of the urea in the glomerulus is excreted in the urine, although up to 40% is reabsorbed by passive diffusion during passage of the filtrate through renal tubules of hydration . Small amount of urea (<10% of total) are excreted through often used as index of glomerular function but creatinine is more accurate and reliable assessment because urea production is increased by high protein intake, dehydration, in catabolic stales and absorption of amino acid and peptide after gastrointestinal tract hemorrhage while production is decreased in patient with low protein intake, malnutrition, repeated dialysis, and sometime patient with liver disease. (7\9) Differentiation of the cause of abnormal urea concentration is aided by calculation urea nitrogen/creatinine ratio which is normally 10:1, 20:1. (11) A low blood urea nitrogen/ creatinine ratio is observed in conditions associated with decrease urea production such as low protein intake, patients on repeating dialysis, nephritic syndrome malnutrition, acute tubular necrosis, excessive fluid (may cause over hydration lead to low BUN value), sever muscle injury, syndrome of inappropriate antidiuretic hormone secretion (SIDH), excessive alcohol consumption. Normal changes in renal flow during pregnancy will also lower BUN. (12,10) Various study show signs of malnutrition in 23-76% of hemodialysis (HD) and 18-50% of peritoneal dialysis (PD) Patient. (13,14)

1.2.3. Creatinine:
Creatinine is break down product creatine, which is an important part of muscle. Female have usually a lower creatinine than male, because usually have less muscle mass. It's synthesized in the liver from arginine, glycine and methionine then transported to muscle and converted to phosphor-creatine. Creatine phosphate loss phosphoric acid and creatine loss water to form creatinine which passes to plasma. (7) Creatinine is excreted into circulation and relative constant rate that has been shown to be proportional to individual's muscle mass. It is removed from the circulation by glomerular filtration and excreted in the urine, additional amount of

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creatinine are secreted by glomerular filtration and excreted in the urine, additional amount of creatinine are secreted by proximal tubules. Small amount may also be reabsorbed by renal tubules, especially at low flow rate. (15)However some reports indicated that the protein content in the diet and excessive exercise may cause slight increase in plasma creatinine concentration. (16,17)

1.2.4. The Renal Failure:
Due to many causes kidneys function could be impaired leading to what is known as renal failure (RF) and can be classified as either acute or chronic. Failure of renal function may occur rapidly producing the syndrome of acute renal failure (ARF). This is potentially reversible since, if the patient survives the acute illness, normal renal function can be regained. However, chronic renal failure (CRF) develops insidiously, often over many years, and is irreversible, leading to endstage renal failure. 1.2.4.1. Acute renal failure (ARF): Acute renal failure (ARF) is characterized by a rapid loss of renal function, with retention of urea, creatinine, hydrogen ion and other metabolic products and, usually but not always, oliguria (<400 ml urine/24h) .Although potentially reversible, the consequences to homoeostatic mechanisms are so profound that this condition continue to be associated with a high mortality furthermore ARF often develops in patients who are already severely ill. (9) ARF is conventionally divided into three categories, according to whether renal functional impairment is related to the decrease in renal blood flow (prerenal), to intrinsic damage to the kidneys (intrinsic or renal), or to urinary tract obstruction (post renal). Should any of these occur in a patient whose renal function is already impaired, the consequences are likely to be more serious. (9) 1.2.4.2. Chronic renal failure: CRF is slowly progressive, irreversible cessation of renal function manifesting as biochemical, metabolic, fluid, electrolyte and acid-base imbalances. Often a gradual decline in glomerular filtration rate (GFR) occurs over a period of years, however for diagnosis of chronic renal failure GFR must be reduced for at least 3-6 ml/min. (18) CRF implies persistent impairment of both glomerular and tubular function of gradual onset and severity that the kidneys are no longer able to keep internal environment normal. And as the name indicated, CRF defined as deterioration in renal function lasting longer than 3months. (19)

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CRF is often progressive, whatever the initial causes, because loss of nephrons lead to further destruction of intact nephrons. This progressive loss of renal function is due to several mechanisms including adaptive changes in glomerular haemodynamics, direct effect of hypertension on glomerular structure and function and phosphate retention. Progressive renal failure is associated histologically with progressive glmerulosclerosis, tubulointerstitial fibrosis and vascular-sclerosis. (20) Chronic renal failure may rarely follow an episode of acute oliguric renal failure .It is more usually the end result of a variety of chronic conditions which include glomerulonephritis, obstructive uropathy, polycystic, renal artery stenosis and tubular dysfunction. In most case of acute oliguric renal disease there it diffuses damage involving the majority of nephrons and, if untreated, this would lead to early death and patient who survives long enough to develop chronic renal disease most have some functioning nephrons. Histological examination shows that not all nephrons are equally affected some may be completely destroyed, other may be almost normal, and yet others may have more damage to some parts of the nephron than to other some of the effects of chronic renal disease can be explained by this patchy distribution of damage. (21) 1.2.4.2.1. Etiology of CRF: The cause of CRF may be classified as the following (22): • Congenital and inherited disease; such as polycystic kidney disease. • Vascular disease; such as vasculitides and arteriosclerosis. • Glomerular disease; including primary and secondary glomerulonephritis. • Interstitial diseases; including chronic pyelonephritis vesicoureteric reflux, tuberculosis, analgesic nephropathy, nephrocalcinosis, schistosomiasis, diabetic nephropathy and hypertension. • Obstructive uropathy; obstruction of the urinary tract by stones, fibrosis or tumors. Studies on patient starting dialysis in Europe in 1987 showed that glomerulonephritis account for about 24.4% of cases followed by pyelonephritis (16.6%), diabetes mellitus (DM) (13%), renal vascular disease (9.8%) and Acute poly cystic Kidney Disease (APKD )(8.2%). In about 24% of cases the cause was unknown and the remainders are due to miscellaneous cause. (23) One of the most important changes over decade is the increase in the patients with diabetic

