635
Figure 21.33 Macroscopic patterns of hepatocellular carcinoma.
Pathogenesis of hepatocellular carcinoma can be explained 2 Cytologic features: The typical cytologic features in
on the basis of genetic mutations induced by one of the above the HCC consist of cells resembling hepatocytes having
major etiologic factors. In many cases, this mutated gene has vesicular nuclei with prominent nucleoli. The cytoplasm
been identified as inactivation of tumour suppressor is granular and eosinophilic but becomes increasingly
oncogene p53 by HBV that results in disruption of normal basophilic with increasing malignancy. Aside from these
growth control. In this regards, the role of X-protein (HBxAg) features, a few other cytologic variants are: pleomorphism,
generated from X-gene of HBV has been found to contribute bizarre giant cell formation, spindle-shaped cells, tumour
to carcinogenesis by binding to p53. cells with clear cytoplasm, presence of bile within dilated
canaliculi, and intracytoplasmic Mallory’s hyalin.
MORPHOLOGIC FEATURES. Grossly, HCC may form
one of the following 3 patterns of growth, in decreasing Immunohistochemically, hepatocellular carcinoma cells
order of frequency (Fig. 21.33): stain positively with AFP, EMA, keratin etc. CHAPTER 21
i) Expanding type: Most frequently, it forms a single, FIBROLAMELLAR CARCINOMA. A clinicopathologic
yellow-brown, large mass, most often in the right lobe of variant of the HCC is fibrolamellar carcinoma of the liver
the liver with central necrosis, haemorrhage and found in young people of both sexes. The tumour forms a
occasional bile-staining (Fig. 21.34). It may be deceptively
encapsulated.
ii) Multifocal type: Less often, multifocal, multiple masses,
3-5 cm in diameter, scattered throughout the liver are seen.
iii) Infiltrating (Spreading) type: Rarely, the HCC forms
diffusely infiltrating tumour mass.
Microscopically, the tumour cells in the typical HCC
resemble hepatocytes but vary with the degree of
differentiation, ranging from well-differentiated to highly
anaplastic lesions. Most of the HCC have trabecular
growth pattern. The tumour cells have a tendency to
invade and grow along blood vessels. Thus important The Liver, Biliary Tract and Exocrine Pancreas
diagnostic features are the patterns of tumour cells and their
cytologic features:
1. Histologic patterns: These include the following:
i) Trabecular or sinusoidal pattern is the most common. The
trabeculae are made up of 2-8 cell wide layers of tumour
cells separated by vascular spaces or sinusoids which are
endothelium-lined (Fig. 21.35).
ii) Pseudoglandular or acinar pattern is seen sometimes. The
tumour cells are disposed around central cystic space
formed by degeneration and breakdown in solid
trabeculae.
iii) Compact pattern resembles trabecular pattern but the
tumour cells form large solid masses with inconspicuous Figure 21.34 Hepatocellular carcinoma. Sectioned surface shows
sinusoids. a single, large mass (arrow) with irregular borders and having central
iv) Scirrhous pattern is characterised by more abundant areas of necrosis, while rest of the hepatic parenchyma in the upper part
of the picture shows many nodules of variable sizes owing to co-existent
fibrous stroma. macronodular cirrhosis.
636
Figure 21.35 Hepatocellular carcinoma, typical microscopic pattern. The tumour cells resembling hepatocytes show pleomorphism and are
seen forming 2-8 cell wide trabeculae which are separated by endothelium-lined sinusoidal spaces.
single large mass which may be encapsulated and occurs in plastic syndrome are eobsereved such as hypercalcaemia,
the absence of cirrhosis. hypoglycaemia, gynaecomastia and acquired porphyria.
Laboratory findings yield nonspecific results like
Histologically, the tumour is composed of eosinophilic anaemia, markedly elevated serum alkaline phosphatase as
polygonal cells (oncocytes) forming cords and nests which found in cirrhosis, and high serum alpha-foetoprotein (AFP).
are separated by bands of fibrous stroma (Fig. 21.36). Elevated AFP level is quite specific; very high levels of AFP
(above 500 ng/ml) are observed in 70-80% cases of HCC but
The prognosis of fibrolamellar carcinoma is better than
other forms of HCC. lacks sensitivity since AFP is also found elevated in yolk sac
tumour, cirrhosis, chronic hepatitis, massive liver necrosis
SECTION III
CLINICAL FEATURES. Hepatic cancer may remain and normal pregnancy. Ultrasound of the liver has been
undetected initially because it often occurs in patients with reported to be more sensitive than elevated AFP level. An
underlying cirrhosis. The usual features consist of abnormal type of prothrombin, des-γ-carboxy prothrombin,
hepatomegaly with palpable mass in the liver, right upper is also elevated and correlates well with AFP levels.
quadrant pain or tenderness, and less often, jaundice, fever SPREAD. The HCC can have both intrahepatic and
and haemorrhage from oesophageal varices. Ascites with extrahepatic spread which faithfully reproduces the structure
RBCs and malignant cells is found in about half the patients. of the primary tumour:
Rarely, systemic endocrine manifestations due to paraneo-
Intrahepatic spread occurs by haematogenous route and
forms multiple metastases in the liver.
Extrahepatic spread occurs via hepatic or portal veins to
Systemic Pathology
different sites, chiefly to lungs and bones, and by lymphatic
route to regional lymph nodes at the porta hepatis and to
mediastinal and cervical lymph nodes.
The causes of death from the HCC are cachexia, massive
bleeding from oesophageal varices, and liver failure with
hepatic coma.
Cholangiocarcinoma
Cholangiocarcinoma is the designation used for carcinoma
arising from bile duct epithelium within the liver (peripheral
cholangiocarcinoma). Carcinomas arising from the large hilar
ducts (hilar cholangiocarcinoma) and from extrahepatic ducts
are termed bile duct carcinomas (page 644). None of the
etiologic factors related to HCC have any role in the genesis
of cholangiocarcinoma. However, the etiological factors
involved in it are exposure to radio-opaque dye thorotrast,
anabolic steroids, clonorchiasis and fibrocystic disease. The
tumour affects older people and the clinical features are those
Figure 21.36 Fibrolamellar carcinoma liver. of HCC but with prominence of jaundice.
637
Figure 21.37 Metastatic tumour deposits in the liver as seen on sectioned surface. Characteristic features include multiple, variable-sized,
nodular masses, often under the capsule, producing umbilication on the surface.
MORPHOLOGIC FEATURES. Grossly, the tumour is frequent primary tumours metastasising to the liver, in
firm to hard and whitish. descending order of frequency, are those of stomach, breast,
Microscopically, the tumour has glandular structure. The lungs, colon, oesophagus, pancreas, malignant melanoma
tumour cells resemble biliary epithelium but without bile and haematopoietic malignancies. Sarcomas rarely
secretion. They form various patterns such as tubular, metastasise to the liver. Occasionally, metastatic involvement
ductular or papillary. The stroma consists of fibrous tissue may be present in the absence of obvious evidence of primary
with little or no capillary formation. Occasionally, tumour. Aside from general features of disseminated
mucinous, signet-ring and adenosquamous type of malignancy such as anorexia, cachexia and anaemia, the
patterns are found. An uncommon variant is combined patients have hepatomegaly with nodular free margin. There CHAPTER 21
hepatocellular-cholangiocarcinoma. is little hepatic dysfunction until late in the course of hepatic
metastatic disease.
Hepatoblastoma (Embryoma) MORPHOLOGIC FEATURES. Grossly, most metastatic
Hepatoblastoma is a rare malignant tumour arising from carcinomas form multiple, spherical, nodular masses
primitive hepatic parenchymal cells. It presents before the which are of variable size. Liver is enlarged and heavy,
age of 2 years as progressive abdominal distension with weighing 5 kg or more. The tumour deposits are white,
anorexia, failure to thrive, fever and jaundice. It is more well-demarcated, soft or haemorrhagic. The surface of the
common in boys. The concentration of serum AFP is high. liver shows characteristic umbilication due to central
The tumour grows rapidly and causes death by necrosis of nodular masses (Fig. 21.37).
haemorrhage, hepatic failure or widespread metastases. Histologically, the metastatic tumours generally
reproduce the structure of the primary lesions (Fig. 21.38).
MORPHOLOGIC FEATURES, Grossly, the tumour is
circumscribed and lobulated mass measuring 5-25 cm in
size, having areas of cystic degeneration, haemorrhage
and necrosis. The Liver, Biliary Tract and Exocrine Pancreas
Microscopically, hepatoblastoma consists of 2
components:
i) Epithelial component contains 2 types of cells—
‘embryonal’ hepatocytes are small with dark-staining,
hyperchromatic nuclei and scanty cytoplasm, and ‘foetal’
hepatocytes are larger with more cytoplasm that may be
granular or clear. The epithelial cells are organised in
trabeculae, ribbons or rosettes.
ii) Mesenchymal component includes fibrous connective
tissue, cartilage and osteoid of variable degree of
maturation. Extramedullary haematopoiesis is a frequent
accompaniment.
Secondary Hepatic Tumours
Metastatic tumours in the liver are more common than the
primary hepatic tumours. Most frequently, they are blood-
borne metastases, irrespective of whether the primary Figure 21.38 Metastatic deposits from undifferentiated sarcoma in
tumour is drained by portal vein or systemic veins. Most the liver.
638 duplication and heterotopic tissue. However, congenital cystic
BILIARY SYSTEM
lesions of the bile ducts (as also of the liver) are more
NORMAL STRUCTURE frequently diagnosed. These conditions include: congenital
intrahepatic biliary dilatation (Caroli’s disease), choledochal
ANATOMY. The gallbladder is a pear-shaped organ, 9 cm cysts, polycystic liver disease and congenital hepatic fibrosis.
in length and has a capacity of approximately 50 ml. It They are found in various combinations and are usually
consists of the fundus, body and neck that tapers into the cystic inherited. All of them may be complicated by malignant
duct. The two hepatic ducts from right and left lobes of the change.
liver unite at the porta hepatis to form the common hepatic
duct which is joined by the cystic duct from the gallbladder CHOLELITHIASIS (GALLSTONES)
to form the common bile duct. The common bile duct enters Gallstones are formed from constituents of the bile (viz.
the second part of the duodenum posteriorly. In about 70% cholesterol, bile pigments and calcium salts) along with other
of cases, it is joined by the main pancreatic duct to form the organic components. Accordingly, the gallstones commonly
combined opening in the duodenum (ampulla of Vater). In contain cholesterol, bile pigment and calcium salts in varying
30% cases, the common bile duct and the pancreatic duct proportions. They are usually formed in the gallbladder, but
open separately into the duodenum (see Fig. 21.1). The sometimes may develop within extrahepatic biliary passages,
common bile duct in its duodenal portion is surrounded by and rarely in the larger intrahepatic bile duct.
longitudinal and circular muscles derived from the RISK FACTORS. The incidence of gallstones varies
duodenum forming sphincter of Oddi.
markedly in different geographic areas, age, gender, diet and
HISTOLOGY. Histologically, the gallbladder, unlike the rest various other risk factors. These factors which largely pertain
of gastrointestinal tract, lacks the muscularis mucosae and to cholesterol stones can be summed up in the old saying
submucosa. The wall of the gallbladder is composed of the that gallstones are common in 4F’s acronym for—‘fat, female,
following 4 layers: fertile (multipara) and forty’. Some of the risk factors in
1. Mucosal layer: It has a single layer of tall columnar lithogenesis are explained below:
epithelium which is thrown into permanent folds that are 1. Geography. Gallstones are quite prevalent in almost the
larger and more numerous in the neck of the gallbladder. entire Western world. American Indians have the highest
Beneath the epithelium is delicate lamina propria that known prevalence. Black Africans and populations in the
contains capillaries, and in the region of the neck, a few acinar Eastern world are relatively free of cholelithiasis.
glands are present. 2. Genetic factors. There is increased frequency of gall-
SECTION III
2. Smooth muscle layer: External to the lamina propria are stones in first-degree relatives of patients with cholelithiasis.
smooth muscle bundles in layers—inner longitudinal, middle Patients of gallstones disease have increased secretion of
oblique, and outer circular. dietary cholesterol in bile than in non-gallstone patients
3. Perimuscular layer: Outer to the muscle layer is a zone inspite of high-cholesterol diet. Recently, mutation in
of fibrous connective tissue with some interspersed fat cells. CYP7A1 gene has been found that results in deficiency of
4. Perimuscular layer: The perimuscular layer is covered enzyme, cholesterol 7-hydroxylase, which has a role in bile
by serosa on the peritoneal surface of the gallbladder. The acid synthesis. This mutation is associated with hypercholes-
peritoneum covers the gallbladder except in the region of terolaemia and gallstones.
gallbladder fossa where it is embedded in the liver. 3. Age. There is steady increase in the prevalence of
The extrahepatic bile ducts are also lined by tall columnar gallstones with advancing age which may be related to
Systemic Pathology
epithelium that overlies the lamina propria. It is surrounded increased cholesterol content in the bile. The incidence
by dense layer of fibromuscular tissue. The ducts which lie increases above the age of 40 and presentation is usually in
between the lobules of the liver and receive bile from the the 50s and 60s.
canaliculi are lined by cuboidal or flattened cells.
4. Sex. Gallstones are twice more frequent in women than
FUNCTIONS. The main function of the gallbladder is to in men. In the United States, autopsy series have shown
store and concentrate the bile secreted by the liver and then gallstones in about 20% of women and 8% of men above the
deliver it into the intestine for digestion and absorption of age of 40. The incidence is higher in multiparous women
fat. The concentrating ability of the gallbladder is due to its than in nulliparous women.
absorptive mucosal surface that has numerous folds. 5. Drugs. Women on oestrogen therapy or on birth control
Normally, the liver secretes approximately 500 ml of bile per pills have higher incidence of gallstones. This is considered
day and the gallbladder concentrates it 5-10 times. The to be due to production of more lithogenic bile as a result of
motility, concentration and relaxation of the gallbladder are cholestatic effect of oestrogen. Similar is the influence of
under the influence of a peptide hormone, cholecystokinin, clofibrate used for lowering blood cholesterol.
released from neuroendocrine cells of the duodenum and 6. Obesity. Obesity is associated with increased cholesterol
jejunum.
synthesis and its excretion resulting in higher incidence of
gallstones in obese patients.
CONGENITAL ANOMALIES
7. Diet. Deficiency of dietary fibre content is linked to higher
Several uncommon congenital anomalies of the biliary prevalence of gallstones. A moderate consumption of alcohol,
system have been described. These include: agenesis, however, seems to protect against gallstones.
8. Gastrointestinal diseases. Certain gastrointestinal 639
disorders such as Crohn’s disease, ileal resection, ileal bypass
surgery etc are associated with interruption in enterohepatic
circulation followed by gallstone formation.
9. Factors in pigment gallstones. All the above factors apply
largely to cholesterol stones. Pigment stones, whether pure
or mixed type, are more frequently associated with
haemolytic anaemias which lead to increased content of
unconjugated bilirubin in the bile. Pigment stones are also
more frequent in cirrhosis and hepatocellular disease.
PATHOGENESIS. The mechanism of gallstone formation
(i.e. lithogenesis) is explained separately below under 2
headings: firstly for cholesterol, mixed gallstones and biliary
sludge; and, secondly for pigment gallstones as under:
PATHOGENESIS OF CHOLESTEROL, MIXED GALL-
STONES AND BILIARY SLUDGE. Cholesterol is essentially
insoluble in water and can be solublised by another lipid.
Normally, cholesterol and phospholipids (lecithin) are
secreted into bile as ‘bilayered vesicles’ but are converted
into ‘mixed miscelles’ by addition of bile acids, the third
constituent. If there is excess of cholesterol compared to the
other two constituents, unstable cholesterol-rich vesicles
remain behind which aggregate and form cholesterol
crystals. Formation of such lithogenic (stone-forming) bile Figure 21.39 Schematic pathogenesis of gallstone formation. (HMG-
is explained by the following mechanisms (Fig. 21.39): CoAR = hydroxy methyl glutaryl-coenzyme A reductase; 7α-OHase = CHAPTER 21
1. Supersaturation of bile: Several etiologic factors listed cholesterol 7 α-OHase hydroxylase; MDR3 = multidrug resistance-
above favour increased secretion of cholesterol in the associated protein 3).
presence of normal bile acids and lecithin in the bile as the
major mechanism for initiation of gallstone formation. These addition and precipitation of more crystals resulting in solid
factors cause enhanced activity of enzyme, HMG-CoA state crystals.
reductase, that normally regulates cholesterol synthesis and 3. Gallbladder hypomotility. Normally, the gallbladder is
its hepatic uptake. Two other disturbances which may capable of emptying and clearing any sludge or debris which
contribute to supersaturation of the bile with cholesterol are might initiate stone formation. This takes place under the
as under: influence of cholecystokinin secreted from small intestine.
i) Reduced bile acid pool: This causes rapid loss of the available However, the motility of gallbladder may be impaired due
bile acids into the small intestine and then into the colon, to decrease in cholecystokinin receptors in the gallbladder
resulting in supersaturation of the bile with cholesterol. resulting in stasis of biliary sludge and lithogenesis. A defect
ii) Increased conversion of cholic acid to deoxycholic acid: This in gallbladder emptying has been found to play a role in
causes increased secretion of deoxycholate in the bile which recurrence of gall-stone formation in patients who undergo
is associated with hypersecretion of cholesterol into the bile. biliary lithotripsy. The Liver, Biliary Tract and Exocrine Pancreas
Mutation in MDR3 gene has been found that causes
defect in phospholipid secretion from bile, resulting in PATHOGENESIS OF PIGMENT GALLSTONES. The
cholesterol supersaturation of bile and cholesterol gallstone mechanism of pigment stone formation is explained on the
formation. Although supersaturation of the bile with basis of following factors:
cholesterol is an important pre-requisite for lithogenesis, this i) Chronic haemolysis resulting in increased level of
in itself is not sufficient for cholesterol precipitation. unconjugated bilirubin in the bile.
ii) Alcoholic cirrhosis.
2. Cholesterol nucleation. Initiation of cholesterol stones iii) Chronic biliary tract infection e.g. by parasitic infestations
occurs by nucleation of cholesterol monohydrate crystals. of the biliary tract such as by Clonorchis sinensis and Ascaris
Accelerated nucleation of cholesterol monohydrate may lumbricoides.
occur either from pro-nucleating factors or from deficiency iv) Demographic and genetic factors e.g. in rural setting and
of anti-nucleating factors: prevalence in Asian countries.
i) Pro-nucleating factors are mucin and non-mucin
glycoproteins secreted by epithelial cells of the gallbladder. TYPES OF GALLSTONES. As stated before, gallstones
ii) Anti-nucleating factors are apolipoproteins AI and AII, and contain cholesterol, bile pigment and calcium carbonate,
some glycoproteins. either in pure form or in various combinations. Accordingly,
Cholesterol monohydrate nucleation probably occurs in gallstones are of 3 major types—pure gallstones, mixed
the mucin gel layer of the gallbladder followed by continued gallstones and combined gallstones. Mixed gallstones are the
640
TABLE 21.12: Features of Gallstones.
Type Frequency Composition Gallbladder Changes Appearance
1. Pure 10% i) Cholesterol Cholesterolosis Solitary, oval, large, smooth, yellow-
gallstones white; on C/S radiating glistening
crystals
ii) Bile pigment No change Multiple, small, jet-black, mulberry-
shaped; on C/S soft black
iii) Calcium carbonate No change Multiple, small, grey-white, faceted;
C/S hard
2. Mixed 80% Cholesterol, bile pigment Chronic cholecystitis Multiple, multifaceted, variable size,
gallstones and calcium carbonate in on C/S laminated alternating dark-
varying combination pigment layer and pale-white layer
3. Combined 10% Pure gallstone nucleus with Chronic cholecystitis Solitary, large, smooth; on C/S
gallstones mixed gallstone shell, or central nucleus of pure gallstone
mixed gallstone nucleus with with mixed shell or vice versa
pure gallstone shell
most common (80%) while pure and combined gallstones acids. They are always multiple, multifaceted so that they
comprise 10% each. In general, gallstones are formed most fit together and vary in size from as tiny as sand-grain to 1
frequently in the gallbladder but may occur in extrahepatic cm or more in diameter. On section, they have distinct
as well as intrahepatic biliary passages. Gallbladder laminated structure with alternating dark pigment layer and
containing pure stones shows no significant inflammatory pale-white layer revealing different combinations of
reaction, whereas chronic cholecystitis is invariably present cholesterol, bilirubin pigment and calcium carbonate, laid
in gallbladder with either mixed or combined gallstones. down in layers at different times (Fig. 21.42, A).
Presence of calcium salts renders gallstones radio-opaque, Mixed gallstones are invariably accompanied by chronic
while cholesterol stones appear as radiolucent filling defects cholecystitis.
in the gallbladder. 3. Combined gallstones. They comprise about 10% of all
SECTION III
The salient features of various types of gallstones are gallstones. Combined gallstones are usually solitary, large
summarised in Table 21.12 and presented below:
and smooth-surfaced. It has a pure gallstone nucleus
1. Pure gallstones. They constitute about 10% of all (cholesterol, bile pigment or calcium carbonate) and outer
gallstones. They are further divided into 3 types according shell of mixed gallstone; or a mixed gallstone nucleus with pure
to the component of bile forming them. These are as under gallstone shell (Fig. 21.42, B).
(Fig. 21.40): Combined gallstones, too, are associated with chronic
i) Pure cholesterol gallstones: They are usually solitary, oval cholecystitis.
and fairly large (3 cm or more) filling the gallbladder. Their
surface is hard, smooth, whitish-yellow and glistening. On CLINICAL MANIFESTATIONS AND COMPLICA-
cut section, the pure cholesterol stone shows radiating TIONS. In about 50% cases, gallstones cause no symptoms
glistening crystals. It may result in deposition of cholesterol and may be diagnosed by chance during investigations for
Systemic Pathology
within the mucosal macrophages of the gallbladder some other condition (silent gallstones). The future course in
producing cholesterolosis which is an asymptomatic condition such asymptomatic silent cases is controversial, most
(Fig. 21.41). Pure cholesterol stones are radiolucent but 10- surgeons advocating cholecystectomy while physicians
20% of them have calcium carbonate in them which renders advising watchful waiting. Follow-up studies, however,
them opaque. show that only about 10% of such cases develop symptoms.
ii) Pure pigment gallstones: These stones composed primarily Symptomatic gallstone disease appears only when
of bile pigment, calcium bilirubinate, and contain less than complications develop. These are as under:
20% cholesterol. They are generally multiple, jet-black and 1. Cholecystitis. The relationship between cholelithiasis and
small (less than 1 cm in diameter). They have mulberry like cholecystitis is well known but it is not certain which of the
external surface. They are soft and can be easily crushed. two comes first. The patients with gallstones develop
The gallbladder usually appears uninvolved. symptoms due to cholecystitis which include typical biliary
iii) Pure calcium carbonate gallstones: They are rare. Calcium colic precipitated by fatty meal, nausea, vomiting, fever
carbonate gallstones are usually multiple, grey-white, small alongwith leucocytosis and high serum bilirubin.
(less than 1 cm in diameter), faceted and fairly hard due to 2. Choledocholithiasis. Gallstones may pass down into the
calcium content. They, too, do not produce any change in extrahepatic biliary passages and the small bowel, or less
the gallbladder wall. often they may be formed in the biliary tree. Patients with
2. Mixed gallstones. Mixed gallstones are the most common gallstone in the common bile duct frequently develop pain
(80%) and contain more than 50% cholesterol monohydarate and obstructive jaundice. Fever may develop due to bacterial
plus an admixture of calcium salts, bile pigments and fatty ascending cholangitis.
641
Figure 21.40 Pure gallstones of various types. Figure 21.42 Mixed and combined gallstones.
