RENAL DISEASE

DR ANTENEH.B(MD,PATHOLOGIST)
CLINICAL MANIFESTATIONS OF RENAL
DISEASES
Azotemia
- Biochemical abnormality that refer to an elevation of the
BUN & creatinine levels & is related to decreased GFR
- Causes

 Prerenal- occurs when there is hypoperfusion of the

kidneys

 Renal –due to intrinsic disease of the kidney

 Postrenal- occurs when urine flow is obstructed below

the level of the kidney
Uremia
 azotemia plus clinical signs/symptoms
 Gastrointestinal – nausea, vomiting, gastritis, colitis
 Neuromuscular – neuropathy, encephalopathy
 Dermatologic – pruritus, dermatitis
 Fluid and electrolyte imbalance – dehydration, edema
 Calcium phosphate and bone – hypocalcemia
 Hematologic – anemia, bleeding
 Cardiopulmonary – hypertension, CHF, pulmonary
edema
Acute nephritic syndrome
 A glomerular syndrome dominated by
 The acute onset usually of grossly visible hematuria
(red blood cells in urine)

 Mild to moderate proteinuria

 Hypertension

 Diffuse edema specially in periorbital area

The nephrotic syndrome
 It is characterized by
 Heavy proteinuria (more than 3.5gm/day)

 Hypoalbuminemia

 Severe edema

 Hyperlipedemia

 Lipiduria
Acute renal failure
 It implies a rapid & frequently reversible deterioration
of renal function.

 Acute renal failure is dominated by oliguria or anuria

with recent onset of azotemia.

 It can result from

 Glomerular disease
 interstitial or vascular disease
 or acute tubular necrosis.
Chronic renal failure
 It characterized by prolonged symptoms & signs of
uremia

 is the end result of all chronic parenchymal diseases.

 The most important causes include

 diabetes mellitus
 hypertension
 glomerulonephritis
 Chronic renal failure progresses through four stages
1. diminished renal reserve
 the GFR is about 50% of normal.
 Serum BUN & creatinine values are normal
 & the patients are asymptomatic

2.renal insufficiency
 the GFR is 20% to 50% of normal.
 Azotemia appears, usually associated with anemia &
hypertension
3. Chronic renal failure
 the GFR is less than 20% to 25% of normal
 Disruption volume & solute composition
 patients develop edema, metabolic acidosis &
hypocalcemia.
 Overt uremia

4. end-stage renal disease

 the GFR is less than 5% of normal; this is the terminal
stage of uremia
CONGENITAL ANOMALIES
 approximately 10% of newborns have potentially
significant malformations of the urinary system

 renal dysplasias and hypoplasias account for 20% of

pediatric chronic renal failure.

 Most arise from acquired developmental defects rather

than as hereditable lesions
Agenesis of the kidney
 Total bilateral agenesis is incompatible with life.

 But unilateral agenesis is uncommon anomaly but is

compatible with normal life .
 The opposite kidney is usually enlarged as a result of
compensatory hypertrophy later leading to chronic
renal failure.
Hypoplasia
 It refers to failure of the kidneys to develop into a
normal size.

 It may occur bilaterally but is more commonly unilateral.

 A truly hypoplastic kidney shows no scars & has a

reduced number of renal lobes & pyramids
Ectopic Kidneys
 a congenital condition in which a kidney is not located
in its normal position

 above the pelvic brim or in the pelvic

 kinking / tortousity of ureters may cause obstruction to

urine flow – infection
Horseshoe Kidneys
 Fusion of the upper or lower poles of the kidneys
produces a horseshoe - shaped structure that is
continuous across the midline anterior to the great
vessels.

 90% of such kidneys are fused at the lower pole, & 10%
are fused at the upper pole

 The anomaly is common & is found in about 1 in 500 to

1000 autopsies.
Multicystic Renal Dysplasia
 sporadic disorder resulting from abnormal metanephric
differentiation

 it can be unilateral or bilateral.

 Most cases are associated with obstructive

abnormalities of the ureter and lower urinary tract
 Grossly
 Affected kidneys are enlarged and multicystic with
abnormal lobar organization

 Histologically
 there are immature ducts surrounded by undifferentiated
mesenchyme, often with cartilage formation.
Cystic Diseases of the Kidney
 Cystic disease of the kidney are heterogenous group
comprising hereditary, developmental & acquired
disorders.

 causes CRF

 confused with renal tumors

Autosomal-Dominant (adult) Polycystic Kidney
Disease
 Inherited autosomal dominant trait.

 Commonest form of congenital cystic disease.

 The kidneys contain bilateral large number of cysts

which enlarge throughout life & destroy the renal
parenchyma & cause renal failure.

 50% of patients develop HTN or uremia in fourth or fifth

decade of life.
Pathogenesis
 ADPKD is caused in most cases by mutations in one of two
genes

 PKD1 mutations (chromosome 16p) account for about 85% of

cases.

 PKD1 encodes polycystin 1, protein

that localizes to tubular epithelial cells

 and has domains that are usually involved in cell-cell and cell-
matrix interactions
 It is thought that the resultant defects in cell-matrix
interactions may lead to alterations in growth,
differentiation, and matrix production by tubular
epithelial cells and to cyst formation.
 PKD2 gene, implicated in 10% of all cases, resides on
chromosome 4

 encodes polycystin-2 which functions as a Ca2+-

permeable cation channel

 Although structurally distinct, polycystins 1 and 2 are

believed to act together by forming heterodimers.

