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CHAPTER EIGHT
PATHOLOGY OF THE URINARY SYSTEM
THE PATHOLOGY OF THE KIDNEY
INTRODUCTION
Diseases of the kidney are divided into four categories depending on which component of
the kidney is primarily affected; these are
1. Glomerular 2. Tubular 3. Interstitial 4. Vascular
This division is useful because
a. The early manifestations of each group of diseases tend to be distinctive.
b. These groups differ in their pathogenesis, for e.g., glomerular diseases are often
immunologically mediated, whereas tubular and interstitial disorders are more likely to
be caused by toxic or infectious agents. However, it should be noted that
1. The interdependence of renal components translated into that damage to one
component is almost always affects secondarily the others.
2. All forms of chronic renal disease tend ultimately to damage all four components of
the kidney thus, eventuates in chronic renal failure (end-stage kidney disease).
Clinical Manifestations of Renal Diseases
These can be grouped into well-defined syndromes, each of which is distinctive to the
component that is primarily affected. At this point certain terms need to be clarified
Azotemia is an "elevation of blood urea, nitrogen and creatinine levels". It is largely
related to a decreased glomerular filtration rate (GFR). Azotemia is divided into
1. Prerenal azotemia, encountered with hypoperfusion of the kidneys, which decreases
GFR as in shock states
2. Renal, which is due to renal parenchymal damage
3. Postrenal that results from urine out flow obstruction below the level of the kidney.
Uremia signifies "azotemia associated with biochemical and systemic clinicopathological
alterations" such as metabolic and endocrine changes, uremic gastroenteritis, peripheral
neuropathy and fibrinous pericarditis.
The major renal syndromes are
Acute nephritic syndrome is characterized by acute onset of usually gross hematuria,
mild to moderate proteinuria, azotemia, edema, and hypertension; it is the classic
presentation of acute poststreptococcal glomerulonephritis.
The nephrotic syndrome is characterized by heavy proteinuria (excretion of >3.5 gm of
protein/day in adults), hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria.
Asymptomatic (microscopic) hematuria or proteinuria, or a combination thereof, is
usually a manifestation of mild glomerular abnormalities.
Acute renal failure refers to recent onset of oliguria or anuria, with azotemia.
Chronic renal failure refers to prolonged symptoms and signs of uremia; it is the end
result of all chronic renal diseases.
Urinary tract infection (UTI) is characterized by bacteriuria and pyuria (bacteria and
leukocytes in the urine. The infection may be symptomatic or asymptomatic, and may
affect the kidney (pyelonephritis) or the bladder (cystitis) only.
Nephrolithiasis (renal stones) is manifested by renal colic, hematuria, and recurrent
stone formation.
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GLOMERULAR DISEASES
The glomerulus consists of an anastomosing network of capillaries invested by two layers
of epithelium; visceral & parietal. The visceral epithelium (podocytes) is an intrinsic part
of the capillary wall, whereas the parietal epithelium lines Bowman space (urinary
space), the cavity in which plasma ultrafiltrate first collects. The glomerular capillary
wall is the filtration unit and consists of the following structures (Fig. 8-1):
1. A thin layer of fenestrated endothelial cells (each hole is about 100 nm in diameter).
2. Glomerular basement membrane (GBM), ultrastructally made up of a thick, dense
central layer (lamina densa), and thinner, lucent peripheral layers, (lamina rara interna &
externa).
3. The visceral epithelial cells (podocytes) that possess foot processes adherent to the
lamina rara externa of the basement membrane. Adjacent foot processes are separated by
25-nm-wide filtration slits bridged by a thin slit diaphragm composed in largely of
nephrin.
4. The entire glomerular tuft is supported by mesangial cells lying between the
capillaries. Basement membrane-like mechanical matrix forms a meshwork through
which the mesangial cells are scattered.
The glomerular basement membrane shows selective permeability, which is size-
dependent and charge-dependent. The major characteristics of glomerular filtration are
1. A high permeability to water and small solutes
2. Almost complete impermeability to molecules of the size and molecular charge of
albumin.
3. More permeability to cations than anions.
The podocyte is decisive to the glomerular barrier function by providing a distal
resistance to the flow of water and a barrier to the filtration of proteins. It is also largely
responsible for synthesis of GBM components.
PATHOGENESIS OF GLOMERULAR DISEASES
Immune mechanisms (antibody-associated & cellular) underlie most primary and many
secondary glomerular diseases.
Circulating Immune Complex-mediated Nephritis (type III hypersensitivity reactions)
With circulating immune complex-mediated disease, the glomerulus is an "innocent
bystander" because it is not responsible for their formation. The antigen in these
complexes may be
1. Endogenous, as in SLE or
2. Exogenous, as in bacterial (streptococcal), viral (hepatitis B), parasitic (Plasmodium
falciparum malaria), and spirochetal (Treponema pallidum) infections.
3. Unknown as often the case in membranous nephropathy.
The antigen-antibody complexes are trapped in the glomeruli, where they produce injury,
mainly through the activation of complement and the recruitment of leukocytes. Electron
microscopy reveals the immune complexes as electron-dense deposits or clumps that are:
1. Mesangial
2. Subendothelial i.e. between the endothelial cells and the GBM
3. Subepithelial i.e. at the outer surface of the GBM and the podocytes
The presence of immunoglobulins and complement in these deposits can be demonstrated
by immunofluorescence microscopy. When fluoresceinated anti-immunoglobulin or anti-
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complement antibodies are used, the immune complexes are seen as granular deposits in
the glomerulus (Fig. 8-2).
Cell-Mediated Immune Glomerulonephritis
T cell-mediated injury may account for some cases of glomerulonephritis (GN) in which
either there are no deposits of antibodies or immune complexes, or the deposits do not
correlate with the severity of damage.
Mediators of Immune Injury
A major pathway of antibody-initiated injury is activation of the complement that leads to
the generation of chemotactic agents (mainly C5a) and thus recruitment of neutrophils
and monocytes. Neutrophils in turn release
1. Proteases, which cause GBM degradation;
2. Oxygen-derived free radicals, which cause cell damage; and
3. Arachidonic acid metabolites, which contribute to reduction in GFR.
In some cases, however, complement-dependent (but not neutrophil-dependent) injury
occurs through the effect of the C5-C9 lytic component (membrane attack complex) of
complement, which causes
1. Epithelial cell detachment and
2. Stimulation of mesangial and epithelial cells to secrete various mediators of cell injury.
3. Up-regulation of transforming growth factor-β (TGF-β) receptors on podocytes; TGF-β
stimulates synthesis of extracellular matrix, thus giving rise to altered GBM composition
and thickening.
Nephritis Caused by In Situ Immune Complexes
Antibodies in this form of injury react directly with planted antigens in the glomerulus.
The best-characterized disease in this group is anti-GBM antibody GN, where
antibodies are directed against fixed antigens in the GBM. It results from the formation of
autoantibodies directed against the GBM. Deposition of these antibodies creates a linear
pattern of staining when visualized with immunofluorescence microscopy (Fig. 8-2); this
is in contrast to the granular pattern described for other forms of immune complex-
mediated nephritis. Sometimes, the anti-GBM antibodies cross-react with basement
membranes of lung alveoli, resulting in combined lung and kidney lesions (Goodpasture
syndrome). Planted antigens also include DNA, bacterial products, aggregated IgG,
which deposit in the mesangium because of their size. Most of these planted antigens
induce a granular pattern of immunoglobulin deposition as seen by immunofluorescence
microscopy.
Other Mechanisms of Glomerular Injury
1. Podocyte injury: this can be induced by antibodies to visceral epithelial cell antigens as
in some cases of focal and segmental glomerulosclerosis. Such injury is reflected by
effacement of podocyte's foot processes associated with proteinuria. In most forms loss of
normal slit diaphragms is a key feature in the development of proteinuria.
2. Nephron Loss: any renal disease destroying sufficient nephrons to the extent of
reducing the GFR to 30%-50% of normal shows relentless progression to end-stage renal
failure. Such individuals develop proteinuria, and their kidneys show widespread
glomerulosclerosis. The latter is initiated by the adaptive hypertrophy of the remaining
unaffected glomeruli to maintain renal function. These adaptations ultimately lead to
further endothelial and epithelial cell injury, which is followed by capillary collapse and
obliteration, increased deposition of mesangial matrix, and eventually by segmental or
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global sclerosis of glomeruli. This results in further reductions in the nephron mass and a
vicious cycle of continuing glomerulosclerosis.