3. Mucocele. Mucocele or hydrops of the gallbladder is CHOLECYSTITIS
distension of the gallbladder by clear, watery mucinous Cholecystitis or inflammation of the gallbladder may be
secretion resulting from impacted stones in the neck of the acute, chronic, or acute superimposed on chronic. Though
gallbladder.
chronic cholecystitis is more common, acute cholecystitis is
4. Biliary fistula. An uncommon complication of a surgical emergency.
cholelithiasis is formation of fistulae between one part of the
biliary system and the bowel, and rarely between the Acute Cholecystitis
gallbladder and the skin. In many ways, acute cholecystitis is similar to acute appen- CHAPTER 21
5. Gallstone ileus. A gallstone in the intestine may be dicitis. The condition usually begins with obstruction,
passed in the faeces without causing symptoms. followed by infection later.
Occasionally, however, gallstones in the intestine may cause ETIOPATHOGENESIS. Based on the initiating mechanisms,
intestinal obstruction called gallstone ileus.
acute cholecystitis occurs in two types of situations—acute
6. Gallbladder cancer. There is a small and doubtful risk calculous and acute acalculous cholecystitis.
of development of cancer of the gallbladder in cases with Acute calculous cholecystitis. In 90% of cases, acute
cholelithiasis (page 643). cholecystitis is caused by obstruction in the neck of the
gallbladder or in the cystic duct by a gallstone. The commo-
nest location of impaction of a gallstone is in Hartmann’s
pouch. Obstruction results in distension of the gallbladder
followed by acute inflammation which is initially due to
chemical irritation. Later, however, secondary bacterial
infection, chiefly by E. coli and Streptococcus faecalis,
supervenes. The Liver, Biliary Tract and Exocrine Pancreas
Acute acalculous cholecystitis. The remaining 10% cases
of acute cholecystitis do not contain gallstones. In such cases,
a variety of causes have been assigned such as previous
nonbiliary surgery, multiple injuries, burns, recent childbirth,
severe sepsis, dehydration, torsion of the gallbladder and
diabetes mellitus. Rare causes include primary bacterial
infection like salmonellosis and cholera and parasitic
infestations.
MORPHOLOGIC FEATURES. Except for the presence or
absence of calculi, the two forms of acute cholecystitis are
morphologically similar.
Grossly, the gallbladder is distended and tense. The
serosal surface is coated with fibrinous exudate with
congestion and haemorrhages. The mucosa is bright red.
The lumen is filled with pus mixed with green bile. In
calculous cholecystitis, a stone is generally impacted in
Figure 21.41 Cholesterolosis of the gallbladder. The lamina propria
of the mucosa shows foamy macrophages. the neck or in the cystic duct. When obstruction of the
642
Figure 21.43 Chronic cholecystitis with cholelithiasis. A, Mixed
gallstones, diagrammatic view. The wall of the gallbladder is thickened
and the lumen is packed with well-fitting, multiple, multi-faceted, mixed
gallstones. B, Chronic cholecystitis with cholesterol cholelithiasis. The
wall of gallbladder is thickened. The lumen contains a single, large, oval,
and hard yellow-white gallstone.
cystic duct is complete, the lumen is filled with purulent MORPHOLOGIC FEATURES. Grossly, the gallbladder
exudate and the condition is known as empyema of the is generally contracted but may be normal or enlarged
gallbladder. (Fig. 21.43). The wall of the gallbladder is thickened which
Microscopically, wall of the gallbladder shows marked on cut section is grey-white due to dense fibrosis or may
SECTION III
inflammatory oedema, congestion and neutrophilic be even calcified. The mucosal folds may be intact,
exudate. There may be frank abscesses in the wall and thickened, or flattened and atrophied. The lumen
gangrenous necrosis with rupture into the peritoneal commonly contains multiple mixed stones or a combined
cavity (gangrenous cholecystitis). stone.
Histologically, the features are as under (Fig. 21.44):
CLINICAL FEATURES. The patients of acute cholecystitis 1. Thickened and congested mucosa but occasionally
of either type have similar clinical features. They present with mucosa may be totally destroyed.
severe pain in the upper abdomen with features of peritoneal 2. Penetration of the mucosa deep into the wall of the
irritation such as guarding and hyperaesthesia. The
gallbladder is tender and may be palpable. Fever, gallbladder up to muscularis layer to form Rokitansky-
leucocytosis with neutrophilia and slight jaundice are Aschoff’sinuses.
3. Variable degree of chronic inflammatory reaction,
Systemic Pathology
generally present. Early cholecystectomy within the first consisting of lymphocytes, plasma cells and macrophages,
three days has a mortality of less than 0.5% and risk of present in the lamina propria and subserosal layer.
complications such as perforation, biliary fistula, recurrent 4. Variable degree of fibrosis in the subserosal and
attacks and adhesions is avoided. However, medical subepithelial layers.
treatment brings about resolution in a fairly large proportion A few morphologic variants of chronic cholecystitis
of cases though chances of recurrence of attack persist.
are considered below:
Cholecystitis glandularis, when the mucosal folds
Chronic Cholecystitis
fuse together due to inflammation and result in formation
Chronic cholecystitis is the commonest type of clinical of crypts of epithelium buried in the gallbladder wall.
gallbladder disease. There is almost constant association of Porcelain gallbladder is the pattern when the
chronic cholecystitis with cholelithiasis. gallbladder wall is calcified and cracks like an egg-shell.
ETIOPATHOGENESIS. The association of chronic Acute on chronic cholecystitis is the term used for
cholecystitis with mixed and combined gallstones is virtually the morphologic changes of acute cholecystitis
always present. However, it is not known what initiates the superimposed on changes of chronic cholecystitis.
inflammatory response in the gallbladder wall. Possibly,
supersaturation of the bile with cholesterol predisposes to CLINICAL FEATURES. Chronic cholecystitis has ill-defined
both gallstone formation and inflammation. In some patients, and vague symptoms. Generally, the patient—a fat, fertile,
repeated attacks of mild acute cholecystitis result in chronic female of forty or fifty, presents with abdominal distension or
cholecystitis. epigastric discomfort, especially after a fatty meal. There is
643
Figure 21.44 Chronic cholecystitis, microscopic appearance. There is penetration of epithelium-lined spaces into the gallbladder wall (Rokitansky-
Aschoff sinus) in an area. There is subepithelial and subserosal fibrosis and hypertrophy of muscularis. Mononuclear inflammatory cell infiltrate is
present in subepithelial and perimuscular layers.
a constant dullache in the right hypochondrium and 1. Cholelithiasis and cholecystitis. The most significant CHAPTER 21
epigastrium and tenderness over the right upper abdomen. association of cancer of the gallbladder is with cholelithiasis
Nausea and flatulence are common. Biliary colic may and cholecystitis, though there is no definite evidence of
occasionally occur due to passage of stone into the bile ducts. causal relationship. Cholelithiasis and cholecystitis are
Cholecystography usually allows radiologic visualisation of present in about 75% cases of gallbladder cancer. On the other
the gallstones. hand, incidence of documented gallbladder cancer in the
presence of cholelithiasis and cholecystitis is about 0.5% only.
Porcelain gallbladdder is particularly likely to become
TUMOURS OF BILIARY SYSTEM
cancerous.
BENIGN TUMOURS 2. Chemical carcinogens. A number of chemical
carcinogens structurally similar to naturally-occurring bile
Benign tumours such as papilloma, adenoma, adenomyoma, acids have been considered to induce gallbladder cancer.
fibroma, lipoma, myxoma, and haemangioma have been These include methyl cholanthrene, various nitrosamines
described in the biliary tract but all of them are exceedingly and pesticides. Workers engaged in rubber industry have
rare. Adenomyoma is more common benign tumour than the higher incidence of gallbladder cancer.
rest. All these tumours resemble their counterparts in The Liver, Biliary Tract and Exocrine Pancreas
morphology elsewhere in the body. 3. Genetic factors. There is higher incidence of cancer of
the gallbladder in certain populations living in the same
MALIGNANT TUMOURS geographic region suggesting a strong genetic component
in the disease. Japanese immigrants and Native Americans
Carcinoma of the gallbladder and carcinoma of the bile ducts of the South-Western America have increased frequency
and ampulla of Vater are among the more frequent malignant while American Indians and Mexicans have lower incidence.
tumours of the biliary tract.
4. Miscellaneous. Patients who have undergone previous
Carcinoma of the Gallbladder surgery on the biliary tract have higher incidence of
subsequent gallbladder cancer. Patients with inflammatory
Primary carcinoma of the gallbladder is more prevalent than bowel disease (ulcerative colitis and Crohn’s disease) have
other cancers of the extrahepatic biliary tract. Like high incidence of gallbladder cancer.
cholelithiasis and cholecystitis, it is more frequent in women
than in men (ratio 4:1) with a peak incidence in 7th decade MORPHOLOGIC FEATURES. The commonest site is the
of life. It may remain undetected until the time it is widely fundus, followed next in frequency by the neck of the
spread and rendered inoperable. gallbladder (Fig. 21.45).
Grossly, cancer of the gallbladder is of 2 types—infil-
ETIOLOGY. A number of etiologic factors have been
implicated. trating and fungating type (Fig. 21.46):
644 Histologically, the following patterns are observed:
1. Most gallbladder cancers are adenocarcinomas (90%).
They may be papillary or infiltrative, well-differentiated
or poorly-differentiated. Most are non-mucin secreting but
some are colloid carcinomas forming mucus pools.
2. About 5% of gallbladder cancers are squamous cell
carcinomas arising from squamous metaplastic epithelium.
3. A few cases show both squamous and adeno-
carcinoma pattern of growth called adenosquamous
carcinoma.
CLINICAL FEATURES. Carcinoma of the gallbadder is
slow-growing and causes symptoms late in the course of
disease. Quite often, the diagnosis is made when gallbladder
is removed for cholelithiasis. The symptomatic cases have
pain, jaundice, noticeable mass, anorexia and weight loss.
In such case, the growth has usually invaded the liver and
other adjacent organs and has metastasised to regional lymph
nodes and more distant sites such as the lung, peritoneum
and gastrointestinal tract.
Carcinoma of Extrahepatic Bile Ducts and
Ampulla of Vater
Figure 21.45 Frequency of cancer in the biliary system.
This is an infrequent neoplasm but is more common than
the rare benign tumours of the biliary tract. Unlike other
1. Infiltrating type appears as an irregular area of diffuse diseases of the biliary passages, it is more common in males
thickening and induration of the gallbladder wall. It may with peak incidence in 6th decade of life.
have deep ulceration causing direct invasion of the
gallbladder wall and liver bed. On section, the gallbladder ETIOLOGY. There is no association between bile duct
SECTION III
wall is firm due to scirrhous growth. carcinoma and gallstones. Bile duct cancers are associated
2. Fungating type grows like an irregular, friable, with a number of other conditions such as ulcerative colitis,
papillary or cauliflower-like growth into the lumen as well sclerosing cholangitis, parasitic infestations of the bile ducts
as into the wall of the gallbladder and beyond. with Fasciola hepatica (liver fluke), Ascaris lumbricoides and
Clonorchis sinensis.
MORPHOLOGIC FEATURES. Extrahepatic bile duct
carcinoma may arise anywhere in the biliary tree but the
most frequent sites, in descending order of frequency, are:
the ampulla of Vater, lower end of common bile duct,
hepatic ducts, and the junction of hepatic ducts to form
Systemic Pathology
common bile duct (see Fig. 21.45).
Grossly, bile duct carcinoma is usually small, extending
for 1-2 cm along the duct, producing thickening of the
affected duct.
Histologically, the tumour is usually well-differentiated
adenocarcinoma which may or may not be mucin-
secreting. Perineural invasion is frequently present.
CLINICAL FEATURES. Obstructive jaundice is the usual
presenting feature which is characterised by intense pruritus.
Pain, steatorrhoea, weight loss and weakness may be present.
The tumour usually metastasises to the regional lymph
nodes.
EXOCRINE PANCREAS
NORMAL STRUCTURE
Figure 21.46 Carcinoma gallbladder. The lumen of the gallbladder
contains irregular, friable papillary growth arising from mucosa (arrow). The human pancreas, though anatomically a single organ,
Two multi-faceted gallstones (mixed) are also present in the lumen. histologically and physiologically has 2 distinct parts—the
exocrine and endocrine parts. The endocrine part of the gland viscidosis) and associated with increased concentrations of 645
is dealt with in Chapter 27 while the exocrine gland is electrolytes in the eccrine glands. The terms ‘cystic fibrosis’
considered here. The whole of pancreas, exocrine and and ‘fibrocystic disease’ are preferable over ‘mucoviscidosis’
endocrine, is embryologically derived from the foregut in view of the main pathologic change of fibrosis produced
endoderm. as a result of obstruction of the passages by viscid mucous
ANATOMY. The pancreas lies obliquely in the concavity of secretions.
the duodenum as an elongated structure about 15 cm in The disease is transmitted as an autosomal recessive trait
length and 100 gm in weight (see Fig. 21.1). It is subdivided with apparent clinical features in homozygotes only. The
into 3 topographic zones: defect is a genetic mutation in CFTR gene, acronym for
1. The head lying in the concavity of the duodenum and the coding protein for cystic fibrosis transmembrane conductance
uncinate process projecting from the head. regulator located on chromosome 7. It is quite common in
2. The body comprises the main part of the gland. the whites (1 per 2000 livebirths). The clinical manifestations
3. The tail is the thin, tapering part of the gland towards may appear at birth or later in adolescence and pertain to
the hilum of the spleen. multiple organs and systems such as pancreatic insufficiency,
intestinal obstruction, steatorrhoea, malnutrition, hepatic
HISTOLOGY. The exocrine pancreas constitutes 80 to 85% cirrhosis and respiratory complications.
of the total gland, while the endocrine pancreas comprises
the remaining part. MORPHOLOGIC FEATURES. Depending upon the
The exocrine part is divided into rhomboid lobules severity of involvement and the organs affected, the
separated by thin fibrous tissue septa containing blood pathologic changes are variable. Most of the changes are
vessels, lymphatics, nerves and ducts. Each lobule is produced as a result of obstruction by viscid mucous.
composed of numerous acini. The acini are lined by pyramid- 1. Pancreas. The pancreas is almost invariably involved
shaped columnar epithelial cells. These secretory epithelial in cystic fibrosis.
cells have microvilli projecting into the lumen from their
surface. The apical portions of these cells contain zymogen Grossly, pancreatic lobules are ovoid rather than
granules in their cytoplasm, while the basal region is deeply rhomboid. Fatty replacement of the pancreas and grossly CHAPTER 21
basophilic and free of zymogen granules. The zymogen visible cysts may be seen.
granules are membrane-bound sacs which fuse with the Microscopically, the lobular architecture of pancreatic
plasma membrane and are then released into the lumina of parenchyma is maintained. There is increased interlobular
the acini. The secretions are carried from the acini by fine fibrosis. The acini are atrophic and many of the acinar
ductal branches into the small ducts in the lobules and ducts contain laminated, eosinophilic concretions. Rarely,
eventually into the main pancreatic duct. The main inflammation, fat necrosis and cyst formation may be seen.
pancreatic duct is formed by fusion of the ventral duct with The islet tissue (endocrine pancreas) generally remains
the dorsal duct; the latter also called the duct of Wirsung, intact. Atrophy of the exocrine pancreas may cause
provides the main drainage for pancreatic secretions into the impaired fat absorption, steatorrhoea, intestinal
duodenum. The pancreatic secretions are delivered into the obstruction and avitaminosis A.
second part of the duodenum either by a combined opening 2. Liver. The bile canaliculi are plugged by viscid
of the pancreatic and bile ducts in the ampulla of Vater, or mucous which may cause diffuse fatty change, portal
less often both open separately into the duodenum. fibrosis and ductular proliferation. More severe involve-
Occasionally, the proximal part of the dorsal duct persists ment may cause biliary cirrhosis (page 625).
as the duct of Santorini.
3. Respiratory tract. Changes in the respiratory passages The Liver, Biliary Tract and Exocrine Pancreas
FUNCTIONS. The main functions of the exocrine pancreas are seen in almost all typical cases of cystic fibrosis. The
is the alkaline secretion of digestive enzymes prominent viscid mucous secretions of the submucosal glands of the
among which are trypsin, chymotrypsin, elastase, amylase, respiratory tract cause obstruction, dilatation and infection
lipase and phospholipase. of the airways. The changes include chronic bronchitis,
bronchiectasis, bronchiolitis, bronchiolectasis,
DEVELOPMENTAL ANOMALIES peribronchiolar pneumonia and inflammatory nasal
polyps.
The significant developmental anomalies of the pancreas are
ectopic or aberrant pancreatic tissue in Meckel’s diverticulum 4. Salivary glands. Pathologic changes in the salivary
(page 561), anomalies of the ducts, and cystic fibrosis. Only glands are similar to those in pancreas and include
the last named requires elaboration here. obstruction of the ducts, dilatation, fibrosis and glandular
atrophy.
Cystic Fibrosis 5. Sweat glands. Hypersecretion of sodium and chloride
in the sweat observed in these patients may be reflected
Cystic fibrosis of the pancreas or fibrocystic disease is a pathologically by diminished vacuolation of the cells of
hereditary disorder characterised by viscid mucous eccrine glands.
secretions in all the exocrine glands of the body (muco-
646 PANCREATITIS leakage of pancreatic enzymes from the ductules into the
Pancreatitis is inflammation of the pancreas with acinic cell interstitial tissue.
injury. It is classified into acute and chronic forms both of Block in exocytosis of pancreatic enzymes occurring from
which are distinct entities. nutritional causes results in activation of these intracellular
enzymes by pancreatic lysosomal hydrolases.
Acute Pancreatitis
MORPHOLOGIC FEATURES. Grossly, in the early stage,
Acute pancreatitis is an acute inflammation of the pancreas
presenting clinically with ‘acute abdomen’. The severe form the pancreas is swollen and oedematous. Subsequently,
of the disease associated with macroscopic haemorrhages in a day or two, characteristic variegated appearance of
grey-white pancreatic necrosis, chalky-white fat necrosis
and fat necrosis in and around the pancreas is termed acute and blue-black haemorrhages are seen. In typical case, the
haemorrhagic pancreatitis or acute pancreatic necrosis. The
condition occurs in adults between the age of 40 and 70 years peritoneal cavity contains blood-stained ascitic fluid and
and is commoner in females than in males. white flecks of fat necrosis in the omentum, mesentery
The onset of acute pancreatitis is sudden, occurring after and peripancreatic tissue. The resolved lesions show areas
a bout of alcohol or a heavy meal. The patient presents with of fibrosis, calcification and ductal dilatation.
abdominal pain, vomiting and collapse and the condition Microscopically, the following features in varying grades
must be differentiated from other diseases producing acute are noticeable:
abdomen such as acute appendicitis, perforated peptic ulcer, 1. Necrosis of pancreatic lobules and ducts.
acute cholecystitis, and infarction of the intestine following 2. Necrosis of the arteries and arterioles with areas of
sudden occlusion of the mesenteric vessels. Characteri- haemorrhages.
stically, there is elevation of serum amylase level within the 3. Fat necrosis.
first 24 hours and elevated serum lipase level after 3 to 4 days, 4. Inflammatory reaction, chiefly by polymorphs, around
the latter being more specific for pancreatic disease. the areas of necrosis and haemorrhages.
Glucosuria occurs in 10% of cases.
COMPLICATIONS. A patient of acute pancreatitis who
ETIOLOGY. The two leading causes associated with acute survives may develop a variety of systemic and local
pancreatitis are alcoholism and cholelithiasis, both of which complications.
are implicated in more than 80% of cases. Less common
causes of acute pancreatitis include trauma, ischaemia, shock, Systemic complications:
SECTION III
extension of inflammation from the adjacent tissues, blood- 1. Chemical and bacterial peritonitis.
borne bacterial infection, viral infections, certain drugs (e.g. 2. Endotoxic shock.
thiazides, sulfonamides, oral contraceptives), hypothermia, 3. Acute renal failure.
hyperlipoproteinaemia and hypercalcaemia from hyperpara-
thyroidism. Rarely, familial pancreatitis is encountered. In a Local sequelae:
proportion of cases of acute pancreatitis, the etiology remains 1. Pancreatic abscess.
unknown (idiopathic pancreatitis). 2. Pancreatic pseudocyst.
3. Duodenal obstruction.
PATHOGENESIS. The destructive changes in the pancreas
are attributed to the liberation and activation of pancreatic Mortality in acute pancreatitis is high (20-30%). Patients
enzymes. Though more than 20 enzymes are secreted by succumb to hypotensive shock, infection, acute renal failure,
exocrine pancreas, 3 main groups of enzymes which bring and DIC.
Systemic Pathology
about destructive effects on the pancreas are as under:
1. Proteases such as trypsin and chymotrypsin play the most Chronic Pancreatitis
important role in causing proteolysis. Trypsin also activates Chronic pancreatitis or chronic relapsing pancreatitis is the
the kinin system by converting prekallikrein to kallikrein, progressive destruction of the pancreas due to repeated mild
and thereby the clotting and complement systems are and subclinical attacks of acute pancreatitis. Most patients
activated. This results in inflammation, thrombosis, tissue present with recurrent attacks of severe abdominal pain at
damage and haemorrhages found in acute haemorrhagic intervals of months to years. Weight loss and jaundice are
pancreatitis. often associated. Later manifestations include associated
2. Lipases and phospholipases degrade lipids and membrane diabetes mellitus and steatorrhoea. Abdominal radiographs
phospholipids. show calcification in the region of pancreas and presence of
3. Elastases cause destruction of the elastic tissue of the blood pancreatic calculi in the ducts.
vessels.
The activation and release of these enzymes is brought ETIOLOGY. Most cases of chronic pancreatitis are caused
about by one of the following mechanisms: by the same factors as for acute pancreatitis. Thus, most
Acinic cell damage caused by the etiologic factors such as commonly, chronic pancreatitis is related to chronic alcoholism
alcohol, viruses, drugs, ischaemia and trauma result in with protein-rich diet, and less often to biliary tract disease.
release of intracellular enzymes. Familial hereditary pancreatitis, though uncommon, is more
Duct obstruction caused by cholelithiasis, chronic frequently chronic than the acute form. Other rare causes of
alcoholism and other obstructing lesions is followed by chronic pancreatitis are hypercalcaemia, hyperlipidaemia
COMPLICATIONS. Late stage of chronic pancreatitis may 647
be complicated by diabetes mellitus, pancreatic insufficiency
with steatorrhoea and malabsorption and formation of
pancreatic pseudocysts (Fig. 21.48).
TUMOURS AND TUMOUR-LIKE LESIONS
Tumour-like masses of the exocrine pancreas include
congenital cystic disease (involving the pancreas, liver and
kidney) and pancreatic pseudocysts. True pancreatic tumours
are classified into benign (e.g. serous cystadenoma, fibroma,
lipoma and adenoma) and malignant (i.e. carcinoma of the
pancreas). Out of all these, only two pancreatic lesions—
pseudocyst and carcinoma of the pancreas, are common and
are discussed below.
Pancreatic Pseudocyst
Pancreatic pseudocyst is a localised collection of pancreatic
juice, necrotic debris and haemorrhages. It develops
following either acute pancreatitis or trauma. The patients
Figure 21.47 Chronic pancreatitis. There is destruction of acinar generally present with abdominal mass producing pain,
tissue and presence of dystrophic calcification. The necrotic tissue is intraperitoneal haemorrhage and generalised peritonitis.
surrounded by mixed inflammatory infiltrate with granulation tissue
formation.
MORPHOLOGIC FEATURES. Grossly, the pseudocyst
may be present within or adjacent to the pancreas. Usually
and developmental failure of fusion of dorsal and ventral it is solitary, unilocular, measuring up to 10 cm in CHAPTER 21
pancreatic ducts. diameter with thin or thick wall (Fig. 21.48).