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nephropathy for renal replacement therapy and DM comes top of the list among the causes of CRF in USA accounting for about 34% of all cases.(24) In tropical countries, including Sudan, endemic diseases are major causes of CRF. Plasmodium malariae and Schistosoma haematobium were reported to be among the most common causes of CRF in Nigeria and Zimbabwe respectively. Other causes include tuberculosis and Schistosoma mansoni causing glomerularnephritis. (25) GFR progressively decreases with loss of functioning nephron. Kidney function should be assessed by estimated "GFR" and CRF is classified on this basis. The GFR should be estimated by serum creatinine. (26) 1.2.4.2.2. Stages of CRF: There are 4 stages of functional deterioration in renal failure (27): I. Diminished renal reserve: • There is mild reduction in renal function. • Creatinine clearance decreases from 120 ml/min to approximately 50 ml/min. • Increase in serum creatinine level from a normal range from 0.7 to 1,5mg/dl. • Renal regulatory, excretory and metabolic function remains intact and the patient is symptom free. II. Renal insufficiency: • Creatinine clearance continues to decrease < 15 ml/min. • Serum creatinine rises to the range of 2.1 to 5 mg/dl. • Initial manifestations of renal insufficiency usually appear. • Further stress due to infection or dehydration intensifies the symptoms requiring therapeutic intervention. III. Renal failure: • Creatinine clearance has decreased to < 10ml/min. • Serum creatinine is greater than 8 mg/dl. • Patient is symptomatic and requires medical management. IV. Uraemic syndrome: • Creatinine clearance is< 5 ml/min. • Serum creatinine is > 12 mg/dl. • Patient develops clinical manifestations in every system of the body. 1.2.4.2.3. End stage of renal failure: End-stage renal disease (ESRD) is a complete or near complete failure of the kidneys to excrete wastes, concentrates urine, and regulates electrolytes. ESRD usually occurs as chronic renal failure worsens to the point where kidney function is

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less than 10% of normal. At this point, the kidney function is so low that without dialysis or kidney transplantation, complications are multiple and severe, and death will occur from accumulation of fluids and waste products in the body. The annual incidence of end stage renal disease (ESRD) varies in different countries. It is estimated to be about 25 per million in developing countries, 58.6 per million in Europe, 169 per million in USA and 194.2 per million in Japan. (20) The incidence of ESRD differs according to age sex and race being more common in males. The incidence of CRF is about 70-140 per million in Sudan, the majority being young patients below 40 years of age. (27) 1.2.4.2.4. Biochemical disturbances: include hypervolaemia, hyper/hyponateremia, hyper/hypo-kalemia, metabolic acidosis, hypocalcaemia and hyperphosphatemia, hyper-prolactineamia, abnormal level of growth hormones, thyroid hormone, and reproductive hormones. Also there may be insulin resistance, gout, hyper-cholesteroleamia, hyper-triglyceridemia, hypothermia and proteincaloric malnutrition. (23,28) 1.2.4.2.5. Investigations necessary for patients suspected of having CRF include the following: Urine analysis: to detect haematouria, proteinuria, glycosuria, pyuria, cast, esinophils, specific gravity, PH and crystal in urine. (29) Urine biochemistry: 24 hours urinary creatinine, urinary electrolytes, osmolality and light chain protein (multiple myeloma). (29) Plasma biochemistry: urea and electrolytes (sodium and potassium), serum creatinine, plasma protein, electrophoresis, serum calcium phosphate, glucose, lipid, and serum alkaline phosphate, lactate dehydrogenase and creatinine phosphokinase, cystatine C for elderly. (29,30) Haematogram and erythrocyte sedimentation rate (ESR): to detect anaemia. High ESR in myeloma.( 29) Immunological and Microbiological investigations: urine culture and sensitivity, serology for hepatitis B and C viruses and for human immunodeficiency virus (HIV), blood film for malaria. (29,30) Radiological investigations: ultra sound abdomen should be done for every patient with renal impairment to assess the size of the kidneys and to exclude treatable conditions such as obstruction, plain abdominal x-rays. (29,30) Renal biopsy: this performed in every patient with unexplained renal failure and normal sized kidneys such as occurs in patients with DM, amyloidosis and rapidly progressive glomerulonephritis (GN).( 29)