THE NEPHROTIC SYNDROME
This refers to a clinical complex that includes
1. Massive proteinuria i.e. daily urine protein loss of 3.5 gm or more in adults
2. Hypoalbuminemia i.e. plasma albumin levels less than 3 gm/dl
3. Generalized edema
4. Hyperlipidemia and lipiduria
The initial event is a derangement in the glomerular capillary walls that leads to increased
permeability to plasma proteins allowing their escape from the plasma into the
glomerular filtrate. With long-standing or extremely heavy proteinuria, serum albumin is
decreased, resulting in hypoalbuminemia. The generalized edema is, in turn, a
consequence of the drop in plasma colloid osmotic pressure as a result of
hypoalbuminemia, and retention of salt and water by the kidney. As fluid escapes from
the vascular tree into the tissues, there is a concomitant drop in plasma volume, with
diminished glomerular filtration. Compensatory secretion of aldosterone, along with the
reduced GFR and reduction of secretion of natriuretic peptides, promotes retention of salt
and water by the kidneys, thus further aggravating the edema. By repetition of this chain
of events, generalized edema (anasarca) may develop. It is possible that
hypoalbuminemia triggers increased synthesis of lipoproteins in the liver & thus
hyperlipidemia. The lipiduria reflects the increased permeability of the GBM to
lipoproteins.
The relative frequencies of the several causes of the nephrotic syndrome vary according
to age. In children 1 to 7 years of age, the nephrotic syndrome is almost always caused by
a primary kidney disease, whereas among adults it is often due to renal manifestations of
a systemic disease. The most frequent systemic causes of the nephrotic syndrome in
adults are
1. Diabetes
2. Amyloidosis
3. SLE
The most important primary glomerular lesions that lead to the nephrotic syndrome
are
1. Focal and segmental glomerulosclerosis (FSGS), which is more important in adults.
2. Minimal-change disease (MCD), which is more important in children
3. Membranous nephropathy
4. Membranoproliferative GN
Minimal-Change Disease (MCD) (Lipoid Nephrosis)
This is the most frequent cause of the nephrotic syndrome in children, mostly between
ages 1 and 7 years (65%). The glomeruli have a normal appearance under light
microscopy; however, electron microscopy shows diffuse effacement of podocyte foot
processes. This is presumably due to a T-cell derived factor that causes podocyte damage.
The cells of the proximal convoluted tubules are often heavily loaded with protein
droplets and lipids secondary to tubular reabsorption of the leaking lipoproteins. The
renal function is preserved in most individuals. The protein loss is confined to the smaller
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serum proteins, chiefly albumin (selective proteinuria). The prognosis in children with
this disorder is generally good; more than 90% of cases respond to a short course of
corticosteroid therapy.
Focal and Segmental Glomerulosclerosis (FSGS) is characterized histologically by
sclerosis (fibrosis) affecting some but not all glomeruli (focal) and involving only
segments of each affected glomerulus (segmental). FSGS is either primary (idiopathic) or
secondary. The former is a common cause of nephrotic syndrome in adults (30%) &
frequent cause in children (10%). The secondary form is seen with
1. HIV immunodeficiency or heroin abuse (HIV nephropathy, heroin nephropathy)
2. IgA nephropathy
3. Maladaptation after nephron loss (see above)
4. Mutations affecting cytoskeletal proteins of podocytes (e.g., nephrin) (inherited form)
Unlike MCD, there is a higher incidence of hematuria and hypertension; the proteinuria is
nonselective, and the response to corticosteroid therapy is poor. At least 50% of
individuals with FSGS develop end-stage renal failure within 10 years of diagnosis. The
pathogenesis of primary FSGS is unknown. As with MCD, permeability-increasing
factors produced by lymphocytes have been proposed. The entrapment of plasma proteins
and lipids occurs in foci of injury where sclerosis develops. FSGS initially affects focally
the juxtamedullary glomeruli. With progression, eventually all levels of the cortex are
affected. The affected segment of the glomerulus shows increased mesangial matrix,
obliterated capillary lumens, and deposition of hyaline masses. (Fig. 8-3) In time,
progression of the disease leads to global sclerosis of the glomeruli with secondary
tubular atrophy and interstitial fibrosis. About 50% of individuals suffer renal failure
after 10 years.
Membranous Nephropathy (Membranous Glomerulonephritis, MGN)
This is a slowly progressive disease, most common in adults 30 to 50 years of age. The
disease is idiopathic (primary) in about 85% of cases. In the remainder it may be
secondary to other disorders, including:
1. Infections (chronic hepatitis B, syphilis, schistosomiasis, malaria)
2. Malignancy, particularly lung and colonic carcinomas and melanoma
3. Autoimmune diseases e.g. SLE
4. Exposure to inorganic salts (gold, mercury)
5. Drugs (penicillamin, captoril, NSIAD)
MGN is a chronic immune complex nephritis. Most idiopathic forms are considered
autoimmune disease caused by antibodies to renal GBM autoantigen. There seems to be a
direct action of C5b-C9 (the membrane attack complex) on the podocyte and mesangial
cells, inducing them to liberate proteases and oxidants that can cause the damage. The
basic change microscopically is diffuse thickening of the GBM (Fig. 8-4). By electron
microscopy, this thickening is caused by subepithelial deposits that are separated from
each other by small, spike-like protrusions of GBM matrix ("spike and dome" pattern);
these can be highlighted by silver stains. With progression, these spikes close over the
deposits, to incorporate them into the GBM. Podocytes show effacement of foot
processes. Eventually the glomeruli become gradually sclerosed. Immunofluorescence
microscopy shows typical granular deposits of immunoglobulins and complement along
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the GBM. The proteinuria is nonselective, involving globulins and albumin molecules.
Overall, only 40% suffer progressive disease terminating in renal failure after 2 to 20
years.
Membranoproliferative Glomerulonephritis (MPGN)
This is manifested histologically not only by GBM thickening but also by proliferation of
glomerular cells. It accounts for up to 10% of cases of primary nephrotic syndrome in
children and adults. Some individuals present only with hematuria or subnephrotic
proteinuria; others have a combined nephrotic-nephritic picture. Two major types of
MPGN (I and II) are recognized; type I is far more common (80% of cases). Different
pathogenic mechanisms are involved in the development of type I and type II disease.
Most cases of type I MPGN seem to be caused by circulating immune complexes, but the
inciting antigen is not known (primary); it also occurs as a secondary form in association
with hepatitis B and C antigenemia, SLE, & extra-renal infections. The fundamental
abnormality in type II appears to be excessive complement activation. By light
microscopy, both types of MPGN are similar. The glomeruli are large, with an
accentuated lobular appearance, and proliferation of mesangial and endothelial cells as
well as leukocytic infiltration (Fig. 8-5). The GBM is thickened, and the glomerular
capillary wall often shows a double contour, or "tram track," appearance, especially
evident in silver or periodic acid-Schiff (PAS) stains. This is caused by "splitting" of the
GBM due to the inclusion within it of processes of mesangial and inflammatory cells.
Types I and II have different ultrastructural and immunofluorescence microscopic
features. The prognosis of MPGN is generally poor in that 40% of the cases progressed to
end-stage renal failure. Type II MPGN (also called dense-deposit disease) has a worse
prognosis.
THE NEPHRITIC SYNDROME
This is a clinical complex, usually of acute onset, characterized by
1. Hematuria
2. Oliguria with azotemia
3. Hypertension
The lesions that cause the nephritic syndrome have in common proliferation of the cells
within the glomeruli, accompanied by leukocytic infiltrate. This inflammatory reaction
injures the capillary walls, permitting escape of red cells into the urine, and induces
hemodynamic changes that lead to a reduction in the GFR. The reduced GFR is
manifested clinically by oliguria, fluid retention, and azotemia. Hypertension is the result
of both the fluid retention and excessive renin release. The acute nephritic syndrome may
be secondary to a systemic disorders such as SLE, or it may be the result of primary
glomerular disease e.g. acute postinfectious GN.
