Review of Literature Chapter 1

Urinary Tract
Structure of Urinary Tract:
The urinary tract consists of the organs, tubes, and muscles that work
together to make, move, store, and release urine, the liquid waste of the
human body. The upper urinary tract includes the kidneys, which filter
wastes and extra fluid from the blood, and the ureters, which carry urine
from the kidneys to the bladder. The lower urinary tract includes the
bladder, a balloon-shaped muscle that stores urine, and the urethra, a tube
that carries urine from the bladder to the outside of the body during
urination. (Linda and Vicente, 2010).

Fig. (1): Child Urinary System (Tortora and Derrickson, 2017).

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Asymptomatic Urinary Abnormalities

Abnormalities detected in routine urinalysis in patients who have no

symptoms of renal or urologic disease are a common finding in clinical
practice. Urinary abnormalities are an index of structural renal disease
(e.g., red cell cast in glomerulonephritis) and other systemic diseases.
Because they are not always intrinsically related, the abnormal results of
the components of the urine analysis may occur alone or in combination
(Parakh et al., 2012).

Asymptomatic urinary abnormalities that are commonly diagnosed by

dipstick and microscopic examination of urine are glycosuria, pyuria,
crystalluria, bacteriuria, hematuria, and proteinuria (Fouad et al., 2016).

Glycosuria: Glycosuria in the absence of hyperglycemia suggests renal

glycosuria or proximal tubular disease (Nodoshan et al., 2015).

Pyuria: Presence of more than 3 to 5 white blood cells/high-power field

in 10 CC fresh voided urine (Humayun et al., 2015).

Crystalluria: Crystals of many types appear in the urine sediment of

asymptomatic patients. Most of them have no diagnostic significance, but
hexagonal cystine crystals are seen only in the urine of patients with
cystinuria (Baumann and Affolter, 2014).

Bacteriuria: Asymptomatic bacteriuria is frequently contaminant in

women, but in pregnant women and in children, it is a useful guide for
further evaluation for urinary tract infection (Geerlings et al., 2001).

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Hematuria and proteinuria: Hematuria and proteinuria can be

symptomatic or asymptomatic and are commonly associated with
significant underlying diseases (Ahmed and Lee, 1997).

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Renal Disorders

Early detection of renal disorders in childhood will lead to effective

intervention and reduction in the number of individuals who subsequently
progress to end-stage renal disease (ESRD). A related concern is whether
the adoption of urinary screening programs is cost effective. The most
common method that is used for screening children for chronic kidney
disease (CKD) involves the measurement of urine samples for hematuria
and/or proteinuria (Ronald and Hogg, 2009). There appears to be a clear
consensus among Japanese, Taiwanese, and Korean investigators that the
screening programs currently in place in these counties have led to early
detection and effective intervention (Urakami et al., 2007).

1. Chronic Kidney Disease

Definition and Stages:

Chronic kidney disease is a global health issue that creates a serious

burden for both individuals and communities. Chronic kidney disease
refers to any alteration in the kidneys that persists for three months or
more, resulting in any degree of kidney damage and/or decline in kidney
function, regardless of the diagnosis of disease (Kidney Disease:
Improving Global Outcomes [KDIGO] CKD Work Group, 2013; Kidney
Health Australia, 2015).

Kidney function is typically assessed using glomerular filtration rate

(Dalton and Haycock, 1999). Filtration of blood by the glomeruli is the
first step in producing urine and is reduced when renal function is
diminished. GFR is determined not through direct measurement but
through measurement of the rate at which the kidneys clear certain
compounds from the blood (Dalton and Haycock, 1999).

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GFR is frequently calculated based on blood levels of creatinine, a

waste product of metabolism which is not reused and is normally
excreted almost entirely by the kidneys. Serum creatinine is inversely
related to glomerular filtration rate. Because creatinine is produced
primarily by muscle tissue, expected creatinine production depends on a
person’s muscle mass. One established method used to estimate GFR in
children with CKD is the Schwartz formula (Schwartz et al., 1976).

Causes of chronic kidney disease include malformation of the kidneys

or urinary tract, cystic or inflammatory conditions that damage or block
renal tubules, and metabolic or autoimmune disorders, such as diabetes or
lupus ("Treatment methods for kidney failure in children," 2006). In
children, the most common causes are hereditary, congenital, or cystic
diseases, to which 32.7% of cases are attributed; glomerulonephritis
25.2%; and secondary glomerulonephritis or vasculitis 11.4% (United
States Renal Data System, 2008a). Structural causes are more common
in younger patients, while patients older than 12 are more likely to have
glomerulonephritis (Warady and Chadha, 2007). The most frequent
single cause of glomerulonephritis is focal segmental glomerulosclerosis
(FSGS), which accounts for 13.2% of pediatric ESRD cases (United
States Renal Data System, 2008).

CKD is classified according to the National Kidney Foundation’s

Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) as stages 1
(mild) through 5 (end-stage renal disease). Stages 1 through 4 are often
referred to collectively as chronic kidney disease, chronic renal
insufficiency, or chronic renal failure (Warady and Chadha, 2007).

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Table 1 shows the GFR limits for CKD stages 1–5, which apply to
children ages 2 years and older.
Table (1): Classification of Chronic Kidney Disease Based on
Glomerular Filtration Rate.

(K/DOQI, 2007).

Clinical Presentation of CKD:

CKD is asymptomatic in its earliest stages (stage I and stage II),

although urine analysis findings or blood pressure may be abnormal. As
CKD progresses to more advanced stages, signs and symptoms greatly
increase. Polydipsia and nocturia (secondary to a reduced capacity to
concentrate the urine) may be one of the earliest symptoms that indicate a
diagnosis of CKD in an otherwise healthy looking child who has
tubulointerstitial kidney disease (Saland et al., 2002).

Symptoms can vary from person to person. Someone in early stage

kidney disease may not feel sick or notice symptoms as they occur. When
kidneys fail to filter properly, waste accumulates in the blood and the
body, a condition called azotemia. Very low levels of azotemia may
produce few, if any, symptoms. If the disease progresses, symptoms
become noticeable (if the failure is of sufficient degree to cause

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symptoms). Renal Failure accompanied by noticeable symptoms is

termed uremia (Dr Per Grinsted, 2013).

Symptoms of RF include high levels of urea in the blood, which can

result in Vomiting and/or diarrhea, which may lead to dehydration,
nausea, weight loss, nocturnal urination, more frequent urination, or in
greater amounts than usual, with pale urine, less frequent urination, or in
smaller amounts than usual with dark coloured urine (Dr Andy Stein,
2007).

A buildup of phosphates in the blood that diseased kidneys cannot

filter out may cause itching, bone damage, nonunion in broken bones and
muscle cramps (caused by low levels of calcium which can be associated
with hyper- phosphatemia) (Amgen, 2009).