Microscopically, the cyst wall is composed of dense
PATHOGENESIS. Acute haemorrhagic pancreatitis seldom fibrous tissue with marked inflammatory reaction. There
develops into chronic pancreatitis, but instead develops is evidence of preceding haemorrhage and necrosis in the
pancreatic pseudocysts following recovery. Pathogenesis of form of deposits of haemosiderin pigment, calcium and
alcoholic and non-alcoholic chronic pancreatitis is explained cholesterol crystals. The lumen of the cyst contains serous
by different mechanisms: or turbid fluid. The cyst does not show any epithelial
1. Chronic pancreatitis due to chronic alcoholism accom- lining.
panied by a high-protein diet results in increase in protein
concentration in the pancreatic juice which obstructs the Carcinoma of Pancreas
ducts and causes damage.
2. Non-alcoholic cases of chronic pancreatitis seen in Pancreatic cancer is the term used for cancer of the exocrine
tropical countries (tropical chronic pancreatitis) result from pancreas. It is one of the common cancers, particularly in
protein-calorie malnutrition. Genetic factors play a role in the Western countries and Japan. In the United States, cancer
some cases of chronic pancreatitis. of the pancreas is the second most common cancer of the
alimentary tract after colorectal cancer, is more common in The Liver, Biliary Tract and Exocrine Pancreas
MORPHOLOGIC FEATURES. Grossly, the pancreas is
enlarged, firm and nodular. The cut surface shows a
smooth grey appearance with loss of normal lobulation.
Foci of calcification and tiny pancreatic concretions to
larger visible stones are frequently found. Pseudocysts
may be present.
Microscopically, depending upon the stage of
development, the following changes are seen (Fig. 21.47):
1. Obstruction of the ducts by fibrosis in the wall and
protein plugs or stones in the lumina.
2. Squamous metaplasia and dilatation of some inter-
and intralobular ducts.
3. Chronic inflammatory infiltrate around the lobules as
well as the ducts.
4. Atrophy of the acinar tissue with marked increase in
interlobular fibrous tissue.
5. Islet tissue is involved in late stage only.
Figure 21.48 Complications of chronic pancreatitis.
648 African Americans and accounts for 5% of all cancer deaths
in that country. It is commoner in males than in females and
the incidence increases progressively after the age of 50 years.
ETIOLOGY. A significant increase in the incidence of
pancreatic cancer has been observed in the UK and US during
the last 50 years. Little is known about etiology of pancreatic
cancer. However, following factors have been implicated in
its etiology:
1. Smoking: Heavy cigarette smokers have higher incidence
than the non-smokers. However, it is not known whether
tobacco metabolites have a direct carcinogenic effect on the
pancreas or by some other unknown mechanism.
2. Diet and obesity: Diet with high total caloric value and
high consumption of animal proteins and fats is related to
higher incidence of pancreatic cancer. Obesity is a risk factor
for pancreatic cancer.
3. Chemical carcinogens: Individuals exposed to β-naph-
thylamine, benzidine and nitrosamines have higher incidence
of cancer of the pancreas.
4. Diabetes mellitus: Patients of long-standing diabetes Figure 21.49 Distribution of carcinoma of the pancreas (numbered
mellitus have a higher incidence. serially) and its major effects.
5. Chronic pancreatitis patients are at increased risk.
6. H. pylori infection has been reported to have association constitutes less than 1% of pancreatic cancers. The
with pancreatic cancer. following histologic patterns of pancreatic carcinoma are
7. Genetic factors have been ound to have association with seen:
pancreatic cancer e.g. its occurrence in first-degree relatives 1. Well-differentiated adenocarcinoma, both mucinous and
in 10% cases, occurrence in certain hereditary syndromes non-mucin secreting type, is the most common pattern.
(Lynch, FPC, HNPCC). Perineural invasion is commonly present and is diagnostic
SECTION III
However, excessive consumption of alcohol or coffee, and of malignancy.
cholelithiasis are not risk factors for pancreatic cancer. A 2. Adenoacanthoma consisting of glandular carcinoma and
combination of mutations in K-RAS gene and CDKN2A gene benign squamous elements is seen in a proportion of cases.
have been found in almost all cases of cancer of the pancreas. 3. Rarely, peculiar tumour giant cell formation is seen with
marked anaplasia, pleomorphism and numerous mitoses.
MORPHOLOGIC FEATURES. The most common loca- 4 Acinar cell carcinoma occurs rarely and reproduces the
tion of pancreatic cancer is the head of pancreas (70%), pattern of acini in normal pancreas.
followed in decreasing frequency, by the body and the
tail of pancreas (Fig. 21.49). CLINICAL FEATURES. Clinical symptoms depend upon
Grossly, carcinoma of the head of pancreas is generally the site of origin of the tumour. Generally, the following
small, homogeneous, poorly-defined, grey-white mass features are present:
Systemic Pathology
without any sharp demarcation between the tumour and 1. Obstructive jaundice. more often and early in the course
the surrounding pancreatic parenchyma. The tumour of of disease in cases with carcinoma head of the pancreas (80%),
the head extends into the ampulla of Vater, common bile and less often in cancer of the body and tail of the pancreas.
duct and duodenum, producing obstructive biliary It is characterised by: dark urine, clay-like stools, pruritus,
symptoms and jaundice early in the course of illness. and very high serum alkaline phosphatase.
Carcinomas of the body and tail of the pancreas, on the 2. Other features. These include: abdominal pain, anorexia,
other hand, are fairly large and irregular masses and weight loss, cachexia, weakness and malaise, nausea and
frequently infiltrate the transverse colon, stomach, liver, vomiting, and migratory thrombophlebitis (Trousseau’s
spleen and regional lymph nodes. syndrome), GI bleeding and splenomegaly.
Microscopically, most pancreatic carcinomas arise from The prognosis of pancreatic cancer is dismal: median
the ductal epithelium which normally comprises less than survival is 6 months from the time of diagnosis. Approxi-
4% of total pancreatic cells, whereas carcinoma of the acini mately 10% patients survive 1 year and the 5-year survival
is poor 1 to 2%.
❑
649
The Kidney and
Chapter 22
Chapter 22
Lower Urinary Tract
KIDNEY
NORMAL STRUCTURE
ANATOMY. The kidneys are bean-shaped paired organs,
each weighing about 150 gm in the adult male and about
135 gm in the adult female. The hilum of the kidney is
situated at the midpoint on the medial aspect where the
artery, vein, lymphatics and ureter are located. The kidney
is surrounded by a thin fibrous capsule which is adherent at
the hilum.
Cut surface of the kidney shows 3 main structures: well-
demarcated peripheral cortex, inner medulla and the innermost
renal pelvis (Fig. 22.1):
The renal cortex forms the outer rim of the kidney and is
about 1 cm in thickness. It contains all the glomeruli and CHAPTER 22
about 85% of the nephron tubules. Remaining 15% nephrons
consisting of collecting tubules, collecting ducts, loops of Figure 22.2 Cross-section of the kidney showing arterial blood
Henle and vasa recta send their loops into the medulla, and supply.
are therefore called juxtamedullary nephrons. This latter part
of the cortex forms faint striations called medullary rays, a of each renal pyramid for passage of urine collected from
misnomer since theses structures are located in the cortex collecting ducts and goes down into minor calyces.
but are destined for medulla. Columns of renal cortical tissue The renal pelvis is the funnel-shaped collection area of
that extend into the space between adjacent pyramids are the urine for drainage into the ureter. The minor calyces (8-
called the renal column (septa) of Bertin; they contain the 18 in number in a normal kidney) collect urine from renal
interlobar arteries. papillae and drain into major calyces (2-3 in a normal kidney).
The renal medulla is composed of 8-18 cone-shaped renal HISTOLOGY. The parenchyma of each kidney is composed
pyramids. The base of a renal pyramid lies adjacent to the of approximately one million microstructures called
outer cortex and forms the cortico-medullary junction, while nephrons. A nephron, in turn, consists of 5 major parts, each
the apex of each called the renal papilla contains the opening having a functional role in the formation of urine: the The Kidney and Lower Urinary Tract
glomerular capsule (glomerulus and Bowman’s capsule), the
proximal convoluted tubule (PCT), the loop of Henle, the
distal convoluted tubule (DCT), and the collecting ducts.
From point of view of diseases of the kidneys, 4 components
of renal parenchyma require further elaboration: renal
vasculature, glomeruli, tubules and interstitium.
1. Renal vasculature. Each kidney is supplied with blood
by a main renal artery which arises from the aorta at the level
of the 2nd lumbar vertebra. It usually divides into anterior
and posterior divisions at the hilum although occasionally these
divisions may even arise directly from the aorta. The anterior
and posterior divisions divide into segmental branches from
which interlobar arteries arise which course between the lobes.
Along their course, they give off the arcuate arteries which
arch between the cortex and medulla. The arcuate arteries,
in turn, give off interlobular arteries which lie in the cortex
perpendicular to the capsular surface in the part overlying
the pyramids and, therefore, are also called straight arteries
Figure 22.1 Cross-section of the kidney showing gross structures. (Fig. 22.2). It is from the interlobular arteries that the afferent
650 capillaries is high. Therefore, renal cortex is more prone to
the effects of hypertension.
ii) The renal medulla, on the other hand, is poorly perfused
and any interference in blood supply to it results in medullary
necrosis.
iii) The divisions and subdivisions of the renal artery up to
arterioles are end-arteries and have no anastomoses. Thus,
occlusion of any of the branches results in infarction of the
renal parenchyma supplied by it.
iv) Since the tubular capillary beds are derived from the
efferent arterioles leaving the glomeruli, diseases affecting
the blood flow through glomerular tuft have significant
effects on the tubules as well.
2. Glomerulus. The glomerulus consists of invagination of
the blind end of the proximal tubule and contains a capillary
tuft fed by the afferent arteriole and drained by efferent
arteriole. The capillary tuft is covered by visceral epithelial
cells (podocytes) which are continuous with those of the
parietal epithelium at the vascular pole. The transition to
proximal tubular cells occurs at the urinary pole of the
glomerulus. The visceral and parietal epithelial cells are
separated by the urinary space or Bowman’s space, into which
glomerular filtrate passes (Fig. 22.4).
Subdivisions of capillaries derived from the afferent
arterioles result in the formation of lobules (up to 8 in number)
within a glomerulus. Each lobule of a glomerular tuft consists
of a centrilobular supporting stalk composed of mesangium
containing mesangial cells and mesangial matrix. The
mesangium is continuous at the hilum with the lacis cells of
SECTION III
the juxtaglomerular apparatus. Besides their role as
supportive cells, mesangial cells are involved in the
production of mesangial matrix and glomerular basement
membrane; they function in endocytosis of leaked macro-
molecules and also possibly in the control of glomerular
Figure 22.3 A schematic illustration of the structure of a nephron blood flow through contractile elements present in these cells.
(in longitudinal section) and associated blood supply.
The major function of glomerulus is complex filtration
from the capillaries to the urinary space. Glomerular filtrate
is quite similar in composition to plasma but lacks proteins
arterioles take their origin, each one supplying a single and cells. Normally, glomerular filtration rate (GFR) is about
glomerulus. From the glomerulus emerge the efferent 125 ml/minute. The barrier to glomerular filtration consists
Systemic Pathology
arterioles. Up to this stage, the arteries and arterioles are end- of the following 3 components (Fig. 22.5):
vessels. The efferent arterioles leaving the glomerulus supply i) Fenestrated endothelial cells lining the capillary loops.
peritubular capillary plexus which anastomoses with the ii) Glomerular basement membrane (GBM) on which the
capillary plexus of another nephron. endothelial cells rest. It further consists of 3 layers—the
The juxtamedullary glomeruli, however, give off a series central lamina densa, bounded by lamina rara interna on
of parallel vessels called vasa recta which descend to the inner endothelial side of the capillary and lamina rara externa on
medulla supplying the loop of Henle and collecting ducts visceral epithelial side of the capillary.
and anastomose at all levels throughout the medulla with iii) Filtration slit pores between the foot processes of the
the ascending vasa recta. These drain into arcuate veins and visceral epithelial cells (podocytes) external to GBM.
then into the veins that accompany the corresponding arteries The barrier to filtration of macromolecules of the size and
and finally through a single renal vein into the inferior vena molecular weight of albumin and larger depends upon the
cava (Fig. 22.3). Lymphatic drainage likewise occurs through following:
lymphatics associated with the intrarenal vasculature leaving A normal lamina densa.
the kidney at the hilum and draining to lateral aortic lymph
nodes. Maintenance of negative charge on both lamina rarae.
The following important inferences can be drawn from A healthy covering of glomerular epithelial cells.
the peculiarities of the renal vasculature: Juxtaglomerular apparatus. The juxtaglomerular apparatus
i) The renal cortex receives about 90% of the total renal (JGA) is situated at the vascular pole of the glomerulus and
blood supply and that the pressure in the glomerular is made up of 3 parts (Fig. 22.4):
651
Figure 22.4 Structure of a nephron. CHAPTER 22
i) The juxtaglomerular cells are modified granular smooth mechanism of the release of renin and its role in hypertension
muscle cells in the media of the afferent arteriole and contain are discussed on page 686.
the hormone, renin. 3. Tubules. The tubules of the kidney account for the
ii) The macula densa is comprised by specialised region of greatest amount of the renal parenchyma. The structure of
the distal tubule when it returns to the vascular pole of its renal tubular epithelium varies in different parts of the
parent glomerulus. The tubular cells here are taller and nephron and is correlated with the functional capacity of that
narrower than elsewhere with the nuclei lying close together. part of the tubule (see Fig. 22.3).
iii) The lacis cells or non-granular cells occupy the space i) Proximal convoluted tubule (PCT). This is the first part
between the macula densa and the arterioles and merge with arising from the glomerulus and is highly specialised part
the glomerular mesangium. functionally. It is lined by cuboidal cells with a brush border
The JGA is intimately concerned with sodium metabolism composed of microvilli and contains numerous The Kidney and Lower Urinary Tract
and is the principal source of renin production. The mitochondria, Golgi apparatus and endoplasmic reticulum.
The major functions of PCT are: active reabsorption of filtered
sodium, potassium, glucose, amino acids, proteins, vitamins,
bicarbonate, phosphate, calcium and uric acid, and passive
reabsorption of 80% of filtered water.
ii) Loop of Henle. The PCT drains into the straight part of
loop of Henle that consists of thin descending, and thin and
thick ascending limbs, both of which have different structure
and function. The descending limb is continuation of PCT,
while ascending limb continues further into distal convoluted
tubule (DCT). The descending segment of loop is lined by
simple epithelium while the ascending limb is lined by
columnar cells. The major function of loop of Henle is active
reabsorption of sodium, potassium and chloride, and passive
diffusion of water resulting in concentrated filtrate of urine.
iii) Distal convoluted tubule (DCT). The DCT represents a
transition from thick ascending limb from the point where
the ascending limb meets the vascular pole of the glomerulus
Figure 22.5 Ultrastructure of glomerular filtration barrier. of its origin, to the early collecting ducts. The lining cells in
652 DCT are cuboidal. The epithelial cells at the point of TABLE 22.1: Renal Function Tests.
beginning of DCT are taller, narrower and more closely
packed to form the macula densa of JGA as already described. 1. URINE ANALYSIS:
The DCT further contributes to urinary concentration and i) Physical examination
(output, colour, specific gravity, pH, osmolality)
acidification, while the macula densa of JGA is the source of ii) Chemical constituents
renin and has a role in sodium metabolism. (protein, glucose, red cells, haemoglobin)
iv) Collecting ducts. The system of collecting ducts is the final iii) Bacteriologic examination
pathway by which urine reaches the tip of renal papilla. The iv) Microscopy
cells lining the collecting ducts are cuboidal but lack the brush 2. CONCENTRATION AND DILUTION TESTS:
border. Collecting ducts reabsorb water under control of i) Concentration test (fluid deprivation test)
ii)
Dilution test (excess fluid intake test)
+
+
ADH, and secrete H and K ions.
3. BLOOD CHEMISTRY:
4. Interstitium. In health, the renal cortical interstitium is i) Urea
scanty and consists of a small number of fibroblast-like cells. ii) Blood urea nitrogen (BUN)
But the medullary interstitium is more plentiful and contains iii) Creatinine
stellate interstitial cells which are considered to produce an iv) β 2 -microglobulin
anti-hypertensive agent and are involved in the metabolism 4. RENAL CLEARANCE TEST:
i)
Inulin or mannitol clearance test
of prostaglandins. ii) Creatinine clearance
iii) Urea clearance
RENAL FUNCTION TESTS iv) Para-aminohippuric acid (PAH) clearance
In general, the kidney performs the following vital functions
in the body: 1. URINE ANALYSIS. The simplest diagnostic tests for
1. Excretion of waste products resulting from protein renal function is the physical, chemical, bacteriologic and
metabolism. microscopic examination of the urine.
+
2. Regulation of acid-base balance by excretion of H ions i) The physical examination includes 24-hour urinary output,
(acidification) and bicarbonate ions. colour, specific gravity and osmolality. Normally urine is
3. Regulation of salt-water balance by hormones secreted both clear, pale or straw-coloured due to pigment urochrome and
700-2500 ml (average 1200 ml) of urine is passed in 24 hours,
intra- and extra-renally. mostly during day time. Specific gravity is used to measure
SECTION III
4. Formation of renin and erythropoietin and thereby playing the concentrating and diluting power of the kidneys.
a role in the regulation of blood pressure and erythropoiesis ii) The chemical tests are carried out to detect the presence of
respectively. protein, glucose, red cells and haemoglobin to assess the
In order to assess renal function, a number of tests have
been devised which give information regarding the following permeability of glomerular membrane. A number of
convenient dipstick tests are available for testing these
parameters: chemical substances and pH. These consist of paper strips
a) Renal blood flow impregnated with appropriate reagents and indicator dyes.
b) Glomerular filtration
c) Renal tubular function ii) The bacteriologic examination of the urine is done by proper
d) Urinary outflow unhindered by any obstruction. and aseptic collection of midstream specimen of urine.
iv) Urine microscopy is undertaken on a fresh unstained
Renal function tests are broadly divided into 4 groups sample. Various components observed on microscopic
Systemic Pathology
(Table 22.1): examination of the urine in renal disease are red cells, pus
1. Urine analysis. cells, epithelial cells, crystals and urinary casts. The casts are
2. Concentration and dilution tests. moulded into cylindrical shapes by passage along tubules
3. Blood chemistry. in which they are formed. They are the result of precipitation
4. Renal clearance tests. of proteins in the tubule that includes not only albumin but
In addition, renal biopsy is performed to confirm the also the tubular secretion of the Tamm Horsfall protein. The
diagnosis of renal disease. Renal biopsy is ideally fixed in latter is a high molecular weight glycoprotein normally
alcoholic Bouin’s solution and examined by routine morpho- secreted by ascending loop of Henle and DCT and probably
logy combined with special stains and further studies as has body defense function normally. Its secretion is increased
under: in glomerular and tubular diseases. Casts may be hyaline type
1. Periodic acid-Schiff stain for highlighting glomerular consisting of only proteins indicating a non-inflammatory
basement membrane. etiology of glomerular filtration of proteins, leucocyte casts
2. Silver impregnation to outline the glomerular and tubular inflammatory in origin, or red cell casts from haematuria.
basement membrane. 2. CONCENTRATION AND DILUTION TESTS. Concen-
3. Immunofluorescence to localise the antigens, complements tration and dilution tests are designed to evaluate functional
and immunoglobulins. capacity of the renal tubules. The ability of the nephron to
4. Electron microscopy to see the ultrastructure of glomerular concentrate or dilute urine is dependent upon both functional
changes. activity of the tubular cells in the renal medulla and the
presence of antidiuretic hormone (ADH). Failure to achieve maintain constant plasma concentration and accurately timed 653
adequate urinary concentration can be due to either defects urine samples are collected. Inulin, a mixture of fructose
within the renal medulla (nephrogenic diabetes insipidus), or polymers, is considered the ideal substance for the clearance
due to the lack of ADH (central diabetes insipidus). test since it is filtered from the glomerulus and is excreted
Traditionally, urinary concentration is determined by unchanged in the urine.
specific gravity of the urine (normal range 1.003 to 1.030, ii) In creatinine clearance test, there is no need of intra-
average 1.018) which in cases of tubular disease remains venous infusion of creatinine since creatinine is normally
constant at approximately 1.010 regardless of changing levels released into plasma by muscle metabolism and a very small
of plasma hydration. However, determination of urinary fraction of this substance is secreted by the tubules. The
specific gravity provides only a rough estimate of osmolarity clearance of creatinine is determined by collecting urine over
of the urine. The tubular disease can be diagnosed in its early 24-hour period and a blood sample is withdrawn during the
stage by water deprivation (concentration) or water excess day. In spite of disadvantages like poor reproducibility and
(dilution) tests. secretion of creatinine by the tubules, the ‘endogenous’
i) In concentration test, an artificial fluid deprivation is creatinine clearance test is easy and routinely employed
induced in the patient for more than 20 hours. If the nephron method of estimating GFR.
is normal, water is selectively reabsorbed resulting in iii) In urea clearance test, the sensitivity is much less than
excretion of urine of high solute concentration (specific the creatinine or inulin clearance because plasma
gravity of 1.025 or more). However, if the tubular cells are concentration of urea is affected by a number of factors (e.g.
nonfunctional, the solute concentration of the urine will dietary protein, fluid intake, infection, trauma, surgery, and
remain constant regardless of stress of water deprivation. corticosteroids) and is partly reabsorbed by the tubules. Like
ii) In dilution test, an excess of fluid is given to the patient. in creatinine clearance, there is no need for intravenous
Normally, renal compensation should result in excretion of infusion of urea.
urine with high water content and lower solute concentration iv) Para-aminohippuric acid (PAH) clearance test is
(specific gravity of 1.003 or less). If the renal tubules are employed to measure renal blood flow (unlike the preceding
diseased, the concentration of solutes in the urine will remain tests which measure GFR). PAH when infused intravenously
constant irrespective of the excess water intake. is both filtered at the glomerulus as well as secreted by the CHAPTER 22
3. BLOOD CHEMISTRY. Impairment of renal function tubules and its clearance is measured by determining its
results in elevation of end-products of protein metabolism. concentration in arterial blood and urine. Normally, renal
This includes increased accumulation of certain substances blood flow is about 1200 ml per minute in an average adult.
in the blood, chiefly urea (normal range 20-40 mg/dl), blood
urea nitrogen (BUN) (normal range 10-20 mg/dl) and PATHOPHYSIOLOGY OF RENAL DISEASE:
creatinine (normal range 0.6-1.2 mg/dl). An increase of these RENAL FAILURE
end-products in the blood is called azotaemia. Traditionally, diseases of the kidneys are divided into 4 major
High levels of creatinine are associated with high levels groups according to the predominant involvement of
of β2-microglobulin in the serum as well as urine, a low- corresponding morphologic components:
molecular weight protein filtered excessively in the urine due 1. Glomerular diseases: These are most often immuno-
to glomerular disease or due to increased production by the logically-mediated and may be acute or chronic.
liver.
2. Tubular diseases: These are more likely to be caused by
4. RENAL CLEARANCE TESTS. A clearance test is toxic or infectious agents and are often acute. The Kidney and Lower Urinary Tract
employed to assess the rate of glomerular filtration and the 3. Interstitial diseases: These are likewise commonly due to
renal blood flow. The rate of this filtration can be measured toxic or infectious agents and quite often involve interstitium
by determining the excretion rate of a substance which is as well as tubules (tubulo-interstitial diseases).
filtered through the glomerulus but subsequently is neither 4. Vascular diseases: These include changes in the nephron
reabsorbed nor secreted by the tubules. The glomerular as a consequence of increased intra-glomerular pressure such
filtration rate (normal 120 ml/minute in an average adult) is as in hypertension or impaired blood flow.
usually equal to clearance of that substance and is calculated In addition, other diseases described in this chapter
from the following equation:
include: congenital anomalies, obstructive uropathy
UV (including urolithiasis) and tumours of the kidneys.