 Thus, mutation in either gene gives rise to the same

phenotype.
Morphology
 Gross
 Kidneys are massively enlarged and composed almost
entirely of cysts up to 3 to 4 cm in diameter.
 Cysts arise anywhere along the nephron and compress
adjacent parenchyma

 Microscopy
 Cysts are lined by cuboidal or flattened epithelium,
may have papillary projections or polyps
Clinical features
 Polycystic kidney disease in adults usually does not
produce symptoms until the fourth decade

 The most common complaint of the patient is flank pain

or at least a heavy, dragging sensation.

 Hypertension of varying severity develops in about 75%

of patients.

 End-stage renal failure occurs at about age 50

 Patients tend to have extrarenal anomalies such as:

 Polycytic liver disease -Asymptomatic liver cysts occur

in one third of patients.

 Intracranial berry aneurysm- Saccular aneurysms (of the

circle of Willis) are present in 10% to 30% of patients
Autosomal-Recessive (childhood) Polycystic Kidney
Disease
 inherited in an autosomal recessive

 The kidneys are affected bilaterally, so that in utero,

there is typically oligohydraminos.

 This lead to plumonary hypoplesia so that newborns do

not have sufficient lung capacity to survive

 Patients who survive infancy may develop congenital

hepatic fibrosis
 In most cases, the disease is caused by mutations of
PKHD1 (chromosome ), encoding for fibrocystin
 Grossly
 The kidneys are enlarged and have a smooth external
appearance.

 Oncut section, numerous small cysts in the cortex

and medulla give the kidney a spongelike appearance
 Microscopically
 cylindrical or, less commonly, saccular dilation

of all collecting tubules.

 The cysts have a uniform lining of cuboidal cells,

reflecting their origin from the collecting ducts

 Inalmost all cases the liver has cysts associated with

portal fibrosis
Simple Cysts
 These occur as multiple or single

 usually cortical ranging 1 to 5cm in diameter.

 They are translucent, lined by a gray, glistening, smooth

membrane, and filled with clear fluid.

 They are usually postmortem finding without clinical

significance.
Glomerular Diseases
 Diseases that injure glomeruli

 constitute some of the major problems in nephrology

 Primary- the kidney is the only or predominant organ

involved

 Secondary- when the glomeruli are affected in the

course of a variety of systemic disease like SLE, HTN,
DM
Pathologic Responses of the Glomerulus to Injury
 Various types of glomerulopathies are characterized by
one or more of four basic tissue reactions
1-Hypercellularity
 Increase in the number of cells in the glomerular tufts

 This hypercellularity results from one or more of the

following:
 Cellular proliferation of mesangial or endothelial cells

 Leukocytic infiltration , consisting of neutrophils,

monocytes or lymphocytes

 Formation of crescents -These are accumulations of

cells composed of proliferating parietal epithelial
cells.
2-Basement membrane thickening
 By light microscopy , this change appear as thickening
of the capillary walls.

 Such thickenings can be due to

 Deposition of amorphous electron dense material,
most often immune complexes, on the endothelial or
epithelial side of the basement membrane
3-Hyalinization & Sclerosis
 Hylainization means accumulation of material that is
homogenous & eosinophilic by light microscopy.

 By electron microscopy, the hyaline is extracellular &

consists of amorphous substance made up of plasma
proteins that have exuded from plasma into glomerular
structures.

 Hyalinosis is the result of endothelial or capillary wall

damage.

 Sclerosis is characterized by accumulations of

extracellular collagenous
4-Intraglomerular thrombosis or accumulation of lipid
 The histologic changes can be further subdivided into
 focal (only in some glomeruli) or diffuse (in all or almost
all the glomeruli)

 and segmental (only a part of the glomerulus) or global

(the entire glomerulus)
Pathogenesis of glomerular injury
 Most forms of primary & secondary glomerulonephritis
are immune mediated

 Most are due to injury caused by Ag-Ab complexes in

the walls of the glomerular capillaries

 Two forms of antibody– associated injury have been

established
1.In situ immune complex deposition
 Antibodies react directly with intrinsic glomerular
antigens or antigens planted in the glomerulus

 Heymann nephritis
 It is an experimental rat model of GN that involves
immunization with renal tubular protein
 immunized rat develop antibodies to a megalin protein
antigen expressed on visceral epithelial cells
 The rats develop membranous nephropathy, resembling
human membranous nephropathy

 On electron microscopy the glomerulopathy is

characterized by the presence of numerous discrete
electron-dense deposits along the subepithelial aspect of
the basement membrane.

 The pattern of immune deposition by

immunofluorescence microscopy is granular rather than
linear
 These subepithelial complexes, with resultant host
responses, can result in a thickened basement membrane
appearance by light microscopy; hence the term
membranous nephropathy

 in the majority of human membranous GN the antigen

that drives a similar process is M-type phospholipase A2
receptor (PLA2R)
 Antibodies against Planted Antigens
 Antibodies react in situ with antigens that are not
normally present in the glomerulus but are “planted” there
 Planted antgnes includes
 DNA
 nucleosomes
 microbial products
 Drugs and
 aggregated proteins
 Immunofluorescence staining shows granular depositis
 Anti-GBM antibody-induced glomerulonephritis
 is an autoimmune disease in which antibodies are
directed against intrinsic fixed antigens of the GBM

 the classic anti-GBM disorder is Goodpasture syndrome,

where the autoantibody binds the
noncollagenous domain of the a3 chain of type IV
collagen.