Failure of kidneys to remove excess fluid may cause swelling of the

legs, ankles, feet, face and/or hands, shortness of breath due to extra fluid
on the lungs (may also be caused by anemia), PKD, which causes large
fluid-filled cysts on the kidneys and sometimes the liver, can cause pain
in the back or side (National Kidney Foundation, 2003).

This can result in feeling tired and/or weak, memory problems,

difficulty concentrating, dizziness, low blood pressure, normally, proteins
are too large to pass through the kidneys, and however, they are able to
pass through when the glomeruli are damaged. This does not cause
symptoms until extensive kidney damage has occurred, after which
symptoms include; Foamy or bubbly urine and Swelling in the hands,
feet, abdomen, or face (Lee, 2011).

Other symptoms include appetite loss, a bad taste in the mouth,

difficulty sleeping, darkening of the skin, excess protein in the blood and

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with high dose penicillin, RF patients may experience seizures (Katzung

and Bertram, 2007).

Effects of CKD:

A decline in GFR representing stage 1 or 2 CKD may be

asymptomatic, although the underlying illness may cause noticeable signs
or symptoms (Bargman and Skorecki, 2008). In later stages, CKD is
associated with alterations to nearly all organ systems. The most
prominent signs and symptoms are anemia, fatigue, reduced appetite,
which can lead to malnutrition, and changes to levels of ions and
hormones that result in homeostatic and metabolic disturbances. Some of
these complications are treatable, but their multiplicity makes the
treatment of CKD complex. Pediatric CKD presents particular challenges
to health care providers because it affects many aspects of a child’s
growth and development (Gerson et al., 2006).

CKD disturbs the normal balance of fluids, electrolytes, and acids and
bases in the blood stream. Many renal disorders result in reduced
excretion of sodium (Bargman and Skorecki, 2008). Higher blood levels
of sodium then promote fluid retention. This contributes to hypertension,
which is one of the most common complications of CKD and often
develops early in the course of the disease. Hypertension accelerates loss
of renal function and increases a patient’s risk for cardiovascular
mortality. CKD is also sometimes associated with hyperkalemia,
increased potassium, which can occur due to decreased renal clearance of
potassium, as a side effect of antihypertensive medications, or as a
consequence of metabolic acidosis. Metabolic acidosis, an acidification of
the blood, can result from inadequate excretion of protons and is common
in severe CKD.

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CKD also disrupts bone turnover and mineral metabolism. Reduced

GFR reduces excretion of phosphate, causing hyperphosphatemia, which
increases synthesis of parathyroid hormone (PTH) (Bargman and
Skorecki, 2008). Under normal circumstances, PTH stimulates renal
excretion of phosphate, so this is a compensatory mechanism. PTH also
stimulates bone turnover. Failing kidneys produce lower levels of
calcitriol, a form of vitamin D which acts to increase calcium absorption.
The resulting lower levels of ionized calcium additionally increase PTH
production, causing further bone turnover, abnormal bone remodeling,
and in severe cases bone pain and fragility.

Cardiovascular complications are the leading cause of death in

pediatric ESRD patients, followed by complications from infection
(United States Renal Data System, 2008b). Hypertension, anemia,
hyperphosphatemia, and hyperparathyroidism all increase patients’ risk
for cardiovascular disease (Bargman and Skorecki, 2008).

In pediatric patients, CKD tends to retard growth and delay puberty

(United States Renal Data System, 2008b). In a 2002 sample of 602
pediatric patients receiving hemodialysis, two-thirds (67%) fell into the
lowest quintile (20%) of height for the general population. On average,
puberty has been reported to be delayed 2 years in children with CKD,
even including those with functioning transplants (Wühl and Schaefer,
1999).

Uremia is also associated with gastrointestinal and neuromuscular

abnormalities (Bargman and Skorecki, 2008). In later stages of CKD,
neuromuscular complications may include muscle twitching, cramps, and
peripheral neuropathy (Bargman and Skorecki, 2008; Fraser and Arieff,
1988).

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Treatment of CKD:

In end-stage renal disease, the normal waste filtration and excretion

functions of the kidneys must be replaced using dialysis or transplantation
(Harmon, 1999). Dialysis methods consist of hemodialysis (HD) and
peritoneal dialysis (PD). In PD, a solution is poured into the abdominal
cavity through a catheter and later drained along with waste products and
excess fluid that would in a healthy person be excreted in urine
("Treatment methods for kidney failure in children," 2006).

Transplantation is considered the best treatment option for most

children with ESRD, and many of these children are sustained by renal
transplants (Harmon, 1999; United States Renal Data System, 2008b). A
kidney can be provided by a living or deceased donor. Patient survival
rates are higher with living donor transplants, which may be performed
preemptively, prior to dialysis. Up to 25% of children with ESRD receive
preemptive renal transplants (Harmon, 1999). Five years after beginning
ESRD treatment, up to 80% of pediatric patients are being maintained on
kidney transplants (United States Renal Data System, 2008b).

In general, children with ESRD who have received transplants fare

better than those maintained on dialysis, because dialysis replaces only
some of the filtration functions of the kidneys and none of their endocrine
functions (Harmon, 1999; Bargman and Skorecki, 2008).

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2. Hematuria
Definitions:

Microscopic hematuria: Is defined as the presence of at least 5 red

blood cells per microliter of urine in the sediment from 10 ml of
centrifuged freshly voided urine. False-negative results by dipstick are
due to the presence of formalin (Used as a urine preservative) or high
urinary concentrations of ascorbic acid. False-positive results may be
due to alkaline urine with a pH >9 , contamination with oxidizing
agents such as hydrogen peroxide used to clean the perineum before
obtaining a specimen or in a child with fever or after exercise (Cohen
and Brown, 2003).

Gross hematuria: (Visible to the nacked eye) may originate from the
glomerulus within the kidney (Brown or cola colored, changes in
erythrocyte morphology, may contain RBCs casts, proteinuria >100 mg
/dl, may be associated with edema, hypertension or renal insufficiency),
or originates from the lower urinary tract (extra glomerular) in such case
the urine has a red or pink color, normal RBC morphology, may contain
clots, and minimal proteinuria on dipstick <100mg /dl. Hematuria
occurs with a prevalence of 0.5-2.0% among preschool-aged children
(Bergstein et al., 2005).

