The Nephrons Initial Filtering Component Biology Essay

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Patients with diabetes are more prone to infection, and the urinary tract being the most common infection site. Many urinary tract infections are asymptomatic and symptomatic urinary tract infections are preceded by asymptomatic bacteriuria[3]. In contrast with men, a higher prevalence of Asymptomatic Bacteriuria has been found in women with diabetes than without the disease. Because more Urinary Tract complications (e.g. Bacteremia, renal abscesses, renal papillary necrosis) are seen in patients with diabetes versus individuals without diabetes and also renal involvement without even the presence of symptoms (eg. Subclinical pyelonephritis) is common , Urinary Tract Infection in patients with Diabetes needs to be always considered.

Various Risk factors of Asymptomatic Bacteriuria with diabetes have been suggested including age, sexual intercourse, duration of metabolic control, and complications of diabetes[3].

Asymptomatic Bacteriuria is defined as the presence of at least 105 colony forming units/ml of 1 or 2 bacterial species in a culture of clean voided mid stream urine from an individual without symptoms of urinary tract infection[4].

Contaminated urine is defined as the presence of at least 3 different micro organisms in 1 urine specimen. On microscopic examination ≥ 1 bacterium / oil immension field on gram staining of unspun, freshly voided urine correlated well with ≥ 105 colony forming units/ml on culture. ≥ 10 leucocytes/mm3 from a clean catch midstream urine sample correlated well with ≥ 105 colony forming units/ml on culture[6].

Asymptomatic bacteriuria is not a separate entity, but an early stage in the course of natural history of urinary tract infection[5].

Asymptomatic Bacteriuria is common in neonates, preschool children, pregnant women, elderly people, diabetics, catheterized patients, patients with abnormal urinary tracts or renal disease. Specifically asymptomatic bacteriuria occurring in DM can cause serious complications like renal and perirenal abscess, gas forming infections such as emphysematous pyelonephritis, and renal papillary necrosis[6].

Though there is no consensus on treatment of Asymptomatic Bacteriuria in various population groups, it was recommended to treat asymptomatic bacteriuria in diabetes mellitus, so as to avoid in the future Asymptomatic Bacteriuria going for symptomatic bacteriuria or complications due to Asymptomatic Bacteriuria[7].

Initially the United States preventive task force recommended periodic testing for asymptomatic bacteriuria in diabetes, pregnant women, pre school children and in persons over age 60 yrs. In general dipsticks combining the leucocyte esterase and nitrite tests should be used to detect Asymptomatic Bacteriuria. However urine culture is a more accurate test than dipstick analysis[8].

However, recently [IDSA] Infectious Disease Society of America came out with a guide lines with no necessity to screen or treat ASB in diabetes patients.

Review of Literature


Nephron (from Greek Î½ÎµÏ†ÏÏŒÏ‚ - nephros, meaning "kidney") is the basic structural and functional unit of the kidney. Its chief function is to regulate the concentration of water and soluble substances like sodium salts by filtering the blood, reabsorbing what is needed and excreting the rest as urine. A nephron eliminates wastes from the body, regulates blood volume and blood pressure, controls levels of electrolytes and metabolites, and regulates blood pH. Its functions are vital to life and are regulated by the endocrine system by hormones such as,antidiuretic hormone, aldosterone, and parathyroid hormone.[1] Each kidney contains 800,000 to 1.5 million nephrons.[2]

Types of nephrons

Two general classes of nephrons are cortical nephrons and  juxta medullary nephrons, both of which are classified according to the length of their associated  Loop of Henle and location of their renal corpuscle. All nephrons have their renal corpuscles in the cortex. Cortical nephrons have their Loop of Henle in the renal medulla near its junction with the renal cortex, while the Loop of Henle of juxtamedullary nephrons is located deep in the renal medulla; they are called juxtamedullary because their renal corpuscle is located near the medulla (but still in the cortex). The nomenclature for cortical nephrons varies, with some sources distinguishing between superficial cortical nephrons and midcortical nephrons, depending on where their corpuscle is located within the cortex[2].

The majority of nephrons are cortical. Cortical nephrons have a shorter loop of Henle compared to juxtamedullary nephrons. The longer loop of Henle in juxtamedullary nephrons create a hyperosmolar gradient that allows for the creation of concentrated urine.

Fig.1 structure of nephron

Each nephron is composed of an initial filtering component (the "renal corpuscle") and a tubule specialized for reabsorption and secretion (the "renal tubule"). The renal corpuscle filters out large solutes from the blood, delivering water and small solutes to the renal tubule for modification.

Renal corpuscle

Composed of a glomerulus and the bowman's capsule, the  renal corpuscle (or malphigian corpuscle) is the beginning of the nephron. It is the nephron's initial filtering component.

The glomerulus is a capillary tuft that receives its blood supply from an afferent arteriole of the renal circulation. The glomerular blood pressure provides the driving force for water and solutes to be filtered out of the blood and into the space made by bowmans capsule. The remainder of the blood (only approximately 1/5 of all plasma passing through the kidney is filtered through the glomerular wall into the Bowman's capsule) passes into the efferent arteriole. The diameter of efferent arteriole is comparatively less than that of afferent arteriole. It then moves into the vasa recta, which are only found in juxtamedullary nephrons and not cortical nephrons. The vasa recta are collecting capillaries intertwined with the convoluted tubules through the interstitial space, in which the reabsorbed substances will also enter. This then combines with efferent venules from other nephrons into the renal vein, and rejoins the main bloodstream[2].