C = _______ where The major morphologic involvements of the kidneys in
P the initial stage is confined to one component (glomeruli,
C is the clearance of the substance in ml/ minute; tubules, interstitium or blood vessels), but eventually all
U is the concentration of the substance in the urine; components are affected leading to end-stage kidneys.
V is the volume of urine passed per minute; and Regardless of cause, renal disease usually results in the
P is the concentration of the substance in the plasma. evolution of one of the two major pathological syndromes:
The substances which are used for clearance tests include acute renal failure and chronic renal failure. The term ‘azotaemia’
inulin, mannitol, creatinine and urea. is used for biochemical abnormality characterised by
i) In inulin or mannitol clearance tests, an intravenous elevation of the blood urea nitrogen (BUN) and creatinine
infusion of the substance inulin or mannitol is given to levels, while ‘uraemia’ is defined as association of these
654 biochemical abnormalities with clinical signs and symptoms. of less than 400 ml per day. The decline in formation of the
The pathophysiological aspects of acute and chronic renal urine leads to accumulation of waste products of protein
failure are briefly discussed below. metabolism in the blood and resultant azotaemia, metabolic
acidosis, hyperkalaemia, hypernatraemia and hypervolaemia
Acute Renal Failure (ARF) due to secondary effects of circulatory overload and
pulmonary oedema. The specific gravity of the urine is low
Acute renal failure (ARF) is a syndrome characterised by but the concentration of sodium in urine tends to be elevated.
rapid onset of renal dysfunction, chiefly oliguria or anuria,
and sudden increase in metabolic waste-products (urea and ii) Diuretic phase: With the onset of healing of tubules, there
creatinine) in the blood with consequent development of is improvement in urinary output. This is believed to occur
uraemia. due to drawing of water and sodium by preceding high levels
of creatinine and urea as they move through the nephron so
ETIOPATHOGENESIS. The causes of ARF may be classified as to be excreted. Since tubular cells have not regained normal
as pre-renal, intra-renal and post-renal in nature. functional capacity, the urine is of low or fixed specific
1. Pre-renal causes. Pre-renal diseases are those which cause gravity.
sudden decrease in blood flow to the nephron. Renal iii) Phase of recovery: Full recovery with healing of tubular
ischaemia ultimately results in functional disorders or epithelial cells occurs in about half the cases, while others
depression of GFR, or both. These causes include inadequate terminate in death. The process of healing may take up to
cardiac output and hypovolaemia or vascular disease causing one year with restoration of normal tubular function.
reduced perfusion of the kidneys. 3. Pre-renal syndrome. The ARF occurring secondary to
2. Intra-renal causes. Intra-renal disease is characterised by disorders in which neither the glomerulus nor the tubules
disease of renal tissue itself. These include vascular disease are damaged, results in pre-renal syndrome. Typically, this
of the arteries and arterioles within the kidney, diseases of pattern is seen in marginal ischaemia caused by renal arterial
glomeruli, acute tubular necrosis due to ischaemia, or the obstruction, hypovolaemia, hypotension or cardiac
effect of a nephrotoxin, acute tubulointerstitial nephritis and insufficiency. Due to depressed renal blood flow, there is
pyelonephritis. decrease in GFR causing oliguria, azotaemia (elevation of
3. Post-renal causes. Post-renal disease is characteristically BUN and creatinine) and possible fluid retention and
caused by obstruction to the flow of urine anywhere along oedema. Since the tubular cells are functioning normally, the
the renal tract distal to the opening of the collecting ducts. nephron retains its ability to concentrate the glomerular
SECTION III
This may be caused by a mass within the lumen or from wall filtrate according to the adaptive needs.
of the tract, or from external compression anywhere along
the lower urinary tract—ureter, bladder neck or urethra. Chronic Renal Failure (CRF)
It is important to note that ARF originating in pre- and Chronic renal failure is a syndrome characterised by
post-renal disease, such as by renal ischaemia or renal progressive and irreversible deterioration of renal function
infection, eventually leads to intra-renal disease. Thus, full- due to slow destruction of renal parenchyma, eventually
blown ARF reflects some degree of nephron damage.
terminating in death when sufficient number of nephrons
CLINICAL FEATURES. The clinical features will depend have been damaged. Acidosis is the major problem in CRF
to a large extent on the underlying cause of ARF and on the with development of biochemical azotaemia and clinical
stage of the disease at which the patient presents. However, uraemia syndrome.
one of the following three major patterns usually emerge:
Systemic Pathology
ETIOPATHOGENESIS. All chronic nephropathies can lead
1. Syndrome of acute nephritis. This is most frequently to CRF. The diseases leading to CRF can generally be
associated with acute post-streptococcal glomerulonephritis classified into two major groups: those causing glomerular
and rapidly progressive glomerulonephritis. Renal pathology, and those causing tubulointerstitial pathology. Though
dysfunction results from extensive proliferation of epithelial this classification is useful to facilitate study, the disease
cells in the glomeruli with consequent mild increase in rarely remains confined to either glomeruli or tubulo-
glomerular permeability and decrease in GFR. The interstitial tissue alone. In the final stage of CRF, all parts of
characteristic features are: mild proteinuria, haematuria, the nephron are involved.
oedema and mild hypertension. Fluid retention in acute 1. Diseases causing glomerular pathology. A number of
nephritis syndrome appears to be due to both diminished glomerular diseases associated with CRF have their patho-
GFR and increased salt and water reabsorption in distal genesis in immune mechanisms (page 662). Glomerular
nephron.
destruction results in changes in filtration process and leads
2. Syndrome accompanying tubular pathology. When the to development of the nephrotic syndrome characterised by
ARF is caused by destruction of the tubular cells of the proteinuria, hypoalbuminaemia and oedema. The important
nephron as occurs in acute tubular necrosis (page 679), the examples of chronic glomerular diseases causing CRF are
disease typically progresses through 3 characteristic stages covered under two headings: primary and systemic.
from oliguria to diuresis to recovery. i) Primary glomerular pathology: The major cause of CRF is
i) Oliguric phase: The initial oliguric phase lasting on an chronic glomerulonephritis, usually initiated by various
average from 7 to 10 days is characterised by urinary output types of glomerulonephritis such as membranous glomerulo-
nephritis, membranoproliferative glomerulonephritis, lipoid CLINICAL FEATURES. Clinical manifestations of full- 655
nephrosis (minimal change disease) and anti-glomerular blown CRF culminating in uraemic syndrome are described
basement membrane nephritis. under 2 main headings: primary (renal) uraemic manifes-
ii) Systemic glomerular pathology: Certain conditions originate tations and secondary (systemic or extra-renal) uraemic
outside the renal system but induce changes in the nephrons manifestations.
secondarily. Major examples of this type are systemic lupus A. Primary uraemic (renal) manifestations. Primary
erythematosus, serum sickness nephritis and diabetic symptoms of uraemia develop when there is slow and
nephropathy. progressive deterioration of renal function. The resulting
2. Diseases causing tubulointerstitial pathology. Damage imbalances cause the following manifestations:
to tubulointerstitial tissues results in alterations in 1. Metabolic acidosis. As a result of renal dysfunction, acid-
reabsorption and secretion of important constituents leading base balance is progressively lost. Excess of hydrogen ions
to excretion of large volumes of dilute urine. Tubulointer- occurs, while bicarbonate level declines in the blood, resulting
stitial diseases can be categorised according to initiating in metabolic acidosis. The clinical symptoms of metabolic
etiology into 4 groups: vascular, infectious, toxic and acidosis include: compensatory Kussmaul breathing,
obstructive. hyperkalaemia and hypercalcaemia.
i) Vascular causes: Long-standing primary or essential 2. Hyperkalaemia. A decreased GFR results in excessive
hypertension produces characteristic changes in renal arteries accumulation of potassium in the blood since potassium is
and arterioles referred to as nephrosclerosis (page 687). normally excreted mainly in the urine. Hyperkalaemia is
Nephrosclerosis causes progressive renal vascular occlusion further worsened by metabolic acidosis. The clinical features
terminating in ischaemia and necrosis of renal tissue. of hyperkalaemia are: cardiac arrhythmias, weakness,
ii) Infectious causes: A good example of chronic renal infec- nausea, intestinal colic, diarrhoea, muscular irritability and
tion causing CRF is chronic pyelonephritis. The chronicity flaccid paralysis.
of process results in progressive damage to increasing 3. Sodium and water imbalance. As GFR declines, sodium
number of nephrons leading to CRF. and water cannot pass sufficiently into Bowman’s capsule
iii) Toxic causes: Some toxic substances induce slow tubular leading to their retention. Release of renin from
injury, eventually culminating in CRF. The most common juxtaglomerular apparatus further aggravates sodium and CHAPTER 22
example is intake of high doses of analgesics such as water retention. The main symptoms referable to sodium and
phenacetin, aspirin and acetaminophen (chronic analgesic water retention are: hypervolaemia and circulatory overload
nephritis). Other substances that can cause CRF after with congestive heart failure.
prolonged exposure are lead, cadmium and uranium. 4. Hyperuricaemia. Decreased GFR results in excessive
iv) Obstructive causes: Chronic obstruction in the urinary tract accumulation of uric acid in the blood. Uric acid crystals may
leads to progressive damage to the nephron due to fluid back- be deposited in joints and soft tissues resulting in gout.
pressure. The examples of this type of chronic injury are 5. Azotaemia. The waste-products of protein metabolism
stones, blood clots, tumours, strictures and enlarged prostate. fail to be excreted resulting in elevation in the blood levels
Regardless of the initiating cause, CRF evolves of urea, creatinine, phenols and guanidines causing
progressively through 4 stages: biochemical abnormality, azotaemia. The secondary
1. Decreased renal reserve. At this stage, damage to renal manifestations of uraemia are related to toxic effects of these
parenchyma is marginal and the kidneys remain functional. metabolic waste-products.
The GFR is about 50% of normal, BUN and creatinine values B. Secondary uraemic (extra-renal) manifestations. A The Kidney and Lower Urinary Tract
are normal and the patients are usually asymptomatic except number of extra-renal systemic manifestations develop
at times of stress. secondarily following fluid-electrolyte and acid-base
2. Renal insufficiency. At this stage, about 75% of imbalances. These include the following:
functional renal parenchyma has been destroyed. The GFR 1. Anaemia. Decreased production of erythropoietin by
is about 25% of normal accompanied by elevation in BUN diseased kidney results in decline in erythropoiesis and
and serum creatinine. Polyuria and nocturia occur due to anaemia. Besides, gastrointestinal bleeding may further
tubulointerstitial damage. Sudden stress may precipitate aggravate anaemia.
uraemic syndrome. 2. Integumentary system. Deposit of urinary pigment such
3. Renal failure. At this stage, about 90% of functional renal as urochrome in the skin causes sallow-yellow colour. The
tissue has been destroyed. The GFR is approximately 10% of urea content in the sweat as well as in the plasma rises. On
normal. Tubular cells are essentially nonfunctional. As a evaporation of the perspiration, urea remains on the facial
result, the regulation of sodium and water is lost resulting skin as powdery ‘uraemic frost’.
in oedema, metabolic acidosis, hypocalcaemia, and signs and 3. Cardiovascular system. Fluid retention secondarily
symptoms of uraemia. causes cardiovascular symptoms such as increased workload
4. End-stage kidney. The GFR at this stage is less than 5% on the heart due to the hypervolaemia and eventually
of normal and results in complex clinical picture of uraemic congestive heart failure.
syndrome with progressive primary (renal) and secondary 4. Respiratory system. Hypervolaemia and heart failure
systemic (extra-renal) symptoms. cause pulmonary congestion and pulmonary oedema due
656 to back pressure. Radiologically, uraemic pneumonitis shows
characteristic central, butterfly-pattern of oedema and
congestion in the chest radiograph.
5. Digestive system. Azotaemia directly induces mucosal
ulcerations in the lining of the stomach and intestines.
Subsequent bleeding can aggravate the existing anaemia.
Gastrointestinal irritation may cause nausea, vomiting and
diarrhoea.
6. Skeletal system. The skeletal manifestations of renal
failure are referred to as renal osteodystrophy (Chapter 28).
Two major types of skeletal disorders may occur:
i) Osteomalacia occurs from deficiency of a form of vitamin
D which is normally activated by the kidney (page 248). Since
vitamin D is essential for absorption of calcium, its deficiency
results in inadequate deposits of calcium in bone tissue.
ii) Osteitis fibrosa occurs due to elevated levels of
parathormone. How parathormone excess develops in CRF
is complex. As the GFR is decreased, increasing levels of
phosphates accumulate in the extracellular fluid which, in
turn, cause decline in calcium levels. Decreased calcium level
triggers the secretion of parathormone which mobilises
calcium from bone and increases renal tubular reabsorption
of calcium thereby conserving it. However, if the process of
resorption of calcium phosphate from bone continues for
sufficient time, hypercalcaemia may be induced with
deposits of excess calcium salts in joints and soft tissues and
weakening of bones (renal osteodystrophy).
SECTION III
CONGENITAL MALFORMATIONS
Approximately 10% of all persons are born with potentially Figure 22.6 Cystic diseases of kidney.
significant malformations of the urinary system. These range
in severity from minor anomalies which may not produce to accompanied pulmonary hypoplasia), haemorrhage, and
clinical manifestations to major anomalies which are neoplastic transformation.
incompatible with extrauterine life. About half of all patients Potter divided developmental renal cystic lesions into
with malformations of the kidneys have coexistent anomalies three types—I, II and III. A simple classification including
either elsewhere in the urinary tract or in other organs. all cystic lesions of the kidney is given in Table 22.2 and
Malformations of the kidneys are classified into 3 broad Fig. 22.6. Non-neoplastic lesions are discussed below while
groups:
I. Abnormalities in amount of renal tissue. These include: TABLE 22.2: Classification of Cystic Lesions of the Kidney.
Systemic Pathology
anomalies with deficient renal parenchyma (e.g. unilateral
or bilateral renal hypoplasia) or with excess renal tissue (e.g. A. NON-NEOPLASTIC CYSTIC LESIONS
renomegaly, supernumerary kidneys). I. Renal multicystic dysplasia (Potter type II)
II. Anomalies of position, form and orientation. These are: II. Polycystic kidney disease (PKD)
renal ectopia (pelvic kidney), renal fusion (horseshoe kidney) 1. Adult (autosomal dominant) polycystic kidney disease
(ADPKD) (Potter type III)
and persistent foetal lobation. 2. Infantile (autosomal recessive) polycystic kidney disease
III. Anomalies of differentiation. This group consists of the (ARPKD) (Potter type I)
more important and common morphologic forms covered III. Medullary cystic disease
under the heading of ‘cystic diseases of the kidney’ described 1. Medullary sponge kidney (MSK)
in detail below. 2. Nephronophthiasis-medullary cystic disease complex
IV. Simple renal cysts
CYSTIC DISEASES OF KIDNEY V. Acquired renal cysts
Cystic lesions of the kidney may be congenital or acquired, VI. Para-renal cysts
non-neoplastic or neoplastic. Majority of these lesions are B. NEOPLASTIC CYSTIC LESIONS
congenital non-neoplastic. Cystic lesions in the kidney may I. Cystic nephroma (page 694)
occur at any age, extending from foetal life (detected on II. Cystic partially-differentiated nephroblastoma (CPDN)
ultrasonography) to old age. Their clinical presentation may
include: abdominal mass, infection, respiratory distress (due III. Multifocal cystic change in Wilms’ tumour (page 696)
neoplastic cystic lesions of the kidney are described later 657
(page 694).
I. Multicystic Renal Dysplasia
The term ‘multicystic renal dysplasia’ or Potter type II is used
for disorganised metanephrogenic differentiation with
persistence of structures in the kidney which are not
represented in normal nephrogenesis. Renal dysplasia is the
most common form of cystic renal disease in the newborn
and infants. The condition may occur sporadically or maybe
familial and part of a syndrome of other anomalies. It is
commonly associated with obstructive abnormalities of the
ureter and lower urinary tract such as obstruction of
pelviureteric junction (PUJ), ureteral atresia and urethral
obstruction.
MORPHOLOGIC FEATURES. Renal dysplasia may be
unilateral or bilateral. The dysplastic process may involve
the entire renal mass or a part of it.
Grossly, the dysplastic kidney is almost always cystic. The Figure 22.7 Renal cystic dysplasia. There are cysts lined by flattened
kidney or its affected part is replaced by disorderly mass epithelium while the intervening parenchyma consists of primitive
of multiple cysts resembling a bunch of grapes. Normal connective tissue and cartilage.
renal parenchyma is almost totally obscured by the mass
while calyces and pelvis may not be recognised. The ureter autosomal dominant with mutation in PKD gene: mutation in
is invariably abnormal, being either absent or atretic. PKD-1 gene located on chromosome 16 in over 85% cases
Histologically, the characteristic feature is the presence (ADPKD-1) while remainder 15% cases have mutation in CHAPTER 22
of undifferentiated mesenchyme that contains smooth PKD-2 gene located on chromosome 4 (ADPKD-2). Family
muscle, cartilage and immature collecting ducts. The cysts history of similar renal disease may be present. The true adult
in the mass represent dilated tubules lined by flattened polycystic renal disease is always bilateral and diffuse.
epithelium which are surrounded by concentric layers of Though the kidneys are abnormal at birth, renal function is
connective tissue (Fig. 22.7). Glomeruli and tubules are retained, and symptoms appear in adult life, mostly between
scanty, primitive or absent. the age of 30 and 50 years.
CLINICAL FEATURES. Unilateral renal dysplasia is
frequently discovered in newborn or infants as a flank mass. MORPHOLOGIC FEATURES. Grossly, kidneys in
Often, renal dysplasia is associated with other congenital ADPKD are always bilaterally enlarged, usually symme-
malformations and syndromes such as ventricular septal trically, heavy (weighing up to 4 kg) and give it a lobulated
defect, tracheo-esophageal fistula, lumbosacral appearance on external surface due to underlying cysts .
meningomyelocele and Down’s syndrome. The cut surface shows cysts throughout the renal The Kidney and Lower Urinary Tract
The prognosis of unilateral renal dysplasia following parenchyma varying in size from tiny cysts to 4-5 cm in
removal of the abnormal kidney is excellent while bilateral diameter (Fig. 22.8,A). The contents of the cysts vary from
renal dysplasia results in death in infancy unless renal clear straw-yellow fluid to reddish-brown material. The
transplant is done. renal pelvis and calyces are present but are greatly
distorted by the cysts and may contain concretions
II. Polycystic Kidney Disease (Fig. 22.9). The cysts, however, do not communicate with
Polycystic disease of the kidney (PKD) is a disorder in which the pelvis of the kidney—a feature that helps to distinguish
major portion of the renal parenchyma is converted into cysts polycystic kidney from hydronephrosis of the kidney on
of varying size. The disease occurs in two forms: sectioned surface (page 692).
A. An adult type inherited as an autosomal dominant disease; Histologically, the cysts arise from all parts of nephron.
and It is possible to find some cysts containing recognisable
glomerular tufts reflecting their origin from Bowman’s
B. An infantile type inherited as an autosomal recessive
disorder. capsule, while others have epithelial lining like that of
distal or proximal tubules or collecting ducts. The
A. ADULT POLYCYSTIC KIDNEY DISEASE intervening tissue between the cysts shows some normal
renal parenchyma. With advancement of age of the
Adult (autosomal dominant) polycystic kidney disease patient, acquired lesions such as pyelonephritis,
(ADPKD) is relatively common (incidence 1:400 to 1: 1:1000) nephrosclerosis, fibrosis and chronic inflammation are
and is the cause of end-stage renal failure in approximately seen with increasingly frequency.
4% of haemodialysis patients. The pattern of inheritance is
658 berry aneurysms of the circle of Willis. Any acquired renal
disease is more prone to occur in polycystic kidneys.
B. INFANTILE POLYCYSTIC KIDNEY DISEASE
The infantile (autosomal recessive) form of polycystic kidney
disease (ARPKD) is distinct from the adult form and is less
common (incidence 1:20,000 births). It is transmitted as an
autosomal recessive trait and the family history of similar
disease is usually not present. The condition occurs due to a
mutation in chromosome 6—6p21, PKHD1 (polycystic kidney
and hepatic disease 1). It is invariably bilateral. The age at
presentation may be perinatal, neonatal, infantile or juvenile,
but frequently serious manifestations are present at birth and
result in death from renal failure in early childhood.
MORPHOLOGIC FEATURES. Grossly, the kidneys are
bilaterally enlarged with smooth external surface and
Figure 22.8 Polycystic kidney disease. Diagrammatic representation retained normal reniform shape. Cut surface reveals small,
of comparison of gross appearance of the two main forms.
fusiform or cylindrical cysts radiating from the medulla
and extend radially to the outer cortex. This gives the
CLINICAL FEATURES. The condition may become sectioned surface of the kidney sponge-like appearance
clinically apparent at any age but most commonly manifests (Fig. 22.8,B). No normal renal parenchyma is grossly
in 3rd to 5th decades of life. The most frequent and earliest recognised. Pelvis, calyces and ureters are normal.
presenting feature is a dull-ache in the lumbar regions. In Histologically, the total number of nephrons is normal.
others, the presenting complaints are haematuria or passage Since the cysts are formed from dilatation of collecting
of blood clots in urine, renal colic, hypertension, urinary tract tubules, all the collecting tubules show cylindrical or
infections and progressive CRF with polyuria and saccular dilatations and are lined by cuboidal to low
proteinuria. columnar epithelium. Many of the glomeruli are also
ADPKD is considered a systemic disease. About a third cystically dilated.
SECTION III
of patients with ADPKD have cysts of the liver (Chapter 21).
Other associated congenital anomalies seen less frequently
are cysts in the pancreas, spleen, lungs and other organs. CLINICAL FEATURES. The clinical manifestations depend
Approximately 15% of patients have one or more intracranial on age of the child. In severe form, the gross bilateral cystic
renal enlargement may interfere with delivery. In infancy,
renal failure may manifest early. Almost all cases of infantile
polycystic kidney disease have associated multiple
epithelium-lined cysts in the liver or proliferation of portal
bile ductules. In older children, associated hepatic changes
evelop into what is termed congenital hepatic fibrosis which
may lead to portal hypertension and splenomegaly.
Systemic Pathology
The contrasting features of the two main forms of the
polycystic kidney disease are presented in Table 22.3.
III. Medullary Cystic Disease
Cystic disease of the renal medulla has two main types:
A. Medullary sponge kidney, a relatively common and
innocuous condition; and
B. Nephronophthiasis-medullary cystic disease complex, a
common cause of chronic renal failure in juvenile age group.
A. MEDULLARY SPONGE KIDNEY
Medullary sponge kidney consists of multiple cystic
Figure 22.9 Adult (autosomal dominant) polycystic kidney disease dilatations of the papillary ducts in the medulla. It has an
(ADPKD). The kidney is enlarged and heavy. Sectioned surface shows autosomal dominant transmission. The condition occurs in
loss of demarcation between cortex and medulla and replacement of the adults and may be recognised as an incidental radiographic
entire renal parenchyma by cyst s varying in diameter from a few finding in asymptomatic cases, or the patients may complain
millimeters to 4-5 cm. These cysts are not communicating with the pelvi-
calyceal system. The renal pelvis and calyces are distorted due to cystic of colicky flank pain, dysuria, haematuria and passage of
change. sandy material in the urine. Renal function remains largely
TABLE 22.3. Contrasting Features of Autosomal Dominant (Adult) and Autosomal Recessive (Infantile) Polycystic Kidney Disease 659
(ADPKD versus ARPKD).