Acute postinfectious (Poststreptococcal) GN is typically associated with streptococcal
infection, but other infectious agents may be responsible. The latter include certain
pneumococcal and staphylococcal infections, as well as some common viral diseases
such as mumps, measles, chickenpox, and hepatitis B and C. The classic case of
poststreptococcal GN develops in a child 1 to 4 weeks after recovery from
"nephritogenic" strains of β-hemolytic, group A streptococcal infection, usually of the
pharynx or skin. Immune complex deposition is involved in the pathogenesis. The
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relevant antigens are probably streptococcal proteins. Serum complement levels are low
and serum anti-streptolysin O antibody titers are elevated. Characteristically the histology
shows a uniformly increased cellularity of the glomerular tufts that affects nearly all
glomeruli (Fig. 8-6). This increased cellularity is caused both by proliferation and
swelling of both endothelial and mesangial cells as well as by a neutrophilic and
monocytic
infiltrate.
Electron
microscopy
shows
subepithelial
"humps".
Immunofluorescence displays these immune complexes as scattered granular deposits of
IgG and complement within the capillary walls. Recovery occurs in most children.
Conversely up to 50% of adults develop end-stage renal disease.
IgA Nephropathy (Berger Disease) usually affects children and young adults as an
episode of gross hematuria occurring within 1 or 2 days of a nonspecific upper
respiratory tract infection, to lasts several days and then subsides, only to recur every few
months. IgA nephropathy is one of the most common causes of recurrent microscopic or
gross hematuria and is the most common glomerular disease revealed by renal biopsies
worldwide. The pathogenic hallmark is the deposition of IgA in the mesangium. IgA
nephropathy may be viewed as a localized (renal) variant of Henoch-Schönlein purpura,
which is also characterized by IgA deposition in the mesangium but it is a systemic
syndrome characterized by purpuric rash, abdominal pain and arthritis. Microscopically,
the glomeruli may be normal or show one of the following:
1. Focal proliferative GN
2. Diffuse mesangioproliferative GN (Fig. 8-7)
3. Crescentic GN (rare).
The characteristic immunofluorescence picture is of mesangial deposition of IgA.
Electron microscopy shows mesangial electron-dense deposits. Serum IgA is increased in
50% of patients due to its increased production in the marrow presumably in response to
respiratory or GIT exposure to viruses, bacteria, or food proteins. The deposition of IgA
and IgA-immune complexes in the mesangium activate the alternative complement
pathway and initiate glomerular injury. Slow progression to chronic renal failure occurs
in up to 50% of cases.
Rapidly Progressive (Crescentic) Glomerulonephritis (RPGN; CrGN)
This is a clinical syndrome associated, irrespective of the etiology, with glomerular
crescents; these are produced by proliferation of the parietal epithelial cells associated
with infiltration by monocytes and macrophages(Fig. 8-8). CrGN is characterized
clinically by
1. Rapidly progressive loss of renal function
2. Nephritic syndrome
3. Severe oliguria (often)
4. Death from renal failure within weeks to months (if untreated).
A practical classification divides CrGN into three groups on the basis of immunologic
findings. In each group, the disease may be associated with a known disorder or it may be
idiopathic.
Type I (Anti-GBM Antibody)
a. Idiopathic
b. Goodpasture syndrome
This group is characterized by linear IgG deposits along the GBM. In some of these
individuals the anti-GBM antibodies also bind to pulmonary alveolar capillary basement
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membranes to produce the clinical picture of pulmonary hemorrhages associated with
renal failure (Goodpasture syndrome). In idiopathic cases the renal involvement occurs
in the absence of pulmonary disease. Anti-GBM antibodies are present in the serum and
are helpful in diagnosis. Immunofluorescence is characteristic with strong linear staining
of deposited IgG and C3 along the GBM; these deposits are not visualized by electron
microscopy.
Type II (Immune Complex)
a. Idiopathic
b. Postinfectious/infection related
c. SLE
d. Henoch-Schönlein purpura/IgA nephropathy
In all of these cases, immunofluorescence shows the characteristic granular pattern of
staining of the GBM and/or mesangium for immunoglobulin and/or complement. In
addition to the crescents, segments of glomeruli show evidence of the underlying GN.
Type III (Pauci-Immune) ANCA Associated
a. Idiopathic
b. Wegener granulomatosis
c. Microscopic angiitis
This group is defined by the lack morphologically of both anti-GBM antibodies and
immune complex deposition. Most of these individuals have antineutrophil cytoplasmic
antibodies (ANCA) in the serum. The latter have a role in some vasculitides. Therefore,
in some cases type there is a component of a systemic vasculitis. In the idiopathic form
the disease is limited to the kidney. The uninvolved segments of glomeruli appear
normal. Immunofluorescence studies for immunoglobulin and complement are negative
(cf. type I and II), and there are no ultrastructural deposits.
The onset of RPGN is much like that of the nephritic syndrom. Proteinuria sometimes
approaching nephrotic range may occur. The prognosis can be related to the number of
crescents; those with crescents in less than 80% of the glomeruli have a better prognosis
than those with higher percentages of crescents.
CHRONIC GLOMERULONEPHRITIS is one of the outcomes of the various
glomerular diseases already discussed (Fig. 8-9). It is an important cause of end-stage
renal disease. Among all individuals who require chronic hemodialysis or renal
transplantation, 30% to 50% have the diagnosis of chronic GN. By the time chronic GN
is discovered, the glomerular changes are so advanced that it is difficult to detect the
nature of the original lesion. Classically, the kidneys are symmetrically contracted with
red-brown surface. Microscopically, the feature common to all cases is advanced scarring
of the glomeruli, sometimes to in the point of complete sclerosis (Fig. 8-10). There is
relentless progression to uremia and death. The rate of progression is extremely variable.
Renal dialysis and kidney transplantation alter this course and allow long-term survival.
TUBULO-INTERSTITIAL DISEASES
Most forms of tubular injury also involve the interstitium, so the two are discussed
together. Under this heading are two categories
1. Inflammatory involvement of the tubules and interstitium (tubulo-interstitial nephritis)
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2. Ischemic or toxic tubular necrosis leading to acute renal failure
TUBULOINTERSTITIAL NEPHRITIS (TIN) is a group of inflammatory diseases of
the kidneys primarily involving the interstitium and tubules. The glomeruli are spared or
affected late in the course. TIN is subdivided into
1. Bacterial TIN, the renal pelvis is prominently involved (pyelonephritis)
2. Nonbacterial TIN ; these include tubular injury resulting from
a. drugs
b. metabolic disorders (e.g. hypokalemia)
c. physical injury (e.g. irradiation)
d. viral infections
e. immune reactions
Pyelonephritis
This is divided into acute and chronic forms
Acute pyelonephritis is a common bacterial suppurative inflammation of the kidney
(nephritis) and renal pelvis (pyelitis); hence the term pyelonephritis. The great majority
of cases of pyelonephritis are associated with lower UTI (cystitis, prostatitis, and
urethritis). E. coli is by far the most common offender. Other important organisms are
Proteus, Klebsiella, Enterobacter, and Pseudomonas; these are usually associated with
recurrent infections, especially due to urinary tract instrumentations (e.g. cystoscopy,
catheterization) or congenital or acquired anomalies of the lower urinary tract (e.g.
vesicoureteral reflux or polycystic kidney disease, presence of stones, prostatic
hyperplasia in the elderly).
Pathogenesis
Bacteria can reach the kidneys either through the bloodstream (hematogenous) or from
the lower urinary tract (ascending infection). The former is exemplified by acute
pyelonephritis complicating septicemia or infective endocarditis. Ascending infection
from the lower urinary tract is the most common & is an important route by which
bacteria reach the kidney. The evolution of acute pyelonephritis occurs through the
following steps
1. Bacterial adhesion to the urethral urothelium is influenced by genetically determined
properties of both the urothelium and the offending bacteria.
2. Gaining access to the bladder is by growth expansion of the colonies and by moving
against urine flow; the latter is overcome by urethral instrumentation, including
catheterization and cystoscopy. In the absence of instrumentation, UTI most commonly
affects females because of factors that facilitate entry of bacteria to the bladder; these are
a. Close proximity of the urethra to the enteric bacteria-loaded rectum favoring
colonization
b. Short urethra
c. Trauma to the urethra during sexual intercourse (honeymoon cystitis)
3. Outflow obstruction: normally, bladder urine is sterile as a result of the antimicrobial
properties of the bladder mucosa and the flushing action of periodic voiding of urine.
