Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia, that is, high blood glucose due to derangement in carbohydrate, fat, and protein metabolism that are associated with absolute or relative deficiencies in insulin secretion, insulin action or both 1,2. The insulin hormone is responsible for regulating blood glucose. Diabetes is a chronic health condition that can lead to several other medical problems if not managed properly 3. Diabetic patients normally present symptoms such as polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger) and weight loss.
In America, estimated new cases of diabetes diagnosed each day are 1,800, or approximately 655,000 new cases each year6. According to the World Health Organization (WHO), diabetes affects more than 170 million people worldwide, and this number will rise to 370 million by 2030 9,10. In Zimbabwe, though there is lack of current statistics on the disease and its prevalence, diabetes is among the top five chronic conditions seen in the out-patients clinic. The latest survey was done in 2005 which noted that the prevalence of diabetes among the adult population was 10% with a large number of people not aware that they had raised blood sugar levels.
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Diabetes mellitus is classified primarily into Type I and Type II, which are the main groups, gestational diabetes and diabetes secondary to other diseases and conditions such as, following pancreatic surgery.
Type I is the insulin dependent diabetes mellitus which is mainly idiopathic (cause unknown) or caused by autoimmune disorders. This condition arises because of an absolute insulin deficiency due to destruction of islet cells in the pancreas.4 This group comprises of less than 10% of patients who are diabetic 2,3,4. The onset is usually acute, developing over a period of a few days to weeks. Over 95 percent of persons with type I Diabetes mellitus develop the disease before the age of 25.
Type II Diabetes mellitus arises from insufficient production of the hormone insulin from beta cells of the pancreas and in conditions where the peripheral receptors; primarily muscles, liver and fat tissue, do not respond adequately to normal insulin levels, known as insulin resistance.4 Instead of converting glucose into energy, glucose backs up into the bloodstream. This group makes up about 90% of cases of diabetes and has a slow and insidious onset.2,11 It usually occurs in people who are over forty years of age, obesity, sedentary life style, poor diet, hypertension and have family history of diabetes. It is also common in women especially those with a history of gestational diabetes, which is defined as any degree of glucose intolerance which onset or first recognized during pregnancy. It was formerly known as adult onset but now it is increasingly found in young people especially in the 21st Century.3,5 The epidemiological data shows that about 80% of Type II diabetic patients are considered to be obese, having a body mass index (BMI) greater than or equal to 30 kg/m2, whereas the other 20% are above their ideal weight or have a BMI of 25 to 29.9 kg/m2. 7 Diet alone can be used as a way of controlling Type II diabetes or by a combination of medications (oral hypoglycemics or insulin), exercise, and diet.8
A study by the Nigerian National Non-Communicable Disease Survey, reported a prevalence rate of about 2.2% for diabetic mellitus with over 90% Type II diabetics in Nigeria. Epidemiological data shows there are increasing incidences of Type II Diabetic mellitus and diabetic patients are at an increased risk of developing complications such as: nephropathy, retinopathy, neuropathy and atherosclerosis 3,8,13. This has made it become a global health concern since about one third of Type II will eventually have progressive deterioration of renal function 10,11.
Kidneys are a pair of vital bean-shaped organs in the body. In adults each kidney is about 10-14 cm in length, 6 cm in width and is 4 cm thick. Each weighing about 150 grammes.14 They are located at the rear of the abdominal cavity in the retroperitoneum just below the rib cage one on each side of the spine. The main function of kidneys is to receive blood from the paired renal arteries and draining it into the paired renal veins. Kidneys are an essential part of the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid-base balance, and regulation of blood pressure 14. The kidneys are one of the most important sophisticated organs in the body which mainly serve as a natural filter of the blood keeping the body chemically balanced. They remove waste which is diverted to the urinary bladder. In producing urine, the kidneys excrete nitrogenous wastes such as urea, creatinine, uric acid, ammonium, other acids, electrolytes and extra water. The kidneys also are responsible for the reabsorption of water, glucose, and amino acids.
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A normal person's kidneys process about 150 litres of blood to sift out of the body about 1500 ml of waste products produced by metabolism processes daily15. The actual filtering of wastes occurs in tiny units inside the kidneys called nephrons which are the urine-producing functional structures of the kidney. Each kidney has about a million functional nephrons, spanning the cortex and medulla 14,15. The initial filtering portion of a nephron is the renal corpuscle (glomerulus), located in the cortex, which is followed by a renal tubule that passes from the cortex deep into the medullary pyramids.
Kidney failure is when kidneys are no longer able to remove and maintain the level of fluid and salts that the body needs. Diabetes mellitus often damages the kidneys especially when the disease is not controlled by keeping blood glucose levels within the normal range.