 Such autoantibodies typically yield a linear

immunofluorescence staining pattern
2 .Circulating Immune Complex Glomerulonephritis
 Glomerular injury is caused by the trapping of circulating
antigen antibody complexes within glomeruli
 The antigen may be endogenous like in SLE or exogenous
like that follows certain infections
 Immune complex deposits can be
subendothelial, subepithelial, or mesangial
 immunofluorescence staining shows a granular pattern
 Mechanisms of Glomerular Injury Following Immune
Complex Formation
 Whatever the antigen may be, antigen-antibody
complexes formed or deposited in the glomeruli may
elicit a local inflammatory reaction that produces injury.
 The antibodies may activate complement and engage Fc
receptors on leukocytes and perhaps glomerular
mesangial or other cells, leading to inflammation.
 The glomerular lesions may exhibit leukocytic
infiltration and proliferation of mesangial and
endothelial cells.
NEPHRITIC SYNDROME
 Glomerular diseases presenting with a nephritic
syndrome are often characterized by inflammation in the
glomeruli
 The nephritic patient usually presents with
 Hematuria
 red cell casts in the urine
 azotemia and oliguria
 mild to moderate hypertension.
 Proteinuria and edema are common, but these are not as
severe as those encountered in the nephrotic syndrome
Acute Proliferative (Poststreptococcal, Postinfectious)
Glomerunephritis
 Characterized histologically by diffuse proliferation of
glomerular cells, associated with influx of leukocytes.

 These lesions are typically caused by immune

complexes.

 The most common underlying infections are

streptococcal, but the disorder also has been associated
with other infections.
Poststreptococcal Glomerulonephritis
 It usually appears 1 to 4 wks after a streptococcal
infection of the pharynx or skin (impetigo).

 Only certain strains of group A β-hemolytic streptococci

are nephritogenic.

 There are granular immune deposits in the glomeruli,

indicative of an immune complex–mediated mechanism
 The streptococcal antigenic component responsible for
the immune reaction had long eluded identification

 but many evidence suggests streptococcal pyogenic

exotoxin B (SpeB) as the principal antigenic determinant
in most but not all cases of poststreptococcal
glomerulonephritis
Morphology
 Light microscopy
 There is diffuse GN with global hypercellularity due to
neutrophil and monocyte infiltration, as well as
endothelial, mesangial, and epithelial cell proliferation.

 Immunofluorescence
 shows granular mesangial and GBM IgG, IgM, and C3
deposition.

 Electron microscopy (EM)

 shows subepithelial, humplike deposits.
Clinical features
 Classic case; young child abruptly develops malaise,
fever, nausea oliguria and hematuria 1 -4 weeks after
recovery from sore throat

 Red cell casts in the urine, mild proteinuria periobital

edema mild to moderate HTN

 More than 95% affected children eventually recover and

about 1% develop RPGN

 1-2% may undergo slow progression to chronic GN

Rapidly Progressive (Cresentric) glomerulonephritis
 Syndrome associated with severe glomerular injury & does
not denote a specific etiologic.

 It is characterized clinically by rapid & progressive loss of

renal function associated with severe oliguria and signs of
nephritic syndrome

 If untreated death from renal failure within wks to months

 The most common histologic picture is the presence of

crescents in most of the glomeruli, hence the name
crescentic glomerulonephritis
Classification & Pathogenesis
 RPGN can be caused by a number of different diseases.

 In 50% it is idiopathic.

 In general, glomerular injury is immunologically

mediated

 Based on immunologic finding, RPGN is classified into

three groups
I-Anti GBM antibody-induced disease
 It is characterized by linear deposits of Ig G & C3 in the
GBM

 In some of the patients, the anti-GBM antibodies cross-

react with pulmonary alveolar basement membrane

 This produce a clinical picture of pulmonary hemorrhage

associated with renal failure (Good pasture syndrome)

 The antigen common to the alveoli and GBM is a

peptide within the noncollagenous portion of the α3
chain of collagen type IV
II-Immune complex –mediated disease
 It is a complication of any of the immune complex
nephritides , including postinfectious
glomerulonephritis , SLE and Ig A nephropathy

 Immunoflorescence studies reveal the granular pattern

of staining characteristics of immune complex deposition
III-Pauci-immune type
 It is defined by the lack of anti-GBM antibodies or
immune complex by IF or EM.