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Table (2): False Positive Tests for Hematuria (Red Urine without RBCs).
HEME POSITIVE
Hemoglobin (Hemolytic anemia )
Myoglobin (Rhabdomyolysis syndrome, skeletal muscle injury )
HEME NEGATIVE
Drugs
Phenazopyridine (Pyridium) Chloroquine Phenolphthalein
Deferoxamine Ibuprofen Iron sorbitol
Metronidazole Phenothiazines Rifampin
Nitrofurantoin Salicylates Sulfasalazine
Dyes (Vegetable/Fruit): Beets, Blackberries, Food coloring
Metabolites
Homogentisic acid Tyrosinosis Melanin
Porphyrin Methemoglobin Urates
(Meyers, 2004).

Table (3): Causes of Glomerular Hematuria in Children.

Glomerular Hematuria
lsolated Renal Disease Multisystem Disease
 lgA nephropathy (Berger disease)  SLE nephritis
 Alport syndrome (Hereditary nephritis)  HSP nephritis
 Thin glomerular basement membrane  Wegener granulomatosis
nephropathy  Polyarteritis nodosa
 Post infectious GN (Post streptococcal  Good pasture syndrome
GN)  Hemolytic uremic
 Membranous nephropathy syndrome
 Membranoproliferative GN  Sickle cell glomerulopathy
 Focal segmental glomerulosclerosis  HIV nephropathy
 Antiglomerular basement membrane
disease
(Bergstein et al., 2005).

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Table (4): Causes of Extraglomerular Hematuria.

Extraglomerular Hematuria
Upper Urinary Tract Lower Urinary Tract
 Tubulointerstitial :  Inflammation
Pyelonephritis - Interstitial nephritis Cysitis
Nephrocalcinosis - Acute tubular necosis Urethritis
 Vascular :  Urolithiasis
Arterial/venous thrombosis  Coagulopathy
Nut cracker syndrome  Trauma
Malformation (Aneurysms, hemangiomas)  Heavy exercise

 Crystalluria:
Calcium oxalatr – Uric acid
 Hemoglobinopathy:
Sickle cell trait/disease
 Anatomic:
Hydronephrosis- Cystic kidney disease –
Multicystic dysplasia.
 Tumor:
Wilms- Rhbdomyosarcoma- Angiomyolipoma.
(Bergstein et al., 2005).

Poststreptococcal Glomerulonephritis:

Acute post-streptococcal glomerulonephritis (PSGN), first described

as a complication of scarlet fever in 18th century, is the prototype of post-
infectious glomerulonephritis. It is an immune complex-mediated disease
that is usually associated with recent streptococcal infection of skin or
throat. While the annual incidence in developing countries is nine cases
per 100,000 inhabitants (Rodriguez-Iturbe and Hass, 2016), the
incidence in developed countries has been declining. It is estimated to be
0.3 cases per 100,000 persons-year (Rodriguez-Iturbe and Musser,
2008). The typical clinical features vary from asymptomatic microscopic

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hematuria to acute nephritic syndrome (gross hematuria, proteinuria,

edema, hypertension, and elevated serum creatinine). The prognosis is
excellent especially in children with recovery within one week in a
typical case. The requirement of chronic hemodialysis is rare (Rodriguez-
Iturbe and Hass, 2016). However, some patients can develop rapidly
progressive glomerulonephritis associated with crescents formation on
renal biopsy. The current practice is to consider pulse corticosteroids in
these particular cases although it is not proven to be beneficial
(Zaffanello et al., 2010). However, the role of steroids in patients with
progressive renal failure without severe histological features has not been
studied to our knowledge.

Immunoglobulin A (IgA) nephropathy:

It is the most common chronic glomerular disease worldwide. Focal

and segmental mesangial proliferation and increased mesangial matrix are
seen in the glomerulus. Some children display generalized mesangial
proliferation that may be associated with crescent formation and scarring.
IgA is the predominant immunoglobulin deposited in the mesangium but
lesser amounts of IgG, IgM, C3, and properdin are common. Familial
clustering of IgA nephropathy cases suggests the importance of genetic
factors. (Delos and Wyatt, 2004).

Although IgA nephropathy does not lead to significant kidney

damage in most children, progressive disease develops in 20-30 % of
children at 15-20 years after disease onset. Therefore, most children with
IgA nephropathy will not display progressive renal dysfunction until
adulthood, prompting the need for careful long-term follow-up. Poor
prognostic indicators include persistent hypertension, diminished renal
function, and heavy or prolonged proteinuria. A worse prognosis is

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suggested by histological evidence of diffuse mesangial proliferation,

extensive glomerular crescents, glomerulosclerosis and tubulointerstitial
changes, including inflammation and fibrosis (Delos et al., 2005).

Thin Glomerular Basement Membrane Disease:

Thin GBM disease (TGBMD) is defined by the presence of

persistent microscopic hematuria and isolated thinning of the GBM on
electron microscopy. Isolated hematuria in multiple family members
without renal dysfunction is referred to as benign familial hematuria.
TGBMD may be sporadic or transmitted as an autosomal dominant trait.
Microscopic hematuria is usually persistent and often initially observed
during childhood. Hematuria may initially present in adulthood and may
be intermittent. Episodic gross hematuria may also be present,
particularly after a respiratory illness. There is no treatment. Progressive
renal insufficiency, hypertension, proteinuria, and extrarenal
manifestations of TGBMD are rare. GBM thinning may also be seen in
IgA nephropathy (Savige et al., 2003).

Alport syndrome (AS):

It is the most common of several types of hereditary nephritis. It

may be X linked disease (85%) : The patients have a X linked disease
caused by mutation in the COL4AS gene encoding the alpha 5 chain of
type 1V collagen, a major component of basement membrane. It may be
autosomal recessive disease (10%): It is caused by mutations in the
COL4A3 and COL4A4 genes on chromosome 2 encoding the alpha 3 and
alpha 4 chains respectively, of type 4 collagen. Autosomal dominant
disease (5%): It is linked to the COL4A3-COL4A4 gene locus. The
etiology is unknown; it may be related to the composition of the basement
membrane collagen. The mean age of onset is 6 years. It is manifested by

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renal involvement, all patients have asymptomatic microscopic hematuria

and 50% of patients will have single or recurrent episodes of gross
hematuria commonly occurring 1-2 days after an upper respiratory
infection. Proteinuria is common by the 2nd decade often > 1 g /24 hour
and is frequently in male more than female. It can be associated with
bilateral sensorineural hearing loss, ocular abnormalities, and platelets
abnormalities. The prognosis is progressive renal dysfunction leading to
end stage renal disease occur before 30 yr in 75% of males with X linked
disease, and 12% by age 40 and 30% by age 60 in females (Kashtan,
2004).