The bowmans capsule, also called the glomerular capsule, surrounds the glomerulus. It is composed of a visceral inner layer formed by specialized cells called podocytes, and a parietal outer layer composed of a single layer of flat cells called simple squamous epithelium. Fluids from blood in the glomerulus are filtered through the visceral layer of podocytes, and the resulting glomerular filtrate is further processed along the nephron to form urine.

Renal tubule

The renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus.[5] After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron.

The components of the renal tubule are:

Proximal convoluted tubule (lies in cortex and lined by simple cuboidal epithelium with brushed borders which help to increase the area of absorption greatly.)

Loop of Henle (hair-pin like i.e. U-shaped and lies in medulla)

Descending limb of loop of Henle

Ascending limb of loop of Henle

The ascending limb of loop of Henle is divided into 2 segments: Lower end of ascending limb is very thin and is lined by simple squamous epithelium. The distal portion of ascending limb is thick and is lined by simple cuboidal epithelium.

Thin ascending limb of loop of Henle

Thick ascending limb of loop of Henle (enters cortex and becomes DCT-distal convoluted tubule.)

Distal convoluted tubule


The nephron carries out nearly all of the kidney's functions. Most of these functions concern the reabsorption and secretion of various solutes such as ions (e.g., sodium), carbohydrates (e.g.,glucose),and  aminoacids  (e.g., glutamate). Properties of the cells that line the nephron change dramatically along its length; consequently, each segment of the nephron has highly specialized functions.

The proximal tubule as a part of the nephron can be divided into an initial convoluted portion and a following straight (descending) portion. Fluid in the filtrate entering the proximal convoluted tubule is reabsorbed into the peritubular capillaries, including approximately two-thirds of the filtered salt and water and all filtered organic solutes (primarily glucose and amino acids).

The loop of Henle, also called the nephron loop or the loop of Hundley, is a U-shaped tube that extends from the proximal tubule. It consists of a descending limb and ascending limb. It begins in the cortex, receiving filtrate from the proximal convoluted tubule, extends into the medulla as the descending limb, and then returns to the cortex as the ascending limb to empty into the distal convoluted tubule. The primary role of the loop of Henle is to concentrate the salt in the interstitium, the tissue surrounding the loop.

Considerable differences distinguish the descending and ascending limbs of the loop of Henle. The descending limb is permeable to water and noticeably less impermeable to salt, and thus only indirectly contributes to the concentration of the interstitium. As the filtrate descends deeper into the hypertonic interstitium of the renal medulla, water flows freely out of the descending limb by osmosis until the tonicity of the filtrate and interstitium equilibrate. Longer descending limbs allow more time for water to flow out of the filtrate, so longer limbs make the filtrate more hypertonic than shorter limbs.

Unlike the descending limb, the thin ascending limb of loop of Henle is impermeable to water, a critical feature of the countercurrent exchange mechanism employed by the loop. The ascending limb actively pumps sodium out of the filtrate, generating the hypertonic interstitium that drives countercurrent exchange. In passing through the ascending limb, the filtrate grows hypotonic since it has lost much of its sodium content. This hypotonic filtrate is passed to the distal convoluted tubule in the renal cortex.

The distal convoluted tubule has a different structure and function to that of the proximal convoluted tubule. Cells lining the tubule have numerous mitochondria to produce enough energy (ATP) for active transport to take place. Much of the ion transport taking place in the distal convoluted tubule is regulated by the endocrine system. In the presence of parathyroid hormone, the distal convoluted tubule reabsorbs more calcium and excretes more phosphate. When aldosterone is present, more sodium is reabsorbed and more potassium excreted. Atrial natriuretic peptide causes the distal convoluted tubule to excrete more sodium. In addition, the tubule also secretes hydrogen and ammonium to regulate pH.

After traveling the length of the distal convoluted tubule, only about 1% of water remains, and the remaining salt content is negligible.

Collecting duct system

Each distal convoluted tubule delivers its filtrate to a system of collecting ducts, the first segment of which is the collecting tubule. The collecting duct system begins in the renal cortex and extends deep into the medulla. As the urine travels down the collecting duct system, it passes by the medullary interstitium which has a high sodium concentration as a result of the loop of Henle's countercurrent multiplier system.

Though the collecting duct is normally impermeable to water, it becomes permeable in the presence of antidiuretic hormone (ADH). ADH affects the function of  aquaporins, resulting in the reabsorption of water molecules as it passes through the collecting duct. Aquaporins are membrane proteins that selectively conduct water molecules while preventing the passage of ions and other solutes. As much as three-quarters of the water from urine can be reabsorbed as it leaves the collecting duct by osmosis. Thus the levels of ADH determine whether urine will be concentrated or diluted. An increase in ADH is an indication of dehydration, while water sufficiency results in low ADH allowing for diluted urine.

Lower portions of the collecting organ are also permeable to urea, allowing some of it to enter the medulla of the kidney, thus maintaining its high concentration (which is very important for the nephron).

Urine leaves the medullary collecting ducts through the renal papillae, emptying into the renal calyces, the renal pelvis, and finally into the urinary bladder via the ureter.

Because it has a different origin during the development of the urinary and reproductive organs than the rest of the nephron, the collecting duct is sometimes not considered a part of the nephron. Instead of originating from the meta nephrogenic blastema, the collecting duct originates from the ureteric bud.

Juxtaglomerular apparatus

The juxtaglomerular apparatus is a specialized region of the nephron responsible for production and secretion of the enzyme renin, involved in the renin-angiotensin system. This apparatus occurs near the site of contact between the thick ascending limb and the afferent arteriole. It contains three components: the macula densa, juxtaglomerular cells, and extraglomerular mesangial cells.

urinary system

Fig:2 urinary system

The urinary system or urinary tract is the organ system that produces, stores, and eliminates urine. In humans it includes two kidneys, two ureters, the bladder and the urethra. The female and male urinary system are very similar, they differ only in the length of the urethra.