 Most patients have antineutrophil cytoplasmic antibodies

(ANCA) which are usually associated with vasculitidis
such as wegner granulomatosis or microscopic
polyarteritis
Morphology
 Light microscopy
 distinctive crescents formed by parietal cell
proliferation and inflammatory cell migration into
Bowman space

 Immunofluorescence
 reveals linear staining in anti-GBM disease, granular
deposits in immune complex disease, and little to no
staining for pauci-immune disease.
 Electro microscopy
 classically exhibits distinct ruptures in the GBM
 subepithelial electron-dense deposits can also occur in
type II disease
Clinical Course
 All forms of RPGN typically present with hematuria, red
cell casts, moderate proteinuria, and variable
hypertension and edema.
 In Goodpasture syndrome, the course may be dominated
by recurrent hemoptysis.
 Serum analyses for anti-GBM, antinuclear antibodies,
and ANCA are diagnostically helpful.
 Renal involvement is usually progressive over the course
of a few weeks, culminating in severe
oliguria
Nephrotic syndrome
 Certain glomerular diseases virtually always produce the
nephrotic syndrome.

 In addition, many other forms of primary and secondary

glomerulopathies may underlie the syndrome
Pathophysiology
The manifestation of nephrotic syndrome include
1.Massive proteinuria
-daily loss of 3.5gm or more of protein

-Increased permeability resulting from either structural

or physiochemical alteration allow protein to escape
from the plasma into the glomerular filtrate.

-Masive proteinuria results.

 The largest proportion of protein lost in the urine is
albumin , but globulins are also excreted in some
diseases

 Highly selective proteinuria

 consists of low – molecular weight proteins ( such as
albumin , transferrin)

 Poorly selective proteinuria

 consists of high-molecular weight globulins in
addition to albumin
2. Hypoalbuminemia
 plasma albumin less than 3gm/dL

 The heavy proteinuria leads to depletion of serum

albumin

 When serum albumin levels become below the

compensatory synthetic abilities of the liver,
hypoalbuminemia occurs
3. Generalized edema
 is the consequence of the loss of colloid osmotic
pressure of the blood with subsequent accumulation of
fluid in the interstitial tissue.

 There is also sodium & water retention which aggravate

the edema.

 Edema is characteristically soft & pitting, most marked

in the periorbital regions & dependent portions of the
body
4. Hyperlipidemia & lipiduria
 The pathogenesis of hyperlipidemia is complex.

 It could be due to increased synthesis of lipoprotein in

the liver, abnormal transport of circulating lipid particles
& decreased catabolism.

 lipiduria follows hyperlipidemia because lipoproteins

leak across the glomerular capillary wall
 The patients are vulnerable to infection (especially with
staphylococci & pneumococci).
 It could be due to loss of immunoglobulins or low-
molecular weight complement components in the
urine

 Thrombotic & thromboembolic complications can be

seen
 It in part due to loss of anticoagulant factors (eg
antithrombin III) through the leaky glomeruli.
Causes
 The relative frequencies of the several causes of the
nephrotic syndrome vary according to age & geography

 Primary glomerular diseases

 Membranous GN
 Minimal change disease
 Focal segmental glomerulosclerosis
 Membranoproliferative GN
 Systemic disease
 DM
 Amyloidosis
 SLE
Membranous glomerulopathy (Membranous
nephropathy)
 It is the most common cause of the nephrotic syndrome
in adults.

 It is characterized by diffuse thickening of the

glomerular capillary wall

 due to the accumulation of electron-dense, Ig-containing

deposits along the subepithelial side of the basement
membrane.
 In about 85% of cases, no associated condition can be
uncovered - idiopathic

 It can occur also in association with other systemic

diseases & etiologic agents
 Drugs (penicillamine, captopril, gold, NSAIDs)
 Underlying malignant tumors
 SLE
 Infections such as malaria, schistosomiasis, hepatitis
B, hepatitis C
Pathogenesis
 Membranous GN is a form of chronic immune complex
nephritis.

 Although circulating complexes of known exogenous

(e.g., hepatitis B virus) or endogenous (DNA in SLE)
antigen can cause MGN

 primary (formerly idiopathic) membranous nephropathy

is an autoimmune disease caused in most cases by
antibodies to a renal autoantigen.
 A major recent advance came from the identification of
the M-type phospholipase A2 receptor (PLA2R) as the
antigen that underlies 60% to 70% of human
membranous nephropathy

 How does the glomerular capillary wall become leaky in

membranous nephropathy?

 It is postulated that C5b–C9 activates glomerular

epithelial and mesangial cells, inducing them to liberate
proteases and oxidants, which cause capillary wall injury
and increased protein leakage
Morphology
 light microscopy
 the glomeruli exhibit uniform, diffuse thickening of
the glomerular capillary wall.

 electron microscopy
 subepithelial GBM deposits is seen

 Immunoflorescence microscopy
 demonstrates diffuse GBM granular staining for Ig
and complement
Clinical course
 This disorder usually presents with the insidious onset of the
nephrotic syndrome or, in 15% of patients, with
nonnephrotic proteinuria.

 Hematuria and mild hypertension are present in 15% to 35%

of cases.

 It is necessary in any patient to first rule out the secondary

causes

 Although proteinuria persists in more than 60% of patients,

only 10% die or progress to renal failure.
Minimal Change Disease (Lipoid Nephrosis)
 Most common cause of nephrotic syndrome in children

 With a peak incidence between ages 2 and 6.

 The disease occasionally follows a respiratory infection

or routine immunization
Pathogenesis
 The current favored hypothesis is that MCD results from
immune dysfunction and elaboration of a circulating
cytokine(s) that affects visceral epithelial cells

 And loss of glomerular polyanions that form part of the

normal permeability barrier and results in increased
leakiness.
Morphology
 Light microscopy
 shows normal glomeruli.