Lupus nephritis:

Approximately two thirds of children with systemic lupus

erythematosus have renal involvement. Various combinations of gross
hematuria and proteinuria (sometimes in the nephrotic range) and
hypertension are found. However, the degree of hematuria does not
necessarily directly correlate with the severity of the renal lesions. The
incidence of systemic lupus erythematosus is 0.6 per 100,000 children
and adolescents, with a higher frequency among persons of African,
Hispanic, or Asian descent. Although more common in girls, the female
predominance is not as pronounced in children as in adults. In SLE
environmental stimuli interacting with certain genetic determinants or
acquired immune defects are generally acknowledged to result in a
polyclonal B cell immune response, with various antibodies deposited in
target tissues, such as the kidney and other organs. The degree of renal
involvement should be determined histologically. The currently accepted
classification is based on the World Health Organization (WHO) system
and some modification using the International Study of Kidney Disease in

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Children (ISKDC) sub classification. Findings may range from mild

glomerulitis to diffuse proliferative glomerulonephritis (Quigley, 2008).

World Health Organization (WHO) Classification of Lupus Nephritis:

Is based on light, immunoflurescent, and electron microscopy.

WHO class I nephritis: No histologic abnormalities.

WHO class II nephritis: It may show mild class11-A, or moderate 11-B

mesangial hypercellularity and increased matrix in light microscopy.
Some glomeruli have mesangial deposits containing Ig and complement
in immunoflurescent microscopy.

WHO class III nephritis: Focal and segmental mesangial proliferation,

and occasional glomeruli show capillary wall necrosis, crescent
formation, and sclerosis lesions in light microscopy, almost all glomeruli
show mesangial deposits, and some glomeruli show also subendothelial
deposits in immunoflurescent, and electron microscopy. All class II and
some class III patients reveal hematuria, proteinuria < 1 gm / day with
normal renal function

WHO class IV nephritis: It is the most common and the most severe
form of lupus nephritis. In light microscopy all glomeruli show
mesangial proliferation. The capillary walls are thickened (sub
endothelial deposits) and they commonly show necrosis, crescent
formation and scarring. In immunoflurescent, and electron microscopy
massive mesangial and subendothelial deposits of Ig and complement in
all glomeruli is revealed. Some class III and all class IV patients present
with hematuria and proteinuria with reduced renal function, nephrotic
syndrome or acute renal failure.

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WHO class V nephritis: It is the least common form of lupus nephritis.

It resembles idiopathic membranous glomerulopathy histologically,
except for mild to moderate mesangial proliferation. It commonly present
with nephritic syndrome (Perfumo and Martini, 2005).

Henoch–Schonlein Purpura Nephritis:

It is a small vessel vasculitis characterized by a purpuric rash,

arthritis, abdominal pain, and glomerulonephritis. The symptoms and
signs of HSP nephritis typically appear 1-3 weeks after upper respiratory
tract infection. Although the pathogenesis of HSP nephritis remains
unknown but this disease appears to be mediated by the formation of
immune complexes containing polymeric IgA I within capillaries of the
skin, intestine, and glomerulus. The diagnosis of HSP is based on the
constellation of clinical findings. Presentation with isolated microscopic
hematuria alone carries the best prognosis whereas presentation with
acute nephritic and or nephrotic syndrome carries the highest risk of
developing hypertension or chronic renal failure (Halling et al., 2005).

Goodpasture Disease:

Pulmonary hemorrhage and glomerulonephritis associated with

antibodies commonly directed against specific epitopes of type IV
collagen within the alveolar basement membrane of the lung and
glomerular basement membrane (anti–GBM). In some patients, anti-
GBM nephritis occurs without pulmonary hemorrhage and presents as
rapidly progressive glomerulonephritis. Good pasture disease is rare in
childhood. Patients usually present with hemoptysis associated with
pulmonary hemorrhage that can be life-threatening. Renal manifestations
include acute nephritic syndrome with hematuria, proteinuria, and
hypertension. Progressive renal dysfunction occurs within days to weeks.

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The serum complement C3 level is normal. Diagnosis is suggested by

renal biopsy (Hudson, 2004).

Diagnostic Approach to a Child with Hematuria:

The evaluation of a child with hematuria depends upon the type of

hematuria (microscopic or gross) and the child's recent history,
symptoms, and physical examination (Meyers, 2004).

History:

* History of recent upper respiratory, skin or gastrointestinal infection

suggests acute GN, HUS, or HSP nephritis.

* Rash and joint complaints suggest HSP or SLE nephritis.

* Frequency, dysuria, and unexplained fever suggest a urinary tract

infection

* Renal colic suggests nephrolithiasis.

* Headache, visual changes, epistaxis, or heart failure suggests significant

HTN.

* History of trauma: Child abuse must always be suspected in a child

with un explained bruising and hematuria.

* Family history of similar condition: Hereditary glomerular diseases

include hereditary nephritis (Alport syndrome), thin glomerular
basement membrane disease, SLE nephritis and IgA nephropathy. Other
hematuric renal disorders with a hereditary component include
polycystic kidney disease, urolithiasis and sickle cell disease/ trait.
(Meyers, 2004)

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Physical Examination:

 Hypertension, body edema, or signs of congestive heart failure: They

suggest acute glomerulonephritis

 Flank mass: It may signal hydronephrosis (obstructive uropathy),

cystic disease, renal vein thrombosis or tumor (as Wilms tumor).

 Several malformation syndromes associated with renal disease: They

include VATER syndrome (vertebral body anomalies, anal atresia,
tracheo-esophageal fistula, and renal dysplasia).

 Hematuria associated with neurological or cutaneous abnormalities:

renal cystic disease, or tumors associated with several syndromes,
including tuberous sclerosis, Von Hippel-Landau and Zellweger
syndrome (Bergstien et al., 2005).

Urine Analysis:

Glomerular hematuria is frequently associated with brown, cola-

colored or burgundy urine, proteinuria >100 mg/dl via dipstick,
microscopic examination of the urine should be performed. Urinary
microscopic findings of RBC casts, and deformed urinary RBCs
(particularly acanthocytes). Hematuria originating within the convoluted
or collecting tubules may be associated with the presence of leukocyte or
renal tubular epithelial cell casts. Lower urinary tract sources of hematuria
may be associated with gross hematuria, blood clots, normal urinary RBC
morphology by microscopy, and minimal proteinuria on dipstick (<100
mg/dl) (Meyers, 2004). However, persistent microscopic hematuria is
less common (<0.5%) indicating that investigation of isolated microscopic
hematuria should only be investigated once persistence has been
established in at least 3 different specimens taken over a period of 2–3

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weeks. Dipstick assessment of first degree relatives for the presence of

hematuria should also be undertaken to identify benign familial hematuria
(also known as thin basement membrane disease), a non-progressive
autosomal dominant condition that does not require any specific treatment
(Steven, 2005).