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1.2.5. Dialysis: Dialysis or kidney transplantation is the only treatments for ESRD. The physical condition of the person and other factors determines which of these is used. Dialysis related techniques do not replace the endocrine function of the kidney: patients on long-term dialysis require treatment with erythropoietin and vitamin D derivatives. Patients who undergo renal transplantation are free of these restrictions, but must take immunosuppressive drugs to prevent rejection. (9) Dialysis is the procedure that is a substitute for many of duties of the kidneys. It removes nitrogenous end-products of catabolism and begins the correction of the salt, water, and acid-base derangements associated with renal failure. It can allow individual to be productive and helps the body by performing the function of failed kidneys, but it does not correct the endocrine functions of the kidney. (32) Indications for starting dialysis for chronic renal failure are empirical and vary among physicians. Some begin dialysis when residual glomerular filtration rate (GFR) falls below 10 mL/min /1.73 m2 body surface area (15 mL/min/1.73 m2 in diabetics.) Others institute treatment when the patient loses the stamina to sustain normal daily work and activity. Most agree that, in the face of symptoms (nausea, vomiting, anorexia, fatigability) and signs of uremia (pericardial friction rub, refractory pulmonary edema, metabolic acidosis), dialysis treatments are urgently indicated. (32) There are two types of dialysis hemodialysis and peritoneal dialysis, each one have advantages and disadvantages. Early diagnosis of CRF and adequate follow up reduces the need of dialysis. Intervention to promote early diagnosis of CRF and improve compliance with regular nephrological follow up can be important to reduce the morbidity and mortality of patients with CRF. (32) 1.2.5.1. Hemodialysis: Hemodialysis remains the major modality of renal replacement therapy in the world. Since the 1970s the drive for shorter dialysis time with high urea clearance rates has led to the development of high-efficiency hemodialysis. In the 1990s, certain biocompatible features and the desire to remove amyloidogenic microglobulin have led to the popularity of high-flux dialysis. During the 1990s, the use of high-efficiency and high-flux membranes has steadily increased and use of conventional membrane has declined. Despite the increasing use of these new hemodialysis modalities the clinical risks and benefits of high-performance therapies are not well defined.(33)

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Currently, treatment quantity is not only defined by time but also by dialyzer characteristics, i.e., blood and dialysate flow rates. In the past, when the efficiency of dialysis and blood flow rates tended to be low, treatment quantity was satisfactorily defined by time. Today, however, treatment time is not a useful expression of treatment quantity because efficiency per unit time is highly variable. It is defined as the movements of solute and water from the patient blood across semi-permeable membrane into dialysate. The dialyzer may be also used to remove large volumes of fluid, accomplished by ultra filtration in which hydrostatic pressure causes the bulk flow of plasma water(with relatively fewer solutes) through the membrane. The rate of the blood flow through semi permeable machine is maintained at 200-300ml/min and the rate of flow of dialysate is 500ml/min. (32) Dialysis machine assures the dialysate entering the dialyzer is safe for the patient treatment by: • Regulate temperature; • Regulate conductivity; • Regulate PH; • Measure pressure and flow; • Detect a blood leak; • Alerts the user if something wrong; • Bypass the dialyzer if dialysate is not safe. Factor to be considerable be for initiating hemodialysis (HD) in the patients with CRF include co-morbid conditions and patients preference. The timing of therapy is dictated by serum chemical parameters and symptoms. Haemodialysis usually started when creatinine clearance decreases below 10 ml/min, which usually corresponds to a serum creatinine of 8-10 mg/dl. However, more important than absolute laboratory values is the presence of uraemic syndrome. (34) There is unknown absolute contraindication for HD but relative contraindication included advanced malignancy, sever psychiatric illness, cerebrovascular event, myocardial infarction and elderly. (28) Complications of HD include clotting, bleeding or infection at the site of fistula, dialysis encephalopathy, peripheral neuropathy, hypotension, anaphylactic reactions, hard water syndrome, hemolytic reactions, air embolism, disequilibrium syndrome and transmission of infection, mainly hepatitis B virus (HBV), hepatitis C virus (HCV) and Human immunodeficiency Virus (HIV), for which routine screening is performing before dialysis and there are usually separate machines for infected patients. The prevalence of HCV infection was estimated to be about