 Immunofluorescence
 shows no immune deposits.

 Electron microscopy
 reveals diffuse effacement of the foot processes
(“fusion”) of visceral epithelial cells.
 The cells of the proximal tubules are often laden with
lipid and protein, reflecting tubular reabsorption of
lipoproteins passing through diseased glomeruli (thus,
the historical name lipoid nephrosis for this disease)
Clinical course
 Despite massive proteinuria, renal function remains good

 The proteinuria usually is highly selective, most protein

consisting of albumin.

 Most children (>90% ) with minimal change disease

respond rapidly to corticosteroid therapy.

 However in some it may recur or the patients may

become on steroid dependent or resistant.
 Focal Segmental Glomerulosclerosis
FSGS occurs as follows:
 As a primary (idiopathic) disorder; this is the most
common cause

 Secondary to other known disorders (e.g., heroin

abuse, human immunodeficiency virus [HIV]
infection, sickle cell disease, obesity).

 After glomerular necrosis due to other causes (e.g.,

IgA nephropathy).
 As an adaptive response to loss of renal tissue( e.g.,
reflux nephropathy , analgesic abuse, or unilateral
renal agenesis).

 Secondary to mutations of proteins that maintain the

glomerular filtration barrier (e.g., podocyte proteins,
such as podocin, and α- actinin 4, or slit diaphragm
proteins, such as nephrin).
Idiopathic Focal Segmental Glomerulosclerosis
 accounts for 10% and 35% of pediatric and adult
nephrotic syndrome, respectively.
 The clinical signs differ from those of minimal-change
disease in the following respects
 A greater incidence of hematuria, reduced GFR, and
hypertension.
 Proteinuria is typically nonselective.
 Poor response to corticosteroids.
 Higher rate of progression to ESRD (50% within 10
years).
Pathogenesis
 The primary glomerular lesion in all FSGS is visceral
epithelial damage (effacement or detachment) in affected
glomerular segments

 Multiple different mechanisms can cause this epithelial

damage
 including circulating cytokines and genetically
determined defects affecting components of the slit
diaphragm complex
Morphology
 Light microscopy
 is characterized by sclerosis of some but not all
glomeruli (thus focal); in affected glomeruli, only a
portion of the capillary tuft is involved (thus
segmental).
 Immunofluorescence
 show IgM and C3 in sclerotic areas or mesangium.
 Electron microscopy
 ireveals diffuse foot process effacement with focal
epithelial detachment
Clinical Course
 In addition to proteinuria (which is relatively
nonselective) patients often present with hematuria,
reduced GFR, and hypertension.

 Responses to corticosteroid therapy are variable

In general, children have a better prognosis than

adults do

 progression to chronic renal failure occurs in more than

20%
Membranoproliferative Glomerulonephritis
 It is characterized histologically by alterations in the
basement membrane, proliferation of glomerular cells &
leukocytic infiltration

 MPGN accounts for 10% to 20% of cases of nephrotic

syndrome in children & young adults

 MPGN can be associated with other systemic disorders

& known etiologic agents (secondary MPGN) or may be
idiopathic (primary MPGN)
 Pathogenesis
primary MPGN is categorized into two forms:
 Type I (most common) is most likely a consequence of
antigenantibody complex deposition and complement
activation

 The antigens in the complexes can originate from

 infection (e.g., hepatitis B or C, endocarditis, HIV)
 SLE
 or malignancy, but in most cases the source is
unknown.
 Type II (dense deposit disease) is due to activation of the
alternate complement pathway;

 most such patients have C3 nephritic factor

in the serum, an autoantibody against C3 convertase that
stabilizes C3 convertase activity

 Binding of the antibody stabilizes the convertase,

protecting it from enzymatic degradation and thus
favoring persistent C3 activation
MORPHOLOGY
 By light microscopy, both types are similar.

 The glomeruli are large and show lobular

proliferation of mesangial cells as well as infiltrating
leukocytes.

 The GBM is thickened, and the glomerular capillary

wall often shows a double contour or "tram track"
appearance
 In type I MPGN
 Electron microscopy is characterized by subendothelial electron-
dense deposits

 Immunofluorescence there is granular deposition of IgG, C3,

C1q, and C4

 Type II MPGN (dense-deposit disease)

 Electron microscopy shows deposition of dense material in
lamina densa of GBM is seen

 immunofluorescence shows irregular glomerular C3

immunofluorescence outside of the dense deposits
Clinical Features
 Most patients present in adolescence or young adulthood
with nephrotic syndrome, occasionally with hematuria.

 Although steroids may slow the progression,

approximately 50% of patients develop chronic renal
failure within 10 years.
Other Glomerular Diseases
 IG A nephropathy/Berger disease
 Characterized by presence of Ig A deposition in
mesangium of all glomeruli

 It is a frequent cause of recurrent gross or microscopic

hematuria

 is probably the most common cause of

glomerulonephritis worldwide.
Pathogenesis
 patients with IgA nephropathy, plasma polymeric IgA is
increased, and circulating IgA-containing immune
complexes are present in some patients
 genetic or acquired abnormality of immune regulation is
responsible to increased IgA synthesis in response to
respiratory or gastrointestinal exposure to environmental
agents (e.g., viruses, bacteria, food proteins).
 IgA nephropathy occurs with increased frequency in
individuals with gluten enteropathy (celiac disease)
 Morphology
 light microscopy
 glomeruli can appear nearly normal, showing only
subtle mesangial hypercellularity, or can have focal
proliferative or sclerotic lesions.