Feature ADPKD ARPKD
1. Inheritance Autosomal dominant Autosomal recessive
2. Cytogenetic defect Chromosome 16 (85%): ADPKD-1 Chromosome 6
Chromosome 4 (15%): ADPKD-2
3. Mutations PKD 1 gene (85%) 6p21 PKHD1
PKD 2 gene (15%)
4. Incidence 1:400 to 1:1000 1:20,000
5. Age at presentation Adults (3rd to 5th decades) Infancy, perinatal
6. G/A Symmetric bilateral enlargement Micro- and macrocysts radiating from medulla to
outer cortex
7. M/E Macrocysts Enlarged, sometimes asymmetric, sponge-like
Cysts derived from all parts of nephron Cysts from dilated collecting ducts
(glomeruli, tubules)
8. Other manifestations Intracranial aneurysms, cysts of other organs None
normal or may be mildly impaired in long-standing disease IV. Simple Renal Cysts
with secondary complications of infection and calculus Simple renal cysts are a very common postmortem finding.
formation. They are seen in about half of all persons above the age of 50
MORPHOLOGIC FEATURES. Grossly, the kidneys may years. Since these cysts are rare in infants and children, they
be enlarged, normal or shrunken in size depending upon appear to be acquired rather than congenital lesions. Simple
the extent of secondary pyelonephritis. On cut surface, cysts of the kidneys are rarely responsible for symptoms.
the characteristic feature is the presence of several, small However, symptoms may result from rupture, haemorrhage CHAPTER 22
(less than 0.5 cm diameter), cystically dilated papillary or infection. The association between simple cysts and
ducts, which may contain spherical calculi. hypertension is common.
Microscopically, the cysts are lined by tall columnar, MORPHOLOGIC FEATURES. Grossly, simple renal
cuboidal, transitional or squamous epithelium. Renal cysts are usually solitary but may be multiple. They are
cortex may show secondary pyelonephritis but cortical commonly located in the cortex. Their size varies from a
cysts are never a component of medullary sponge kidney. few millimeters to 10 cm in diameter. The wall of cyst is
characteristically yellowish-white and translucent. The
B. NEPHRONOPHTHIASIS-MEDULLARY cyst usually contains clear straw-coloured fluid which may
CYSTIC DISEASE COMPLEX
become rust-coloured due to haemorrhage.
This form of medullary cystic disease, also called juvenile Microscopically, the lining of the cyst is by flattened
nephronophthiasis or uraemic sponge kidney, is a progressive epithelium. The cyst wall contains variable amount of
renal disease. It is classified into infantile, juvenile and collagenised fibrous tissue which may occasionally have
adolescent type depending upon the age at presentation, deposits of haemosiderin or calcium salts. The Kidney and Lower Urinary Tract
juvenile form being the most common. It is the most common
form of genetic cause of end-stage renal disease in children V. Acquired Renal Cysts
and adolescents. The condition has an autosomal recessive A number of acquired conditions give rise to renal cysts.
inheritance. Familial occurrence is common. The clinical These include the following:
manifestations are due to impaired urinary concentration 1. Patients with end-stage renal disease on prolonged
consequent upon the medullary lesions and consist of poly- dialysis (dialysis-associated cystic disease).
uria, polydipsia and enuresis. Other features include renal
osteodystrophy, growth retardation, anaemia and 2. Hydatid (echinococcal) cyst.
progressive renal failure leading to uraemia. 3. Tuberculosis of the kidney.
4. Cystic degeneration in carcinoma of kidney.
MORPHOLOGIC FEATURES. Grossly, the kidneys are 5. Traumatic intrarenal haematoma.
moderately reduced in size and granular and have narrow 6. Drug-induced cystic disease in experimental animals.
cortices. Cut surface reveals minute cysts, majority of
which are present at the cortico-medullary junction. VI. Pararenal Cysts
Microscopically, the cysts are lined by flattened or Cysts occurring adjacent to a kidney are termed pararenal
cuboidal epithelium. There is widespread nonspecific cysts. These include the following:
chronic inflammatory infiltrate and interstitial fibrosis. 1. Pyelocalyceal cysts
Many glomeruli are hyalinised but tubular atrophy is 2. Hilar lymphangiectatic cysts
more pronounced due to marked thickening of tubular 3. Retroperitoneal cysts
basement membrane. 4. Perinephric pseudocysts from trauma.
660 GLOMERULAR DISEASES underlying condition. A firm diagnosis, however, can be
established by examination of renal biopsy under light,
DEFINITION AND CLASSIFICATION electron and immunofluorescence microscopy.
Glomerular diseases encompass a large and clinically A number of clinical syndromes are recognised in
significant group of renal diseases. Glomerulonephritis (GN) glomerular diseases. The following are six major glomerular
or Bright’s disease is the term used for diseases that primarily syndromes commonly found in different glomerular diseases:
involve the renal glomeruli. It is convenient to classify nephritic and nephrotic syndromes;
glomerular diseases into 2 broad groups: acute and chronic renal failure;
I. Primary glomerulonephritis in which the glomeruli are the asymptomatic proteinuria and haematuria.
predominant site of involvement. These are briefly described below.
II. Secondary glomerular diseases include certain systemic and I. ACUTE NEPHRITIC SYNDROME. This is the acute
hereditary diseases which secondarily affect the glomeruli. onset of haematuria, proteinuria, hypertension, oedema and
Though this division is widely followed, it is somewhat
arbitrary since many primary forms of glomerulonephritis oliguria following an infective illness about 10 to 20 days
have systemic effects, and many systemic diseases may earlier.
initially present with glomerular involvement. Many 1. The haematuria is generally slight giving the urine smoky
classifications of different types of glomerulonephiritis have appearance and erythrocytes are detectable by microscopy
been described, but most widely accepted classification is or by chemical testing for haemoglobin. Appearance of red
based on clinical presentation and pathologic changes in the cell casts is another classical feature of acute nephritic
glomeruli given in Table 22.4. syndrome.
2. The proteinuria is mild (less than 3 gm per 24 hrs) and is
CLINICAL MANIFESTATIONS usually non-selective (nephritic range proteinuria).
3. Hypertension is variable depending upon the severity
The clinical presentation of glomerular disease is quite
variable but in general four features—proteinuria, haema- of the glomerular disease but is generally mild.
turia, hypertension and disturbed excretory function, are 4. Oedema in nephritic syndrome is usually mild and
present in varying combinations depending upon the results from sodium and water retention (page 97).
5. Oliguria is variable and reflects the severity of glomerular
SECTION III
involvement.
TABLE 22.4: Clinicopathologic Classification of Glomerular The underlying causes of acute nephritic syndrome may
Diseases.
be primary glomerulonephritic diseases (classically acute
I. PRIMARY GLOMERULONEPHRITIS glomerulonephritis and rapidly progressive glomerulo-
1. Acute GN nephritis) or certain systemic diseases (Table 22.5).
i) Post-streptococcal
ii) Non-streptococcal II. NEPHROTIC SYNDROME Nephrotic syndrome is a
2. Rapidly progressive GN constellation of features in different diseases having varying
3. Minimal change disease pathogenesis; it is characterised by findings of massive
4. Membranous GN proteinuria, hypoalbuminaemia, oedema, hyperlipidaemia,
5. Membrano-proliferative GN
6. Focal proliferative GN lipiduria, and hypercoagulability.
7. Focal segmental glomerulosclerosis (FSGS) 1. Heavy proteinuria (protein loss of more than 3 gm per
Systemic Pathology
8. IgA nephropathy 24 hrs) is the chief characteristic of nephrotic syndrome
9. Chronic glomerulonephritis
(nephrotic range proteinuria). In children, protein loss is
II. SECONDARY SYSTEMIC GLOMERULAR DISEASES correspondingly less. A small amount of protein (20 to 150
1. Lupus nephritis (SLE) mg/day) normally passes through the glomerular filtration
2. Diabetic nephropathy barrier and is reabsorbed by the tubules. But in case of
3. Amyloidosis (page 82) increased glomerular permeability to plasma proteins, excess
4. Polyarteritis nodosa (page 402) of protein is filtered out exceeding the capacity of tubules
5. Wegener’s granulomatosis (page 403) for reabsorption and, therefore, appears in the urine. Another
6. Goodpasture’s syndrome (page 494)
7. Henoch-Schönlein purpura (page 331) feature of protein loss is its ‘selectivity’. A highly-selective
8. Systemic infectious diseases (bacterial e.g. bacterial endocarditis, proteinuria consists mostly of loss of low molecular weight
syphilis, leprosy; viral e.g. HBV, HCV, HIV; parasitic e.g. proteins, while a poorly-selective proteinuria is loss of high
falciparum malaria, filariasis) molecular weight proteins in the urine. In nephrotic
9. Idiopathic mixed cryoglobulinaemia
syndrome, proteinuria mostly consists of loss of albumin
III. HEREDITARY NEPHRITIS (molecular weight 66,000) in the urine.
1. Alport’s syndrome 2. Hypoalbuminaemia is produced primarily consequent
2. Fabry’s disease to urinary loss of albumin, and partly due to increased renal
3. Nail-patella syndrome
catabolism and inadequate hepatic synthesis of albumin.
III.ACUTE RENAL FAILURE. As already described above, 661
TABLE 22.5: Causes of Acute Nephritic Syndrome.
acute renal failure (ARF) is characterised by rapid decline in
I. PRIMARY GLOMERULONEPHRITIS renal function. ARF has many causes including glomerular
1. Acute GN disease, principally rapidly progressive GN and acute diffuse
i) Post-streptococcal proliferative GN.
ii) Non-streptococcal
2. Rapidly progressive GN IV.CHRONIC RENAL FAILURE. Glomerular causes of
3. Membranoproliferative GN chronic renal failure (CRF) have already been described.
4. Focal GN
5. IgA nephropathy These cases have advanced renal impairment progressing
over years and is detected by significant proteinuria,
II. SYSTEMIC DISEASES haematuria, hypertension and azotaemia. Such patients
1. SLE generally have small contracted kidneys due to chronic
2. Polyarteritis nodosa glomerulonephritis.
3. Wegener’s granulomatosis
4. Henoch-Schonlein purpura V. ASYMPTOMATIC PROTEINURIA. Presence of
5. Cryoglobulinaemia
proteinuria unexpectedly in a patient may be unrelated to
renal disease (e.g. exercise-induced, extreme lordosis and
Often, the plasma albumin level is 1 to 3 gm/dl (normal 3.5 orthostatic proteinuria), or may indicate an underlying mild
to 5.5 gm/dl) and there is reversed albumin-globulin ratio. glomerulonephritis. Association of asymptomatic
The concentration of other proteins in the plasma such as haematuria, hypertension or impaired renal function with
immunoglobulins, clotting factors and antithrombin may fall asymptomatic proteinuria should raise strong suspicion of
rendering these patients more vulnerable to infections and underlying glomerulonephritis.
thrombotic and thromboembolic complications.
VI. ASYMPTOMATIC HAEMATURIA. Asymptomatic
3. Oedema in nephrotic syndrome appears due to fall in microscopic haematuria is common in children and young
colloid osmotic pressure consequent upon hypo-
albuminaemia. Sodium and water retention further TABLE 22.6: Causes of Nephrotic Syndrome.
contribute to oedema. Nephrotic oedema is usually CHAPTER 22
peripheral but in children facial oedema may be more I. PRIMARY GLOMERULONEPHRITIS
prominent (page 99). 1. Minimal change disease (most common in children)
2.
Membranous GN (most common in adults)
4. Hyperlipidaemia is a frequent accompaniment of 3. Membranoproliferative GN
nephrotic syndrome. The exact mechanism of its genesis is 4. Focal segmental glomerulosclerosis
not clear. It is hypothesised that the liver faced with the stress 5. Focal GN
of massive protein synthesis in response to heavy urinary 6. IgA nephropathy
protein loss, also causes increased synthesis of lipoproteins. II. SYSTEMIC DISEASES
There are increased blood levels of total lipids, cholesterol, 1. Diabetes mellitus
triglycerides, VLDL and LDL but decrease in HDL. Low 2. Amyloidosis
blood level of HDL is partly due to its loss in the urine. 3. SLE
5. Lipiduria occurs following hyperlipidaemia due to III. SYSTEMIC INFECTIONS
excessive leakiness of glomerular filtration barrier. 1. Viral infections (HBV, HCV, HIV)
2. Bacterial infections (bacterial endocarditis, syphilis, leprosy) The Kidney and Lower Urinary Tract
6. Hypercoagulability. Patients with nephrotic syndrome 3. Protozoa and parasites (P. falciparum malaria, filariasis)
may develop spontaneous arterial or venous thrombosis,
renal vein thrombosis and pulmonary embolism due to IV. HYPERSENSITIVITY REACTIONS
various factors. These include: increased urinary loss of 1. Drugs (heavy metal compounds like gold and mercury, other
drugs like penicillamine, trimethadione and tolbutamide,
antithrombin III, hyperfibrinogenaemia from increased heroin addiction)
synthesis in the liver, decreased fibrinolysis, increased 2. Bee stings, snake bite, poison ivy
platelet aggregation and altered levels of protein C and S. V. MALIGNANCY
The causes of nephrotic syndrome are diverse and are 1. Carcinomas
listed in Table 22.6. The morphology of individual types is 2. Myeloma
described later. But it must be mentioned here that: 3. Hodgkin’s disease
in children, primary glomerulonephritis is the cause in VI. PREGNANCY
majority of cases of the nephrotic syndrome; most frequent Toxaemia of pregnancy
is lipoid nephrosis (65%); and VII. CIRCULATORY DISTURBANCES
in adults, on the other hand, systemic diseases (diabetes, 1. Renal vein thrombosis
amyloidosis and SLE) are more frequent causes of nephrotic 2. Constrictive pericarditis
syndrome. The most common primary glomerular disease VIII. HEREDITARY DISEASES
in adults is membranous glomerulonephritis (40%). 1. Alport’s disease
Features of nephritic and nephroic syndromes have been 2. Fabry’s disease
contrasted in Table 22.7. 3. Nail-patella syndrome
662
TABLE 22.7: Contrasting Features of Acute Nephritic and Nephrotic Syndromes.
Feature Acute Nephritic Syndrome Nephrotic Syndrome
1. Proteinuria Mild (< 3 gm per 24 hrs) Heavy (> 3 gm per 24 hrs)
2. Hypoalbuminaemia Uncommon Present
3. Oedema Mild, in loose tissue Marked, generalised peripheral
+
+
4. Mechanism of Oedema Na and water retention ↓ ↓ ↓ ↓ ↓ plasma osmotic pressure, Na and
water retention
5. Haematuria Present, microscopic Absent
6. Hypertension Present Present in advanced disease
7. Hyperlipidaemia Absent Present
8. Lipiduria Absent Present
9. Oliguria Present Present in advanced disease
10. Hypercoagulability Absent Present
adolescents and has many diverse causes such as diseases sis of some forms of glomerular diseases in human beings
of the glomerulus, renal interstitium, calyceal system, ureter, (Table 22.9).
bladder, prostate, urethra, and underlying bleeding disorder,
congenital abnormalities of the kidneys or neoplasia. I. IMMUNOLOGIC MECHANISMS
Glomerular haematuria is indicated by the presence of red Experimental studies and observations in humans have
blood cells, red cell casts and haemoglobin in the urine. revealed that immunologic mechanisms, most importantly
Glomerular haematuria is frequently associated with antigen-antibody complexes, underlie most forms of
asymptomatic proteinuria.
glomerular injury. The general principles of these
mechanisms in different forms of glomerular diseases are
PATHOGENESIS OF GLOMERULAR INJURY
discussed below, while specific features pertaining to
Most forms of primary GN and many of the secondary individual types of GN are described separately later.
glomerular diseases in human beings have immunologic
SECTION III
pathogenesis. This view is largely based on immuno- A. Antibody-Mediated Glomerular Injury
fluorescence studies of GN in humans which have revealed
glomerular deposits of immunoglobulins and complement 1. IMMUNE COMPLEX DISEASE. Majority of cases of
in patterns that closely resemble those of experimental glomerular disease result from deposits of immune
models. The consequences of injury at different sites within complexes (antigen-antibody complexes). The immune
the glomerulus in various glomerular diseases can be complexes are represented by irregular or granular glomer-
assessed when compared with the normal physiologic role ular deposits of immunoglobulins (IgG, IgM and IgA) and
of the main cells involved i.e. endothelial, mesangial, visceral complement (mainly C3). Based on the experimental models
epithelial, and parietal epithelial cells as well as of the GBM as and studies in human beings, the following 3 patterns of
summed up in Table 22.8. glomerular deposits of immune complexes in various
Immunologic mechanisms underlying glomerular glomerular diseases have been observed as illustrated in
Systemic Pathology
injury are primarily antibody-mediated (immune-complex Fig. 22.10:
disease). There is evidence to suggest that cell-mediated i) Exclusive mesangial deposits are characterised by very mild
immune reactions in the form of delayed type hypersensiti- form of glomerular disease.
vity can also cause glomerular injury in some situations. ii) Extensive subendothelial deposits along the GBM are
In addition, a few secondary mechanisms and some non- accompanied by severe hypercellular sclerosing glomerular
immunologic mechanisms are involved in the pathogene- lesions.
TABLE 22.8: Relationship of Physiologic Role of Glomerular Components with Consequences in Glomerular Injury.
Component Physiologic Function Consequence of Injury Related Glomerular Disease
1. Endothelial cells i) Maintain glomerular perfusion Vasoconstriction Acute renal failure
ii) Prevent leucocyte adhesion Leucocyte infiltration Focal/diffuse proliferative GN
iii) Prevent platelet aggregation Intravascular microthrombi Thrombotic microangiopathies
2. Mesangial cells Control glomerular filtration Proliferation and increased matrix Membranoproliferative GN
3. Visceral epithelial cells Prevent plasma protein filtration Proteinuria Minimal change disease, FSGS
4. GBM Prevents plasma protein filtration Proteinuria Membranous GN, ? MPGN
5. Parietal epithelial cells Maintain Bowman’s space Crescent formation RPGN
663
Figure 22.10 Diagrammatic representation of ultrastructure of a portion of glomerular lobule. It shows three patterns of irregular or granu lar
glomerular deposits in immune-complex disease.
iii) Subepithelial deposits are seen between the outer surface result of combination of antibodies with autologous non-
of the GBM and the podocytes. basement membrane antigens or nonglomerular antigens CHAPTER 22
Deposits may be located at one or more of the above sites planted on glomeruli. Currently, this mechanism is
in any case of glomerular injury. considered responsible for most cases of immune complex
It was widely believed earlier that glomerular deposits GN. Classic experimental model of in situ immune complex
result from circulating immune complexes. Now, it has been GN is Heymann nephritis (autologous immune complex
shown that glomerular deposits are formed by one of the nephritis) induced in rats by immunising animals with
following two mechanisms: homologous preparations of proximal tubular brush border.
i) Local immune complex deposits. Formation of The rats develop antibodies to brush border antigens and
glomerular deposits of immune complex in situ occurs as a thereby membranous GN that closely resembles human
TABLE 22.9: Pathogenetic Mechanisms in Glomerular Diseases.
Mechanism Related Glomerular Disease
I. IMMUNOLOGIC MECHANISMS The Kidney and Lower Urinary Tract
A. Antibody-mediated glomerular injury
1. Immune-complex disease Immune-complex mediated GN (Acute diffuse proliferative GN,
membranous GN, membranoproliferative GN, IgA nephropathy;
secondary glomerular disease in SLE, malaria etc.)
2. Anti-glomerular basement membrane (Anti-GBM) disease Goodpasture's disease
3. Alternate pathway disease Membranoproliferative GN type II
4. Other mechanisms (anti-neutrophil cytoplasmic antibodies— Vasculitis
ANCA, anti-endothelial cell antibodies—AECA)
B. Cell-mediated glomerular injury Pauci-immune GN (type III RPGN)
C. Secondary pathogenetic mechanisms Mediate glomerular injury in various primary and
secondary glomerular diseases
II. NON-IMMUNOLOGIC MECHANISMS
1. Metabolic Diabetic nephropathy, Fabry's disease
2. Haemodynamic Hypertensive nephrosclerosis, FSGS
3. Deposition Amyloid nephropathy
4. Infectious HIV-nephropathy, immune-complex GN in SABE
5. Drugs NSAIDs-associated minimal change disease
6. Inherited Alport's syndrome, nail-patella syndrome
664 membranous GN. The examples of planted non-glomerular deposits, reflecting activation of alternate pathway of
antigens are cationic proteins, lectins, DNA, bacterial products complement. Such patients have circulating anti-comple-
(e.g. a protein of group A streptococci), viral and parasitic mentary nephritic factor (C3NeF) which is an IgG antibody
products and drugs. and acts as an autoantibody to the alternate C3 convertase,
ii) Circulating immune complex deposits. This mechanism leading to persistent alternate pathway activation.
used to be considered very important for glomerular injury The deposits in alternate pathway disease are charac-
but now it is believed that circulating immune complexes teristically electron-dense under electron microscopy;
cause glomerular damage under certain circumstances only. glomerular lesions in such cases are referred to as dense-
These situations are: their presence in high concentrations deposit disease.
for prolonged periods, or when they possess special Alternate pathway disease occurs in most cases of type
properties that cause their binding to glomeruli, or when host II membranoproliferative GN, some patients of rapidly
mechanisms are defective and fail to eliminate immune progressive GN, acute diffuse proliferative GN, IgA
complexes. The antigens evoking antibody response may be nephropathy and in SLE.
endogenous (e.g. in SLE) or may be exogenous (e.g. Hepatitis 4. OTHER MECHANISMS OF ANTIBODY-MEDIATED
B virus, Treponema pallidum, Plasmodium falciparum and INJURY. A few autoantibodies have been implicated in some
various tumour antigens). The antigen-antibody complexes patients of focal segmental glomerulosclerosis and few other
are formed in the circulation and then trapped in the types of GN. These antibodies include the following:
glomeruli where they produce glomerular injury after i) Anti-neutrophil cytoplasmic antibodies (ANCA). About
combining with complement. 40% cases of rapidly progressive GN are deficient in
Immune complex GN is observed in the following human
diseases: immunoglobulins in glomeruli (pauciimmune GN) and are
positive for ANCA against neutrophil cytoplasmic antigens
i) Primary GN e.g. acute diffuse proliferative GN, memb- in their circulation. ANCA causes endothelial injury by
ranous GN, membranoproliferative GN, IgA nephropathy generation of reactive oxygen radicals. ANCA-mediated
and some cases of rapidly progressive GN and focal GN. vasculitis is also seen in Wegenger’s granulomatosis and
ii) Systemic diseases e.g. glomerular disease in SLE, malaria, Churg-Strauss syndrome.
syphilis, hepatitis, Henoch-Schonlein purpura and idiopathic
mixed cryoglobulinaemia. ii) Anti-endothelial cell antibodies (AECA). Auto-
antibodies against endothelial antigens have been detected
2. ANTI-GBM DISEASE. Less than 5% cases of human GN in circulation in several inflammatory vasculitis and
SECTION III
are associated with anti-GBM antibodies. The constituent of glomerulonephritis. These antibodies increase the
GBM acting as antigen appears to be a component of collagen adhesiveness of leucocytes to endothelial cells.
IV of the basement membrane. The experimental model of
anti-GBM disease is Masugi nephritis (nephrotoxic serum B. Cell-mediated Glomerular Injury
nephritis) produced in rats by injection of heterologous (Delayed-type Hypersensitivity)
antibodies against GBM prepared in rabbits by immunisation
with rat kidney glomerular tissue. There is evidence to suggest that cell-mediated immune
Anti-GBM disease is classically characterised by reactions may be involved in causing glomerular injury,
interrupted linear deposits of anti-GBM antibodies (mostly IgG; particularly in cases with deficient immunoglobulins (e.g.
rarely IgA and IgM) and complement (mainly C3) along the in pauci-immune type glomerulonephritis in RPGN).
glomerular basement membrane. These deposits are detected Cytokines and other mediators released by activated T cells
Systemic Pathology
by immunofluorescence microscopy or by electron stimulate cytotoxicity, recruitment of more leucocytes and
microscopy. fibrogenesis. CD4+ T lymphocytes recruit more macrophages
Anti-GBM disease is characteristically exemplified by while CD8+ cytotoxic T lymphocytes and natural killer cells
glomerular injury in Goodpasture’s syndrome in some cases cause further glomerular cell injury by antibody-dependent
of rapidly progressive GN. About half to two-third of the cell toxicity. Soluble factor derived from T lymphocytes is
patients with renal lesions in Goodpasture’s syndrome have implicated in proteinuria in minimal change disease and focal
pulmonary haemorrhage mediated by cross-reacting GS.
autoantibodies against alveolar basement membrane (page However, cell-mediated injury is yet less clear than
494). antibody-mediated glomerular injury.