With outflow obstruction or bladder dysfunction, these natural defenses are
overwhelmed, setting the stage for UTI. Obstruction at the level of the urinary bladder
(e.g. by prostatic hyperplasia) results in incomplete bladder emptying and hence
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increased residual volume of urine (urine stasis). In the presence of stasis, bacteria
introduced into the bladder can multiply freely, without being flushed out or destroyed by
the bladder mucosa. From the contaminated bladder urine, the bacteria ascend along the
ureters to infect the renal pelvis and parenchyma. Thus, UTI is particularly frequent in
association with benign prostatic hyperplasia in male and uterine prolapse in females.
UTI is also frequent in diabetics because of the increased susceptibility to infection and
neurogenic bladder, which in turn predisposes to urine stasis.
4. Vesicoureteral reflux (VUR): incompetence of the vesicoureteral orifice allows
bacterial ascent along the ureter & then into the pelvis. The normal ureteral insertion into
the bladder is a competent one-way valve that prevents retrograde flow of urine,
especially during micturition, when the intra-vesical pressure rises. An incompetent
vesicoureteral orifice allows the reflux of bladder urine into the ureters; this is termed
vesicoureteral reflux (VUR). Up to 40% of young children with UTI have this anomaly,
which is usually a congenital defect. (Fig. 8-11) VUR can also be acquired in individuals
with a flaccid bladder resulting from spinal cord injury and with neurogenic bladder
dysfunction secondary to diabetes. The effect of VUR is similar to that of an obstruction
in that after voiding there is residual urine in the urinary tract, which favors bacterial
growth. Furthermore, VUR affords a ready mechanism by which the infected bladder
urine can be pushed up to the renal pelvis and further into the renal parenchyma through
open ducts at the tips of the papillae (intrarenal reflux).
Gross features of acute pyelonephritis
One or both kidneys may be involved. The affected kidney may be normal in size or
enlarged.
Characteristically, discrete, yellowish, raised abscesses are grossly apparent on the
renal surface (Fig. 8-12 A). They are variably scattered and may coalesce to form a single
large abscess.
When obstruction is prominent, the pus may fill the renal pelvis, calyces, and ureter,
producing pyonephrosis.
Microscopic features
The characteristic feature of acute pyelonephritis is suppurative inflammation within
the renal parenchyma. Both the tubules & interstitium are involved. (Fig. 8-12 B).
Large numbers of intratubular neutrophils frequently extend into the collecting ducts,
giving rise to the characteristic white cell casts found in the urine.
Typically, the glomeruli are not affected.
Papillary necrosis (necrotizing papillitis)
This is an infrequent form of pyelonephritis, which may be encountered
1. In diabetics
2. With significant urinary tract obstruction
3. Chronic interstitial nephritis associated with analgesic abuse
This lesion consists of ischemic and suppurative necrosis of the renal papillae (tips of the
renal pyramids). The pathognomonic gross feature is sharply defined gray-white to
yellow necrosis of the apical two-thirds of the pyramids. The involvement ranges from
one to all papillae. (Fig. 8-13) Microscopically, the papillae show characteristic
coagulative necrosis, with surrounding neutrophilic infiltrate.
Chronic Pyelonephritis (CPN) and Reflux Nephropathy
For the pathological diagnosis of CPN two criteria must be met
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1. Grossly visible scarring deformity of the pelvicalyceal system
2. Microscopic predominance of interstitial inflammation & fibrosis
CPN is an important cause of chronic renal failure. It can be divided into two forms:
1. Chronic obstructive pyelonephritis: recurrent infections superimposed on obstructive
lesions lead to recurrent bouts of renal inflammation and scarring, which eventually cause
chronic pyelonephritis. The disease can be bilateral, as with congenital anomalies of the
urethra (posterior urethral valves), or unilateral, such as occurs with calculi and unilateral
obstructive lesions of the ureter.
2. Chronic reflux-associated pyelonephritis is the more common form and results from
superimposition of a UTI on congenital vesicoureteral reflux and intrarenal reflux. Reflux
may be unilateral or bilateral; thus, the resultant renal damage is either unilateral or
bilateral.
Gross features (Fig. 8-14 A).
One or both kidneys may be involved, either diffusely or in patches. Even when
involvement is bilateral, the kidneys are not equally damaged and therefore are not
equally contracted. This uneven involvement is useful in differentiating CPN from the
more symmetrically contracted kidneys of benign nephrosclerosis and chronic GN.
The hallmark of CPN is scarring involving the pelvis &/or calyces leading to papillary
blunting and marked calyceal deformities
Microscopic features (Fig. 8-14 B)
These are largely non-diagnostic since similar alterations may be seen with other
tubulo-interstitial disorders such as analgesic nephropathy.
The parenchyma shows the following features:
- Interstitial fibrosis with infiltration by lymphocytes, plasma cells, and sometimes
neutrophils
- Dilation or contraction of tubules, with atrophic lining epithelium. Many of the dilated
tubules contain pink to blue colloid-like casts; the overall appearance is reminiscent of
thyroid tissue, hence the descriptive term thyroidization.
Chronic inflammation with fibrosis involving the pelvi-calyceal mucosa and wall. This
is an important feature that is used in the differentiation from other conditions that give
otherwise similar parenchymal changes.
Vascular changes of benign arteriolosclerosis caused by the frequently associated
hypertension.
Although glomeruli may be normal, some are sclerosed (glomerulosclerosis). Such
changes represent maladaptive changes secondary to nephron loss.
Absence of significant bacteriuria should not rule out CPN. If the disease is bilateral and
progressive, tubular dysfunction occurs with loss of concentrating ability, manifested by
polyuria and nocturia. Some persons with CPN or reflux nephropathy ultimately develop
glomerular lesions of global sclerosis and secondary FSGS. These are associated with
proteinuria and eventually contribute to progressive chronic renal failure.
Drug-Induced Interstitial Nephritis (DIN)
Drugs are important causes of renal injury. There are two forms of DITN:
1. Acute DIN: this is most frequently occurs with such drugs as methicillin, ampicillin,
rifampin, thiazide diuretics, NSAID, phenindione, and cimetidine. Most likely, the drugs
12
act as haptens that bind to a cytoplasmic or extracellular component of the secreting
tubular cells and become immunogenic. The resultant tubulointerstitial injury is either
caused by IgE (type I) or cell-mediated (type IV) immune reactions to tubular cells. The
interstitium shows infiltration by principally lymphocytes and macrophages but
eosinophils and neutrophils may be present (Fig. 8-15). With some drugs (e.g.,
methicillin, thiazides, rifampin), interstitial non-necrotizing granulomas with giant cells
may be seen. The glomeruli are normal. NSAID may cause membranous GN-like
reaction associated with nephrotic syndrome. It is important to recognize drug-induced
renal damage, because withdrawal of the offending drug is followed by recovery.
2. Analgesic Nephropathy: with the intake of large quantities of analgesics, patients may
develop chronic interstitial nephritis, often associated with renal papillary necrosis. Most
people who develop this nephropathy consume mixtures containing some combination of
aspirin, paracetamol, caffeine, and codeine for long periods. Papillary necrosis is the
initial event, and the interstitial nephritis in the overlying renal parenchyma is a
secondary phenomenon. Cessation of analgesic intake may stabilize or even improve
renal function. A complication of analgesic abuse is the increased incidence of
transitional-cell carcinoma of the renal pelvis or bladder in persons who survive the renal
failure.
Acute Tubular Necrosis (ATN)
This is a clinicopathologic entity characterized acute renal failure due to necrosis of
tubular epithelial cells. It is the most common cause of acute renal failure. ATN is a
reversible renal lesion that arises in clinical settings that have in common a period of
inadequate blood flow to the peripheral organs, often in the setting of marked
hypotension and shock. The pattern of ATN associated with shock is called ischemic
ATN. Hemolytic crises including mismatched blood transfusions, and myoglobinuria,
also produce a picture resembling ischemic ATN.
A second pattern, called nephrotoxic ATN, is caused by a variety of poisons, including
heavy metals (e.g., mercury); organic solvents (e.g., carbon tetrachloride); and drugs such
as gentamicin and other antibiotics, and radiographic contrast agents.