The kidneys are bean-shaped organs that lie in the abdomen, retroperitoneal to the organs of digestion, around or just below the rib cage and close to the lumbar spine. The organ is about the size of a human fist and is surrounded by what is called Peri-nephric fat, and situated on the superior pole of each kidney is an adrenal gland. The kidneys receive their blood supply of 1.25 L/min (25% of the cardiac output) from the renal arteries which are fed by the abdominal aorta. This is important because the kidneys' main role is to filter water soluble waste products from the blood. The other attachment of the kidneys are at their functional endpoints the ureters, which lies more medial and runs down to the trigone of urinary bladder. The kidneys perform a number of tasks, such as: concentrating urine, regulating electrolytes, and maintaining acid-base homeostasis. The kidney excretes and re-absorbs electrolytes (e.g. sodium, potassium and calcium) under the influence of local and systemic hormones. pH balance is regulated by the excretion of  bound acids and ammonium ions. In addition, they remove urea, a nitrogenous waste product from the metabolism of amino acids. The end point is a hyper osmolar solution carrying waste for storage in the bladder prior to urination.[2]

Humans produce about 2.9 litres of urine over 24 hours, although this amount may vary according to circumstances. Because the rate of filtration at the kidney is proportional to the glomerular filtration rate, which is in turn related to the blood flow through the kidney, changes in body fluid status can affect kidney function. Hormones exogenous and endogenous to the kidney alter the amount of blood flowing through the glomerulus. 

diabetes mellitus

Diabetes mellitus, or simply diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced.[2] This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger)[1].

There are three main types of diabetes mellitus (DM). Type 1 DM results from the body's failure to produce insulin, and presently requires the person to inject insulin or wear an insulin pump. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes". Type 2 DM results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. This form was previously referred to as non insulin-dependent diabetes mellitus (NIDDM) or "adult-onset diabetes". The third main form, gestational diabetes occurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level. It may precede development of type 2 DM[1].

Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of glucocorticoids, and several forms of monogenic diabetes.

All forms of diabetes have been treatable since insulin became available in 1921, and type 2 diabetes may be controlled with medications. Both types 1 and 2 are chronic conditions that cannot be cured. Pancreas transplants have been tried with limited success in type 1 DM.

Globally, as of 2012, an estimated 346 million people have type 2 diabetes[3].



Globally, as of 2010, an estimated 285 million people had diabetes, with type 2 making up about 90% of the cases.[4]  Its incidence is increasing rapidly, and by 2030, this number is estimated to almost double.[32] Diabetes mellitus occurs throughout the world, but is more common (especially type 2) in the more developed countries. The greatest increase in prevalence is, however, expected to occur in Asia and Africa, where most patients will probably be found by 2030.[32] The increase in incidence in developing countries follows the trend of urbanization and lifestyle changes, perhaps most importantly a "Western-style" diet. This has suggested an environmental (i.e., dietary) effect, but there is little understanding of the mechanism(s) at present, though there is much speculation, some of it most compellingly presented.


India has more diabetics than any other country in the world, according to the International Diabetes Foundation, although more recent data suggest that China has even more. The disease affects more than 50 million Indians - 7.1% of the nation's adults - and kills about 1 million Indians a year.The average age on onset is 42.5 years. The high incidence is attributed to a combination of genetic susceptibility plus adoption of a high-calorie, low-activity lifestyle by India's growing middle class.


Insulin is the principal hormone that regulates uptake of glucose from the blood into most cells (primarily muscle and fat cells, but not central nervous system cells). Therefore, deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.

Humans are capable of digesting some carbohydrates, in particular those most common in food; starch, and some disaccharides such as sucrose, are converted within a few hours to simpler forms, most notably the monosaccharide glucose, the principal carbohydrate energy source used by the body. The rest are passed on for processing by gut flora largely in the colon. Insulin is released into the blood by beta cells (β-cells), found in the islets of Langerhans in the pancreas, in response to rising levels of blood glucose, typically after eating. Insulin is used by about two-thirds of the body's cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage.

Insulin is also the principal control signal for conversion of glucose to glycogen for internal storage in liver and muscle cells. Lowered glucose levels result both in the reduced release of insulin from the β-cells and in the reverse conversion of glycogen to glucose when glucose levels fall. This is mainly controlled by the hormone glucagon, which acts in the opposite manner to insulin. Glucose thus forcibly produced from internal liver cell stores (as glycogen) re-enters the bloodstream; muscle cells lack the necessary export mechanism. Normally, liver cells do this when the level of insulin is low (which normally correlates with low levels of blood glucose).

Higher insulin levels increase some anabolic ("building up") processes, such as cell growth and duplication, protein synthesis, and fat storage. Insulin (or its lack) is the principal signal in converting many of the bidirectional processes of metabolism from a catabolic to an anabolic direction, and vice versa. In particular, a low insulin level is the trigger for entering or leaving ketosis (the fat-burning metabolic phase).

If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or resistance), or if the insulin itself is defective, then glucose will not have its usual effect, so it will not be absorbed properly by those body cells that require it, nor will it be stored appropriately in the liver and muscles. The net effect is persistent high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis.

When the glucose concentration in the blood is raised beyond its renal threshold (about 10 mmol/L, although this may be altered in certain conditions, such as pregnancy), reabsorption of glucose in the proximal renal tubule is incomplete, and part of the glucose remains in the urine (glycosuria). This increases the osmotic pressure of the urine and inhibits reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells and other body compartments, causing dehydration and increased thirst.