Urine Culture:

The child with persistent asymptomatic isolated hematuria of greater

than 2 weeks duration poses a dilmma as the extent to which one should
pursue diagnostic evaluation. It is recommended that the initial evaluation
of these children includes a urine culture (Bergstien et al., 2005).

Radiological Imaging:

Renal and bladder ultrasonography should be considered to rule out

structural lesions such as tumor, cystic disease, hydronephrosis, or
urolithiasis or injury to kidneys, ureters or bladder (Bergstien et al.,
2005). Kidneys that are smaller than normal indicate a decrease in renal
mass due to congenital maldevelopment (e.g., renal hypoplasia), poor
growth, or loss of nephrons due to an underlying disorder or injury (Spira
et al., 2009).

The children with a normal evaluation with ultrasound should have

their serum creatinine values checked annually and their blood pressure
and urine checked every 3 months until hematuria resolves. If the
microscopic hematuria does not resolve but the child has no symptoms
and no protein in the urine, the child will be monitored over time. The
child may be referred to a pediatric nephrologists if hematuria persists
(Bergstien et al., 2005). BUN, creatinine, electrolytes, albumin,
cholesterol, complement, anti- streptococcal antibody, antinuclear

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antibody (ANA), anti-DNA and tests for hepatitis B, hepatitis C, and

human immunodeficiency virus (HIV) infection should be done (Gekle,
2007)

Voiding Cysto Urethrogram (VCUG) is only required in patients

with a recurrent UTI, renal scarring, hydroureter, or hydronephrosis.

Cystoscopy should be reserved for the evaluation of the rare child

with a bladder mass noted on ultrasound, urethral abnormalities caused by
trauma, posterior urethral valves, or tumor.

Renal Biopsy is indicated for children with persistent microscopic

hematuria or recurrent gross hematuria associated with decreased renal
function, proteinuria, or hypertension (Bergstien et al., 2005).

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Confirm hematuria with Dipstick positive

 Urine dipstick Evaluate
STEP 1
for pigment
 Urine microscopic examination No RBC seen

Significant red blood cell (RBC) seen

Symptoms and signs of acute nephritic Urine protein/creatinine

STEP 2
Syndrome, e.g., edema, hypertension, oliguria Ratio, serum urea, creatinine,
N Yes electrolytes, albumin
Serum complements C3 and
No C4, ASOT or anti-DANse B
ANA, Anti-dsDNA antibody,
Macroscopic hematuria: excludeNo preceding exercise.
ANCA (if Pulmonary
STEP 3 Isolated microscopic hematuria: repeat urinalysis weekly
hemorrhage Present)
x 2 (without exercise).
Investigate if persistent hematuria.

Urine phase contrast microscopy

STEP 4 Urine protein/creatinine ratio.

NON-GLOMERULAR GLOMERULAR
Isomorphic RBC, no casts, no proteinuria Dysmorphic RBC, RBC casts, proteinuria
STEP 5

 Serum urea, creatinine, electrolytes

 Urine calcium/creatinine ratio  24-hour urine protein and creatinine
 Urine culture clearance
 Urine adenovirus culture  Serum complements C3 and C4
 Renal ultrasound and Doppler  Serum lgA
 Coagulation screen (full blood count,  Renal ultrasound
PT, PTT)  Test parents and siblings for
 Abdominal X-ray (in cases of renal hematuria
calculi)  Consider audiology
 24-hour urine calcium, uric acid ,  Consider renal biopsy if indicated
oxalate, cystine (in cases of renal
calculi). Investigations normal
 CT abdomen (in cases of trauma or intermittent hematuria
tumor)
 Magnetic resonance angiography (if Follow up with yearly urinalysis
nutcracker syndrome is suspected)

Fig. (2): Algorithm for Investigating Hematuria.

(Yap and Weng, 2008).

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3. Proteinuria

Definition:
The normal rate of protein excretion in the urine is less than 4 mg/
m2 per hour or less than 150 mg/1.73 m2 per day throughout childhood in
both boys and girls. Abnormal proteinuria is defined as 4 to 40 mg/ m2
per hour, and more than 40 mg/ m2 per hour is defined as nephrotic range
proteinuria (Hogg et al., 2000).
It can represent the early stages of chronic kidney disease, which
can progress to kidney failure. It is also a marker of and probably an
independent risk factor for atherosclerotic diseases, such as coronary
artery disease or stroke. People with proteinuria have an increased risk of
death (Grimm et al., 1997).

Mechanisms of Proteinuria:
There are four primary mechanisms of excessive protein excretion:
(1) altered glomerular permeability resulting in increased filtration of
normal plasma proteins (2) inadequate tubular reabsorption of the small
amounts of normally filtered proteins (3) glomerular filtration of
circulating abnormal amounts of low-molecular mass proteins that exceed
the reabsorptive capacity of the tubules and (4) increased secretion of
tissue proteins associated with inflammatory or neoplastic conditions
(Kashif et al., 2003).

Quantification of Proteinuria:
Proteinuria can be quantified by different means. Urine dipstick
testing, spot urine specimen analysis, timed urine collection, and the
sulfosalicylic acid test are the most commonly employed tests (Amir and
Robert, 2008).

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Dipstick Test:
Dipstick test primarily detect albuminuria and are less sensitive for
(and may miss) other forms of proteinuria (e.g., low molecular weight
proteins, Bence Jones protein, gamma globulins). The depth of color of
the dipstick reaction increases in a semi-quantitative manner with
increasing urinary protein concentrations. Because the dipstick reaction
cannot accurately measure protein excretion, persistent proteinuria should
be quantitated by a more-precise method (Jerry, 1999).

Spot Urine Analysis:

Spot urine analysis for protein-to-creatinine ratio (UPCR) and
albumin-to-creatinine ratio (UACR) are currently preferred to the 24-hour
urine collection for quantification of daily proteinuria given the greater
convenience of spot urine sampling. Measurement of UACR was shown
to be as good as a 24-hour urine collection for the quantification of
proteinuria (Chitalia et al, 2001).

24-Hour protein measurement:

It is essential to know how much protein is being excreted to predict
long-term prognosis. Quantitative measurement of protein in a 24-hour
urine collection remains the gold standard, especially since protein
excretion may vary with the circadian rhythm (Chesley, 1993).

Sulfosalicylic Acid Test:

The sulfosalicylic acid test detects all types of urinary proteins. This
characteristic makes the sulfosalicylic acid test useful in the diagnosis of
multiple myeloma, which is characterized by urinary excretion of
immunoglobulin light chains (these are not detected by urine dipstick
testing). A sulfosalicylic acid test should not be used as a screening test

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because it cannot detect small quantities of monoclonal free light chains.

In the latter case, examination of 24-hour urine samples using
electrophoresis and immunofixation is more sensitive (Keren, 1999).