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34.9% among Sudanese patients on HD and there was no correlation between the prevalence rate and blood transfusion and nosocomial transfusion may be the main factor responsible for the high prevalence rate. (35) HCV infection is associated with considerable morbidity and isolation of serologically positive patient is the best method to prevent transmission of HCV infection by HD. (36) 1.2.5.2. Peritoneal dialysis: Peritoneal dialysis is a technique whereby infusion of dialysis solution into the peritoneal cavity is followed by a variable dwell time and subsequent drainage. Continuous ambulatory peritoneal dialysis (CAPD) is a continuous treatment consisting of four to five exchanges of two litters of dialysis fluid per day. Continuous cyclic peritoneal dialysis is a continuous treatment carried out with an automated cycler machine.(33) During peritoneal dialysis, solutes and fluids are exchanged between the capillary blood and the intraperitoneal fluid through a biologic membrane, the peritoneum. The three-layered peritoneal membrane consists of: i. The mesothelium, a continuous monolayer of flat cells, and their basement membranes; ii. The interstitium; iii. The capillary wall, consisting of a continuous layer of mainly nonfenestrated endothelial cells, supported by a basement membrane. The mesothelial layer is considered to be less of a transport barrier to fluid and solutes, including macromolecules, than is the endothelial layer. The capillary endothelial cell membrane is permeable to water through aquaporins (0.2 to 0.4 nm). In addition, small solutes and water are transported through ubiquitous small pores (0.4 to 0.55 nm). Sparsely populated large pores (0.25 nm) transport macromolecules passively. Diffusion and convection move small molecules through the interstitium with its gel and sol phases, which are restrictive owing to the phenomenon of exclusion. The lymphatic vessels located primarily in the subdiaphragmatic region drain fluid and solutes from the peritoneal cavity through bulk transport. Peritoneal dialysis like hemodialysis may be performed in various setting and with a number of different techniques. Chronic peritoneal dialysis was attempted in the late 1940s but was relatively unsuccessful until development of a permanent peritoneal catheterin1968. (32)

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1.2.6. The measure of the dose of renal replacement treatment: The measure of delivered dose of renal replacement treatment (RRT) can be described by various terms: efficiency, intensity, frequency, and clinical efficacy. Efficiency of RRT is represented by the concept of clearance (K), i.e., the volume of blood cleared of a given solute over a given time. The clearance (K) depends on solute molecular size, transport modality and circuit operational characteristics (blood flow, dialysate flow, ultrafiltration rate, hemodialyzer type and size).(33) Intensity of RRT can be defined by the product “clearance - time” (Kt). Kt is more useful than K in comparing various RRT. A further step in assessing dose must include frequency of the intensity (Kt) application over a particular period. This additional dimension is given by the product of intensity frequency (Kt - treatment days/week). This concept offers the possibility to compare disparate treatment schedules (intermittent, alternate day, daily, continuous). However, it does not take into account the size of the pool of solute that needs to be cleared. This requires the dimension of efficacy.(33) Other dose measurement methods have been used in patients with end-stage renal failure. The time-averaged blood urea concentration (TACUREA) is a function of dialysis dose, but it also is of the urea generation rate (G) from protein intake. As such, it is not a good indicator of RRT dose per session.(33) The urea reduction rate (URR) is very useful method because of its simplicity. It permits easy monitoring of the amount of dialysis therapy delivered to individual patients, as well as across dialysis units, groups of units, states, regions, or countries, because monthly predialysis and postdialysis urea nitrogen values are routinely measured. The urea reduction rate (URR) was first popularized by Lowrie and Lew in 1991 as a method of measuring amount of dialysis that correlated with patient outcome. URR is formally defined as the urea reduction ratio. So for the quantification of the dialysis dose two parameters are most commonly used namely the normalized dose of dialysis (Kt/V value) and the urea reduction rate (URR).33 Hemodialysis is a life-sustaining procedure for the treatment of patients with end-stage renal disease. In acute renal failure the procedure provides for rapid correction of fluid and electrolyte abnormalities that pose an immediate threat to the patient’s well-being. In chronic renal failure, hemodialysis results in a dramatic reversal of uremic symptoms and helps improve the patient’s functional status and increase patient survival. To achieve these goals the dialysis prescription must ensure that an adequate amount of dialysis is delivered to the patient.(33)

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Numerous studies have shown a correlation between the delivered dose of hemodialysis and patient morbidity and mortality. Therefore, the delivered dose should be measured and monitored routinely to ensure that the patient receives an adequate amount of dialysis. One method of assessing the amount of dialysis delivered is to calculate the Kt/V. The Kt/V is a unit less value that is indicative of the dose of hemodialysis. Efficacy of RRT represents the effective solute removal outcome that results from the administration of a given treatment to a given patient. It can be described by a fractional clearance of a given solute (Kt/V), where V is the volume of distribution of the marker molecule in the body. Kt/V is an established maker of adequacy of dialysis for small solute correlating with medium term survival in chronic hemodialysis patients. Urea is typically used as a marker molecule in end-stage kidney disease to guide treatment dose.(33) The Kt/V is best described as the fractional clearance of urea as a function of its distributional volume. The fractional clearance is operationally defined as the product of dialyzer clearance (K) and the treatment time (t). Recent guidelines suggest that the Kt/V be determined by either formal urea kinetic modeling using computational software or by use of the Kt/V natural logarithm formula. The delivered dose also may be assessed using the urea reduction ratio (URR). (33) A number of factors contribute to the amount of dialysis delivered as measured by either the Kt/V or URR. Increasing blood flow rates to 400 mL/min or higher and increasing dialysate flow rates to 800 mL/min are effective ways to increase the amount of delivered dialysis.(33) When increases in blood and dialysate flow rates are no longer effective, use of a high-efficiency membrane can further increase the dose of dialysis (KoA) >600 mL/min, where KoA is the constant indicating the efficiency of dialyzers in removing urea). Eventually, increases in blood and dialysate flow rates, even when combined with a high-efficiency membrane, result in no further increase in the urea clearance rate. At this point the most important determinant affecting the dose of dialysis is the amount of time the patient is dialyzed.(33)

Factors resulting in reduction of the prescribed dose of haemodialysis delivered (33):
i. • • • • Compromised urea clearance: Access recirculation. Inadequate blood flow from the vascular access. Dialyzer clotting during dialysis (reduction of effective surface area). Blood pump or dialysate flow calibration error.