Type 1 diabetes

Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the islets of Langerhans in the pancreas, leading to insulin deficiency. This type can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in which beta cell loss is a T-cell-mediated autoimmune attack.[6] There is no known preventive measure against type 1 diabetes, which causes approximately 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Type 1 diabetes can affect children or adults, but was traditionally termed "juvenile diabetes" because a majority of these diabetes cases were in children.

"Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally used to describe to dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be used.[7] There are many reasons for type 1 diabetes to be accompanied by irregular and unpredictable hyperglycemias, frequently with ketosis, and sometimes serious hypoglycemias, including an impaired counterregulatory response to hypoglycemia, occult infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (e.g., Addison's disease). These phenomena are believed to occur no more frequently than in 1% to 2% of persons with type 1 diabetes.

Type 2 diabetes

Type 2 diabetes mellitus is characterized by insulin resistance, which may be combined with relatively reduced insulin secretion[1].The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor. However, the specific defects are not known. Diabetes mellitus cases due to a known defect are classified separately. Type 2 diabetes is the most common type.

In the early stage of type 2, the predominant abnormality is reduced insulin sensitivity. At this stage, hyperglycemia can be reversed by a variety of measures and medications that improve insulin sensitivity or reduce glucose production by the liver.


The cause of diabetes depends on the type.

Type 1 diabetes is partly inherited, and then triggered by certain infections, with some evidence pointing at Coxsackie B4 virus. A genetic element in individual susceptibility to some of these triggers has been traced to particular HLA genotypes (i.e., the genetic "self" identifiers relied upon by the immune system). However, even in those who have inherited the susceptibility, type 1 DM seems to require an environmental trigger. The onset of type 1 diabetes is unrelated to lifestyle.

Type 2 diabetes is due primarily to lifestyle factors and genetics.

The following is a comprehensive list of other causes of diabetes:

Genetic defects of β-cell function

Maturity onset diabetes of the young

Mitochondrial DNA mutations

Genetic defects in insulin processing or insulin action

Defects in proinsulin conversion

Insulin gene mutations

Insulin receptor mutations

Exocrine pancreatic defects

Chronic pancreatitis


Pancreatic neoplasia

Cystic fibrosis


Fibrocalculous pancreatopathy


Growth hormone excess (acromegaly)

Cushing syndrome





Cytomegalovirus infection

Coxsackievirus B



Thyroid hormone

β-adrenergic agonists



The classical symptoms of untreated diabetes are loss of weight, polyuria (frequent urination), polydipsia (increased thirst) and polyphagia(increased hunger).[12] Symptoms may develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in type 2 diabetes.

Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis; type 1 should always be suspected in cases of rapid vision change, whereas with type 2 change is generally more gradual, but should still be suspected. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.

Diabetic emergencies

People (usually with type 1 diabetes) may also present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone, a rapid, deep breathing known as Kussmaul breathing, nausea, vomiting and abdominal pain, and altered states of consciousness.

A rare but equally severe possibility is hyperosmolar non ketotic state, which is more common in type 2 diabetes and is mainly the result of dehydration.


File:Main symptoms of diabetes.png



<7.8 (<140)

<6.1 (<110)


Impaired fasting glycaemia

<7.8 (<140)

≥ 6.1(≥110) & <7.0(<126)


Impaired glucose tolerance

≥7.8 (≥140)

<7.0 (<126)


Diabetes mellitus

≥11.1 (≥200)

≥7.0 (≥126)


Diabetes mellitus is characterized by recurrent or persistent hyperglycemia, and is diagnosed by demonstrating any one of the following:[11]

Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)

Plasma glucose â‰¥ 11.1 mmol/l (200 mg/dL) two hours after a 75 g oral glucose load as in a glucose tolerance test

Symptoms of hyperglycemia and casual plasma glucose ≥ 11.1 mmol/l (200 mg/dl)

Glycated hemoglobin (Hb A1C) ≥ 6.5%[20]

A positive result, in the absence of unequivocal hyperglycemia, should be confirmed by a repeat of any of the above methods on a different day. It is preferable to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete and offers no prognostic advantage over the fasting test.[21] According to the current definition, two fasting glucose measurements above 126 mg/dl (7.0 mmol/l) is considered diagnostic for diabetes mellitus.

People with fasting glucose levels from 110 to 125 mg/dl (6.1 to 6.9 mmol/l) are considered to have impaired fasting glucose.[22] Patients with plasma glucose at or above 140 mg/dL (7.8 mmol/L), but not over 200 mg/dL (11.1 mmol/L), two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two prediabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus, as well as cardiovascular disease.[23]

Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.[24]


All forms of diabetes increase the risk of long-term complications. These typically develop after many years (10-20), but may be the first symptom in those who have otherwise not received a diagnosis before that time. The major long-term complications relate to damage to blood vessels. Diabetes doubles the risk of cardiovascular disease.[13] The main "macrovascular" diseases (related to atherosclerosis of larger arteries) are ischemic heart disease (angina and myocardial infarction), stroke and peripheral vascular disease.

Diabetes also causes "microvascular" complications-damage to the small blood vessels.[14] Diabetic retinopathy, which affects blood vessel formation in the retina of the eye, can lead to visual symptoms, reduced vision, and potentially blindness. Diabetic nephropathy, the impact of diabetes on the kidneys, can lead to scarring changes in the kidney tissue, loss of small or progressively larger amounts of protein in the urine, and eventually chronic kidney disease requiring dialysis. Diabetic neuropathy is the impact of diabetes on the nervous system, most commonly causing numbness, tingling and pain in the feet and also increasing the risk of skin damage due to altered sensation. Together with vascular disease in the legs, neuropathy contributes to the risk of diabetes-related foot problems (such as diabetic foot ulcers) that can be difficult to treat and occasionally require amputation.