3. ALTERNATE PATHWAY DISEASE. As apparent from C. Secondary Pathogenetic Mechanisms
the above mechanisms, the complement system, in (Mediators of Immunologic Injury)
particular C3, contributes to glomerular injury in most
forms of GN. Deposits of C3 are associated with the early Secondary pathogenetic mechanisms are a number of
components C1, C2 and C4 which are evidence of classic mediators of immunologic glomerular injury operating in
pathway activation of complement. But in alternate man and in experimental models. These include the
pathway activation, there is decreased serum C3 level, following:
decreased serum levels of factor B and properdin, normal 1. NEUTROPHILS. Neutrophils are conspicuous in certain
serum levels of C1, C2 and C4 but C3 and properdin are forms of glomerular disease such as in acute diffuse prolife-
found deposited in the glomeruli without immunoglobulin rative GN, and may also be present in membranoproliferative
GN and lupus nephritis. Neutrophils can mediate glomerular to increased deposition of mesangial matrix and proliferation 665
injury by activation of complement as well as by release of of mesangial cells, endothelial and epithelial cell injury, and
proteases, arachidonic acid metabolites and oxygen-derived eventually to progressive glomerulosclerosis and end-stage
free radicals. These agents cause degradation of GBM and renal failure.
cell injury.
SPECIFIC TYPES OF GLOMERULAR DISEASES
2. MONONUCLEAR PHAGOCYTES. Many forms of
human and experimental proliferative GN are associated Classification of different forms of glomerular diseases is
with glomerular infiltration by monocytes and macrophages. already presented in Table 22.4. Features of individual types
Accumulation of mononuclear phagocytes is considered an are described below and a summary of major forms of
important constituent of hypercellularity in these forms of primary glomerulonephritis is given in Table 22.11 at the
GN aside from proliferation of mesangial and endothelial end of this discussion.
cells. Activated macrophages release a variety of biologically
active substances which take part in glomerular injury. I. PRIMARY GLOMERULONEPHRITIS
Acute Glomerulonephritis
3. COMPLEMENT SYSTEM. The pathogenetic role of
classical and alternate pathway of activation of complement (Synonyms: Acute Diffuse Proliferative GN,
has already been highlighted above. Besides the components Diffuse Endocapillary GN)
of complement which mediate glomerular injury via Acute GN is known to follow acute infection and charac-
neutrophils already mentioned, C5bC6789 (MAC, acronym teristically presents as acute nephritic syndrome. Based on
for membrane attack complex, also called terminal complex) etiologic agent, acute GN is subdivided into 2 main groups:
is capable of inducing damage to GBM directly. acute post-streptococcal GN and acute non-streptococcal GN,
the former being more common.
4. PLATELETS. Platelet aggregation and release of
mediators play a role in the evolution of some forms of GN. ACUTE POST-STREPTOCOCCAL GN
Increased intrarenal platelet consumption has been found to
occur in some forms of glomerular disease. Acute post-streptococcal GN, though uncommon and
sporadic in the Western countries, is a common form of GN CHAPTER 22
5. MESANGIAL CELLS. There is evidence to suggest that in developing countries, mostly affecting children between
mesangial cells present in the glomeruli may be stimulated 2 to 14 years of age but 10% cases are seen in adults above 40
to produce mediators of inflammation and take part in years of age. The onset of disease is generally sudden after
glomerular injury. 1-2 weeks of streptococcal infection, most frequently of the
throat (e.g. streptococcal pharyngitis) and sometimes of the
6. COAGULATION SYSTEM. The presence of fibrin in
early crescents in certain forms of human and experimental skin (e.g. streptococcal impetigo).
GN suggests the role of coagulation system in glomerular ETIOPATHOGENESIS. The relationship between
damage. Fibrinogen may leak into Bowman’s space and act streptococcal infection and this form of GN is now well
as stimulus for cell proliferation. Crescents usually transform established. Particularly nephritogenic are types 12,4,1 and
into scar tissue under the influence of fibronectin which is Red Lake of group A β-haemolytic streptococci (compare the
regularly present in crescents in human glomerular disease. etiologic agent with that of RHD, page 438). The glomerular
lesions appear to result from deposition of immune
II. NON-IMMUNOLOGIC MECHANISMS complexes in the glomeruli. The evidences cited in support The Kidney and Lower Urinary Tract
are as under:
Though most forms of GN are mediated by immunologic i) There is epidemiological evidence of preceding strepto-
mechanisms, a few examples of glomerular injury by non- coccal sore throat or skin infection about 1-2 weeks prior to
immunologic mechanisms are found: the attack.
1. Metabolic glomerular injury e.g. in diabetic nephropathy ii) The latent period between streptococcal infection and onset
(due to hyperglycaemia), Fabry’s disease (due to sulfatidosis). of clinical manifestations of the disease is compatible with
2. Haemodynamic glomerular injury e.g. systemic hyper- the period required for building up of antibodies.
tension, intraglomerular hypertension in FSGS. iii) Streptococcal infection may be identified by culture or
3. Deposition diseases e.g. amyloidosis. may be inferred from elevated titres of antibodies against
4. Infectious diseases e.g. HBV, HCV, HIV, E. coli-derived streptococcal antigens. These include the following:
nephrotoxin. anti-streptolysin O (ASO);
5. Drugs e.g. minimal change disease due to NSAIDs. anti-deoxyribonuclease B (anti-DNAse B);
6. Inherited glomerular diseases e.g. Alport’s syndrome, nail- anti-streptokinase (ASKase);
patella syndrome. anti-nicotinyl adenine dinucleotidase (anti-NADase); and
The evolution of end-stage renal failure in glomerular injury anti-hyaluronidase (AHase).
is explained on the basis of adaptive glomerular hypertrophy iv) There is usually hypocomplementaemia indicating
of unaffected glomeruli that results in increased glomerular involvement of complement in the glomerular deposits.
blood flow and increased glomerular capillary pressure v) It has also been possible to identify antigenic component
inducing intraglomerular hypertension. These events lead of streptococci which is cytoplasmic antigen, endostreptosin.
666
chiefly polymorphs and sometimes monocytes (acute
exudative lesion). There may be small deposits of fibrin
within the capillary lumina and in the mesangium.
ii) Tubules—Tubular changes are not very striking.
There may be swelling and hyaline droplets in tubular
cells, and tubular lumina may contain red cell casts.
iii) Interstitium—There may be some degree of interstitial
oedema and leucocytic infiltration.
iv) Vessels—Changes in arteries and arterioles are seldom
present in acute GN.
Electron microscopic findings, aside from confirming the
light microscopic findings, demonstrate the characteristic
electron-dense irregular deposits (‘humps’) on the
epithelial side of the GBM. These deposits represent the
immune complexes (Fig. 22.13).
Immunofluorescence microscopy reveals that the irregular
deposits along the GBM consist principally of IgG and
complement C3.
CLINICAL FEATURES. Typically, the patient is a young
child, presenting with acute nephritic syndrome (page 660),
Figure 22.11 Flea-bitten kidney. The kidney is enlarged in size and
weight. The cortex shows tiny petechial haemorrhages visible through having sudden and abrupt onset following an episode of sore
the capsule (arrow). throat or skin infection 1-2 weeks prior to the development
of symptoms. The features include microscopic or
intermittent haematuria, red cell casts, mild non-selective
MORPHOLOGIC FEATURES. Grossly, the kidneys are proteinuria (less than 3 gm per 24 hrs), hypertension,
symmetrically enlarged, weighing one and a half to twice periorbital oedema and variably oliguria. Less often, the
the normal weight. The cortical as well as sectioned surface presentation may be as nephrotic syndrome. In adults, the
show petechial haemorrhages giving the characteristic features are atypical and include sudden hypertension,
SECTION III
appearance of flea-bitten kidney (Fig. 22.11). oedema and azotaemia. Development of hypertension in
Light microscopic findings are as under (Fig. 22.12): either case is a poor prognostic sign.
i) Glomeruli—The glomeruli are affected diffusely. They Prognosis varies with the age of the patient. Children
are enlarged and hypercellular. The diffuse hyper- almost always (95%) recover completely with reversal of
cellularity of the tuft is due to proliferation of mesangial, proliferative glomerular changes. Complications arise more
endothelial and occasionally epithelial cells (acute often in adults and occasionally in children. These include
proliferative lesions) as well as by infiltration of leucocytes, development of rapidly progressive GN, chronic GN,
uraemia and chronic renal failure.
Systemic Pathology
Figure 22.12 Acute post-streptococcal GN, light microscopic appearance. There is increased cellularity due to proliferation of mesangial cells,
endothelial cells and some epithelial cells and infiltration of the tuft by neutrophils and monocytes.
is characterised by formation of ‘crescents’ (crescentic GN) 667
outside the glomerular capillaries (extracapillary GN).
‘Crescents’ are formed from the proliferation of parietal
epithelial cells lining Bowman’s capsule with contribution
from visceral epithelial cells and the invading mononuclear
cells. The stimulus for crescent formation appears to be the
presence of fibrin in the capsular space. RPGN occurs most
frequently in adults, with a slight male preponderance.
Prognosis of RPGN in general is dismal.
ETIOPATHOGENESIS. A number of primary glomerular
and systemic diseases are characterised by formation of
crescents. Based on the etiologic agents and pathogenetic
mechanism, patients with RPGN are divided into 3 groups
(Table 22.10):
RPGN in systemic diseases (anti-GBM type);
post-infectious RPGN (immune-complex type); and
pauci-immune RPGN.
Following three serologic markers are used for
categorising RPGN:
Figure 22.13 Acute glomerulonephritis, diagrammatic represen- i) serum C3 level,
tation of ultrastructure of a portion of glomerular lobule showing ii) anti-GBM antibody; and
characteristic electron-dense irregular deposits or ‘humps’ on the epithelial iii) anti-neutrophil cytoplasmic antibody (ANCA).
side of the GBM.
Type I RPGN: Anti-GBM disease. A number of systemic
ACUTE NON-STREPTOCOCCAL GN diseases such as Goodpasture’s syndrome, SLE, vasculitis,
About one-third cases of acute GN are caused by organisms Wegener’s granulomatosis, Henoch-Schonlein purpura and CHAPTER 22
other than haemolytic streptococci. These include other idiopathic mixed cryoglobulinaemia are associated with
bacteria (e.g. staphylococci, pneumococci, meningococci, crescentic GN. Goodpasture’s syndrome is the characteristic
Salmonella and Pseudomonas), viruses (e.g. hepatitis B virus, example of anti-GBM disease and is described below:
mumps, infectious mononucleosis and varicella), parasitic Goodpasture’s syndrome. Goodpasture’s syndrome is
infections (e.g. malaria, toxoplasmosis and schistosomiasis) characterised by acute renal failure due to RPGN and
and syphilis. The appearance of renal biopsy by light pulmonary haemorrhages (page 494). The condition is more
microscopy, EM and immunofluorescence microscopy is common in males in 3rd decade of life. The disease results
similar to that seen in acute post-streptococcal GN. The from damage to the glomeruli by anti-GBM antibodies which
prognosis of non-streptococcal GN is not as good as that of cross-react with alveolar basement membrane and hence,
streptococcal GN. produce renal as well as pulmonary lesions. The evidences
in support are the characteristic linear deposits of anti-GBM
Rapidly Progressive Glomerulonephritis antibodies consisting of IgG and complement along the GBM,
(Synonyms: RPGN, Crescentic GN, Extracapillary GN) The Kidney and Lower Urinary Tract
detection of circulating anti-GBM antibodies and induction
RPGN presents with an acute reduction in renal function of glomerular lesions with injection of anti-GBM antibodies
resulting in acute renal failure in a few weeks or months. It experimentally in monkeys. Pulmonary lesions can be experi-
TABLE 22.10: Distinguishing Features of Three Main Categories of Rapidly Progressive Glomerulonephritis.
Feature Type I RPGN Type II RPGN Type III RPGN
(Anti-GBM Disease) (Immune Complex Disease) (Pauci-immune GN)
1. Clinical syndrome Nephritic Nephritic Nephritic
2. Pathogenetic type Anti-GBM lmmune-complex Pauci-immune
3. Immunofluorescence Linear Ig and C3 Granular Ig and C3 Sparse or absent Ig and C3
4. Serologic markers
i) Serum C3 level Normal Low-to-normal Normal
ii) Anti-GBM antibody Positive Negative Negative
iii) ANCA Negative Negative Positive
5. Underlying cause Idiopathic Idiopathic Idiopathic
Goodpasture’s syndrome, SLE, Post-infectious Polyarteritis nodosa,
vasculitis, Wegener’s granulomatosis, (post-streptococcal GN) Wegener’s granulomatosis
Henoch-Schonlein purpura
668
Figure 22.14 RPGN (post-infectious type), light microscopic appearance. There are crescents in Bowman’s space forming adhesions between
the glomerular tuft and Bowman’s capsule. The tuft shows hypercellularity and leucocytic infiltration.
mentally induced if the lungs are previously injured by viral cells and leucocytic infiltration. Fibrin thrombi are
or bacterial infection or exposed to hydrocarbons. The frequently present in the glomerular tufts.
Goodpasture’s antigen appears to be a component of collagen ii) Tubules—Tubular epithelial cells may show hyaline
type IV.
droplets. Tubular lumina may contain casts, red blood
Type II RPGN: Immune complex disease. A small propor- cells and fibrin.
tion of cases of post-streptococcal GN, particularly in adults iii) Interstitium—The interstitium is oedematous and
and sometimes of non-streptococcal origin, develop RPGN. may show early fibrosis. Inflammatory cells, usually
The evidences in support of post-infectious RPGN having lymphocytes and plasma cells, are commonly distributed
SECTION III
immune complex pathogenesis are granular deposits of in the interstitial tissue.
immune complexes of IgG and C3 along the glomerular iv) Vessels—Arteries and arterioles may show no change,
capillary walls, lowering of blood complement levels and but cases associated with hypertension usually show
demonstration of circulating complexes. severe vascular changes.
Type III RPGN: Pauci-immune GN. These include cases of Electron microscopic findings vary according to the type
Wegener’s granulomatosis and microscopic polyarteritis of RPGN. Post-infectious RPGN cases show electron-dense
nodosa. The pathogenesis of pauci-immune GN is yet not subepithelial granular deposits similar to those seen in
fully defined. However, majority of these patients are ANCA- acute GN, while cases of RPGN in Goodpasture’s
positive, implying a defect in humoral immunity. Serum syndrome show characteristic linear deposits along the
complement levels are normal and anti-GBM antibody is GBM (Fig. 22.15).
negative. There is little or no glomerular immune deposit
Systemic Pathology
(i.e. pauci-immune). Immunofluorescence microscopy shows following
patterns in various types of RPGN:
MORPHOLOGIC FEATURES. Grossly, the kidneys are linear pattern of RPGN in Goodpasture’s syndrome
usually enlarged and pale with smooth outer surface (large (type I RPGN), containing IgG accompanied by C3 along
white kidney). Cut surface shows pale cortex and congested the capillaries.
medulla. Granular pattern of post-infectious RPGN (type II
Light Microscopic findings vary according to the cause RPGN) consisting of IgG and C3 along the capillary wall.
but in general following features are present (Fig. 22.14): Scanty or no deposits of immunoglobulin and C3 in
pauci-immune GN (type III RPGN).
i) Glomeruli—Irrespective of the underlying etiology,
all forms of RPGN show pathognomonic ‘crescents’ on the CLINICAL FEATURES. Generally, the features of post-
inside of Bowman’s capsules. These are collections of pale- infectious RPGN are similar to those of acute GN, presenting
staining polygonal cells which commonly tend to be as acute renal failure. The patients of Goodpasture’s
elongated. Eventually, crescents obliterate the Bowman’s syndrome may present as acute renal failure and/or
space and compress the glomerular tuft. Fibrin deposition associated intrapulmonary haemorrhage producing
is invariably present alongside crescents. Besides the recurrent haemoptysis. Prognosis of all forms of RPGN is
crescents, glomerular tufts may show increased cellularity poor. However, post-infectious cases have somewhat better
as a result of proliferation of endothelial and mesangial outcome and may show recovery.
minimal amounts of high molecular weight proteins such as 669
α2-macroglobulin. The basis for selective proteinuria appears
to be as under:
i) Reduction of normal negative charge on GBM (page 650)
due to loss of heparan sulfate proteoglycan from the GBM.
ii) Change in the shape of epithelial cells producing foot
process flattening due to reduction of sialoglycoprotein cell
coat.
Adults having MCD, however, have non-selective protein-
uria, suggesting more extensive membrane permeability
defect.
MORPHOLOGIC FEATURES. Grossly, the kidneys are
of normal size and shape.
By light microscopy, the findings are as under
(Fig. 22.16,A):
i) Glomeruli—The most characteristic feature is no
apparent abnormality in the glomeruli except for slight
Figure 22.15 RPGN, diagrammatic representation of ultrastructure increase in the mesangial matrix at the most (minimal
of a portion of glomerular lobule showing epithelial crescent formation change disease or nil lesion).
and subepithelial granular deposits.
ii) Tubules—There is presence of fine lipid vacuolation
and hyaline droplets in the cells of proximal convoluted
Minimal Change Disease tubules and, hence, the older name of the condition as
(Synonyms: MCD, Lipoid Nephrosis, Foot Process ‘lipoid nephrosis’.
Disease, Nil Deposit Disease)
iii) Interstitium—There may be oedema of the CHAPTER 22
Minimal change disease (MCD) is a condition in which the interstitium.
nephrotic syndrome is accompanied by no apparent change iv) Vessels—Blood vessels do not show any significant
in glomeruli by light microscopy. Its other synonyms, lipoid change.
nephrosis and foot process disease, are descriptive terms for
fatty changes in the tubules and electron microscopic By electron microscopy, the most characteristic feature of
appearance of flattened podocytes respectively. Minimal the disease is identified which is diffuse flattening of foot
change disease accounts for 80% cases of nephrotic syndrome processes of the visceral epithelial cells (podocytes) and,
in children under 16 years of age with preponderance in boys hence, the name foot process disease or podocytopathy
(ratio of boys to girls 2:1). In fact, historically, lipoid nephrosis (Fig. 22.16,B). Unlike other forms of GN, no deposits are
was the first condition associated with nephrotic sndrome. seen and the GBM is normal.
By immunofluorescence microscopy, no deposits of
ETIOPATHOGENESIS. The etiology of MCD remain complement or immunoglobulins are recognised (nil
elusive. However, following two groups have been deposit disease).
identified: The Kidney and Lower Urinary Tract
i) Idiopathic (majority of cases). CLINICAL FEATURES. The classical presentation of MCD
ii) Cases associated with systemic diseases (Hodgkin’s is of fully-developed nephrotic syndrome with massive and
disease, HIV infection) and drug therapy (e.g. NSAIDs, highly selective proteinuria, but hypertension is unusual. Most
rifampicin, interferon-α). frequently, the patients are children under 16 years (peak
incidence at 6-8 years of age).
The following features point to possible immunologic The onset may be preceded by an upper respiratory
pathogenesis for MCD: infection, atopic allergy or immunisation.
i) Absence of deposits by immunofluorescence microscopy. The disease characteristically responds to steroid therapy.
ii) Normal circulating levels of complement but presence In spite of remissions and relapses, long-term prognosis is
of circulating immune complexes in many cases. very good and most children become free of albuminuria
iii) Universal satisfactory response to steroid therapy. after several years.
iv) Evidence of increased suppressor T cell activity with
elaboration of cytokines (interleukin-8, tumour necrosis Membranous Glomerulonephritis
factor) which probably cause foot process flattening and (Synonym: Epimembranous Nephropathy)
altered charge on the GBM. Membranous GN is characterised by widespread thickening
v) Detection of a mutation in nephrin gene in cases of of the glomerular capillary wall and is the most common
congenital MCD has focused attention on genetic basis. cause of nephrotic syndrome in adults. In majority of cases
Nephrotic syndrome in MCD in children is characterised (85%), membranous GN is truly idiopathic, while in about
by selective proteinuria containing mainly albumin, and 15% of cases it is secondary to an underlying condition (e.g.
670
Figure 22.16 Minimal change disease. A, Light microscopy shows a normal glomerulus while tubules show cytoplasmic vacuolation and
proteinaceous material. B, Diagrammatic representation of ultrastructure of a portion of glomerular lobule showing diffuse fusion or flattening of foot
processes of visceral epithelial cells (podocytes). The GBM is normal and there are no deposits.
SLE, malignancies, infections such as chronic hepatitis B and MORPHOLOGIC FEATURES. Grossly, the kidneys are
C, syphilis, malaria and drugs). enlarged, pale and smooth.
ETIOPATHOGENESIS. Idiopathic membranous GN is an Light microscopy shows the following findings
immune complex disease. The deposits of immune complex (Fig. 22.17):
are formed locally because circulating immune complexes i) Glomeruli—The characteristic finding is diffuse
are detected in less than a quarter of cases. Since leucocytic thickening of the glomerular capillary walls with all the
infiltration is not a feature of membranous GN, damage to glomeruli being affected more or less uniformly. As the
SECTION III
the GBM is mediated directly by complement. While disease progresses, the deposits are incorporated into
nephritogenic antigen against which autoantibodies are enormously thickened basement membrane, producing
formed in idiopathic membranous GN is not known yet, the ‘duplication’ of GBM which is actually formation of a new
antigen in cases of secondary membranous GN is either an basement membrane. These basement membrane changes
endogenous (e.g. DNA in SLE) or exogenous one (e.g. are best appreciated by silver impregnation stains (black
hepatitis B virus, tumour antigen, treponema antigen, drug colour) or by periodic acid-Schiff stain (pink colour). There
therapy with penicillamine). Currently, pathogenesis of is no cellular proliferation in the glomerular tufts.
membrane alteration in membranous GN is believed to be ii) Tubules—The renal tubules remain normal except in
by MAC (membrane attack complex i.e. C35b-C9) terminal the early stage when lipid vacuolation of the proximal
complex on podocytes. convoluted tubules may be seen.
Systemic Pathology
Figure 22.17 Membranous GN, light microscopic appearance. Glomeruli are normocellular but the capillary walls are diffusely thickened due
to duplication of the GBM.
increase in cellularity of the mesangium associated with 671
increased lobulation of the tuft, and irregular thickening of
the capillary wall.
ETIOPATHOGENESIS. Etiology of MPGN is unknown
though in some cases there is evidence of preceding
streptococcal infection. Based on ultrastructural,
immunofluorescence and pathogenetic mechanisms, three
types of MPGN are recognised:
Type I or classic form is an example of immune complex
disease and comprises more than 70% cases. It is charac-
terised by immune deposits in the subendothelial position.
Immune-complex MPGN is seen in association with systemic
immune-complex diseases (e.g. SLE, mixed cryoglo-
bulinaemia, Sjögren’s syndrome), chronic infections (e.g.
bacterial endocarditis, HIV, hepatitis B and C) and
malignancies (e.g. lymphomas and leukaemias).