Pathogenesis
The decisive events in both ischemic and nephrotoxic ATN are believed to be
1. Tubular injury and
2. Severe disturbances in blood flow to tubular cells.
Tubular epithelial cells are sensitive to both anoxia & toxins.
Toxic injury eventuates in decreased Na
+
reabsorption by proximal tubules and hence
increased sodium delivery to distal tubules. The latter, through a tubulo-glomerular
feedback system, contributes to vasoconstriction and thus ischemia.
The debris resulting from shedding of tubular cells results can block urine outflow, and
eventually increases intratubular pressure, thereby decreasing GFR.
Additionally, fluid from the damaged tubules could leak into the interstitium, resulting
in increased interstitial pressure and collapse of the tubules.
Ischemic tubular cells also express chemokines, cytokines, and adhesion molecules that
recruit and immobilize leukocytes that can participate in tissue injury.
Ischemic renal injury is also characterized by severe hemodynamic alterations that
cause reduced GFR. The major one is intrarenal vasoconstriction, which results in both
13
reduced glomerular plasma flow and reduced oxygen delivery to the functionally
important tubules in the outer medulla.
Vasoconstriction is mediated by sublethal endothelial injury, leading to increased
release of the endothelial vasoconstrictor endothelin and decreased production of
vasodilatory nitric oxide and prostaglandins.
Pathological features
Ischemic ATN is characterized by
Necrosis of short segments mostly of the proximal tubule; thus necrosis may be missed
in biopsy samples.
Frequently a variety of tubular injuries are noted in the epithelial cells of proximal
convoluted tubules e.g. brush borders attenuation, blebbing and sloughing, vacuolization
and detachment of tubular cells into the urine.
Presence of proteinaceous casts in the distal tubules and collecting ducts. They consist
of Tamm-Horsfall protein (secreted normally by tubular epithelium) along with
hemoglobin and other plasma proteins.
When crush injuries have produced ATN, the casts are composed of myoglobin.
The interstitium usually shows generalized edema along with a mild inflammatory
infiltrate consisting of polymorphonuclear leukocytes, lymphocytes, and plasma cells.
Toxic ATN (Fig. 8-16)
The microscopic picture is basically similar, with some differences. Necrosis is more
diffuse but again most prominent in the proximal tubule, and the tubular basement
membranes are generally spared.
If the patient survives for a week, epithelial regeneration becomes apparent in the form
of a low cuboidal epithelial covering and mitotic activity in the persisting tubular
epithelial cells.
Except where the basement membrane is destroyed, regeneration is total and complete.
DISEASES OF RENAL BLOOD VESSELS
Changes affecting renal blood vessels are both frequent & important for the following
reasons
1. The renal vasculature is secondarily involved in almost all diseases of the kidney.
2. Various forms of systemic arteritis also involve renal vessels & such involvement is
clinically important.
3. The kidney is intimately involved in the pathogenesis of both essential and secondary
hypertension.
Benign Nephrosclerosis (BNS)
Some degree of BNS is present in many of those older than 60 years of age. The
frequency and severity of the lesions are increased at any age when hypertension or
diabetes mellitus are present. It is not clear whether BNS is the cause of hypertension or
conversely, hypertension just accelerates an age-related vascular sclerosis. However,
many renal diseases cause hypertension, which in turn is associated with BNS. Thus, this
renal lesion is often seen superimposed on other primary kidney diseases.
Gross features: (Fig. 8-17)
The kidneys are symmetrically shrunken, with diffuse fine granularity of the surface.
Microscopical features
14
The basic change is hyaline thickening of the walls of the small arteries and arterioles
(hyaline arteriolosclerosis). This appears as a homogeneous, pink, hyaline thickening that
reduces the lumen (Fig. 8-17).
The narrowing of the lumen results in markedly decreased blood flow through the
affected vessels and thus producing ischemic atrophy of all structures of the kidney. In
advanced cases the glomeruli become globally sclerosed. Diffuse tubular atrophy and
interstitial fibrosis are often present.
BNS rarely causes severe damage to the kidney. However, all persons with this lesion
usually show some functional impairment.
Malignant Nephrosclerosis
Malignant hypertension occurs in only about 5% of hypertensive patients. It may occur
de novo, or suddenly complicates mild hypertension.
Pathogenesis
The following sequence of events is suggested.
1. Initially, there is renal arteriolar vascular damage, mostly from long-standing benign
hypertension. The result is increased permeability of the small vessels to fibrinogen and
other plasma proteins, endothelial cell injury, and platelet deposition.
2. This leads to occurrence of fibrinoid necrosis of arterioles and small arteries with
thrombosis.
3. Platelet-derived and other growth factors cause intimal smooth muscle hyperplasia that
results in hyperplastic arteriolosclerosis (typical of malignant hypertension) associated
with further narrowing of the vascular lumina. The kidneys become markedly ischemic.
4. With severe involvement of the renal afferent arterioles, the renin-angiotensin system
is stimulated. A self-perpetuating cycle is thus created in which angiotensin II causes
intrarenal vasoconstriction, and the resultant renal ischemia stimulates renin secretion.
5. Aldosterone levels are elevated; the salt retention contributes to the elevation of blood
pressure.
The consequences of the markedly elevated blood pressure on the blood vessels
throughout the body are known as malignant arteriolosclerosis, and the renal disorder is
referred to as malignant nephrosclerosis.
Gross feature:
The kidneys, which may be normal in size or slightly shrunken display small, pinpoint
petechial hemorrhages on the cortical surface due to rupture of arterioles or glomerular
capillaries. These give the kidney a peculiar, flea-bitten appearance (Fig. 8-18).
Microscopic: (Fig. 8-18)
There is fibrinoid necrosis of the arterioles. The vessel walls show a homogeneous,
granular eosinophilic appearance.
In the small arteries and large arterioles, proliferation of intimal smooth muscle cells
produces hyperplastic arteriolosclerosis in which the intimal smooth muscle cells show
concentric arrangement (onion-skin appearance). This lesion causes marked narrowing of
arterioles and small arteries, to the point of total obliteration.
Necrosis may also involve glomeruli, with microthrombi within the glomeruli &
necrotic arterioles.
The full-blown syndrome of malignant hypertension is characterized by diastolic
pressures greater than 120 mm Hg, papilledema, encephalopathy, cardiovascular
abnormalities, and renal failure. At the onset of rapidly rising blood pressure there is
15
marked proteinuria and microscopic, or sometimes macroscopic, hematuria followed
soon by renal failure. The syndrome is a true medical emergency. About 50% of patients
survive at least 5 years. Ninety percent of deaths are caused by uremia and the other 10%
by cerebral hemorrhage or cardiac failure.
CYSTIC DISEASES OF THE KIDNEY
These are a heterogeneous group comprising
a. hereditary b. developmental but nonhereditary c. acquired disorders.
They are important for several reasons:
1. They are practically common and often present diagnostic problems
2. Some are major causes of chronic renal failure (adult polycystic disease)
3. They can occasionally be confused clinically with malignant tumors.
Simple Cysts are a common but have no clinical significance. They can be multiple or
single, commonly up to 5 cm in diameter. They are translucent; filled with clear fluid;
lined by a single layer of cuboidal or flattened epithelium.
Dialysis-associated acquired cysts occur with prolonged dialysis in those with end-stage
renal disease. They may bleed, causing hematuria. Occasionally, renal adenomas or
carcinomas arise in the walls of these cysts.
Autosomal Dominant (Adult) Polycystic Kidney Disease (ADPKD) is characterized
by multiple expanding cysts of both kidneys that ultimately destroy the intervening
parenchyma. ADPKD is responsible for 10% of all chronic renal failures. It is caused by
inheritance of one of two autosomal dominant genes of very high penetrance. The
kidneys may be very large (up to 4 kg for each), and thus are readily palpable
abdominally. Grossly the kidney is composed of a mass of cysts of varying sizes (up to 4
cm). The cysts are filled with fluid (clear, turbid, or hemorrhagic) (Fig 8-19).
Microscopically, the cysts have often atrophic, lining. The pressure of the expanding
cysts leads to ischemic atrophy of the intervening renal substance. Evidence of
superimposed hypertension or infection is common. ADPKD in adults usually does not
produce symptoms until the fourth decade, by which time the kidneys are quite large.