Urine Protein Electrophoresis:

Qualitative evaluation of proteinuria can be done using
immunoelectrophoresis. In Bence- Jones proteinuria there is a
monoclonal peak in the gamma region, whereas a broad heterogeneous
peak in the gamma region indicates tubular proteinuria, in which the
protein molecules are usually smaller than albumin (Kashif et al., 2003).

Clinical Classification:
There are two major categories: isolated (proteinuria in an
asymptomatic patient with no evidence of a systemic or a renal disease,
or any abnormality of the urine sediment) and disease-related (proteinuria
associated with clear evidence of a renal or systemic disease).
1- Isolated proteinuria:
A- Benign isolated proteinuria:
- Functional proteinuria
- Idiopathic transient proteinuria
- Orthostatic (postural) proteinuria
a- Transient
b- Fixed and reproducible
B- Persistent isolated proteinuria
2- Disease-related proteinuria:
A- Non-nephrotic proteinuria (often tubulointerstitial or
vascular renal disease, or systemic disease such as
hypertension, some glomerular disorders)
B- Nephrotic proteinuria (usually a glomerular disorder,
secondary to a systemic disease or a primary glomerular
disease)
(Wingo and Clapp, 2000).

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Functional Proteinuria:
This is a common form of proteinuria that may occur in association
with fever, strenuous exercise, exposure to cold, and emotional stress
(Robershaw et al., 1993). It should be noted that certain serious illnesses,
such as congestive heart failure, obstructive sleep apnea, and other acute
medical illnesses, can be associated with proteinuria without evidence of
intrinsic renal disease (Sklar and Chaudhary, 1988).
This form is referred to as functional because there is no intrinsic
defect in renal structure or function. The proteinuria is related to changes
in renal hemodynamics that favor increased glomerular filtration of
plasma proteins. It usually resolves within several days after the
precipitating event and is not associated with progressive renal disease.
Both increased glomerular permeability and decreased tubular
reabsorption have been implicated in proteinuria after exercise
(Poortmans et al., 1988).

Idiopathic Transient Proteinuria:

This form of proteinuria is very common, especially in children,
adolescents, and young adults. The patients are asymptomatic and the
proteinuria is discovered incidentally on routine urine examination. The
urine sediment is unremarkable and the proteinuria typically disappears
on subsequent testing. There are no long-term risks for this transient
phenomenon, which probably reflects a physiologic alteration in renal
hemodynamics. The approach to this problem is to repeat the urine
protein testing two to three times on additional samples to determine
whether the proteinuria is indeed transient, intermittent, or persistent
before embarking on an extensive evaluation (Von Bonsdorff et al,1981).

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Idiopathic Intermittent Proteinuria:

Patients with this form demonstrate proteinuria independent of body
position on a significant number (approximately 50%) of but not all
randomly collected urine samples. Most patients have normal renal
function and blood pressure (Muth, 1965).
Orthostatic (Postural) Proteinuria:
Children with this disorder excrete normal or slightly increased
amounts of protein in the supine position. In the upright position, the
amount of protein in the urine may increase tenfold or more. The
proteinuria is usually discovered at routine urinalysis (Devarajan, 1993).
Persistent Isolated Proteinuria:
It is characterized by isolated proteinuria detected in the majority of
randomly collected urine samples. The proteinuria is persistent and
excessive in both recumbent and upright positions. Persistent isolated
proteinuria has been considered almost invariably a sign of structural
renal disease (Cameron, 1990).

Proteinuria with Significant Renal Disease:

8h3ufpt906;' It is important to note that persistent isolated
proteinuria may be the initial clinical manifestation of any progressive
disease, such as the primary glomerular entities focal segmental
glomerulosclerosis or membranous glomerulonephritis, or a secondary
glomerular disease, such as diabetic glomerulosclerosis. However, in
renal or systemic diseases, the proteinuria is more often associated with
edema, hypertension, impaired renal function, or abnormal urinary
sediment, and thus cannot be considered isolated (Wingo et al, 2000).

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Review of Literature Chapter 1

Non-Nephrotic Proteinuria:
Although non isolated proteinuria in the range of less than 2 g/24
hours does not exclude a glomerular disease, with this range of
proteinuria, one should consider tubulointerstitial or vascular disorders.
These include interstitial nephritis, reflux nephropathy, polycystic kidney
disease, drug-induced renal disease, heavy metal exposure, and the
nephropathies associated with hypercalcemia and hyperuricemia. Various
systemic diseases that afflict the kidney, such as hypertension, systemic
lupus erythematosus (SLE), and plasma cell dyscrasias can cause this
degree of proteinuria (Mogensen, 1984).
Microalbuminuria, a type of glomerular proteinuria, is defined as
the excretion of 30 to 300 mg of albumin/24 hours, with the total protein
excretion less than 150 mg/24 hours. Microalbuminuria is often detected
early in the course of diabetes and is a useful predictor of the progression
to diabetic nephropathy in patients with insulin-dependent diabetes
(Molitch et al, 2004).
Tubular proteinuria is present in many patients who excrete less
than 2 g/24 hours. It results from impaired reabsorption by the proximal
tubule of proteins that are normally filtered by the glomeruli. It is
characterized by the excretion of proteins of smaller molecular mass,
such as insulin and lysozyme (Amir and Robert, 2008).
Overload proteinuria occurs when the increased plasma
concentration of a protein leads to filtration through the normal glomeruli
at a rate that is beyond the capacity of the tubules to reabsorb the protein.
Overproduction of monoclonal light chains in multiple myeloma is a
common cause of overload proteinuria (Kumar and Muchmore, 1990).

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Nephrotic Proteinuria:
The fully developed nephrotic syndrome includes the tetrad of
proteinuria, hypoalbuminemia, edema, and hyperlipidemia. The heavy
urinary loss of protein leads to serious complications, such as increased
thromboembolic events, renal tubular dysfunction, and increased
susceptibility to infections (Wingo et al., 2000).
Nephrotic syndrome is characterized by alterations of perm
selectivity at the glomerular capillary wall, resulting in its inability to
restrict the urinary loss of protein. Nephrotic range proteinuria is defined
as proteinuria exceeding 1000 mg/m² per day or spot (random) urinary
protein-to creatinine ratio exceeding 2 mg/mg. The proteinuria in
childhood nephrotic syndrome is relatively selective, constituted
primarily by albumin (Bagga and Mantan, 2005).
The condition is primary (idiopathic) in 95 percent cases. An
underlying disorder that might be identified in less than 5 percent cases
includes systemic lupus erythematosus, Henoch Schönlein purpura,
amyloidosis and infection with HIV, parvovirus B19 and hepatitis B and
C viruses (Bagga and Srivastava, 2005).
More than 80 percent patients with nephrotic syndrome show
minimal change disease (MCD) characterized by normal renal histology
on light microscopy. The remaining is contributed by focal segmental
glomerulosclerosis (FSGS) and mesangioproliferative glomerulonephritis
(MesPGN). MCD and FSGS are often considered to represent the same
pathophysiological process. Membranoproliferative glomerulonephritis
and membranous nephropathy are uncommon conditions in childhood
(Srivastava et al., 1975).