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ii. • • • • iii. • • •

Reduction in treatment time: Premature discontinuation of dialysis for staff or unit convenience. Premature discontinuation of dialysis per patient request. Delay in starting treatment owing to patient or staff tardiness. Time on dialysis calculated incorrectly. Laboratory or blood sampling errors: Dilution of predialysis BUN blood sample with saline. Drawing of predialysis BUN blood sample after start of the procedure. Drawing postdialysis BUN > 5 minutes after the procedure.

1.7. Rationale:
Increasing number of patients, who need hemodialysis (HD), is a great challenge for every society. Intermittent hemodialysis is widely used as renalreplacement therapy in patients with acute renal failure, but an adequate dose has not been defined. Since mortality rate will increase due to inadequate dialysis, determining the efficacy of hemodialysis and improving its quality is very important. To the best of my knowledge there is no such study available in Sudanese subjects residing in Sudan. So this prospective study was performed to determine the efficacy of three session intermittent hemodialysis, as compared with two session intermittent hemodialysis, among Sudanese patients with chronic renal failure.

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1.8. The objectives of the study 1.8.1. General Objective:
• To determine the efficacy of hemodialysis among Sudanese patients with chronic renal failure.

1.8.2. Specific Objectives:
• To calculate (kt/v) value and urea reduction rate (URR) among Sudanese patients with chronic renal failure undergoing haemodialysis. • To compare between the two different protocols of haemodialysis, two sessions per week and three sessions per week, in each protocol the duration of dialysis is four hours. • To evaluate serum concentration of urea and creatinine in patients with chronic renal failure before and after haemodialysis procedure. • To compare the efficacy of haemodialysis in Sudanese patients with international standards.

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CHAPTER TWO
MATERIALS AND METHODS
2.1 Study Design:
This is an analytical, cross-sectional, and hospital-based study.

2.2 Study Area:
The study was conducted at Khartoum Center for Haemodialysis and Renal Transplantation, and Mawadah Hospital in Khartoum, Sudan. 2.3 Study Population and sample size: The study was conducted on fifty patients of chronic renal failure (29 males, 21 females) with range of (18 -64 years) under haemodialysis treatment. Patients were divided into two test groups; group A (35 patients (21males, 14females)) underwent dialysis two sessions weekly and group B (15 patients (8 males, 7 females)) underwent dialysis three sessions weekly for approximately four hours. From targeted population, two serum samples one before and one after haemodialysis were collected from each patient. The patients’ weights, blood pressure and the time of dialysis session were recorded.

2.4 Study Period:
The study was conducted during the period from Nov 2008 to Mar 2009.

2.5. Inclusion Criteria:
The inclusion criteria for the study included patients on haemodialysis (HD) treatment for at least three months. The time dialysis session was four hours. And the investigations were pertained to adults only.

2.6. Exclusion Criteria:
The exclusion criteria for the study included patients on haemodialysis (HD) treatment for less than three months and the time dialysis session less than four hours and the investigations for children were being drafted.

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2.7. Ethical Consideration:
i. ii. The objectives of the study were explained to all individuals participating in this study. All patients in this study were given informed written consent before blood samples were taken. Each sample was encoded to ensure anonymity.

2.8. Data Collection and Clinical Assessment:
Clinical assessment was done by a medical doctor. A questionnaire was specifically designed to obtain information which helps in either including or excluding certain individuals in or from the study. Also the clinical data was obtained from history and recorded in a questionnaire sheet.

2.9. Collection of Blood Samples:
From each patient, 5 ml of pre- and post-dialysis blood were drawn using standard procedure and placed in serum tubes prior to analysis, using disposable syringes. All blood samples were allowed to clot at room temperature and then centrifuged at 4000 RPM to obtain serum.

2.10. Statistical Analysis:
The patients were participated in the study of haemodialysis efficacy. Delivered dialysis dose was calculated from pre- and post-dialysis blood urea, session duration and the weight of the patient. Appropriate descriptive and analytical statistical procedures were followed using statistical package for social science (SPSS) (Version 15), t test was applied to compare the means of the efficacy (kt/v), urea reduction rate (URR) and the concentration of serum urea and creatinine in the test group subjects. The relationship of Kt/V, URR, and urea and creatinine concentration with duration of haemodialysis treatment and others physiological variables (age and sex) were studied using correlation analysis.