Intermittent gross hematuria commonly occurs. The most important complications are
hypertension and urinary infection. Saccular aneurysms of the circle of Willis are present
in up to 30% of patients, and these individuals have a high incidence of subarachnoid
hemorrhage. Asymptomatic liver cysts occur in one-third of patients.
Nwr
Autosomal Recessive (Childhood) Polycystic Kidney Disease (ARPKD) is a rare
developmental anomaly that is genetically distinct from ADPKD. Perinatal, neonatal,
infantile, and juvenile subcategories have been defined, depending on time of
presentation and the presence of associated hepatic lesions. Both kidneys are invariably
involved with numerous small cysts that give them a sponge-like appearance (Fig. 8-20).
The cysts are lined by cuboidal cells. ARPKD is associated with multiple epithelium-
lined cysts in the liver. Young infants may die quickly from hepatic or renal failure.
Medullary Cystic Disease (MCD)
This is of two major types of
1. Medullary sponge kidney a relatively common and usually harmless condition and
16
2. Nephronophthisis-medullary cystic disease complex, which is associated with renal
dysfunction. On the basis of the time of onset they are divided into, infantile, juvenile
(the most common), adolescent, and adult types. They may be associated with other
extra-renal abnormalities including cerebellar malformations, and liver fibrosis.
Pathologic features of medullary cystic disease include small contracted kidneys with
numerous small cysts lined by flattened or cuboidal epithelium, typically at the cortico-
medullary junction (Fig. 14- ). Progression to end-stage renal disease occurs within a 5-
to 10-year period. The disease is difficult to diagnose, since the cysts may be too small to
be seen with imaging techniques and may not be apparent on renal biopsy if the cortico-
medullary junction is not well sampled.
URINARY OUTFLOW OBSTRUCTION
Renal Stones (Urolithiasis) these are frequent (1% of all autopsies) and mostly form in
the kidney. The majority (80%) are composed of either calcium oxalate or calcium
oxalate mixed with calcium phosphate; 10% are of magnesium ammonium phosphate,
and the remainder 10% are either uric acid or cystine stones. The most important cause is
increased urine concentration of the stone's constituents (supersaturation). Those who
develop calcium stones have
1. Hypercalciuria not associated with hypercalcemia due to either
a. Absorption of calcium from the gut in excessive amounts (i.e. absorptive
hypercalciuria)
b. Primary renal defect of calcium reabsorption (renal hypercalciuria).
Hypercalcemia is present in only 5% to 10% (due to hyperparathyroidism, vitamin D
intoxication, or sarcoidosis) and consequent hypercalciuria. In 20% of this subgroup,
there is excessive excretion of uric acid in the urine, which favors calcium stone
formation; the urates provide a nidus for calcium deposition. A high urine pH favors
crystallization of calcium phosphate and stone formation. Magnesium ammonium
phosphate stones almost always occur in persistently alkaline urine due to UTIs,
particularly with urea-splitting bacteria (as Proteus vulgaris and the Staphylococci). Gout
and diseases involving rapid cell turnover (as the leukemias), lead to high uric acid levels
in the urine and uric acid stones. About half of the individuals with uric acid stones,
however, have no hyperuricemia but unexplained tendency to excrete persistently acid
urine (under pH 5.5), which favors uric acid stone formation (cf. stones containing
calcium phosphate).
Common sites of formation are renal pelvis and calyces as well as the bladder. Stone may
be small with smooth or jagged surface. Occasionally, progressive accumulation of salts
leads to the development of branching structures known as staghorn calculi, which create
a cast of the renal pelvis and calyceal system (Fig. 8-22). These massive stones are
usually composed of magnesium ammonium phosphate; these do not produce symptoms
or significant renal damage. Smaller stones may pass into the ureter, producing a typical
intense pain known as renal colic. Often at this time there is gross hematuria. The clinical
significance of stones lies in their capacity to obstruct urine flow or to produce sufficient
trauma to cause ulceration and bleeding. In either case, they predispose the sufferer to
bacterial infection.
17
Hydronephrosis refers to dilation of the renal pelvis and calyces, with accompanying
atrophy of the renal parenchyma, caused by obstruction to the outflow of urine. The
obstruction may be sudden or insidious, and it may occur at any level of the urinary tract,
from the urethra to the renal pelvis. The most common causes are
1. Congenital: e.g. urethral atresia, ureteric or urethral valves, aberrant renal artery
2. Acquired:
a. Foreign bodies: calculi
b. Tumors of the prostate or bladder (benign or malignant)
c. Contiguous malignant disease: (retroperitoneal lymphoma, carcinoma of the cervix or
uterus)
d. Inflammation: prostatitis, ureteritis, urethritis
e. Neurogenic: Spinal cord damage with paralysis of the bladder
f. Normal pregnancy: mild and reversible
Bilateral hydronephrosis occurs only when the obstruction is below the level of the
ureters. If blockage is at the ureters or above, the lesion is unilateral. Sometimes
obstruction is complete, allowing no urine to pass; usually it is only partial.
Pathogenesis
Even with complete obstruction, glomerular filtration persists for some time, and the
filtrate subsequently diffuses back into the lymphatic and venous systems. Because of the
continued filtration, the affected calyces and pelvis become dilated, often markedly so.
The unusually high pressure thus generated in the renal pelvis, as well as that transmitted
back through the collecting ducts, causes compression of the renal blood vessels. Both
arterial insufficiency and venous stasis result. The most severe effects are seen in the
papillae, because they are subjected to the greatest increases in pressure. Accordingly, the
initial functional disturbances are largely tubular, manifested primarily by impaired
concentrating ability. Thereafter the glomerular filtration begins to diminish. Serious
irreversible damage occurs in about 3 weeks with complete obstruction, and in 3 months
with incomplete obstruction.
Gross features
The changes vary with the degree and speed of obstruction
- With subtotal or intermittent obstruction, the kidney is massively enlarged consisting
almost entirely of the greatly distended pelvicalyceal system. The renal parenchyma
shows compression atrophy, with obliteration of the papillae and flattening of the
pyramids (Fig. 8-23).
- With sudden complete obstruction, glomerular filtration is reduced relatively early,
and as a consequence, renal function may cease while dilation is still slight.
Depending on the level of the obstruction, one or both ureters may also be dilated
(hydroureter).
Microscpic features
Early lesions show tubular dilation, followed by atrophy and fibrous replacement with
relative sparing of the glomeruli. Eventually, in severe cases the glomeruli also become
atrophic and disappear, converting the entire kidney into a thin shell of fibrous tissue.
With sudden and complete obstruction, there may be coagulative necrosis of the renal
papillae.
18
In uncomplicated cases the accompanying inflammatory reaction is minimal.
Complicating pyelonephritis, however, is common.
Course & prognosis
Bilateral complete obstruction produces anuria. When the obstruction is below the
bladder, there is bladder distention. Incomplete bilateral obstruction causes polyuria
rather than oliguria, as a result of defects in tubular concentrating mechanisms. Unilateral
hydronephrosis may remain completely silent. Removal of obstruction within a few
weeks usually permits full return of function; however, with time the changes become
irreversible.
TUMORS
The kidney is the site of benign and malignant tumors. In general, benign tumors (such as
small cortical adenomas or medullary fibromas) have no clinical significance. The most
common malignant tumors of the kidney in descending order of frequency are
1. Renal cell carcinoma
2. Nephroblastoma (Wilms tumor)
3. Transitional cell carcinoma of the calyces and pelvis
Renal Cell Carcinoma (RCC)
This is derived from the renal tubular epithelium and represents the most common
primary malignant tumor of the kidney (80%). The mea age of incidence is 50 to 70
years. Risk factors include smoking, hypertension, obesity, occupational exposure to
cadmium, and acquired polycystic disease complicating chronic dialysis (30-fold). RCC
are currently classified according to the molecular origins of these tumors. The three most
common forms are
1. Clear Cell Carcinomas (80% of RCCs): these are made up of cells with clear or
granular cytoplasm. The majority are sporadic, but may occur in familial forms or in
association with von Hippel-Lindau disease (VHLD). The latter is autosomal dominant
and characterized by predisposition to a variety of neoplasms including bilateral & often
multiple RCC of clear cell type. Patients with VHLD inherit a germ-line mutation of the
VHL gene on chromosome 3 and lose the second allele by somatic mutation. Thus, the
loss of the normal copies of both these tumor suppressor genes gives rise to clear cell
carcinoma. It has been also confirmed that homozygous loss of the VHL gene seems to be
the common underlying molecular abnormality in both sporadic and familial forms of
clear cell carcinomas.