Diabetes mellitus is a chronic disease which cannot be cured except in very specific situations. Management concentrates on keeping blood sugar levels as close to normal ("euglycemia") as possible, without causing hypoglycemia. This can usually be accomplished with diet, exercise, and use of appropriate medications (insulin in the case of type 1 diabetes, oral medications, as well as possibly insulin, in type 2 diabetes).

Patient education, understanding, and participation is vital, since the complications of diabetes are far less common and less severe in people who have well-managed blood sugar levels.[25][26]The goal of treatment is an HbA1C level of 6.5%, but should not be lower than that, and may be set higher.[27] Attention is also paid to other health problems that may accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.[27]


Epidemiologically, urinary tract infections are sub-divided into catheter associated or nosocomial infection or non catheter associated community acquired infections. Infections in either category may be symptomatic or Asymptomatic. Acute community infections are very common and account for more than 7 million Hospital visits annually in the united states. There infections occur in 1-3% of school girls and then increased markedly in incidence with the onset of sexual activity in adolescence. The vast majority of acute infections involve women. Acute symptomatic Urinary Tract Infection's are unusual in men under the young age group of 50 yrs. The development of asymptomatic bacteriuria parallels that of symptomatic infections and in rare among men under 50 years but common among women between 20 and 50 years. Asymptomatic bacteriuria is more among elderly men and women with rates as high as 10-50% in some studies.

Causative organisms of Urinary Tract Infection's are the most common organism are Gram Negative Bacilli

Escherichia coli - 70-80%

Klebsiella - 2-3%

Proteus - 2-4%

Enterococcus - 1-2%

Gram positive cocci

Staphylococcus saprophyticus - 10-15%

More commonly serratia and pseudomonas assure increasing important in recurrent infections and in infections associated with urological manipulation, calculi or obstruction.

Proteus species and klebsiella species by virtue of urease production and through the production of extracellular slime and polysaccharides, predispose to stone formation and are isolated more frequently from patients with calculi.

Chlamydia trachomatis, Neisseria gonorrhea, and herpes simplex virus are etiological important. These agents are found most frequently in young, sexually active women with new sexual partners.

The causative role of non-bacterial pathogens in Urinary Tract Infection's remains poorly defined. Urea plasma urealyticum has frequently been isolated from the urethra and urine of patients with acute dysuria and frequency but is also found in specimens from many patients without urinary symptoms.

Mycoplasma hominis have been isolated from prostatic and renal tissues of patients with acute prostatitis and pyelonephritis, and are probably irresponsible for some of the infections as well. Candida and other fungal infection is common and sometimes progressive to symptomatic invasive infection.

Mycobacterial infection of Urinary Tract Infection is also a common cause of Asymptomatic Bacteriuria.


The urinary tract should be viewed as a single anatomic unit that is united by a single column of urine extending from the urethra to the kidney.

Routes of Entry to the urinary tract

Ascending Infection

Mostly the infections of kidney units from organisms desired from gastrointestinal tract to the urethra and periurethra tissues into the bladder and then by the catheter to renal pelvis with subsequent invasion of renal medulla.

Hematogenous infection

Accounts for less than 3% cases of Urinary Tract Infection and pyelonephritis. The major cases of hematogenous infection are staphylococcus aureus, salmonella species, pseudomonas aeruginosa, Enterococcus faecalis

Lymphatic spread

Spread of infection along the lymphatic channels connecting bowel and urinary tract is possible.



In females the urethra is prone for gram negative bacilli infection because it is close to the perineum and its short length and its termination beneath the labia. In addition use of spermicidal compounds with a diaphragm or a cervical cap or of spermicide coated condoms dramatically alters the normal introital bacterial flora and has been associated with marked increase of colonization of E. coli and the risk of Urinary Tract Infection. In males who are a 50 years old and who have no H/o Heterosexual or Homosexual rectal intercourse, Urinary Tract Infection is exceedingly uncommon. Men & women who are infected with HIV are at increased risk of both bacteriuria and Urinary Tract Infection. Lack of circumcision has been identified as a risk factor for Urinary Tract Infection in both neonates & young men.

Pregnancy: 2-9 of Pregnant women 20-30% of pregnant women with Asymptomatic Bacteriuria subsequently develop pyelonephritis. Catheterization during or after delivery causes additional infections.

Obstruction: Any obstruction in free flow of urine tumour, stricture, stone, or prostatic hypertrophy results in increased frequency of Urinary Tract Infection.


Interference with nerve supply to the bladder, as in spinal cord onjury, Tabes dorsalis, multiple sclerosis. Diabetes and other diseases may be associated with Urinary Tract Infection. In additional factor operative in there causes is bone demineralization due to immobilization, which causes hypercalciuria, calculus formation & obstructive uropathy.

Vesicoureteral Reflux: Anatomically impaired vesicoureteral function facilities reflux of bacteria and thus Urinary Tract Infection.


Virulence factors of E.coli - surface antigen & toxins

Somatic Polysaccharide surface 0 antigen

Exerts endotoxic activity

Protects bacillus from phagocytosis

Protects bacillus from bactericidal effects of complement.

K antigens or envelop

P fibriae binds specifically to the P blood group substance on human erythrocytes and uroepithelial cells.

The E.coli serotypes commonly responsible for Urinary tract infections are those normally found in the faces, o group 1,2,4,6,7 strains carrying K antigens are more commonly responsible for pyelonephritis.


Increasing evidence suggests that host genetic factors influence susceptibility to Urinary Tract Infection. A maternal History of Urinary Tract Infections is found more among women who have experienced recurrent Urinary Tract Infection's than among controls. It has also been demonstrated that non-secretions of blood group antigens are at increased risk of Urinary Tract Infection.