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Clinical Approach to Proteinuria:

History:
The primary objective in the evaluation of the patient with
proteinuria, taking a careful history of hematuria, polyuria, or nocturia to
determine if there is significant renal disease or not. Does the patient have
significant edema, indicating the nephrotic syndrome? Is the proteinuria
persistent or orthostatic? Are there other signs or symptoms indicating
systemic disease? History of drug intake, nonsteroidal anti-inflammatory
medication. Family history of renal failure or deafness should be obtained
(Quigley, 2008).
Physical examination:
Examination may reveal evidence of renal failure, such as growth
failure and anemia. Blood pressure must be measured, hypertension
important prognostic indicator in chronic renal disease. Signs of nephrotic
syndrome generalized edema, ascitis, pleural effusion and scrotal edema
(in male). Associated signs of systemic illnesses, such as palpable
purpuric rash, joint swelling , palpable flank masses (Yap and Weng lau,
2008).
Investigations:
Isolated proteinuria is benign in the vast majority of children, if the
child has signs and symptoms that suggest renal disease, a detailed
investigation should be started early. The presence of hematuria in
addition to proteinuria, a detailed evaluation for renal disease should be
performed. The first step is to determine whether the proteinuria is
persistent, the next step is to quantify the amount of proteinuria (Lin
et al., 2000).
If spot urine protein to creatinine ratio is more than 0.02 g/mmol or
0.2 mg/mg, it is advisable to confirm the presence of significant
proteinuria with a 24-hour urinary total protein collection. If the24-hour

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Review of Literature Chapter 1

urinary total protein is greater than 0.3 g/1.73 m2 per day, it is useful to
evaluate for renal disease (Ruggenenti et al, 2001).
Urine examination:
Microscopic examination of the fresh urine sample for blood, cast
and crystals is required. A clean catch urine sample for culture may be
necessary to rule out occult urinary tract infection. Tubular proteinuria is
suspected if the urinary excretion of β 2-microglobulin, α1-microglobulin
and retinol-binding protein exceeds 0.04, 2.2, and 0.024 mg/mmol
creatinine or 4 ×10-4, 0.022, and 2.4 ×10-4 mg/mg creatinine, respectively
( Bergon et al, 2002).
Blood examination:
Renal function with serum urea, creatinine and electrolytes should
be assessed. Creatinine clearance gives a more accurate picture of renal
function. Serum total protein, albumin and cholesterol must be measured.
Hypoproteinemia and hyperlipidemia are indicator of nephrotic syndrome
(Yap and Weng lau, 2008).
Immune system tests:
In the absence of an obvious cause of proteinuria, the workup should
also include measurements of antinuclear antibody (ANA), antineutrophil
cytoplasmic antibodies (ANCA), complement levels (C3 and C4), and the
erythrocyte sedimentation rate to evaluate for rheumatologic diseases (eg,
systemic lupus erythematosus, Wegener granulomatosis, Goodpasture
syndrome, cryoglobulinemia), lymphoproliferative diseases, and solid
organ cancers ( Kashif et al., 2003).
Renal imaging:
Renal ultrasonography is performed to identify anatomical
abnormality of the kidneys or urinary tract, which can result in a
reduction of nephron mass. A significant difference in the size of kidneys

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Review of Literature Chapter 1

may suggest underlying reflux nephropathy. Renal Doppler sonography is

helpful in hypertensive nephropathy due to renal artery stenosis (Park
et al., 2002).
Repeat urine
Urine dipstick protein Trace
dipstick
protein
Negative
≥1+ ≥1+ of trace
Obtain 1st morning urine for Repeat urine dipstick 6
protein/ceartinine ratio and urinalysis months to 1 year later
with microscopic examination consider discharge if urine
dipstick protein negative
or trace

Urine protein/creatinine ratio

> 0.02 g/mmol (0.2 mg/mg) Urine protein/creatinine ratio ≤ 0.02 g/mmol
± microscopic hematuria (02 mg/mg) and no microscopic hematuria

24 hour urinary total protein

Possibilities

≤ 0.3 g/1.73m2/day Repeat urine tests 1.

Urine dipstick
6 month later
2 False positive
>0.3 g/1.73 m /day
Further evaluation
History (drugs, family history)
2. Transient proteinuria
Physical examination (including BP)
Investigations:
 Serum urea ,creatinine, electrolytes 3.
 Serum total cholesterol
 Serum albumin Postural/orthostatic proteiuria
 Serum complements C3 and C4 consider:
 Serum lgA  24-hour urinary total protein
 ANA or anti-dsDNA antibodies,  Renal Doppler ultrasound
ANCA (if indicated) (if nutcracker syndrome is
 Hepatitis B and C, HIV serology suspected)
(if indicated)
 Renal ultrasound
 Consider renal biopsy

Fig. (3): Algorithm for investigating proteinuria.

(Yap and Weng, 2008).

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4. Urinary Tract Infection

Definition:

Urinary tract infection (UTI) is an inflammatory response of the

urothelium to microorganisms (mostly bacterial invasion) that is usually
associated with pyuria and bacteriuria. Bacteriuria is the presence of
bacteria in the urine and implies that these bacteria are from the urinary
tract and not contaminants from the skin, vagina, or prepuce. Pyuria is
the presence of white blood cells in the urine and is generally indicative
of an inflammatory response of the urothelium to bacterial invasion
(Schaeffer, 2002).

Asymptomatic bacteriuria (ASB):

Asymptomatic bacteriuria was defined as the presence of at least
105 colony-forming units (CFU) /mL of one or two of the same
microorganisms in a culture of clean-voided midstream urine from a
patient without a fever or symptoms of a UTI (Geerlings et al, 2001).

Routes of infection:

1. Ascending Route:
Most bacteria enter urinary tract from the fecal reservoir via ascent
through the urethra into the bladder. This route is enhanced in individuals
with poor hygiene, perineal fecal soilage and patients with intermittent or
indwelling catheters. Although cystitis is restricted to the bladder, in
approximately 30% of instances there is further extension of the infection
into the upper urinary tract. The weight of clinical and experimental
evidence suggests that most episodes of pyelonephritis are due to
retrograde ascent of bacteria from the bladder through the ureter to the
renal pelvis and parenchyma. Once the bacteria reach the renal pelvis
they can enter the renal parenchyma by means of collecting tubules. This

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process is exacerbated by ureteral obstruction or vesicoureteral reflux,

particularly when it is associated with intrarenal reflux (Schaeffer, 2002).