2. Papillary Renal Cell Carcinomas (10%). These tumors are frequently multifocal and
bilateral and like clear cell carcinomas, they occur in familial and sporadic forms.
However, they have no abnormality of chromosome 3. The cause is the MET proto-
oncogene. It is the increased dosage of the MET gene (due to duplications of
chromosome 7) seems to encourage neoplastic growth abnormal growth in the proximal
tubular epithelial cell precursors. In support of this, trisomy of chromosome 7 is see n
commonly in the familial cases. In the sporadic cases, although there is duplication of
chromosome 7, there is no mutation of the MET gene.
3. Chromophobe RCCs: these are the least common; they arise from intercalated cells of
collecting ducts. Their name indicates that the tumor cells stain more darkly than cells in
clear cell carcinomas. These tumors are unique in having multiple losses of entire
chromosomes, including chromosomes 1 and 2. In general, they have a good prognosis.
19
Pathologic features
Clear cell carcinoma
Gross features: (Fig. 8-24 A)
There is usually solitary spherical mass; large when symptomatic.
The cut surface is variegated; yellow-orange to gray-white with red areas of
hemorrhage. There are prominent areas of cystic degeneration.
Although the margins of the tumor are well defined, with enlargement extension may
occur in two directions
1. Into the pelvicalyceal system & as far down as the ureter.
2. Into the renal vein, then the inferior vena cava & even into the right side of the
heart.
Microscopic features
The classic lipid- & glycogen-laden clear cells have well defined cell membranes. The
nuclei are usually small and round (Fig. 8-24 B).
These cells are mixed to varying extent with cells having granular pink cytoplasm.
Some tumors exhibit marked degrees of anaplasia, with numerous mitotic figures and
markedly enlarged, hyperchromatic, pleomorphic nuclei (sarcomatoid RCC).
The stroma is usually scant but highly vascularized.
Papillary renal cell carcinomas
Exhibit papilla formation with fibrovascular cores.
They tend to be bilateral and multiple.
The cells can have clear or, more commonly, pink cytoplasm.
The classical triad of painless hematuria (the most frequent), a palpable abdominal mass,
and dull flank pain is characteristic. RCCs are well-known for their association with
several paraneoplastic syndromes. Polycythemia may occur; it results from excessive
secretion of erythropoietin by the tumor. Uncommonly, these tumors also produce a
variety of hormone-like substances, resulting in hypercalcemia, hypertension, Cushing
syndrome, etc. In many individuals the primary tumor remains silent and is discovered
only after its metastases have produced symptoms. Common locations for metastases are
the lungs and the bones. Forty percent of patients die of the disease.
Wilms Tumor (WT) (nephroblastoma)
This is not only the most common primary renal tumor of children (mostly between the
ages of 2 and 5 years) but also the third most common organ cancer in those younger than
10 years. WT may arise sporadically or be familial. Some congenital malformations are
associated with an increased risk of developing Wilms' tumor such as aniridia, mental
retardation, gonadal dysgenesis and renal abnormalities. These conditions are associated
with inactivation of the Wilms' tumor 1 (WT1) gene, located on chromosome11. This
gene is critical to normal renal and gonadal development. Patients with the Beckwith
syndrome (BWS); characterized by enlargement of individual body organs (e.g., tongue,
kidneys, or liver) or hemihypertrophy of the entire body segments. In addition to Wilms'
tumors, patients with BWS are also at increased risk for developing other cancers e.g.
hepatoblastoma.
Gross features
20
WT tends to be large, well-circumscribed mass with soft, homogenous, tan to gray cut
section accentuated with occasional foci of hemorrhage, necrosis and cystic degeneration
(Fig 14-25 A).
Microscopic features
In WT there are attempts to recapitulate different stages of nephrogenesis.
WT contain a variety of tissue components, but all derived from the mesoderm.
The classic triphasic combination of blastemal, stromal, and epithelial cell types is
observed in most lesions (Fig. 14-25 B).
- The blastemal component is represented by sheets of small blue cells
- The epithelial component (differentiation) is represented by abortive tubules or
glomeruli.
- The stromal component is represented usually by fibroblastic cells or myxoid
areas, although skeletal muscle "differentiation" and other mesenchymal
elements may be seen.
The presence of anaplasia correlates with underlying p53 mutations, and the
emergence of resistance to chemotherapy.
Clinically, there is a readily palpable abdominal mass, which may extend across the
midline and down into the pelvis. Fever and abdominal pain, with hematuria, are less
frequent. The prognosis of Wilms' tumor is generally very good, and excellent results are
obtained with a combination of nephrectomy and chemotherapy. WTs with diffuse
anaplasia, especially those with extra-renal spread, have the least favorable outcome.
RENAL PELVIS, URETER, URINARY BLADDER & URTHERA
URETERS
Congenital Anomalies these are rare, and mostly of little clinical significance. However,
some may contribute to urine outflow obstruction. Incompetent ureterovesical junction
predisposes to pyelonephritis. The majority of double ureters are unilateral and of no
clinical significance. A congenital ureteropelvic junction obstruction is the most
common cause of hydronephrosis in infants and children. There is agenesis of the kidney
on the opposite side in a significant number of cases
. Diverticula are saccular
outpouchings acting as pockets of stasis and secondary infections. Hydroureter with
elongation and tortuosity may be congenital leading to hydronephrosis if untreated.
Ureteritis may be one component of UTI. With long-standing chronic ureteritis, there
may be aggregation of lymphocytes in the subepithelial region causing fine granular
mucosal surface (ureteritis follicularis), or the mucosa may become sprinkled with tiny
cysts (ureteritis cystica). Identical changes are found in the bladder. The two most
common tumors and tumor-like lesions
are fibroepithelial polyps and leiomyomas.
Primary malignant tumors are similar to those arising in the renal pelvis, calyces, and
bladder; the majority are transitional cell carcinomas. They cause obstruction and are
most frequently during the sixth and seventh decades. They can be multiple and may
occur concurrently with similar tumors in the bladder or renal pelvis.
Obstructive lesions of the ureters
A great variety of pathologic lesions may obstruct the ureters and give rise to
hydroureter, hydronephrosis, and sometimes pyelonephritis. The more important causes
include
21
1. impacted small stones
2. strictures (congenital or acquired),
3. primary carcinoma,
4. pregnancy,
5. retroperitoneal fibrosis & cancers of the rectum, bladder, prostate, ovaries, uterus and
cervix.
Sclerosing Retroperitoneal Fibrosis is a fibrous proliferative inflammatory process
encasing the retroperitoneal structures including the ureters and causing hydronephrosis.
Two thirds of the cases are idiopathic. The remaining cases are attributed to drugs (ergot
derivatives, β-adrenergic blockers), adjacent inflammatory conditions or malignant
disease. It may be associated with mediastinal fibrosis, sclerosing cholangitis, and Riedel
thyroiditis. This suggests that the disorder is systemic in distribution but preferentially
involves the retroperitoneum. An autoimmune reaction, sometimes triggered by drugs,
has been proposed.
URINARY BLADDER
Congenital anomalies
Diverticula are pouch-like evaginations of the bladder wall that may be congenital, but
more commonly acquired due to persistent urethral obstruction (e.g. prostatic hyperplasia
or neoplasia). In both forms, there are frequently multiple sac-like pouches that range
from less than 1 cm to 10 cm in diameter. Most diverticula are small and asymptomatic,
but may be sites of urinary stasis that predispose to infection and the formation of bladder
calculi.
Exstrophy is a developmental failure in the anterior wall of the abdomen and the bladder,
so that the bladder communicates directly through a large defect with the surface of the
body. The exposed bladder mucosa may undergo colonic glandular metaplasia and is
subjected to infections. There is an increased risk of carcinoma.
Vesicoureteral reflux is the most common and serious anomaly that contributes to renal
infection and scarring.