Normal flora of the vagina

Flushing effect of urine flow and voiding


Bladder glycocalyx

Tomm-horsfall glycoprotein



IgA, IgM, IgG Antibodies


Collection of midstream specimens of urine.

Suprapubic aspiration of urine

Bladder catheterisation

Collection of Midstream Urine collection specimen


Patient must have a full bladder

Retract the fore skin if present

Clean glans penis with swab

Void into toilet with foreskin retracted until half done

Without interrupting stream catch sample in sterile bottle

Complete voiding


Patient must have a full bladder

Patient removes underclothing and stands legs either side of toilet

Separate labia with left hand

Cleans vulva front to back with sterile swab

Void downward into toilet until half done

Without interrupting stream catch urine in sterile bottle

Complete voiding

The method of urine sample collection is followed because the distal urethra contains bacteria normally so voided urine is contaminated so Midstream Urine collection is done.


This method is used when it is impossible to obtain uncontaminated samples or in symptomatic patients with low bacterial counts. This method is not usually followed


Patient must have a full bladder which can be percussed if not percussible or in doubt, give 300ml of water and 20mg of furosemide orally and wait for 1 hr. If still in doubt and especially in obese subjects, localize bladder using ultrasound. When patient supine chose site in midline 2.5cm above symphysis pubis, clean skin with spirit impregnated sterile gauze. Insert a 21 gauge 1.5" needle, attached to a 10ml syringe, directly downwards and aspirate urine. Withdraw needle and collect urine local anesthetics may be used.

Bladder Catheterisation:

It is nearly unnecessary to catheterize patients for collection of urine sample because catheter may introduce infection in the bladder and results in false positive cultures.


Urine being an excellent superfine medium for growth of most bacteria, it must be plated immediately or refrigerated at 4oc. Bacterial counts in refrigerated urine remains constant for as long as 24 hrs.

BD urine culture kit, a urine transport tube containing boric acid, glycerol, sodium formate, preserve bacteria without refrigeration for as long as 24 hrs when greater than 105 CFU/ml were present in initial urine specimen.

SAGE products care of III preservative system also available.

Both above products preserve bacterial inability in urine for 24 hours in the absence of antibodies. A new lyophilized system appears to stabilize microbial population for 24 hrs in the presence of antibiotics. For population of patients from whom colony counts of organisms of less than 105 /ml might be clinically significant, planting within 2 hour collection is recommended. None of the kits have any advantage over refrigeration.


Grams stain method

Earliest least expensive and probably the most sensitive and reliable screening method for identifying urine samples that contain greater than 10 CFU/ ml

A drop of well mixed urine is allowed to dry. The smear is gram stained and examined under oil immersion (1000 x ) . Presence of atleast one organism per oil immersion field, examining 20 fields correlated with significant bacteriuria in 90% cases. The gram stain should not be relied on for detecting polymorphonuclear leucocytes in urine.


The test is based on ;the absence of nitrite in normal urine. The presence of nitrite, Detected by a simple test indicates the presence of nitrate inducing bacteria in urine. A positive test suggests the presence of atleast 105 organisms per ml of urine. This test detects Escherchia coli, klebsiella, proteus, staplylococcus, and pseudomonas species. False negative tests occurs in the presence of yeast, some gram positive cocci, urinary ascorbic acid, frequent voiding, urobilinogen.

3.Catalase test

This test depends on the generation of oxygen bubbles by catalase produced by the bacteria when hydrogen peroxide is added to the infected urine. False positive results occur in the hematuria.

4. Triphenyl Tetrazolium chloride test

The respiratory activity of growing bacteria, reduce 2,3,5 triphenlytetrazolium chloride to red insoluble triphenyl formogen false positive, false negative results are in the range of 5-10%. This test not used widely.

Glucose oxidase test

Depends on the bacterial metabolism of glucose normally present in urine. In the presence of infection glucose is not detected. False negative tests occur with high urine low rather and frequent voiding, an infected urine must be present in the bladder for some 1 hour before the glucose is metabolized completely. False positive results occur in glycosuric patients.

6.Leucocyte esterase test

This test detects the presence of pyuria by measurement of esterase activity within leucocytes, even in ;the absence of intact neutrophils. On its own it is relatively sensitive. However this test has been combined with griess test sensitivity and ESS-SS-Specificity. On study showed the negative predictive value of the combined tests to be 97.5% therefore if both tests are negative the possibility of a positive urine culture is remote.

7 . Dipslide culture methods

Agar counted slides are immersed in urine or even exposed to the stream of urine during voiding, incubated and growth is estimated by colony counting, by colour change of indications.

8.Automated tests

Based on detection of adenosine triphosphate (ATP) by measuring light emitted by the reaction of lacifenin luciterase. These tests are expensive and takes time.

9. BAC- T screen bacteriuria detection device

In this method the urine is forced through a filter paper, which retains microorganisms, somatic cells and other particles. A dye is then added to the filter paper to visualize the particulate matter that has adhered. The intensity of colour relates to number of particles. This procedure takes approximately one minute, has been shown to detect greater than 90% of all positive urine specimens even in 102 organisms per ml are consider to be significant.

A manual filtration method using the reagents on ;the Bac-T screen in the filtrate checks out Urinary Tract Infection.

Another promising recently introduced manual system combines filtration with differential media to quantitate and identify presumptively uropathogens with results available within 4 hrs.

None of the screening methods are as sensitive or as reliable on a culture. These tests may have a role in ;the immediate diagnostic. Screening of symptomatic patients and may be if some value in mass screening programs. They are not a substitute for urine culture.