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2.11. Methods: 2.11.1. Estimation of Serum Creatinine by kinetic Jaffe Reaction (29, 39)
2.11.1.1. Principle: Creatinine under alkaline conditions reacts with picrate forming a reddish complex. The formation rate of the complex measured through the increase of absorbance in a prefixed interval of time is proportional to the concentration of creatinine in the sample.
Creatinine + Picric Acid
pH >12 (37deg.C)

Red Addition Complex

2.11.1.2. Reagents: Reagent (A) Reagent (B)

Sodium hydroxide
(Alkaline buffer)

0.4 mol/L 25mmol/L

Picric acid

Equal volumes of Reagent (A) and Reagent (B) were mixed and were allowed to stand for 30 minutes at room temperature before use. 2.11.1.3. Procedure: • Working reagent, samples and standard were pre-incubated to reaction temperature (370C). • The following volumes were pipetted into a cuvette:
Working Reagent Sample or Control 1.0 ml 100 µl

• The contents of each cuvette were mixed and inserted into the spectrophotometer. • The concentration of creatinine in the test was read using 500 nm. • The results were given in mg/dL. 2.11.1.4. Linearity: the linearity was up to 20 mg/dl. Samples with concentration higher than 20 mg/dl were diluted 1in 4 with saline and were assayed again and the results were multiplied by 4. 2.11.1.5. Reference values: (11,29) Serum creatinine: For male: 0.9 - 1.3 mg/dl; For female: 0.6 -1.1 mg/dl.

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2.11.2. Estimation of serum urea by enzymatic method: (11)
2.11.2.1. Principle: Urea is hydrolyzed in the presence of water and urease to produce ammonia and carbon dioxide. In a modified Berthelot’s reaction the ammonium ions react with hypochloride and salicylate to form indophenol (a green dye). The absorbance increase at 578 nm is proportional to the urea concentration in the sample. Urea + H2O
urease

2NH4+ + CO2
nitroprusside

NH4+ + Salicylate + NaClO 2.12.2.2. Reagents: Reagent (A1)

Indophenol

Sodium salicylate 62 mmol/L Sodium nitroprusside 3.4 mmol/L Phosphate buffer (PH6.9) 20 mmol/L Urease >500 U/L Reagent (A2) Sodium hypochlorite 7 mmol/L Reagent (B) Sodium hydroxide 150 mmol/L Reagent B was provided ready to use. The working urease reagent (A) was prepared by mixing 1 ml of Reagent (A2) with 24 ml of Reagent (A1) and was allowed to stand for 30 minutes at room temperature before use. 2.11.2.3. Procedure: Working reagent, samples and standard were pre-incubate to reaction temperature (370C). The following volumes were pipetted into a tube: Sample / Control 10 µl Enzyme Reagent (A) 1 ml The contents were mixed and incubated the tube for 5 min at 370C. Then pipetted: Reagent (B) 1 ml The contents were mixed and incubated the tube for 5 min. at 370C. • The contents of each tube were transferred to a cuvette and were inserted into the spectrophotometer. • The concentration of serum urea in the test was read using 600 nm. • The results were given in mg/dL.

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2.11.2.4. Linearity: the linearity was up to 300 mg/dl. Samples with concentration higher than 300 mg/dl were diluted 1in 2 with saline and assayed again and the results were Multiplied by 2. 2.11.2.5. Reference values: (11) Serum urea: 15 - 40 mg/dL; BUN: 7 – 18 mg/dL; 2.12. Quality control: Normal and pathological control sera were used with every batch and no errors were detected.

2.13. Calculations:
I. Kt/V urea was calculated from natural logarithm formula: (33) Kt/Vurea = -Ln (R - 0.008 x t) + (4 - 3.5 x R) /W In which: Ln: is the natural logarithm; R: is the postdialysis urea/pre-dialysis urea; t: is the dialysis session length in hours; W: is the patients’ post-dialysis weight in kilograms. II. Urea reduction rate (URR) was calculated from the formula: (33) URR = (1 - Upost/Upre) X100 In which: Upost: is the post-dialysis serum urea concentration; Upre: is the pre-dialysis serum urea concentration.

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CHAPTER THREE
RESULTS
3.1. Study Group:
In the present study, a total number of 50 patients with chronic renal failure (29 (58%) males and 21 (42%) females) had an average age of 41 year with a range between 18-64 years. These patients were divided into two test groups; group A (n = 35) underwent haemodialysis two sessions weekly and group B (n = 15) three sessions weekly for four hours.

3.2. The efficacy of haemodialysis (kt/v value):
Figure (4.1) shows no significant difference between the means of kt/v of group A (1.15 ± 0.33) and group B (1.31 ± 0.27), (P = 0.10). In table (4.1) and figure (4.2) there is no significant difference between the means of kt/v of the males of group A (1.07 ± 0.22) and the males of group B (1.18 ± 0.22), (P = 0.25). There is no significant difference between the means of kt/v of the females of group A (1.28 ± 0.42) mg/dl and females group B (1.47 ± 0.24) mg/dl, (P = 0.20). In figure (4.3) it is clear that only 34.3% of the patients of group A have kt/v > 1.2, and 65.7% have kt/v < 1.2. While 60% of the patients of group B have kt/v > 1.2 and 40% of them with kt/v < 1.2.