 Immunofluorescence
 reveals IgA, C3, and properdin deposition,

 Electron microscopy
 shows mesangial electrondense deposits
Clinical Features
 Patients typically present with gross or microscopic
hematuria following a respiratory, GI, or urinary
infection.

 The hematuria typically lasts for several days, then

subsides, only to recur.

 Chronic renal failure develops in 15% to 40% over a

period of 20 years
Chronic glomeruonephritis
 It is an end stage of glomeruli damage
 It due to progression of various types of
glomerulonephritis
 Occasionally no prior history of kidney disease
 The following are the percentages of glomerulonephritis
that progress to chronic GN:
 Poststreptococcal GN (1% to 2%)
 RPGN (90%)
 Membranous GN (30% to 50%)
 FSGS (50% to 80%)
 MPGN (50%)
 IgA nephropathy (30% to 50%)
 Morphology
 Grossly:
 The kidneys are symmetrically contracted with
diffusely granular surfaces and a thinned cortex
 Microscopically:
 Glomeruli are completely effaced by hyalinized
connective tissue, making it impossible to identify the
cause of the antecedent lesion
 there is marked tubular atrophy.
 Associated hypertension leads to marked arteriolar
sclerosis
Clinical features
 Loss of appetite, anemia, vomiting, weakness

 Proteinuria, hypertension, azotemia, edema

 Uremia
 Tubular and Interstitial Diseases
Two major groups of diseases
 Ischemic or toxic tubular injury leading to acute tubular
necrosis & acute renal failure

 Inflammatory reactions of the tubules & interstitium

(Tubulointerstitial nephritis)
Acute tubular necrosis
 It is characterized morphologically by destruction of
tubular epithelial cells & clinically by acute suppression
of renal function.

 ATN accounts for 50% of acute renal failure

 Causes
 Ischemic ATN
 Moss common type
 due to reduced renal perfusion

 Nephrotoxic ATN
 Due to Drugs ( genta ,cephalosporin ,….) and toxins

( mercury, insecticides , lead,…)

Pathogenesis
 The critical events in both ischemic and nephrotoxic ATI
are
(1) Tubular injury and

(2) Persistent and severe disturbances in blood flow

1) Tubular injury
 Tubular epithelial cells, especially those of proximal
tubules, are particularly sensitive to ischemia and are also
vulnerable to toxins.
 Several factors predispose the tubules to toxic injury
 increased surface area for tubular reabsorption
 active transport systems for ions and organic acids
 a high rate of metabolism and oxygen consumption that
is required to perform these transport and reabsorption
functions,
 and the capability for resorption and concentration of
toxins
 Ischemia causes numerous structural and functional
alteration in epithelial cells.

 Ischemia causes a reversible loss of cell polarity with

redistribution of membrane proteins (e.g., sodium-
potassium ATPase) from the basolateral to the luminal
surface of the tubular cells.

 Resulting in abnormal ion transport across the cells and

increased sodium delivery to distal tubules, which incites
vasoconstriction via tubuloglomerular feedback
 Ischemic tubular cells express cytokines and adhesion
molecules, thus recruiting leukocytes which participate
injury.
 In time, injured cells detach from the basement
membranes and cause luminal obstruction, increased
intratubular pressure, and further decrease in GFR
 In addition, glomerular filtrate in the lumen of the
damaged tubules can leak back into the interstitium,
resulting in interstitial edema, increased interstitial
pressure, and further damage to the tubule
(2) Persistent and severe disturbances in blood flow
 Ischemic renal injury is also characterized by
hemodynamic alterations that cause reduced GFR.

 The major one is intrarenal vasoconstriction, which

results in both reduced glomerular blood flow and
reduced oxygen delivery to the functionally important
tubules in the outer medulla
 Morphology.
 Ischemic ATN
 focal tubular epithelial necrosis at multiple points
along the nephron
 Usually accompanied by rupture of basement
membranes (tubulorrhexis) and occlusion of tubular
lumens by casts

 Nephrotoxic ATN
acute tubular necrosis most obvious in the proximal
convoluted tubules
Clinical features
 The clinical course of ATN may be divided into the
following
 Initiation phase (up to 36 hours)
 Dominated by the inciting event
 there is a slight decline in urine output and a rise in
BUN

 Maintenance phase:
 This phase is marked by oliguria
 salt and water overload,
 hyperkalemia, metabolic acidosis, and rising BUN
 Recovery phase:
 This phase is heralded by rising urine volumes
(up to 3 L/day) with water, sodium, and especially
potassium losses (hypokalemia becomes a concern).

 Eventually, renal tubular function is restored and the

concentrating ability improves
Tubulointerstitial nephritis
 A group of inflammatory diseases of the kidneys that
primarily involves the interstitium and tubules

 On the basis of clinical features and the character of the

inflammatory exudate, TIN, regardless of the etiologic
agent, can be divided into acute and chronic categories.
Acute tubulointerstitial nephritis
 has rapid clinical onset

 characterized hisologically by interstitial edema,

leukocytic infiltration of the interstium & tubules.