Nitrite dipstick is subject to false-negatives, because 4 to 6 hours is required for bacteria to convert nitrate to nitrite in bladder urine, and some infecting organisms are nitrite negative. In a study of bacteriuria screening in infants ,85% of nitrite tests were false negative compared with culture. A 53% false-negative rate was also reported in an obstetric population with dipstick screening of nitrite[28].


The quantitative urine culture remains the optimal screening test[28].

Pour plate dilution technique:

This is an extremely accurate method but time consuming. It is used as a standard of comparison for other methods. Here double dilution series of urine or two fold dilution of urine are spread over the culture plate. The number of colonies in each plate in head in 24 hours and 48 hours and colonies calculated.

Surface culture methods:

Serial 10 fold dilution of urine are plated by surface culture method Number of colonies are calculated at end of 24 hr & 48 hrs.

Both the above methods are too complicated for routine diagnostic ---- for which semi quantitative techniques are more conveniently calibrated bacteriologic loop technique.

Most commonly employed method. In this standard platinum loops or disposable sterile loops are designed to deliver either 0.01 ml or 0.001ml of urine used.

The urine should be mixed thoroughly before plating flame a wire calibrated inoculating loop, allow it to cool without touching any surface if disposable plastic tips are not used. Insert the loop vertically into the urine to allow urine to adhere to the loop spread the loopful of urine to the surface of blood agar loop is touched to the center of the plate, from which the inoculums is spread in a line across the diameter in the plate, without flaming or reentering urine loop in drawn across the entire plate crossing the first inoculums without inflaming insert the loop vertically into the urine again for transfer of a loopful to an indicator medium. Incubate plates for atleast 24 hours at 35o to 37o c in air. The colonies are counted on each plate. The number of colonies CFUs are multiplied by 1000 ( if a 0.001ml loop is used) or by 100 if a 0.01ml of loop was used to determine the number of microorganisms per ml in the original specimen. The former medium gives quantitative measurement of bacteriuria while the later a presumptive diagnosis of the bacterium. The isolated are identified by their properties.

Reincubate plates with no growth or tiny colonies for an additional 24 hours before discarding plates. Since antimicrobial treatment or other factors may inhabit initial growth.

Antibiotic sensitivity test

Antibiotic sensitivity tests may be done directly using the urine samples as inocula and the results confirmed by repeating the tests with individual isolates.

Localization of urinary tract infection

Localisation of urinary tract infection to the bladder or kidney in women and to the bladder, kidney or prostate in men, importantly influences the clinical manifestation, response to treatment likelihood and pattern of recurrent infection and long term prognosis associated with these patients. In diabetic patients with urinary tract infection half of patients have upper urinary tract infection. This stratification of patients by site of infection becomes critical. While an ideal procedure for localization of urinary tract infection does not exist, the following techniques are available.

Invasive Method

Ureteral Catheterization

This method was cystoscopy followed by collection of bladder urine samples for quantitative culture. The bladder is then irrigated, repeatedly to wash out bladder organisms. This is confirmed by collecting further samples at the end of the washout procedure. Catheters are then placed along the ureters and left in the place to collect uretheral urine for quantitative culture. A diagnosis of upper tract infection is based on evidence of a 10 fold increase in bacterial counts in ureteral urine compared with post wash out bladder urine. This technique is invasive, not without morbidity and with considerable urological exploration. This method can identify unilateral Upper Urinary Tract Instrumentation.

Bladder washout technique

This method is now usually considered to be the most acceptable gold standard against which all newer techniques should be compared.

To do the washout test, a triple human catheter is inserted, a specimen is collected for culture and the bladder is emptied of urine. Next 100ml of sterile saline, containing 5mg gentamicin or 2 mg of neomycin and 1,25,000 units of topical streptokinase - stretodornace ( two ampoules of the drug) is injected into the catheter and allowed to remain for 30 min. The bladder is then emptied of urine, washed out with two litres of sterile saline and a post washout culture specimen is obtained. Subsequently, five additional urine specimens are collected 10 min are collected 10 minutes apart and the catheter is withdrawn. After quantitative urine cultures have been done in all specimen patients are classified to have lower tract infection if all post-washout culture specimen or upper tract infection if bacterial count > 102/ml occur in at least 4 of specimen 3 to 7 and there is a long increase in count between specimen 2 and the later specimen.

False positive results occur in those patients who have intermittent shedding of microorganisms from kidney and in patients with vesicoureteric reflux.



The ability to concentrate urine is used to localize urinary tract infection. Renal infection results in a decreased concentrating ability; but not the bladder infection. Bilateral infection produces greater concentrating defect. Treatment usually produces a return of normal concentrating ability.


Wacker and Dorfman found that urinary lactate dyhydrogenase activity was elevated in upper urinary tractr infection. Recently LDH - iso - enzyme 5 has been investigated as a localization tool.

False positive results occur in the presence of pyuria, haematuria, proteinuria. So that test is insensitive and non specific.

Measurement of urinary β glucuronidase activity as a localization tool is suggested by Ronald. In patients with upper urinary tract infection, this enzyme level is high

Vigano and associates suggests measuring the renal tubule cell enzyme N Actyl-β-D- Glucosaminidase to localize upper urinary tract infection.


Serum levels of antibody directed against the lipopolysaccharide antigen present on bacteria, particularly that of E.Coli are commonly raised in patients with upper tract infection and absent in those with bladder infection. This is most diagnostically useful when an acute increase in antibody titres is demonstrated on serial samples taken over the period of the infection. Sensitivity and specificity of this test is still doubtful.