3.3. Urea reduction rate (URR):
Figure (4.4) shows no significant difference between the means of URR of group A (66.8 ± 10.4) and group B (72.2 ± 7.3), (P = 0.07). Table (4.1) and figure (4.5) shows no significant difference between the means of URR of the males of group A (64.8 ± 7.5) and the males of group B (68.5 ± 6.7), (P = 0.24). And also there is no significant difference between the means of URR of the females of group A (69.7 ± 13.4) mg/dl and group B (76.4 ± 5.7) mg/dl, (P = 0.13). In figure (4.6) 60% of the patients of group A have URR > 65%, 40% of them have URR < 65%, 87% of the patients of group B have URR > 65% and only 13% of them with URR < 65%.

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3.4. Serum urea concentration:
Table (4.2) and figure (4.7) shows no significant difference between the means of pre-dialysis serum urea concentrations of group A (160.5 ± 43.1) and group B (141.7 ± 25.7), (P = 0.13), while shows a significant difference between the means of post-dialysis serum urea concentrations of group A (53.4 ± 21.9) and group B (39.2 ± 11.7), (P = 0.005). Table (4.2) and figure (4.8) shows a significant difference between the means of pre-dialysis serum urea concentrations of the males of group A (168.5 ± 31) and the males of group B (134 ± 28), (P = 0.01) but there is no significant difference between the means of pre-dialysis serum urea concentrations of the females of group A (148.4 ± 57) mg/dl and group B (150 ± 22) mg/dl, (P = 0.91). There is a significant difference between the means of post-dialysis serum urea concentrations of the males of group A (59.5 ± 18) and the males of group B (42 ± 14), (P = 0.03). There is no significant difference between the means of post-dialysis serum urea concentrations of the females of group A (44.2 ± 24) mg/dl and group B (35.1 ± 8.1) mg/dl, (P = 0.22).

3.5. Serum creatinine concentration:
Table (4.1) and figure (4.9) shows no significant difference between the means of pre-dialysis serum creatinine concentrations of group A (9.5 ± 2.7) and group B (9.3 ± 1.7), (P = 0.81). There is no significant difference between the means of post-dialysis serum creatinine concentrations of group A (3.8 ± 1.6) mg/dl and group B (3.6 ± 1.0) mg/dl, (P = 0.72). Table (4.1) and figure (4.10) shows no significant difference between the means of pre-dialysis serum creatinine concentrations of the males of group A (10.6 ± 2.6) and the males of group B (9.4 ± 2.1), (P = 0.28). And there is no significant difference between the means of pre-dialysis serum creatinine concentrations of the females of group A (7.8 ± 1.9) mg/dl and the females of group B (9.1 ± 1.2) mg/dl, (P = 0.91). There is no significant difference between the means of post-dialysis serum creatinine concentrations of the males of group A (4.5 ± 1.5) and the males of group B (3.9 ± 1.3), (P = 0.30) but there is a significant difference between the means of post-dialysis serum creatinine concentrations of the females of group A (2.7 ± 0.85) mg/dl and the females of group B (3.3 ± 0.42) mg/dl, (P = 0.03).

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Table (4.1): The means of URR and KT/V of group A and group B:

variable

Group A
(2 sessions/week)

Group B
(3 sessions/week)

P

n=35
Urea reduction (URR) (%) rate Males: 64.8±7.5 Females:69.7±13.4

n=15
Males: 68.5±6.7 Females:76.4±5.7 0.24 0.13

Dialysis efficacy (kt/v)

Males: 1.07±0.22 Females:1.28±0.42

Males: 1.18±0.22 Females:1.47±0.24

0.25 0.20

• • •

The table shows the mean ± SD and probability (P). T- Test was used for comparison. P < 0.05 is considered significant.

23

Figure (4.1): The means of the haemodialysis efficacy (KT/V) of the test groups.

24

Figure (4.2): The means of the haemodialysis efficacy (KT/V) of the males and females of group A and group B.

25

Figure (4.3): The distribution of the haemodialysis efficacy (KT/V) among the test groups.

26

Figure (4.4): The means of the urea reduction rate (URR) of the test groups.

27

Figure (4.5): The means of urea reduction rate (URR) of the males and females of group A and
group B.

28

Figure (4.6): The distribution of urea reduction rate (URR) among the test groups.

29

Table (4.2): The means of pre- and post-dialysis serum urea and creatinine concentration of group A and group B:

variable

Group A
(2 sessions/week)

Group B
(3 sessions/week)

P

n=35
Pre-dialysis serum urea (mg/dl) Post-dialysis serum urea (mg/dl) Pre-dialysis serum creatinine (mg/dl) Post-dialysis serum creatinine (mg/dl) • • • Male: 168.5 ± 31 Females: 148.4±57 Males: 59.5 ± 18 Females: 44.2±24 Males: 10.6 ± 2.6 Females: 7.8±1.9 Males: 4.5 ± 1.5 Females:2.7±0.85

n=15
Male: 134 ± 28 Females:150±22 Male: 42 ± 14 Females:35.1±8.1 Male: 9.4 ± 2.1 Females:9.1±1.2 Male: 3.9 ± 1.3 Females: 3.3±0.42 0.01* 0.91 0.03* 0.28 0.28 0.07 0.30 0.03*

The table shows the mean ± SD and probability (P). T- Test was used for comparison. * P < 0.05 is considered significant.