2. Hematogenous Route:
Infection by this route is uncommon in normal individuals.
However, the kidney occasionally is secondarily infected in-patient with
Staphylococcus aureus bacteremia from oral sites or with Candida
fungemia. Experimental data indicates that infection is enhanced when
the kidney is obstructed (Smellie et al., 1975).
3. Lymphatic Route:
Direct extension of bacteria from the adjacent organs may occur in
unusual circumstances, such as severe bowel infection or retroperitoneal
abscesses. There is little evidence that the lymphatic route plays a
significant role in the vast majority of urinary tract infections (Schaeffer,
2002).

Clinical Pictures of UTIs:

1- Lower UTI (Cystitis): results from an irritation of the lower urinary

tract mucosa. This infection is not invasive. Frequently presented with
one or more of the following criteria:
Dysuria, Urgency, Increased frequency of urination, Supra pubic
tenderness, Small volume voiding, Increased number of white
blood cells in the urine (pyuria) (Orenstein and Wong, 1999).

2- Upper UTI (Pyelonephritis): this infection usually results from

ascension of bacteria to the kidney from the lower urinary tract, but also
can arise by hematogenous spread (e.g. from lungs in patients with
pneumonia). In contrast to cystitis, pyelonephritis is an invasive disease.
Blood cultures are positive in up to 20% of patients who have this
infection (Stamm and Hooton, 1999).

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Symptoms and Signs:

Urinary tract infection must meet at least one of the following criteria:
1. Criterion 1: Patient has at least one of the following signs or
symptoms with no other recognized cause: fever (> 38 ºC), urgency,
frequency, dysuria or suprapubic tenderness and patient have a
positive urine culture that is > 105 microorganisms per cm3.

2. Criterion 2: Patient has at least two of the following signs or

symptoms with no other recognized cause: fever (> 38 ºC), urgency,
frequency, dysuria or suprapubic tenderness and at least one of the
following :
 Pyuria (urine specimen with >10 WBCs /mm3).
OR
 Organisms seen on gram stain of urine (WHO, 2007).

Diagnosis of UTIs:

1- Urine Analysis:
Detection of bacteriuria by urine microscopy, bacteriuria can be
detected microscopically using gram staining of uncentrifuged urine
specimens, gram staining of centrifuged urine, or direct observation of
bacteria in urine specimens (Cardoso et al, 1998).
It is an insensitive test, being reliably positive only if the
concentration of bacteria in the urine is ≥ 10 5 CFU/ml, infections with
bacterial concentrations of 102 - 103 CFU/ml may not be detected by this
test (McNair et al., 2000).

Detection of bacteriuria by nitrite test: bacteriuria can be detected

chemically when bacteria produce nitrite from nitrate. The biochemical
reaction that is detected by the nitrite test is associated with members of
the family of Enterobacteriaceae, but the usefulness of the test is limited

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Review of Literature Chapter 1

because nitrite production is not associated with urinary tract pathogens

such as S. saprophyticus, Pseudomonas spp., or Enterococci (Pappas,
1998). Another limitation to the test is that it requires testing a specimen
of the first urine produced in the morning, as ≥ 4 h are required for
bacteria to convert nitrate to nitrite at levels that are reliably detectable
(Wilson and Gaido, 2004).

Detection of pyuria by leukocyte esterase tests: the most accurate

microscopic method for quantitating pyuria is to measure the urinary
leukocyte excretion rate, leukocyte esterase tests are based on the
hydrolysis of ester substrates by proteins with esterolytic activity. Human
neutrophils produce as many as 10 proteins with esterolytic activity.
These proteins react with ester substrates to produce alcohols and acids
that then react with other chemicals to produce a color change that is
proportional to the amount of esterase in the specimen (Fuller et al.,
2001). The specificity or accuracy for leukocyte esterase is in the range of
78% while the specificity for urine nitrite is about 98% (Rushton and
Long, 2002).

These tests for both nitrite and leukocyte esterase, thus providing
tests for both bacteriuria and pyuria, number of clinical evaluations have
defined the performance characteristics of these tests which concluded:
first, the 2 tests, when used together, perform better than either test
performs when used alone. Second, the tests have better performance
characteristics for detecting bacteriuria at high colony counts than at low
colony counts. Third, these tests have low sensitivity, high specificity,
low positive-predictive values, and high negative-predictive values.
Taken together, the performance characteristics of these tests make them
useful as a way to rule out bacteriuria on the basis of a negative test result
(Wilson and Gaido, 2004).

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2- Urine Culture
Symptomatic infection: a positive result on urine culture (≥ 10 5
microorganism/ml) and one of the following clinical symptoms: fever ≥
38 ºC, urgency, frequency, dysuria, loin pain, loin or suprapubic
tenderness (Eggimann and Pittet, 2001).

Bacterial count of 105 microorganism/ml with no more than two

species is generally considered significant from a midstream urine
specimen, also bacterial count of ≥ 103 microorganism/ml can be
considered significant if obtained from a suprapubic puncture or in the
presence of an antibiotic (Lipsky et al., 1987).

Asymptomatic bacteriuria: patient has a positive urine culture, that

is ≥ 105 microorganism/ml of urine with no more than two species of
microorganisms and patient has no fever (≥ 36 ºC), urgency, frequency,
dysuria, or suprapubic tenderness (Grabe et al., 2015).

Complications of UTI:
Nearly all urinary tract infections are mild, treatable, and have no
long-term consequences. Serious physical complications can occur in
some cases, however, most often in hospitalized patients (Warren, 1997).

1- Obstruction and Wide Spread Infection: very severe upper

urinary tract infections cause obstruction that result in wide spread
and even life threatening infection. Patients who develop UTIs in
the hospital are higher risk for such infections than those outside
the hospital. In one particularly dangerous form of kidney infection
that obstructs the ureter, mortality rates exceed 40% (Wilson and
Gaido, 2004).

2- Kidney Damage: In high risk patients, recurrent UTIs may cause

scarring in the kidneys, which over time can lead to hypertension
and eventual kidney failure (Sobel, 1997).

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3- Urge Incontinence: recurrent UTIs may increase the risk for urge
incontinence. People with urge incontinence experience leakage
and need to urinate frequently (Kunin, 1994).

4- Kidney Stones: can be caused by urinary tract infections due to

bacteria that secrete certain enzymes. These enzymes raise urine
concentrations of ammonia, which composes the crystals forming
stones. The stone-promoting bacteria are usually Proteus
(Orenstein and Wong, 1999).

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