Jodal and colleagues reported that consistently elevated level of C - reactive protein in serum, detected by immune diffusion technique were seen in children with pyelonephritis, not with acute cystitis. This test is less sensitive in evaluating adult Urinary Tract Infection.


Described by Thomas in 1974. This method is widely spread and used now because of its simplicity and apparent reliability.

The test depends upon the demonstration of immunoglobin to somatic or O Antigen on the bacterial cell surface. The presence of immunoglobulins is taken as evidence of invasion of tissues, especially the kidney by bacteria, resulting in an antibody response. IgG, IgM, IgA have all been shown to participate in the antibody coating phenomenon, IgG being predominant. Fluorescein-labelled anti-human immunoglobulin is incubated with infected urine and the number of fluorescent - bacteria present s recorded. Different criterias are used for a positive result. The original criterion of Thomas required 25% of all bacteria seen to be fluorescent to qualify as a positive assay. Subsequent criteria have ranged from 1 to 20 fluorescing bacteria in a search of 200 fields to 2 to 5 fluorescing bacteria in a five minute search.

False positive results occur when vaginal or rectal flora contaminate a urine specimen, proteinuria, prostatitis, haemorrhagic cystitis or bladder infection in the presence of bladder tumors or catheters.

False negative results occur in the range of 16 to 38%, if there is delay in performing the test, particularly if bacterial multiplication continues.

In a first inflection the test may not become positive for 2 weeks.


Described by Robin, using the antibody coated bacteria test in conjunction with single dose therapy, the response to single dose of antibiotics may be used as a localization tool.


Renal scanning with 67Ga citrate has been used to localize infection. A false positive rate of 15% and a false negative rate of 13% have been reported.


Significant concentration of IgG and IgA anti Tamm-Horsfall glycoprotein antibodies have been observed in patients with acute pyelonephritis, especially in the presence of vesicoureteric reflux. But this is not the case in lower urinary tact infection.


Asymptomatic bacteriuria is common in neonates, preschool children, pregnant women, elderly patients, in diabetics, in catheterized patients and in patients with abnormal urinary tracts or renal disease. Asymptomatic bacteriuria is uncommon in non elderly, non pregnant women and in men.

The patients with diabetes mellitus have many potential reasons to have bacteriuria which in many instances may be asymptomatic, including poor control of blood glucose levels, diabetic neuropathy with neurogenic bladder and chronic urinary retention, impairment of leucocyte function, frequent instrumentation of urinary tract, recurrent vaginitis and diabetic microangiopathy, and large vessel renal vascular disease.

The prevalence of asymptomatic bacteriuria is not significantly influenced by the duration of diabetes or the quality of diabetic control. A recent study that evaluated haemoglobin A1c levels in diabetic patients with and without bacteriuria was unble to relate the risk of bacteriuria to the level of haemoglobin A1c at the time of urine culture, thus concluding that factors other than reversible metabolic derangement place the diabetic at risk of bacteriuria.

The prevalence of asymptomatic bacteriuria increase as diabetic retinopathy becomes more severe, as heart disease and peripheral vascular disease become apparent .

Locaization techniques indicate that approximately half of all diabetic patients with bacteriuria have upper urinary tract involvements. Most of these patients are asymptomatic .

The long term consequences of asymptomatic bacteriuria in patients with diabetes mellitus are poorly documented. These patients are at high risk of developing.

1.Acute pyelonephritis

2. Renal corticomedullary abscess

3. Renal carbuncle

4. Emphysematous pyelonephritis

5. Emphysematous cystitis

6.Papillary necrosis

7.Metastatic infection

8. Perinephric abscess

Infectious Diseases Society of America-US Public Health Service Grading System for ranking recommendations

in clinical guidelines.

Category, grade Definition

Strength of recommendation

A Good evidence to support a recommendation for use; should always be offered

B Moderate evidence to support a recommendation for use; should generally be offered

C Poor evidence to support a recommendation; optional.

D Moderate evidence to support a recommendation against use; should generally not be offered.

E Good evidence to support a recommendation against use; should never be offered

Quality of evidence.

I Evidence from ≥1 properly randomized, controlled trial.

II Evidence from ≥1 well-designed clinical trial, without randomization; from cohort or casecontrolled analytic studies (preferably from 11 center); from multiple time-series; or from dramatic results from uncontrolled experiments.

III Evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Recommendations relevant to the diagnosis of urinary tract infections



Diagnosis is based on the results of urine culture with

specimen collected to minimize contamination


For asymptomatic women, two consecutive voided urine

specimens with the same bacterial strain ≥105 CFU/mL B-II

defines bacteriuria

For asymptomatic men, a single voided specimen with B-III

≥105 CFU/mL defines bacteriuria

For men or women, a single catheterized urine specimen A-II

with a single species ≥102 CFU/mL

Pyuria accompanying bacteriuria is not an indication for A-II

antimicrobial treatment

CFU: colony-forming units.

Recommendations for screening for, and treatment of, asymptomatic bacteriuria

(ASB) in selected groups

Recommendation Grade

Pregnant women should be screened for bacteriuria by urine

culture at least once in early pregnancy, and they should A-I

be treated if the results are positive

Screening for, and treatment of, ASB before transurethral A-I

resection of the prostate is recommended

Screening for, and treatment of, ASB is recommended A-III

before other urological procedures for which mucosal

bleeding is anticipated

Recommendations against screening for, and treatment of, asymptomatic


Recommendation Level

Screening for, and treatment of, asymptomatic bacteriuria is not

recommended for:

1. Premenopausal, nonpregnant women A-I

2. Diabetic women A-I

3. Older people living in the community A-II

4. Elderly, institutionalized people A-I

5. People with spinal-cord injury A-I

6. Patients with indwelling catheters A-I