30

Figure (4.7): The means of the pre- and post-haemodialysis urea concentration of the test groups.

31

Figure (4.8): The means of pre and post-dialysis serum urea concentration of the males and females
of group A and group B.

32

Figure (4.9): The means of the pre- and post-haemodialysis creatinine concentration of the test groups.

33

Figure (4.10): The means of pre and post-dialysis serum creatinine concentration of the males and
females of group A and group B.

34

CHAPTER FOUR
DISCUSSION
Adequacy of hemodialysis was considered worldwide. From 1986 onwards mortality of ESRD patients in USA decreased from 35% to 22% while the dialysis dose was increased from Kt/V 0.91 up to 1.19. Most studies (3,5,6) suggest that value of kt/v greater than 1.2 or 1.3 and URR more than 65% as a minimum standard is ideal. And to achieve this we should target a kt/v of 1.3 - 1.4 and should ensure that at least 80% of the patients consistently achieve the above values.(5) The American Renal Physicians Association, Kidney Disease Outcomes Quality Initiative and the British Renal Association recommended that the minimum dose of hemodialysis delivered to each ESRD patient must achieve at least a Kt/V of 1.2 or an average URR >65%. (1,5) European Best Practice Guidelines and the Canadian Society of Nephrology and the South African Renal Society: Recommends Kt/V of 1.2 or URR of 65% as minimum targets for 3-times-weekly dialysis. Units should ensure that at least 80% of patients consistently achieve these targets.( 5) This study dealt with fifty patients with chronic renal failure in two Sudanese haemodialysis centers, showed an average of haemodialysis efficacy (kt/v) of 1.2 ± 0.32 and URR 68.4 ± 9.8, (kt/v 1.15 ± 0.33 URR 66.8 ± 10.4 for group A (2 times/week) and kt/v 1.31 ± 0.27 URR 72.2 ± 7.3 (3 times/week)) meeting the above recommended minimum standard and studies, but fail to meet the guideline of the South African Renal Society which recommended for twice weekly schedule, a Kt/V of 1.8 and URR of 80%. The present study also revealed that 42% (34.3%of group A, 60%of group B) of patients have a Kt/V greater than 1.2. And 30% of patients (28.6% group A, 33.3% of group B) received also insufficient treatment, with a Kt/V between 1.01.2. Severely insufficient dialysis was delivered to 28% (37.1% of group A, 6.7% of group B) of dialysis patients with a Kt/V bellow (1.0). There was a lower haemodialysis efficacy for group A (undergoing two session per week), when compared with group B (undergoing three session per week), but it

35

failed to reach statistical significant difference, mean ± SD: (1.15±0.33) versus (1.31±0.27) (p=0.58). There is no significant difference between the three sessions per week protocol and two sessions per week protocol, but the former gives better results in most cases. A slow and gentle dialysis is optimal. Extended time on dialysis is a gentle dialysis. Charra B, Calemard E and Ruffet M have clearly demonstrated that long, gentle dialysis directly translates into reduced morbidity and mortality
(40)

. By restructuring dialysis patient shifts, it should be possible to

create an individual dialysis regimen for each patient, based primarily upon an individualized dialysis time. From the results we recognize that the kt/v value is more reliable and specific than URR, confirming the findings of Lowrie EG, Zhu X, and Lew NL. (3)The study also recognizes that the response of the female group (especially younger females) to the haemodialysis treatment are better than those of the male group, this is due to the lesser body weight and muscle mass of the females. As expected, serum urea and creatinine were effectively removed during haemodialysis, but the means of post-dialysis concentrations of serum urea (49 ± 20) and serum creatinine (3.7 ± 1.4) were higher when compared to the normal reference values.

36

CHAPTER FIVE
CONCLUSION AND RECOMMENDATIONS
5.1. Conclusion:
This study finds that the efficacy of haemodialysis, in Sudanese patients with chronic renal failure, meets the minimum international standards. Also the study finds that the protocol of three sessions per week gives better results than the protocol of twice sessions weekly. The study revealed that the response of the female group to the haemodialysis treatment is better than those of the male group.

37

5.2. Recommendations:
CRF is becoming a major health problem in Sudan and there should be clear programs for improving and increasing haemodialysis treatment of the patients. Regarding to the low efficacy of hemodialysis (kt/v < 1.0) in 28% of patients, periodic assessment and also investigating the reasons of low efficacy of hemodialysis is needed. Kt/v value and the composition of the dialysate should be requested for all patients undergoing haemodialysis monthly. Large analytical and prospective study, carefully controlled studies are needed to study the efficacy of haemodialysis among Sudanese haemodialysis centers and hospitals. The relationship between prescribed and delivered protocol should be explored in a Sudanese setting. The correlation between hours of dialysis per week and survival needs further research. Increased opportunities in transplantation would improve quality of life and reduce the economic burden.

38

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