Type II or dense deposit disease is the example of alter-
nate pathway disease (page 664) and constitutes about 30%
cases. The capillary wall thickening is due to the deposition
Figure 22.18 Membranous GN, diagrammatic represent ation of of electron-dense material in the lamina densa of the GBM.
ultrastructure of a portion of glomerular lobule showing subepithelial Type II MPGN is an autoimmune disease in which patients
deposits of electron-dense material so that the basement membrane
material protrudes between these deposit s. have IgG autoantibody termed C3 nephritic factor. Type II
cases have an association with partial lipodystrophy, an
unusual condition of unknown pathogenesis characterised
iii) Interstitium—The interstitium may show fine fibrosis by symmetrical loss of subcutaneous fat from the upper half
and scanty chronic inflammatory cells. of the body. CHAPTER 22
iv) Vessels—In the early stage, vascular changes are not Type III is rare and shows features of type I MPGN and
prominent, while later hypertensive changes of arterioles membranous nephropathy in association with systemic
may occur. diseases or drugs.
Electron microscopy shows characteristic electron-dense MORPHOLOGIC FEATURES. Grossly and by light
deposits in subepithelial location. The basement microscopy, all the three types of MPGN are similar.
membrane material protrudes between deposits as ‘spikes’
(Fig. 22.18). Grossly, the kidneys are usually pale in appearance and
Immunofluorescence microscopy reveals granular deposits firm in consistency.
of immune complexes consisting of IgG associated with By light microscopy, the features are as under (Fig. 22.19):
complement C3. In secondary cases of membranous GN i) Glomeruli—Glomeruli show highly characteristic
the relevant antigen such as hepatitis B or tumour antigen changes. They are enlarged with accentuated lobular
may be seen. pattern. The enlargement is due to variable degree of The Kidney and Lower Urinary Tract
mesangial cellular proliferation and increase in mesangial
CLINICAL FEATURES. The presentation in majority of matrix. The GBM is considerably thickened, which with
cases is insidious onset of nephrotic syndrome in an adult. silver stains shows two basement membranes with a clear
The proteinuria is usually of non-selective type. In addition, zone between them. This is commonly referred to as
microscopic haematuria and hypertension may be present ‘double contour’, splitting, or ‘tram track’ appearance.
at the onset or may develop during the course of the disease. ii) Tubules—Tubular cells may show vacuolation and
The changes in membranous GN are irreversible in majority hyaline droplets.
of patients. Progression to impaired renal function and end-
stage renal disease with progressive azotaemia occurs in iii) Interstitium—There may be scattered chronic
approximately 50% cases within a span of 2 to 20 years. Renal inflammatory cells and some finely granular foam cells
vein thrombosis has been found to develop in patients with in the interstitium.
membranous GN due to hypercoagulability. The role and iv) Vessels—Vascular changes are prominent in cases in
beneficial effects of steroid therapy with or without the which hypertension develops.
addition of immunosuppressive drugs is debatable. By electron microscopy and immunofluorescence micros-
copy, the changes are different in the three types of MPGN
Membranoproliferative Glomerulonephritis (Fig. 22.20):
(Synonyms: MPGN, Mesangiocapillary GN) Type I: It shows electron-dense deposits in subendothelial
location conforming to immune-complex character of the
Membranoproliferative GN is another important cause of
nephrotic syndrome in children and young adults. As the disease. These deposits reveal positive fluorescence for
name implies, it is characterised by two histologic features— C3 and slightly fainter staining for IgG.
672
Figure 22.19 Membranoproliferative GN, light microscopic appearance. The glomerular tufts show lobulation and mesangial hypercellularity.
There is increase in the mesangial matrix between the capillaries. There is widespread thickening of the GBM.
Approximately 50% of the patients present with nephrotic
Type II: The hallmark of type II MPGN is the presence of syndrome; about 30% have asymptomatic proteinuria; and
dense amorphous deposits within the lamina densa of the 20% have nephritic syndrome at presentation. The
GBM and in the mesangium. Immunofluorescence studies proteinuria is non-selective. Haematuria and hypertension
reveal the universal presence of C3 and properdin in the
deposits but the immunoglobulins are usually absent. are frequently present. Hypocomplementaemia is a common
Type III: This rare form has electron-dense deposits within feature. With time, majority of patients progress to renal
failure, while some continue to have proteinuria, haematuria
the GBM as well as in subendothelial and subepithelial and hypertension with stable renal function.
SECTION III
regions of the GBM. Immunofluorescence studies show
the presence of C3, IgG and IgM. Prognosis of type I is relatively better and majority of
patients survive without clinically significant impairment of
CLINICAL FEATURES. Clinically, there are many GFR, while type II cases run a variable clinical course.
similarities between the main forms of MPGN. The most
common age at diagnosis is between 15 and 20 years. Focal Proliferative Glomerulonephritis
(Synonym: Mesangial Proliferative GN)
Focal proliferative GN is characterised by pathologic changes
in certain number of glomeruli (focal), and often confined to
one or two lobules of the affected glomeruli (segmental), while
other glomeruli are normal. Focal GN is, thus, a pathologic
Systemic Pathology
diagnosis.
ETIOPATHOGENESIS. It may occur under following
diverse clinical settings:
As an early manifestation of a number of systemic diseases
such as SLE, Henoch-Schonlein purpura, subacute bacterial
endocarditis, Wegener’s granulomatosis, and polyarteritis
nodosa, Goodpasture’s syndrome.
As a component of a known renal disease such as in IgA
nephropathy.
As a primary idiopathic glomerular disease unrelated to
systemic or other renal disease.
The diverse settings under which focal GN is encountered
make it unlikely that there are common etiologic agents or
Figure 22.20 MPGN, diagrammatic representation of ultrastructure pathogenetic mechanisms. However, the observation of
of a portion of glomerular lobule showing features of type I (left half) and mesangial deposits of immunoglobulins and complement
type II (right half) MPGN. Type I (classic form) shows the characteristic suggest immune complex disease and participation of the
subendothelial electron-dense deposit s, while type II (dense deposit
disease) is characterised by intramembranous dense deposit s. mesangium.
673
Figure 22.21 A, Focal GN. The characteristic feature is the cellular proliferation in some glomeruli and in one or two lobules of the affected
glomeruli i.e. focal and segmental proliferative change. B, C, Focal segmental glomerulosclerosis. The features are focal and segmental involvement
of the glomeruli by sclerosis and hyalinosis and mesangial hypercellularity .
in the form of hyalinosis and sclerosis. Currently, the
MORPHOLOGIC FEATURES. By light microscopy, the condition is divided into 3 groups: CHAPTER 22
single most important feature in focal GN is the
abnormality seen in certain number of glomeruli and i) Idiopathic type. This group comprises majority of cases.
generally confined to one or two lobules of the affected It is found in children and young adults with presentation
glomeruli i.e. focal and segmental glomerular involvement of nephrotic syndrome. It differs from minimal change
(Fig. 22.21,A). The pathologic change most frequently disease in having non-selective proteinuria, in being steroid-
consists of focal and segmental cellular proliferation of resistant, and may progress to chronic renal failure. Immuno-
mesangial cells and endothelial cells but sometimes fluorescence microscopy reveals deposits of IgM and C3 in
necrotising changes can be seen. The condition must be the sclerotic segment.
distinguished from focal and segmental glomerulo- ii) With superimposed primary glomerular disease. There
sclerosis (discussed below). may be cases of FSGS with superimposed MCD or IgA
By immunofluorescence microscopy, widespread nephropathy. Those associated with MCD show good
mesangial deposits of immunoglobulins (mainly IgA with response to steroid therapy and progression to chronic renal
or without IgG), complement (C3) and fibrin are failure may occur after a long time. The Kidney and Lower Urinary Tract
demonstrated in most cases of focal GN.
iii) Secondary type. This group consists of focal segmental
CLINICAL FEATURES. The clinical features vary according sclerotic lesions as a secondary manifestation of certain
to the condition causing it. Haematuria is one of the most diseases such as HIV, diabetes mellitus, reflux nephropathy,
common clinical manifestation. Proteinuria is frequently mild heroin abuse and analgesic nephropathy.
to moderate but hypertension is uncommon. The hallmark of pathogenesis of FSGS is injury to visceral
epithelial cells that results in disruption of visceral epithelial
Focal Segmental Glomerulosclerosis cells and resultant nephron loss.
(Synonyms: Focal Sclerosis, Focal Hyalinosis)
MORPHOLOGIC FEATURES. By light microscopy,
Focal segmental glomerulosclerosis (FSGS) is a condition in depending upon the severity of the disease, variable
which there is sclerosis and hyalinosis of some glomeruli and number of glomeruli are affected focally and segmentally,
portions of their tuft (less than 50% in a tissue section), while while others are normal. The affected glomeruli show
the other glomeruli are normal by light microscopy i.e. solidification or sclerosis of one or more lobules of the tuft.
involvement is focal and segmental. The incidence of FSGS Hyalinosis refers to collection of eosinophilic,
has increased over the last decades and is currently homogeneous, PAS-positive, hyaline material present on
responsible for about one-third cases of nephrotic syndrome the inner aspect of a sclerotic peripheral capillary loop.
in the adults. Mesangial hypercellularity is present in appreciable
ETIOPATHOGENESIS. FSGS was previously believed to number of cases. In addition, to glomerular changes, there
be a variant of MCD with accentuation of epithelial damage is interstitial fibrosis and infiltration by mononuclear
674 leucocytes, and tubular epithelial cell atrophy and MORPHOLOGIC FEATURES. By light microscopy, the
degeneration (Fig. 22.21,B, C). pattern of involvement varies. These include: focal
Besides the lesions of focal and segmental scarring, a proliferative GN, focal segmental glomerulosclerosis,
variant of FSGS, collapsing glomerulopathy, has been membranoproliferative GN, and rarely RPGN.
described in HIV patients. It is segmental or global By electron microscopy, finely granular electron-dense
glomerular collapse of the tuft along with the presence of deposits are seen in the mesangium.
hyperpasia and hypertrophy of podocytes producing a By immunofluorescence microscopy, the diagnosis is
pseudo-crescent and a rapid decline in renal function. firmly established by demonstration of mesangial deposits
By electron microscopy, diffuse loss of foot processes of IgA, with or without IgG, and usually with C3 and
as seen in minimal change disease is evident but, in properdin.
addition, there are electron-dense deposits in the region
of hyalinosis and sclerosis which are believed to be CLINICAL FEATURES. The disease is common in children
immune complexes. and young adults. The clinical picture is usually characterised
by recurrent bouts of haematuria that are often precipitated
By Immunofluorescence microscopy, the deposits in the
lesions are shown to contain IgM and C3. by mucosal infections. Mild proteinuria is usually present
and occasionally nephrotic syndrome may develop.
CLINICAL FEATURES. The condition may affect all ages
including children and has male preponderance. The most Chronic Glomerulonephritis
common presentation is in the form of nephrotic syndrome (Synonym: End-Stage Kidney)
with heavy proteinuria. Haematuria and hypertension tend Chronic GN is the final stage of a variety of glomerular
to occur more frequently than in minimal change disease. diseases which result in irreversible impairment of renal
Evidence of renal failure may be present at the onset. function. The conditions which may progress to chronic GN,
in descending order of frequency, are as under:
IgA Nephropathy i) Rapidly progressive GN (90%)
(Synonyms: Berger’s Disease, IgA GN)
ii) Membranous GN (50%)
IgA nephropathy is emerging as the most common form of iii) Membranoproliferative GN (50%)
glomerulopathy worldwide and its incidence has been rising. iv) Focal segmental glomerulosclerosis (50%)
It is characterised by aggregates of IgA, deposited principally v) IgA nephropathy (40%)
in the mesangium. The condition was first described by vi) Acute post-streptococcal GN (1%).
SECTION III
Berger, a French physician in 1968 (Not to be confused with
Buerger’s disease or thromboangiitis obliterans described by However, about 20% cases of chronic GN are idiopathic
an American pathologist in 1908 and discussed on page 404). without evidence of preceding GN of any type.
ETIOPATHOGENESIS. The etiology of IgA nephropathy MORPHOLOGIC FEATURES. Grossly, the kidneys are
remains unclear: usually small and contracted weighing as low as 50 gm
i) It is idiopathic in most cases. each. The capsule is adherent to the cortex. The cortical
ii) Seen as part of Henoch-Schonlein purpura. surface is generally diffusely granular (Fig. 22.22). On cut
iii) Association with chronic inflammation in various body section, the cortex is narrow and atrophic, while the
systems (e.g. chronic liver disease, inflammatory bowel medulla is unremarkable.
disease, interstitial pneumonitis, leprosy, dermatitis Microscopically, the changes vary greatly depending
Systemic Pathology
herpetiformis, uveitis, ankylosing spondylitis, Sjögren’s upon the underlying glomerular disease. In general, the
syndrome, monoclonal IgA gammopathy). following changes are seen (Fig. 22.23).
Pathogenesis of IgA nephropathy is explained on the basis i) Glomeruli—Glomeruli are reduced in number and
of following mechanisms: most of those present show completely hyalinised tufts,
i) In view of exclusive mesangial deposits of IgA and giving the appearance of acellular, eosinophilic masses
elevated serum levels of IgA and IgA-immune complexes, which are PAS-positive. Evidence of underlying
IgA nephropathy has been considered to arise from glomerular disease may be present.
entrapment of these complexes in the mesangium. ii) Tubules—Many tubules completely disappear and
ii) There is absence of early components of the complement there may be atrophy of tubules close to scarred glomeruli.
but presence of C3 and properdin in the mesangial deposits, Tubular cells show hyaline-droplets, degeneration and
which point towards activation of alternate complement tubular lumina frequently contain eosinophilic,
pathway. homogeneous casts.
iii) Since there is close association between mucosal iii) Interstitium—There is fine and delicate fibrosis of the
infections (e.g. of the respiratory, gastrointestinal or urinary interstitial tissue and varying number of chronic
tract), it is suggested that IgA deposited in the mesangium
inflammatory cells are often seen.
could be due to increased mucosal secretion of IgA. iv) Vessels—Advanced cases which are frequently
iv) HLA-B35 association has been reported in some cases. associated with hypertension show conspicuous arterial
Another possibility is genetically-determined abnormality of and arteriolar sclerosis.
the immune system producing an increase in circulating IgA.
675
Figure 22.22 End-stage kidney, gross appearance of short contract kidney in chronic glomerulonephritis. The kidney is small and contracted.
The capsule is adherent to the cortex and has diffusely granular cortical surface.
Patients of end-stage kidney disease on dialysis show these, renal involvement may be the initial presentation,
a variety of dialysis associated changes that include acqui- while in others clinical evidence of renal disease appears long
red cystic disease (page 659), occurrence of adenomas and after other manifestations have appeared. A list of these
adenocarcinomas of the kidney, calcification of tufts and conditions has already been given in Table 22.4. The
deposition of calcium oxalate crystals in tubules. important examples are described below.
CLINICAL FEATURES. The patients are usually adults. The Lupus Nephritis CHAPTER 22
terminal stage of chronic GN is characterised by Renal manifestations of systemic lupus erythematosus (SLE)
hypertension, uraemia and progressive deterioration of renal are termed lupus nephritis. Other clinical manifestations,
function. Besides the primary changes due to chronic renal etiology and pathogenesis of this multi-system autoimmune
failure, there are a variety of systemic manifestations of disease are described in Chapter 4 (page 78). The incidence
uraemia (page 655). These patients eventually die if they do of renal involvement in SLE ranges from 40 to 75%. The two
not receive a renal transplant. cardinal clinical manifestations of lupus nephritis are
The salient features of various types of primary proteinuria and haematuria. In addition, hypertension and
glomerulonephritis are summarised in Table 22.11. casts of different types such as red cell casts, fatty casts and
leucocyte casts in the urinary sediment are found.
II. SECONDARY GLOMERULAR DISEASES Pathogenesis of lesions in lupus nephritis is linked to
Glomerular involvement may occur secondary to certain genes related to major histocompatibility complex and B-cell
systemic diseases or a few hereditary diseases. In some of signaling pathways such as TNF superfamily members. The Kidney and Lower Urinary Tract
Figure 22.23 End-stage kidney in chronic GN, light microscopy. Glomerular tufts are acellular and completely hyalinised. Blood vessels in the
interstitium are hyalinised and thickened while the interstitium shows fine fibrosis and a few chronic inflammatory cells.
676
TABLE 22.11: Comparative Features of Major Forms of Primary Glomerulonephritis.
Type Clinical Pathogenesis Pathology
Features LM EM IFM
1. Acute GN Acute nephrotic Immune complex Diffuse proliferation, Subepithelial Irregular IgG,
syndrome disease (local or leucocytic infiltration deposits C3
circulating) (‘humps’)
2. RPGN Acute renal i) Type I: Proliferation, crescents i) Linear deposits i) Linear IgG, C3
failure anti-GBM type along GBM
ii) Type II: ii) Subepithelial ii) Granular IgG,
immune complex type deposits C3
iii) Type III: iii) No deposits iii) Negative
pauci-immune RPGN
3. Minimal Nephrotic Reduction of normal Normal glomeruli, Loss of foot Negative
change syndrome negative charge on lipid vacuolation in processes, no
disease (highly selective GBM tubules deposits
proteinuria) ?Cell-mediated
mechanism
4. Membranous Nephrotic Immune complex Diffuse thickening Subepithelial Granular IgG, C3
GN syndrome disease (local) of capillary wall deposits (‘spikes’)
5. Membrano- Nephrotic Type I: immune Lobular proliferation Type I: Subendothelial Type I: IgG, C3
proliferative syndrome complex disease of mesangial cells, deposits
GN Type II: dense increased mesangial Type II: Dense Type II: C3
deposit disease matrix, double intramembranous properdin
(alternate pathway contour of GBM deposits Type III: C3
activation) IgG, IgM
Type III: rare, Type III:
with systemic Subendothelial
diseases and drugs and subepithelial
deposits
6. Focal GN Variable, haema- Variable, possibly Focal and segmental Mesangial deposits IgA ± IgG, C3
SECTION III
turia common immune complex proliferation and fibrin
disease
7. Focal Nephrotic i) Idiopathic Focal and segmental Loss of foot IgM, C3
Segmental syndrome ii) With superimposed sclerosis and hyalinosis processes, electron
glomerulo- primary glomerular dense deposits in
sclerosis disease regions of sclerosis
iii) Secondary type and hyalinosis
8. IgA Recurrent Unknown, possibly Variable, commonly Mesangial IgA ± IgG, C3,
nephropathy haematuria, alternate pathway focal proliferative GN electron-dense properdin
mild proteinuria disease deposits
9. Chronic GN Chronic renal Variable Hyalinised glomeruli Variable Variable
Systemic Pathology
failure
(GN = glomerulonephritis; LM = light microscopy; EM = electron microscopy; IFM = immunofluorescence microscopy)
MORPHOLOGIC FEATURES. According to the WHO, reveal granular mesangial deposits of IgG and C3; some-
six patterns of mutually-merging renal lesions are seen in times IgA and IgM are also present in the deposits.
lupus nephritis (also refer to Table 4.9):
Class III: Focal segmental lupus nephritis. This is
Class I: Minimal lesions. On light microscopy, these cases characterised by focal and segmental proliferation of
do not show any abnormality. But examination by electron endothelial and mesangial cells, together with infiltration
microscopy and immunofluorescence microscopy shows by macrophages and sometimes neutrophils.
deposits within the mesangium which consist of IgG and Haematoxylin bodies of Gross may be present.
C3. Subendothelial and subepithelial deposits of IgG, often
with IgM or IgA and C3, are seen.
Class II: Mesangial lupus nephritis. These cases have
mild clinical manifestations. By light microscopy, there is Class IV: Diffuse proliferative lupus nephritis. In this
increase in the number of mesangial cells and of mesangial type, all the morphologic manifestations of lupus are
matrix. Ultrastructural and immunofluorescence studies present in most advanced form. This is the most severe
and the most common form of lupus nephritis. There is disease is 40 times more common in patients of end-stage 677
diffuse proliferation of endothelial, mesangial, and renal disease in diabetes mellitus than in non-diabetics and
sometimes epithelial cells, involving most or all glomeruli. more diabetics die from cardiovascular complications than
Electron microscopy shows large electron-dense deposits from uraemia.
in the mesangium and in the subendothelial region which MORPHOLOGIC FEATURES. Diabetic nephropathy
on immunofluorescence are positive for IgG; sometimes encompasses 4 types of renal lesions in diabetes mellitus:
also for IgA or IgM, and C3. diabetic glomerulosclerosis, vascular lesions, diabetic
Class V: Membranous lupus nephritis. These lesions pyelonephritis and tubular lesions (Armanni-Ebstein
resemble those of idiopathic membranous GN. These lesions).
consist of diffuse thickening of glomerular capillary wall 1. DIABETIC GLOMERULOSCLEROSIS. Glomerular
on light microscopy and show subendothelial deposits of lesions in diabetes mellitus are particularly common and
immune complexes containing IgG, IgM and C3 on account for majority of abnormal findings referable to the
ultrastructural studies. Mesangial hypercellularity is kidney.
present in some cases.
Pathogenesis of these lesions in diabetes mellitus is
Class VI: Sclerosing lupus nephritis. This is end-stage explained by following sequential changes: hyper-
kidney of SLE, akin to chronic GN. Most glomeruli are glycaemia → glomerular hypertension → renal hyper-
sclerosed and hyalinised and there may be remnants of perfusion → deposition of proteins in the mesangium →
preceding lesions. glomerulosclerosis → renal failure. In addition, cellular
infiltration in renal lesions in diabetic glomerular lesions
Although in a given case, the lesions in lupus nephririts
fit into one of the classes described above, it is not unusual is due to growth factors, particularly transforming growth
to find overlapping and progressive transformation of lupus factor-β. Strict control of blood glucose level and control
lesions during the course of disease. of systemic hypertension in these patients retards
progression to diabetic nephropathy.
Diabetic Nephropathy Glomerulosclerosis in diabetes may take one of the 2
Renal involvement is an important complication of diabetes forms: diffuse or nodular lesions: CHAPTER 22
mellitus. End-stage kidney with renal failure accounts for i) Diffuse glomerulosclerosis. Diffuse glomerular
deaths in more than 10% of all diabetics. Renal complications lesions are the most common. There is involvement of all
are more severe, develop early and more frequently in parts of glomeruli. The pathologic changes consist of
type 1 (earlier called insulin-dependent) diabetes mellitus thickening of the GBM and diffuse increase in mesangial
(30-40% cases) than in type 2 (earlier termed non-insulin- matrix with mild proliferation of mesangial cells. Various
dependent) diabetics (about 20% cases). A variety of clinical exudative lesions such as capsular hyaline drops and fibrin
syndromes are associated with diabetic nephropathy that caps may also be present (Fig. 22.24,A) Capsular drop is an
includes asymptomatic proteinuria, nephrotic syndrome, eosinophilic hyaline thickening of the parietal layer of
progressive renal failure and hypertension. Cardiovascular Bowman’s capsule and bulges into the glomerular space. The Kidney and Lower Urinary Tract
Figure 22.24 Diabetic glomerulosclerosis. A, Diffuse lesions. The characteristic features are dif fuse involvement of the glomeruli showing
thickening of the GBM and diffuse increase in the mesangial matrix with mild proliferation of mesangial cells and exudative lesions (fibrin caps and
capsular drops). B, Nodular lesion (Kimmelstiel-Wilson Lesion). There are one or more hyaline nodules within the lobules of glomeruli, surrounded
peripherally by glomerular capillaries with thickened walls.
678 high blood sugar level, the epithelial cells of the proximal
convoluted tubules develop extensive glycogen deposits
appearing as vacuoles. These are called Armanni-Ebstein
lesions. The tubules return to normal on control of
hyperglycaemic state.
Hereditary Nephritis
A group of hereditary diseases principally involving the
glomeruli are termed hereditary nephritis. These include the
following:
1. Alport’s syndrome
2. Fabry’s disease
3. Nail-patella syndrome
1. Alport’s syndrome. Out of various hereditary nephritis,
Alport’s syndrome is relatively more common and has been
extensively studied. This is an X-linked dominant disorder
having mutation in α−5 chain of type IV collagen located on
X-chromosome. It affects males more severely than females.