 Include acute pyelonephritis & acute interstitial nephritis

(non infectious cause)
Chronic interstitial nephritis
 characteized by mononuclear leukocyte infiltration,
interstitial fibrosis & tublar atrophy
 Causes
 Chronic pyelonephritis
 Drugs
 Immune/inflammatory disorders
 Cystic kidney disease
Pyelonephritis
 inflammation of the kidney and the renal pelvis, is
caused by bacterial infection.

 Acute – caused by bacterial infection & is associated

with lower UTI

 Chronic – bacterial infection & other factors

(obstruction, vesicouretral reflux) are involved in
pathogenesis
Etiology & pathogenesis
 The dominant etiologic agents are gram (-) bacilli that
are normal inhabitant of intestinal tract – the most
common are E.coli followed by proteus, Klebsiella &
Enterobacter.

 There are two routes by which bacteria can reach the

kidneys:
(1) through the bloodstream (hematogenous infection)
(2)from the lower urinary tract (ascending infection)
 For ascending infection to occur, number of steps happen
1.colonization of distal urethra and introitus by coliform
bacteria
2.from urethra to the bladder: upward spread via
instrumentation or catheterization
 In the absence of instrumentation, urinary infections
are much more common in females
3.Urinary tract obstruction and stasis of urine.
 Stasisleads the bacteria introduced into the bladder to
multiply unhindered without being flushed out or
destroyed
4. vesicoureteral reflux
 The reflux of bladder urine into the ureters and renal
pelvis

 Due to incompetent vesicoureteral orifice

 VUR is present in 35% to 45% of young children with

UTI.

 It is usually a congenital defect that results in

incompetence of the ureterovesical valve.
 In addition, it may be acquired by bladder infection
itself.

 It is postulated that bacteria themselves or the associated

inflammation can promote reflux by affecting ureteral
contractility

 VUR can also be acquired in patients with flaccid

bladder resulting from spinal cord injury
5. Intrarenal reflux
 infected bladder urine can deep into the renal
parenchyma through open ducts at the tips of the papillae
Acute pyelonephritis
 Acute suppurative inflammation of the kidney

Morphology
 Gross
 Cortical surface shows grayish white areas of
inflammation and abscess formation

 Microscopy
 patchy interstitial suppurative inflammation,
intratubular aggregates of neutrophils, and tubular
necrosis
 Complication-Papillary necrosis, Pyonephrosis and
Perinephric abscess
Clinical features
 Onset is sudden with pain at the costovertebral angle ,
fever, chills & rigor

 Sometimes indication of bladder irritation such as

dysuria, frequency, urgency can occur

 Urine contains leukocyte (pyuria) & pus cast

 Definitive diagnosis is made by urine culture

 Chronic Pyelonephritis and Reflux Nephropathy
 characterized by tubulointerstitial inflammation, renal
scarring and dilated and deformed calyces.
 It can be divided into two forms

1.Reflux nephropathy
 is most common
 It begins in childhood, as a result of infections
superimposed on congenital vesicoureteral reflux and
intrarenal reflux
 it can be unilateral or bilateral.
2.Chronic obstructive pyelonephritis
 occurs when chronic obstruction predisposes the
kidney to infection
 the effects of chronic obstruction also contribute to
parenchymal atrophy

o
Morphology
 Gross
 Irregular and scarred cortical surface usually at poles

 dilated and blunted calyces

 dilated ureter

 retraction and destruction of papillae with “U” shaped

scars
 Microscopy
 The tubules show atrophy in some areas and
hypertrophy or dilation in others

 There are varying degrees of chronic interstitial

inflammation and fibrosis in the cortex and medulla
Clinical features
 both forms of CPN can manifest with the symptoms of
acute pyelonephritis or

 can have a silent, insidious onset, sometimes presenting

only very late in their course with hypertension or
evidence of renal dysfunction

 Some patients may develop focal segmental

glomerulosclerosis
 Urinary tract obstruction (Obstructive Uropathy)
 Obstruction - Increases susceptibility to infection and
stone formation
 Unrelieved obstruction leads to hydronephrosis

 Hydronephrosis – dilation of the renal pelvis and

calyces with progressive atrophy of the kidney due to
chronic obstruction to the outflow of urine
 Common causes

Congenital anomalies, calculi, BPH, tumors,

inflammation, blood clots, pregnancy, uterine prolaps,
neurogenic
Clinical features
 Acute obstruction results in pain due to distension of the
collecting system or renal capsule

 Unilateral hydronephrosis may remain silent for long

periods

 Bilateral partial obstruction manifest with inability to

concentrate urine (nocturia, polyuria)

 Complete bilateral obstruction results in oligouria or

anuria & unless relieved not compatible with life
Urolithiasis/renal calculi/renal stones
 Stone may form at any level in urinary tract but most
arise in kidneys