1.3 Diabetic nephropathy
Diabetic nephropathy is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli16. Diabetes mellitus is a precondition for developing two major early glomerular lesions, glomerular basement membrane (GBM) thickening and mesangial expansion which are not present at the diagnosis of diabetes but are found 2 to 5 years after onset of hyperglycemia 17. The disease is progressive and may cause death two or three years after the initial lesions, and is more frequent in men18 than in women because of differences in lifestyle and testosterone deficiency that is common in men who are diabetic.37
Diabetic nephropathy is the most common cause of chronic kidney failure and End Stage Kidney Failure (ESRD) throughout the world in both developed and emerging nations 16,19. In 1991, it was estimated that diabetes accounted for 40% of the newly diagnosed cases of ESRD20.Normally 10 to 20 years after onset of overt nephropathy about 20% will progress to ESRD since the rate of fall is highly variable from individual to individual. 21,22,23 Patients with Diabetes mellitus should be diagnosed early for nephropathy since they are at a high risk, this will help them in preventing the development or progression of diabetic nephropathy.24
Progressive renal disease is caused by the combination of an initial or ongoing injury and a final common pathway of mal-adaptive response to that injury, a response that involves changes in glomerular hemodynamics and the release of cytokines and vaso-active hormones 25,26.
Pathogenesis of diabetic nephropathy
The progression of diabetic nephropathy is divided into 5 stages.26 In stage I there is hyperfiltration. 26,27,28 Hyperglycaemia causes abnormal glycosylation of cellular proteins which through a series of chemical reactions evolve to form Advanced Glycation End-Products (AGEs). AGEs can induce abnormal cellular changes by signalling through receptors which are expressed by cells in the gromerulus. This abnormal signalling may disrupt important paracrine signalling between podocytes and endothelial cells required for normal maintaince of the filtration membrane, hence damaging nephrons. Hyperglycaemia can also stimulate formation of oxygen radicals that also damage nephrons causing loss of functioning nephrons . The kidneys in healthy individuals try to compensate for damaged nephrons by increasing the Glomerular Filtration Rate (GFR) in order to maintain homeostasis. In order to do this, the kidney secretes intra-renal vaso-active hormones, such as prostaglandin E2, that preferentially dilate afferent arterioles and other hormones such as angiotensin and catecholamines constrict efferent arterioles. Each glomerulus therefore receives more blood at a higher pressure and therefore filters more fluid into tubules. This in turn overworks and damages the glomerular capillary in subtle ways. It causes mesangial cell and glomerular basement membrane injury, and stimulates release of cytokines. All of these effects can produce further relentless injury and scarring of the remaining nephrons with further nephron loss, systemic hypertension and proteinuria. Systemic hypertension, in the setting of a glomerulus with dilated afferent and constricted efferent arterioles and abnormal basement membrane permeability causes even greater degrees of glomerular pressure and injury 25.
Hyperfiltration has been shown to be present in early phases of diabetes, may exist for several years. 25,27,28 Unfortunately, there are no symptoms during the hyperfiltration stage. However, with early detection and proper glycemic control, hyperfiltration is reversible.26,28 Lowering blood pressure, regardless of the type of agent used to do so, retards the onset and progression of diabetic nephropathy.22,28 However, hyperfiltration does not always predict the future development of kidney injury in diabetes.26
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During stage II, the damaged capillaries allow small amounts of albumin to be excreted in the urine. Between 13% and 41% of people have microalbuminuria when first diagnosed with type II diabetes.27,28 Individuals may remain in this stage for several years by achieving proper control of blood glucose levels and blood pressure.26 In this stage GFR begins to decrease as microalbuminuria appears. Although the overall GFR is decreased, the glomerular filtration rate per nephron is increased, and hyperfiltration injury continues. This leads to further nephron loss, proteinuria, glomerular and interstitial scarring, and progressive renal failure.
Stage III is when diabetic nephropathy is first noticeable.26,28 There is accumulation of waste products in the blood which is known as azotemia, some which are toxic. At this stage levels of creatinine and Blood Urea Nitrogen (BUN) increase.26 There is also a loss of molecules such as albumin and glucose in urine which are not supposed to be lost in healthy conditions. Early detection at this stage is vital to preserve kidney function and to delay or prevent ESRD.33 Type II diabetes patients may remain in this stage for several years with proper glycemic control.26
Stage IV is the point when kidney damage is irreversible and is usually known as advanced clinical nephropathy.26 At this stage, due to decreased surface area in kidneys, they will no longer be capable of excreting toxins and accordingly there is a progressive increase in BUN and creatinine levels.11,29 Most people in this stage are hypertensive secondary to increased production of renin. Because hypertension accelerates the progression to ESRD, early detection is vital.30 If not treated at this stage; uremia and death will follow within 7 to 10 years.31
Stage V or ESRD, is when the kidneys fail to function, the overall GFR severely decreased, and hypertension continues to worsen.32 During this final stage, the kidneys cannot excrete toxins; maintain fluid, pH, and electrolyte balances; or secrete important hormones (renin, vitamin D, and erythropoietin). As a result, a multitude of symptoms become apparent that involve most major organ systems in the body.30
Creatinine is a by-product of creatine, a product produced from muscle. Creatinine is filtered by the glomerulus; therefore, serum creatinine level can be used as an indirect measure of glomerular filtration. As GFR diminishes, there is a rise in plasma concentrations of serum creatinine and urea.11 At the early stage of kidney disease, serum creatinine stays within normal range due to strong kidney compensatory abilities. When creatinine begins to rise, the kidneys would have been severely impaired, helpful in tracking the progression of diabetic nephropathy. Poorly controlled diabetes can impair glomerular basement membrane.33 Normal serum creatinine is usually 0,6 - 1,1 mg/dl for women and 0,7 - 1.3 mg/dl for men.34
1.5 Blood Urea Nitrogen
Blood Urea Nitrogen (BUN) is a waste product produced after protein metabolism excreted as urine. It is parameter to diagnose the functionality of the kidney 35. It is a quite sensitive indicator of renal disease, becoming elevated when renal function drops to around 25-50% of normal.36 Normally urea is filtered out of the blood and controlled to a range of 8 -24 mg/dl for men and 6 - 21 mg/dl for women 34. BUN and creatinine are the simplest way to monitor kidney function.