The syndrome consists of sensori-neural deafness and
Figure 22.25 Diabetic nephropathy—nodular (Kimmelstiel-W ilson
or KW) lesions. ophthalmic complications (lens dislocation, posterior
cataracts and corneal dystrophy) associated with hereditary
Fibrin cap is homogeneous, brightly eosinophilic material nephritis. The condition is slowly progressive, terminating
appearing on the wall of a peripheral capillary of a lobule. in end-stage kidney in the 2nd to 3rd decades of life. The
ii) Nodular glomerulosclerosis. Nodular lesions of common presenting features are persistent or recurrent
diabetic glomerulosclerosis are also called as Kimmelstiel- haematuria accompanied by erythrocyte casts, proteinuria
Wilson (KW) lesions or intercapillary glomerulosclerosis. and hypertension.
These lesions are specific for type 1 diabetes (juvenile-
onset diabetes) or islet cell antibody-positive diabetes By light microscopy, the glomeruli have predominant
SECTION III
mellitus. The pathologic changes consist of one or more involvement and show segmental proliferation of
nodules in a few or many glomeruli. Nodule is an ovoid or mesangial cells with increased mesangial matrix and
spherical, laminated, hyaline, acellular mass located occasional segmental sclerosis. Another prominent feature
within a lobule of the glomerulus. The nodules are is the presence of lipid-laden foam cells in the interstitium.
surrounded peripherally by glomerular capillary loops As the disease progresses, there is increasing sclerosis of
which may have normal or thickened GBM (Fig. 22.24,B). glomeruli, tubular atrophy and interstitial fibrosis.
The nodules are PAS-positive and contain lipid and fibrin. Electron microscopy reveals characteristic basement
As the nodular lesions enlarge, they compress the glomer- membrane splitting or lamination in the affected parts of
ular capillaries and obliterate the glomerular tuft glomeruli.
(Fig. 22.25). As a result of glomerular and arteriolar Immunofluorescence studies fail to show deposits of
involvement, renal ischaemia occurs leading to tubular immunoglobulins or complement components.
Systemic Pathology
atrophy and interstitial fibrosis and grossly small,
contracted kidney. 2. Fabry’s disease, another hereditary nephritis is
characterised by accumulation of neutral glycosphingolipids
2. VASCULAR LESIONS. Atheroma of renal arteries is in lysosomes of glomerular, tubular, vascular and interstitial
very common and severe in diabetes mellitus. Hyaline cells.
arteriolosclerosis (Chapter 15) affecting the afferent and 3. Nail-patella syndrome or osteonychodysplasia is a rare
efferent arterioles of the glomeruli is also often severe in hereditary disease having abnormality in α-1 chain of
diabetes. These vascular lesions are responsible for renal collagen V on chromosome 9 associated with multiple
ischaemia that results in tubular atrophy and interstitial osseous defects of elbows, knees and nail dysplasia. About
fibrosis.
half the cases develop nephropathy.
3. DIABETIC PYELONEPHRITIS. Poorly-controlled
diabetics are particularly susceptible to bacterial infec- TUBULAR AND TUBULOINTERSTITIAL DISEASES
tions. Papillary necrosis (necrotising papillitis) (page 682)
is an important complication of diabetes that may result It is difficult to separate the involvement of the tubules and
in acute pyelonephritis. Chronic pyelonephritis is 10 to the interstitium since most forms of tubular diseases also
20 times more common in diabetics than in others. involve the interstitium, while the tubules and interstitium
may be involved secondarily as a part of the diseases of other
4. TUBULAR LESIONS (ARMANNI-EBSTEIN renal components. For the purpose of present discussion, this
LESIONS). In untreated diabetics who have extremely
group of diseases is discussed under 2 headings:
I. Primary tubular diseases that include tubular injury by 679
ischaemic or toxic agents i.e. acute tubular necrosis.
II. Tubulointerstitial diseases that include inflammatory
involvement of the tubules and the interstitium i.e.
tubulointerstitial nephritis.
ACUTE TUBULAR NECROSIS
Acute tubular necrosis (ATN) is the term used for acute renal
failure (ARF) resulting from destruction of tubular epithe-
lial cells. ATN is the most common and most important cause
of ARF characterised by sudden cessation of renal function.
Various other causes of ARF (pre-renal, intra-renal and post-
renal) as well as the clinical syndrome accompanying ATN
(oliguric phase, diuretic phase and phase of recovery) are
described already on page 654. Based on etiology and
morphology, two forms of ATN are distinguished—
ischaemic and toxic; however both forms have a somewhat
common pathogenesis.
Pathogenesis of ATN
The pathogenesis of both types of ATN resulting in ARF is
explained on the basis of the following sequential mechanism
and is illustrated in Fig. 22.26:
i) Renal tubules are highly susceptible to injury by ischaemia
and toxic agents. CHAPTER 22
ii) Tubular damage in ischaemic ATN is initiated by arteriolar
vasoconstriction induced by renin-angiotensin system, while
in toxic ATN by direct damage to tubules by the agent.
iii) Debris of the desquamated epithelium due to necrosis Figure 22.26 Pathogenesis of ATN.
causes tubular obstruction and may block urinary outflow with
consequent reduction of GFR and also produce casts in the 1. Shock (post-traumatic, surgical, burns, dehydration,
urine. obstetrical and septic type).
iv) These events cause increased intratubular pressure resulting 2. Crush injuries.
in damage to tubular basement membrane. 3. Non-traumatic rhabdomyolysis induced by alcohol,
v) Due to increased intratubular pressure, there is tubular coma, muscle disease or extreme muscular exertion
rupture. (myoglobinuric nephrosis).
vi) Damage to tubules is accompanied with leakage of fluid 4. Mismatched blood transfusions, black-water fever The Kidney and Lower Urinary Tract
into the interstitium causing interstitial oedema. (haemoglobinuric nephrosis).
vii)Leakage of tubular fluid into the interstitium increases MORPHOLOGIC FEATURES. Grossly, the kidneys are
interstitial pressure. enlarged and swollen. On cut section, the cortex is often
viii) Leaked fluid incites host inflammatory response. widened and pale, while medulla is dark.
ix) Increased interstitial pressure causes compression of tubules Histologically, predominant changes are seen in the
and blood vessels and setting up a vicious cycle of accentuated tubules, while glomeruli remain unaffected. The
ischaemia and necrosis. interstitium shows oedema and mild chronic
x) Ultimately, it leads to reduced GFR and consequently inflammatory cell infiltrate. Tubular changes are as follows
oliguria. (Fig. 22.27):
1. Dilatation of the proximal and distal convoluted
Ischaemic ATN tubules.
2. Focal tubular necrosis at different points along the
Ischaemic ATN, also called tubulorrhectic ATN, lower nephron.
(distal) nephron nephrosis, anoxic nephrosis, or shock 3. Flattened epithelium lining the tubules suggesting
kidney, occurs due to hypoperfusion of the kidneys resulting epithelial regeneration.
in focal damage to the distal parts of the convoluted tubules. 4. Eosinophilic hyaline casts or pigmented haemoglobin
ETIOLOGY. Ischaemic ATN is more common than toxic and myoglobin casts in the tubular lumina (Fig. 22.28).
ATN and accounts for more than 80% cases of tubular injury. 5. Disruption of tubular basement membrane adjacent
Ischaemia may result from a variety of causes as follows: to the cast may occur (tubulorrhexis).
680 ETIOLOGY. The toxic agents causing toxic ATN are as
under:
1. General poisons such as mercuric chloride, carbon
tetrachloride, ethylene glycol, mushroom poisoning and
insecticides.
2. Heavy metals (mercury, lead, arsenic, phosphorus and
gold).
3. Drugs such as sulfonamides, certain antibiotics (genta-
mycin, cephalosporin), anaesthetic agents (methoxyflurane,
halothane), barbiturates, salicylates.
4. Radiographic contrast material.
MORPHOLOGIC FEATURES. Poisoning with mercuric
chloride provides the classic example that produces
widespread and readily discernible tubular necrosis (acute
mercury nephropathy).
Grossly, the kidneys are enlarged and swollen. On cut
Figure 22.27 Ischaemic ATN. There is focal necrosis along the section, the cortex is pale and swollen, while the medulla
nephron involving proximal convoluted tubule (PCT) as well as distal is slightly darker than normal.
convoluted tubule (DCT). The affected tubules are dilated, their lumina Histologically, the appearance varies according to the
contain casts (hyaline or pigmented haem) and the affected regions are cause of toxic ATN but, in general, involves the segment
lined by regenerating thin and flat epithelium.
of tubule diffusely (unlike ischaemic ATN where the
involvement of nephron is focal). In mercuric chloride
Prognosis of ischaemic ATN depends upon the underlying poisoning, the features are as follows (Fig. 22.28):
etiology. In general, cases that follow severe trauma, surgical 1. Epithelial cells of mainly proximal convoluted tubules
procedures, extensive burns and sepsis have much worse are necrotic and desquamated into the tubular lumina.
outlook than the others. 2. The desquamated cells may undergo dystrophic
calcification.
3. Tubular basement membrane is generally intact.
Toxic ATN
SECTION III
4. The regenerating epithelium, which is flat and thin
Toxic ATN, also called nephrotoxic ATN or toxic nephrosis with few mitoses, may be seen lining the tubular basement
or upper (proximal) nephron nephrosis, occurs as a result membrane.
of direct damage to tubules, more marked in proximal
portions, by ingestion, injection or inhalation of a number of Prognosis of toxic ATN is good if there is no serious
toxic agents. damage to other organs such as heart and liver.
The contrasting features of the two forms of ATN are
presented in Table 22.12.
TUBULOINTERSTITIAL DISEASES
The term tubulointerstitial nephritis is used for inflammatory
Systemic Pathology
process that predominantly involves the renal interstitial
tissue and is usually accompanied by some degree of tubular
damage. A number of primary glomerular, tubular, vascular
and obstructive diseases are secondarily associated with
interstitial reaction. However, the term interstitial nephritis is
reserved for those cases where there is no primary
involvement of glomeruli, tubules or blood vessels. The older
nomenclature, interstitial nephritis, is currently used syno-
nymously with tubulointerstitial nephritis or tubulointerstitial
nephropathy.
A number of bacterial and non-bacterial, acute and
chronic conditions may produce tubulointerstitial nephritis
and are listed in Table 22.13. The important and common
examples among these are discussed below.
Figure 22.28 Toxic ATN. There is extensive necrosis of epithelial
cells involving predominantly proximal convoluted tubule (PCT) diffusely. Acute Pyelonephritis
The necrosed cells are desquamated into the tubular lumina and may
undergo dystrophic calcification. The tubular lumina cont ain casts Acute pyelonephritis is an acute suppurative inflammation
(granular) and the regenerating flat epithelium lines the necrosed tubule. of the kidney caused by pyogenic bacteria.
681
TABLE 22.12. Contrasting Features of Ischaemic and Toxic ATN.
Feature Ischaemic ATN Toxic ATN
1. Synonyms Tubulorrhectic ATN, lower (distal) nephron Nephrotoxic ATN, upper (proximal) nephron
nephrosis, anoxic nephrosis, shock kidney nephrosis, toxic ATN
2. Frequency More common (80% cases) Less common
3. Major etiologies Shock, crush injuries, mismatched blood Poisons, heavy metals, certain drugs
transfusion
4. G/A Kidneys enlarged, swollen, cut section Similar to ischaemic ATN
cortex pale, medulla dark
5. M/E i) Distal tubular damage more prominent i) Proximal tubular damage more prominent
ii) Focal tubular necrosis ii) More diffuse tubular injury
iii) Regenerating epithelium iii) Regenerating epithelium
iv) Casts: Hyaline, pigment, myoglobin iv) Tubular lumina may contained dystrophic
calcification
v) Basement membrane disrupted v) Basement membrane generally intact
6. Prognosis Worse Good
ETIOPATHOGENESIS. Most cases of acute pyelonephritis diabetes mellitus, pregnancy, urinary tract obstruction or
follow infection of the lower urinary tract. The most instrumentation. Bacteria multiply in the urinary bladder and
common pathogenic organism in urinary tract infection produce asymptomatic bacteriuria found in many of these
(UTI) is Escherichia coli (in 90% of cases), followed in cases. After having caused urethritis and cystitis, the bacteria
decreasing frequency, by Enterobacter, Klebsiella, in susceptible cases ascend further up into the ureters against
Pseudomonas and Proteus. The bacteria gain entry into the the flow of urine, extend into the renal pelvis and then the
urinary tract, and thence into the kidney by one of the two renal cortex. The role of vesico-ureteral reflux is not of a great CHAPTER 22
routes: ascending infection and haematogenous infection significance in the pathogenesis of acute chronic pyelo-
(Fig. 22.29): nephritis as it is in chronic pyelonephritis.
1. Ascending infection. This is the most common route of 2. Haematogenous infection. Less often, acute pyelo-
infection. The common pathogenic organisms are inhabitants nephritis may result from blood-borne spread of infection.
of the colon and may cause faecal contamination of the This occurs more often in patients with obstructive lesions
urethral orifice, especially in females in reproductive age
group. This has been variously attributed to shorter urethra
in females liable to faecal contamination, hormonal influences
facilitating bacterial adherence to the mucosa, absence of
prostatic secretions which have antibacterial properties, and
urethral trauma during sexual intercourse. The last named
produces what is appropriately labelled as ‘honeymoon
pyelitis’. Ascending infection may occur in a normal indi- The Kidney and Lower Urinary Tract
vidual but the susceptibility is increased in patients with
TABLE 22.13: Tubulointerstitial Diseases.
A. INFECTIVE
1. Acute pyelonephritis
2. Chronic pyelonephritis
3. Tuberculous pyelonephritis
4. Other infections (viruses, parasites etc)
B. NON-INFECTIVE
1. Acute hypersensitivity interstitial nephritis
2. Analgesic abuse (phenacetin) nephropathy
3. Myeloma nephropathy
4. Balkan nephropathy
5. Urate nephropathy
6. Gout nephropathy
7. Radiation nephritis
8. Transplant rejection (page 65)
9. Nephrocalcinosis
10. Idiopathic interstitial nephritis Figure 22.29 Pathogenesis of reflux nephropathy.
682 in the urinary tract, and in debilitated or immunosuppressed
patients.
MORPHOLOGIC FEATURES. Grossly, well-developed
cases of acute pyelonephritis show enlarged and swollen
kidney that bulges on section. The cut surface shows small,
yellow-white abscesses with a haemorrhagic rim. These
abscesses may be several millimetres across and are
situated mainly in the cortex.
Microscopically, acute pyelonephritis is characterised by
extensive acute inflammation involving the interstitium
and causing destruction of the tubules. Generally, the
glomeruli and renal blood vessels show considerable
resistance to infection and are spared. The acute
inflammation may be in the form of large number of
neutrophils in the interstitial tissue and bursting into
tubules, or may form focal neutrophilic abscesses in the
renal parenchyma.
CLINICAL FEATURES. Classically, acute pyelonephritis has
an acute onset with chills, fever, loin pain, lumbar tenderness, Figure 22.30 Pyonephrosis. The kidney is enlarged and has
dysuria and frequency of micturition. Urine will show increased perinephric fat in the hilum. Sectioned surface shows markedly
dilated pelvis and calyces having irregular and ragged inner surface and
bacteria in excess of 100,000/ml, pus cells and pus cell casts containing necrotic debris and pus.
in the urinary sediment. Institution of specific antibiotics,
after identification of bacteria by culture followed by
sensitivity test, eradicates the infection in majority of patients. bed—reflux nephropathy and obstructive pyelonephritis
(Fig. 22.31):
COMPLICATIONS. Complications of acute pyelonephritis 1. Reflux nephropathy. Reflux of urine from the bladder
are encountered more often in patients with diabetes mellitus into one or both the ureters during micturition is the major
or with urinary tract obstruction. Following are the three cause of chronic pyelonephritis. Vesicoureteric reflux is
SECTION III
important complications of acute pyelonephritis:
particularly common in children, especially in girls, due to
1. Papillary necrosis. Papillary necrosis or necrotising congenital absence or shortening of the intravesical portion
papillitis develops more commonly in analgesic abuse of the ureter so that ureter is not compressed during the act
nephropathy and in sickle cell disease but may occur as a of micturition. Reflux results in increase in pressure in the
complication of acute pyelonephritis as well. It may affect renal pelvis so that the urine is forced into renal tubules which
one or both kidneys. is eventually followed by damage to the kidney and scar
formation (Fig. 22.29). Vesicoureteric reflux is more common
Grossly, the necrotic papillae are yellow to grey-white, in patients with urinary tract infection, whether symptomatic
sharply-defined areas with congested border and resemble or asymptomatic, but reflux of sterile urine can also cause
infarction. The pelvis may be dilated. renal damage.
Microscopically, necrotic tissue is separated from the
Systemic Pathology
viable tissue by a dense zone of polymorphs. The necrotic 2. Obstructive pyelonephritis. Obstruction to the outflow
area shows characteristic coagulative necrosis as seen in of urine at different levels predisposes the kidney to infection
renal infarcts. (page 690). Recurrent episodes of such obstruction and
infection result in renal damage and scarring. Rarely,
2. Pyonephrosis. Rarely, the abscesses in the kidney in recurrent attacks of acute pyelonephritis may cause renal
acute pyelonephritis are extensive, particularly in cases with damage and scarring.
obstruction. This results in inability of the abscesses to drain
and this transforms the kidney into a multilocular sac MORPHOLOGIC FEATURES. Grossly, the kidneys show
filled with pus called as pyonephrosis or renal carbuncle rather characteristic appearance. The kidneys are usually
(Fig. 22.30). small and contracted (weighing less than 100 gm) showing
unequal reduction, which distinguishes it from other
3. Perinephric abscess. The abscesses in the kidney may forms of contracted kidney. The surface of the kidney is
extend through the capsule of the kidney into the perinephric irregularly scarred; the capsule can be stripped off with
tissue and form perinephric abscess. difficulty due to adherence to scars. These scars are of
variable size and show characteristic U-shaped
Chronic Pyelonephritis depressions on the cortical surface. There is generally
Chronic pyelonephritis is a chronic tubulointerstitial disease blunting and dilatation of calyces (calyectasis) and dilated
resulting from repeated attacks of inflammation and scarring. pelvis of the kidney (Fig. 22.32).
Microscopically, predominant changes are seen in
ETIOPATHOGENESIS. Depending upon the etiology and
pathogenesis, two types of chronic pyelonephritis are descri- interstitium and (Fig. 22.33):
683
Figure 22.31 The two major types of mechanisms in chronic pyelonephritis. A, Vesicoureteric reflux causing infection of peripheral papillae
and consequent scars at the poles of the kidney. B, Obstructive pyelonephritis due to obstruction of the urinary tract causing high pressure backflow
of urine and infection of all the papillae and consequent dif fuse scarring of the kidney and thinning of the cortex.
i) Interstitium—There is chronic interstitial inflam- iii) Pelvicalyceal system—The renal pelvis and calyces CHAPTER 22
matory reaction, chiefly composed of lymphocytes, are dilated. The walls of pelvis and calyces show marked
plasma cells and macrophages with pronounced chronic inflammation and fibrosis. Lymphoid follicles
interstitial fibrosis. Xanthogranulomatous pyelonephritis is with germinal centres may be present in the pelvicalyceal
an uncommon variant characterised by collection of foamy walls. The lining epithelium may undergo squamous
macrophages admixed with other inflammatory cells and metaplastic change.
giant cells. iv) Blood vessels—Blood vessels entrapped in the scarred
ii) Tubules—The tubules show varying degree of areas show obliterative endarteritis. There may be changes
atrophy and dilatation. Dilated tubules may contain of hypertensive hyaline arteriolosclerosis.
eosinophilic colloid casts producing thyroidisation of v) Glomeruli—Though glomerular tuft in the scarred
tubules. A few tubules may contain neutrophils. area is usually intact, there is often periglomerular fibrosis. The Kidney and Lower Urinary Tract
Figure 22.32 Small contracted kidney in chronic pyelonephritis with calyectasis. A, Diagrammatic representation. B, External surface of small
and contracted kidney. The kidney is small in size and contracted. The capsule is adherent to the cortex and has irregular scar s on the surface.
C, Sectioned surface shows dilated pelvi-calyceal system with atrophied and thin peripheral cortex and increased hilar fat exte nding inside.
684
Figure 22.33 Chronic pyelonephritis. The scarred area shows atrophy of some tubules and dilat ation of others which contain colloid cast s
(thyroidisation). The tubules are surrounded by abundant fibrous tissue and chronic interstitial inflammatory reaction. The blo od vessels included
are thick-walled and the glomeruli show periglomerular fibrosis.
In advanced cases, there may be hyalinisation of in whom there is persistent sterile pyouria, microscopic
glomeruli. haematuria and mild proteinuria after effective antibiotic
therapy for urinary tract infection. The diagnosis rests on
CLINICAL FEATURES. Chronic pyelonephritis often has identification of M. tuberculosis by repeated culture of urine
an insidious onset. The patients present with clinical picture on L.J. media.
of chronic renal failure or with symptoms of hypertension.
Sometimes, the patients may present with features of acute Myeloma Nephropathy
SECTION III
recurrent pyelonephritis with fever, loin pain, lumbar
tenderness, dysuria, pyouria, bacteriuria and frequency of Renal involvement in multiple myeloma (Chapter 14) is
micturition. Diagnosis is made by intravenous pyelography referred to as myeloma nephropathy or myeloma kidney.
(IVP). Culture of the urine may give positive results. Functional renal impairment in multiple myeloma is a
Longstanding cases of chronic pyelonephritis may develop common manifestation, developing in about 50% of patients.
secondary systemic amyloidosis. The pathogenesis of myeloma kidney is related to excess
filtration of Bence Jones proteins through the glomerulus,
usually kappa (κ) light chains. These light chain proteins are
Tuberculous Pyelonephritis precipitated in the distal convoluted tubules in combination
with Tamm-Horsfall proteins, the urinary glycoproteins. The
Tuberculosis of the kidney occurs due to haematogenous
spread of infection from another site, most often from the precipitates form tubular casts which are eosinophilic and
Systemic Pathology
lungs. Less commonly, it may result from ascending infection often laminated. These casts may induce peritubular inter-
from tuberculosis of the genitourinary system such as from stitial inflammatory reaction. Not all light chains are
epididymis or Fallopian tubes. The renal lesions in nephrotoxic and their toxicity occurs under acidic pH of the
tuberculosis may be in the form of tuberculous pyelonephritis tubular fluid.
or appear as multiple miliary tubercles.
MORPHOLOGIC FEATURES. Grossly, the kidneys may
be normal or small and shrunken.
MORPHOLOGIC FEATURES. Grossly, the lesions in
tuberculous pyelonephritis are often bilateral, usually Histologically, there are some areas of tubular atrophy
involving the medulla with replacement of the papillae while many other tubular lumina are dilated and contain
by caseous tissue. Obstruction may result in tuberculous characteristic bright pink laminated cracked or fractured
pyonephrosis in which thinned out renal parenchyma casts consisting of Bence-Jones proteins called fractured
surrounds dilated pelvis and calyces filled with caseous casts. These casts are surrounded by peritubular
material. interstitial inflammatory reaction including the presence
Histologically, typical granulomatous reaction is seen. of nonspecific inflammatory cells and some multinucleate
Acid-fast bacilli can often be demonstrated in the lesions. giant cells induced by tubular casts.
Nephrocalcinosis
CLINICAL FEATURES. Most patients are young to middle-
aged adults. The clinical presentation is extremely variable Nephrocalcinosis is a diffuse deposition of calcium salts in
but it should always be considered as a possibility in a patient renal tissue in a number of renal diseases, in hypercalcaemia,
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Textbook of Pathology, 6th Edition
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