 Men are affected more often than women

 peak age is b/n 20 & 30 yrs

Pathogenesis
 The most important determinant is an increased urinary
concentration of the stone’s constituents. Such that it
exceeds their solubility in urine (supersaturation).
 Low urine volume may cause supersaturation
 Other factors influencing stone formation include
decreased pH of urine , deficiency of factors inhibiting
crystal formation in urine
 There are 4 main types of calculi in kidneys
1,Calcium stone(75%) – composed of calcium oxalate &
calcium phosphate
 5% of patients with hypercalcemia and hypercalciuria
 About 55% have hypercalciuria without hypercalcemia,
which is caused by several factors, including
 hyperabsorption of calcium from the intestine
(absorptive hypercalciuria)
 an intrinsic impairment in renal tubular reabsorption
of calcium (renal hypercalciuria)
 or idiopathic fasting hypercalciuria with normal
parathyroid function.
2,Triple stone / struvite stone (15%)
 composed of magnesium ammonium phosphate (staghorn
calculi)

 is usually associated with urea splitting bacterial infection

(proteus)

3,Uric acid stone (6%)

 are common in individuals with hyperuricemia

 more than half of such patients are neither hyperuricemic nor

hyperuricosuric and instead have exceptionally acidic urine (pH
< 5.5) that causes uric acid to precipitate
4,Cystine stone(1-2%)
 are caused by genetic defects in the renal reabsorption of
amino acids, including cystine, leading to cystinuria
Morphology
 Stones are unilateral in about 80% of patients.

 Common sites of formation are renal pelvis and calyces

 They tend to be small (average diameter 2-3 mm) and

may be smooth or jagged.
 Occasionally large size with branching filling renal
pelvis and calyceal system –staghorn calculi.
 These massive stones are usually composed of
magnesium ammonium phosphate.
Clinical features
 Urolithiasis may be asymptomatic

 Can produce severe renal colic

 Larger stones often manifest themselves by hematuria.

 Some also predispose to superimposed infection both by

their obstructive nature & by trauma they produce.
Tumors of the Kidney
 Benign Tumors

 Renal Papillary Adenomas

Renal papillary adenomas are common yellow cortical
tumors.

 Histologically, most consist of vacuolated epithelial cells

forming tubules and complex branching papillary
structures
 Angiomyolipoma
 is a hamartomatous lesion composed of vessels,
smooth muscle, and fat

 these are present in 25% to 50% of patients with

tuberous sclerosis.

 They are clinically significant primarily for their

susceptibility to spontaneously hemorrhage
 Oncocytoma
 This is an epithelial tumor composed of large
eosinophilic cells having small, round, benign-appearing
nuclei that have large nucleoli.

 It is thought to arise from the intercalated cells of

collecting ducts

 They are common (5% to 15% of resected renal

neoplasms) and can be large (up to 12 cm)
MALIGNANT TUMORS
 Renal Cell Carcinoma (Adenocarcinoma of the Kidney)

 Represents 3% of all visceral cancers

 Account for 85% or renal cancers in adults

 Common in sixth & seventh decade of life

Epidemiology
 Tobacco is the most important risk factor .

 Other risks include obesity, HTN, unopposed estrogen

therapy, exposure to asbesto

 Most renal cancer are sporadic but 4% are familial

 A genetic predisposition is indicated by a strong

association with von Hippel-Lindau disease.
 Classification of RCC
 Clear cell RCC
 70-80%
 proximal convoluted tubule
 95% sporadic
 Loss VHL (tumor suppressor gene) => increase in
VEGF, ILGF & TGF-ß1=> stimulate cell growth &
angiogenesis
 Morphology
 Gross
 well circumscribed and variegated, with a
combination of cystic, solid, and hemorrhagic areas
 and has a bright yellow color
 Microscopy
 the growth pattern varies from solid to trabecular
(cordlike) or tubular (resembling tubules).
 cells are polygonal with abundant clear cytoplasm,
and there is a delicate arborizing vasculature
 Papillary carcinoma
 10-20%, from proximal/distal convoluted tubule

 can be multifocal and bilateral

 Dialysis related carcinomas are usually papillary

 Trisomies 7, 16, & 17

Gross
 These are typically hemorrhagic and cystic grossly.

Microscopically
 these are composed of cuboidal cells arranged in
papillary formations, often with interstitial foam cells
and psammoma bodies.
 Chromophobe renal cell carcinoma
 5% of RCC

 intercalated cell of cortical collecting duct

 Multiple chromosomal losses & hypodiploidy

 Excellent prognosis compared with others

Gross
 The tumor is well circumscribed and has a light brown color
with central sacr
Microscopy
 The cells have a well-defined cell membrane, faintly
granular cytoplasm, and perinuclear clear halo & solid
pattern of growth
 Collecting duct carcinoma
 1-2% RCC

 from distal collecting (Bellini’s) ducts

 Poorest prognosis of common subtypes with death in

months to a few yrs
 Gross
 Centered in the medullary portion of the kidney and extends
into the renal pelvis
Microscopy
 showing irregular channels lined by highly atypical
epithelium with a hobnail pattern
Clinical features
 The three diagnostic features
- Costovertebral angle pain
- Palpable mass
- Hematuria

 Constituitional symptoms such as fever, malaise,

weakness & weight loss occur

 Renal cell ca produces a number of paraneoplastic

syndromes – HTN, Cushing syndrome etc

 The tumor has tendency to metastasize widely before

giving rise to any local sign & symptom