1.6 Statement of problem
Diabetes mellitus has quickly become a global health problem due to rapidly increasing population growth, aging, urbanization and increasing prevalence of obesity and physical inactivity 33. Intensive management of blood sugar is a treatment regime that aims to keep glucose concentration within normal range preventing progression of diabetic complications. Diabetic nephropathy occurs approximately in one third of type 2 diabetic patients 8,11,12 and is on the rise. This study aims to determine urea and creatinine concentrations in type II diabetic patients attending Parirenyatwa Diabetic clinic. Results obtained will indicate if treatment they are receiving is effectively managing the patients to reduce the risk of renal damage.
To evaluate creatinine and urea concentration in Type II diabetic patients attending Parirenyatwa Diabetic Clinic.
To assess the progressive deterioration of renal function in type II diabetic patients attending Parirenyatwa Diabetic Clinic.
Null hypothesis(H0): Less than one third of type II diabetic patients have elevated values of urea and creatinine .
Alternative hypothesis(H1) : more than one third if type II diabetic patients have elevated values of urea and creatinine.
CHAPTER TWO : MATERIALS AND METHODS
Refer to appendix
2.2. Study site
The project was conducted at Parirenyatwa Group of Hospitals Diabetic Clinic.
2.3 Study design.
A laboratory based cross-sectional study was carried out on the serum samples of diabetic patients attending the Diabetic Clinic at Parirenyatwa Group of Hospital (PGH).
2.4 Study subjects
Patients who have been documented as diabetics for at least 12 months who routinely attend Parirenyatwa Group of Hospitals Diabetic Clinic.
Patients with a history of kidney problems and congestive cardiac failure were excluded from the study.
Pregnant women, smokers and hyperlipidemics
Patient drug history were elucidated to avoid falsely elevated results due to nephrotoxic drugs effect, such as aminoglycosides, cimetidine, cefoxitin, heavy metal chemotherapy drugs and nephrotic drugs14 etc..
2.5 Ethical considerations
Permission to carry out the project was sought from authorities in charge of the Diabetic Clinic, the Consultant and the ward manager.
Ethical approval was sought from the Joint research Ethics Committee of the College of Health Sciences and Parirenyatwa Group of Hospitals (JREC/346/12)
2.6 Sample size
The sample size (n) was calculated to be 239 samples (refer to appendix for calculation) using the assumption that kidneys of one third of type II diabetic patients deteriorates in function.
collection of sample
Residual samples left during routine testing of type II diabetic patients who have been on treatment for more than 12 months were used. Also residual samples from subjects with normal renal function tests and random blood glucose were also collected.
2.7.2 Sample identification and patient confidentiality
After permission from the Diabetic Clinic at Parirenyatwa Group of Hospitals, Public Health Laboratories and the ethical approval from Joint Research Ethics Committee of the College of Health Sciences was given, samples were collected and de-identified for confidentiality by giving numeric codes E001…,to E239[This is part of Ethical considerations].
2.7.3Procedure of the study
Samples were centrifuged at 3 000 revolutions per minute (rpm). The serum was aliquoted into plastic made serum pots using a micropipette to separate with cells and then stored in a refrigerator at a temperature maintained between 2 - 8 oC. Prior to processing of the samples they are brought to room temperature and the analyser was calibrated. After calibration the control samples were run as a quality control measure to make sure the analyser was working as expected. Samples were then processed in batches. The samples were loaded in the sectors of the machine (Mindray BS 120) and assayed for urea and creatinine.
2.7.4 Principle of tests
Estimation of plasma creatinine was done using modified Jaffe's method 9-10. Serum urea was estimated using the Urease-glutamate Dehydrogenase, UV method.
The principle of Jaffe's method
Creatinine + Picric acid OH- Creatinine-picric acid complex
At an alkaline solution, creatinine combines with picric acid to form an orange-red colored complex. The absobency increase is directly proportional to the concentration of creatinine. This method is done using an absorbance of 510nm.
The principle of Urease-glutamate Dehydrogenase, UV method
Urea + 2H2O urease 2 NH4+ + CO2 2-
α-Oxoglutarate +NH4+ + NADH GLDH L-Glutamate + NAD+ +H2O
Urea is hydrolysed by urease, and one of the products, ammonia, helps to turn NADH to NAD+ with the catalysis of GLDH. The absorbency decrease is directly proportional to the concentration of urea. This is measured at 340nm.