Congenital fistulas are abnormal connections between the bladder and the vagina,
rectum, or uterus.
Persistent urachus refers to failure of the urachus to close in part or in whole. When it is
totally patent, a fistulous urinary tract is created that connects the bladder with the
umbilicus. Sometimes, only the central region of the urachus persists, giving rise to
urachal cysts. Carcinomas, mostly adenocarcinomas, may arise in such cysts.
ACUTE & CHRONIC CYSTITIS
The common etiologic agents of bacterial cystitis are the E. coli, followed by Proteus, &
Klebsiella. Women are more likely to develop cystitis due to their shorter urethras.
Bacterial pyelonephritis is frequently preceded by cystitis, with retrograde spread of
microorganisms into the kidneys and their collecting systems. Tuberculous cystitis is
almost always a consequence of renal tuberculosis. Fungal cystitis is usually due to
Candida albican. It is particularly seen in immunosuppressed patients or those receiving
long-term antibiotics. Schistosomal cystitis (Schistosoma haematobium) is common in
certain Middle Eastern countries, notably Egypt. Viruses (e.g., adenovirus), Chlamydia,
and Mycoplasma may also be causes of cystitis. Predisposing factors of cystitis include
1. Urinary obstruction e.g. prostatic hyperplasia, bladder calculi,tumors
22
2. cystocele or diverticula
3. Diabetes mellitus
4. Instrumentation
5. Immune deficiency.
Hemorrhagic cystitis sometimes complicates cytotoxic antitumor drugs (e.g.
cyclophosphamide). Radiation cystitis is due to radiation of the bladder region.
Most cases of cystitis take the form of nonspecific acute or chronic inflammation of the
bladder. Gross features
There is hyperemia of the mucosa.
Hemorrhagic cystitis shows in addition a hemorrhagic component; this form is
sometimes follows radiation injury, antitumor chemotherapy, or adenovirus infection.
Suppurative cystitis is characterized by the accumulation of large amounts of
suppurative exudate.
Ulcerative cystitis refers to cystitis associated with ulceration of large areas of the
mucosa, or sometimes the entire bladder mucosa.
Persistence of the infection leads to chronic cystitis, which shows red, friable, granular,
sometimes ulcerated mucosa. Chronicity is also associated with fibrous thickening and
inelasticity of the bladder wall.
Microscopic features
In acute cystitis there are the expected features of acute inflammation.
In chronic forms there is chronic inflammatory cells infiltration with fibrosis.
Variants of chronic cystitis include Follicular cystitis and Eosinophilic cystitis
Schistomal cystitis: (Fig. 21-26) urogenital bilharziasis is caused by S. haematobium.
Eggs are deposited in the superior rectal vein. From there, they pass through anastomoses
into the veins of the wall of urinary bladder. There they cause granulomatous cystitis with
eosinophilic infiltrate & fibrosis. These granulomas are visible under endoscopy as
minute granules referred to as “sand grain” cystitis. The eggs eventually die in the tissue
with regressive calcification.The condition may be complicated by
a. Extensive fibrosis that may impinge on the ureteric orifices with eventual
hydronephrosis
b. Carcinoma of bladder that is frequently squamous in type; as this form of cystitis can
be associated with squamous metaplasia of the native transitional epithelium.
Special Forms of Cystitis
These are distinctive by either their morphologic appearance or their causation.
1. Interstitial Cystitis (Hunner Ulcer): a painful form of chronic cystitis occurring
most frequently in women. Cystoscopy shows fissures and punctate hemorrhages in the
mucosa, sometimes with chronic mucosal ulcers (Hunner ulcers). Infiltration by mast
cells is characteristic of this disease. The condition may be of autoimmune origin.
2. Malakoplakia is characterized macroscopically by soft, yellow, slightly raised
mucosal plaques 3 to 4 cm in diameter and histologically by infiltration with large, foamy
macrophages with debris of bacterial origin (mostly E. coli) (Fig. 21-27). In addition,
laminated mineralized concretions (Michaelis-Gutmann bodies) are typically present.
Similar lesions have been described in other organs e.g. colon, lungs, bones. It occurs
with increased frequency in immuno-suppressed transplant recipients and as a result of
defects in phagocytic or degradative function of macrophages.
23
3. Polypoid Cystitis is an inflammatory condition resulting from irritation to the
bladder mucosa mostly by indwelling catheters. The urothelium is thrown into broad,
bulbous, polypoid projections as a result of marked submucosal edema.
METAPLASTIC LESIONS
Cystitis Glandularis and Cystitis Cystica: these terms refer to common lesions in
which nests of transitional epithelium (Brunn nests) grow downward into the lamina
propria and undergo transformation of their central epithelial cells into columnar
epithelium lining (cystitis glandularis) or cystic spaces lined by urothelium (cystitis
cystica). The two processes often coexist. In a variant of cystitis glandularis, goblet cells
are present (intestinal metaplasia).
Both variants are common microscopic incidental findings in relatively normal bladders
and are not associated with an increased risk of adenocarcinoma.
Two forms of metaplasia occur in response to injury
1. Squamous Metaplasia
2. Nephrogenic Metaplasia (Nephrogenic Adenoma): the urothelium may be focally
replaced by cuboidal epithelium, which can assume a papillary growth pattern with
subjacent tubular proliferation.
TUMORS OF THE URINARY BLADDER AND COLLECTING SYSTEM (Renal
Calyces, Renal Pelvis, Ureter, and Urethra)
The entire urinary collecting system from renal pelvis to urethra is lined with transitional
epithelium, so its epithelial tumors assume similar morphologic patterns. Tumors in the
collecting system above the bladder are relatively uncommon; those in the bladder,
however, are a more frequent cause of death than are kidney tumors.
Gross features
Four morphologic patterns are recognized that range from small benign papillomas to
large invasive cancers. These tumors are classified into (Fig. 8-28)
1. Benign papilloma (rare)
2. Papillary urothelial neoplasms of low malignant potential, and
3. Urothelial carcinoma (low and high grade)
Papillomas are very rare, small (up to 1 cm) benign tumors with frondlike structures
having a delicate fibrovascular core covered by multilayered, well-differentiated
transitional epithelium. Such lesions are usually solitary. They rarely recur once removed.
Urothelial (transitional) cell carcinomas range from papillary to flat, noninvasive to
invasive and low grade to high grade.
Low-grade carcinomas (Fig. 8-29) are always papillary and are rarely invasive, but they
may recur after removal.
High-grade carcinomas (Fig. 8-30) can be papillary or occasionally flat; they may cover
larger areas of the mucosal surface, invade deeper, and have a shaggier necrotic surface
than do low-grade tumors. Occasionally, these cancers show foci of squamous cell
differentiation, but only 5% of bladder cancers are true squamous cell carcinomas.
Carcinomas of grades II and III infiltrate surrounding structures, spread to regional nodes,
and, on occasion, metastasize widely.
24
Painless hematuria is the dominant clinical presentation of all these tumors. They affect
men three times more frequently than women and usually develop between the ages of 50
and 70 years.
Risk factors of bladder cancer are
1. Exposure to β-naphthylamine (50 times increased risk).
2. Cigarette smoking
3. Chronic cystitis
4. schistosomiasis of the bladder
5. Certain drugs (cyclophosphamide).
A wide variety of genetic abnormalities are seen in bladder cancers; of these, mutations
involving several genes on chromosome 9, p53, and FGFR3 are the most common.
The prognosis of bladder tumors depends on their histologic grade and the depth of
invasion of the lesion; the latter is much more important. Except for benign papillomas,
all tend to recur after removal. Lesions that invade the ureteral or urethral orifices cause
urinary tract obstruction. Overall 5-year survival is 57%. With deep penetration of the
bladder wall the 5-year survival rate is less than 20%.
Papillary tumors occur much less frequently in the renal pelvis than in the bladder, they
nonetheless make up to 10% of primary renal tumors. (Fig. 8-31) Patients present with
painless hematuria, and may develop hydronephrosis. Infiltration of the walls of the
pelvis, calyces, and renal vein worsens the prognosis. Despite removal of the tumor by
nephrectomy, fewer than 50% of patients survive for 5 years.
Cancer of the ureter is fortunately the rarest of the tumors of the collecting system. The 5-
year survival rate is less than 10%.