renal pathology dr rotimi adigun. renal pathology outline introduction glomerular diseases tubular...

RenalPathology

Dr Rotimi Adigun

Renal Pathology Outline

• Introduction• Glomerular diseases• Tubular and interstitial diseases• Diseases involving blood vessels• Cystic diseases• Tumors


• Introduction

Introduction

• Functions of the kidney:– excretion of waste products– regulation of water/salt– maintenance of acid/base

balance– secretion of hormones

• Diseases of the kidney– glomeruli– tubules– interstitium– vessels

• Azotemia: BUN, creatinine• Uremia: azotemia + clinical disease-Pericarditis ,Skin lesions, Gastro intestinal symptoms, Peripheral neuropathy• Acute renal failure: oliguria(urine output between 300-500mls/day• Chronic renal failure: prolonged uremia

Introduction

• Proteinuria<3.5gm/day •Hematuria• Oliguria• Azotemia• Hypertension

Nephritic syndrome

• Massive proteinuria>3.5gm/day• Hypoalbuminemia• Edema• Hyperlipidemia/-uria

Nephrotic syndrome

Introduction


• Introduction

• Glomerular diseases

Normal glomerulus

Nephrin

Nephrin molecules extend towards each other from neighbouring foot processes

Within the cytoplasm of the foot processes,It forms molecular connections.

Mutations in genes encoding these proteins gives rise to nephrotic syndrome.

Characteristics of Glomerular Filtration• Glomerular filtration allows for highly permeable

molecules i.e. water and small solutes to pass through. This is known as glomerular barrier function

• The barrier is completely impermeable to solutes, which are close to the molecular size and molecular charge of albumin

• Cationic (positive) charged molecules are more permeable

• Podocytes contain the slit diaphragm which maintains the integrity by providing a diffusion barrier to the filtration of proteins

Glomerular DiseasesCan be divided into :1. Primary Glomerular Diseases• Nephrotic syndrome• Nephritic • Idiopathic RPGN2. Secondary Glomerular diseases• Nephrotic• Nephritic• RPGN3. Hereditary disorders4.Chronic GN.

Primary Glomerular DiseaseNephrotic• Minimal change disease (MCD)• Focal and segmental glomerulosclerosis• Membranous nephropathy• Membrano-proliferativeNephritic• Acute postinfectious GN• Membranoproliferative GN• IgA nephropathy• Idiopathic RPGN or CrGN• Focal segmental glomerulosclerosis

Secondary glomerular disease

Nephrotic:• D/M Nephropathy• Focal segmental

glomerulosclerosis• Amyloidosis• Drugs

• Hodgkins disease other malignancies

Nephritic• Lupus nepritis- (SLE)• Diabetic nephropathy• Goodpasture syndrome• Microscopic polyangiitis• Wegener’s

granulomatosis• Henoch-Schonlein

purpura• Bacterial endocarditis

related GN• Thrombotic • RPGN-• FSGS

Hereditary Disorders

• Alport syndrome• Fabry disease • Podocyte/slit –diaphragm protein mutations

Pathogenesis of Glomerular Disease

Three mechanisms:• Immunological• Podocyte injury• Nephron lossImmunological:• Most forms of glomerulonephritis (GN) result

from immunologic mechanisms .Three mechanisms of immunological damage:

1) circulating immune complexes ( type III hypersensitivity)

2) in situ immune complexes3) cell mediated immune reaction

( hypothetical mainly)

Pathogenesis of Glomerular Disease

Circulating Immune Complexes• These are Type III hypersensitivity

reactions • Endogenous ( associated with SLE) or

exogenous (bacterial, viral, parasitic) are different antigens involved in the immunological process

• Immunofluorescence microscopy reveals a granular pattern in the glomerulus

Immunological Mechanisms1. In situ immune complex Deposition: Intrinsic

antigens Anti-GBM Disease (good pastures),Heymann antigen(membranous glomerulopathy)

Planted antigens,Exogenous(drugs,NSAIDs) Endogenous(SLE,IGA nephropathy)

2. Circulating Immune complex(tumor antigens, infectious products) Cytotoxic antibodiesActivation

3. Activation of alternative complement(dense deposit disease)

1. Cell mediated immune Injury2. Cytotoxic antibodiesActivation

In Situ Immune Complexes

i. Anti- GBM Ab GN. • ( Ab’s are aimed at the fixed Ag in theGBM.)• Goodpasture syndrome ,anti-GBM Ab’s cross

reacting with basement membranes of lung alveoli and kidney

• Severe glomerular damage i.e. RPGN • Immunofluorescenc• microscopy will create a linear pattern when

these Ab’s deposit.• Anti bodies can also react against antigens

in other parts of the glomerulus.

In Situ Immune Complexes• ii. Antibodies against endogenous Proteins• Heyman Nephritis is the experimental model • Auto-antibodies against glomerular cell

membrane protein in humans. The protein responsible is yet to be identified.

• Complements are activated and immune aggregates from the cell surface forms subepithelial deposits.

• The pattern of immunoflouresence is granular in all of these cases.

• Responsible for Membranous glomerulopathy.

Cell Mediated Immune Response

• There is a proposed theory that cell mediated immune response plays a role in glomerular injury

• Not a proven method of glomerular injury

Mechanisms of Glomerular injury

II. Podocyte injury: Causes of podocyte injury includes: antibodies against podocyte antigens,Toxins or mutations affecting Nephrin or any of the components of the slit –diaphragm.

Ab’s attach to podocyte Ag and cause effacement, detachment of epithelial cells, and leakage of proteins.

Mechanisms of Glomerular injuryIII. Nephron Loss:

Any process that leads to nephron loss =>GFR reduction of between 30-50% leads to end stage renal disease.

• Adaptive changes in the remaining undamaged nephrons , such as, hypertrophy of glomeruli =>, hemodynamic changes and capillary hypertension. =>Will eventually lead to further destruction of epithelial and endothelial cells.

Mechanisms of Glomerular injury

=>to proteinuria , glomerulosclerosis,

• Eventually, capillaries collapse and obliterate, and glomeruli undergo segmental or global sclerosis


• Introduction

• Glomerular diseases– Nephrotic syndrome

• Minimal change disease• Focal segmental

glomerulosclerosis• Membranous nephropathy• Membranoproliferative GN

– Nephritic syndrome• Postinfectious GN• IgA nephropathy


• Introductory stuff


Symptoms of Nephrotic Syndrome

• Massive proteinuria>3.5g/day

• Hypoalbuminemia• Edema• Hyperlipidemia, lipiduria




• Minimal change disease

Causes of Nephrotic Syndrome

Adults: systemic disease• DM,SLE,Drugs,E.T.C, Hodgkins

lymphoma other cancersChildren: minimal change disease• Characterized by loss of foot

processes• Response to steroids in 90% of

children

Minimal Change Disease• #1 cause of nephrotic syndrome in

children• Loss of foot processes• Selective proteinuria• Pathogenesis unknown • Good prognosis• Minimal change is the pattern of

nephrotic syndrome seen in Hodgkins disease

Minimal change disease

Normal glomerulus

MCD- light microscopy

The glomeruli appear normal

Lipid accumulation in proximal tubule cells may be present

Minimal change disease





glomerulosclerosis

Focal Segmental GlomerulosclerosisPrimary or secondarySome (focal) glomeruli show partial (segmental)

hyalinization• Unknown pathogenesis. Continuum with MCD?Primary or Idiopathic :congenital disease,

Genetics(mutation of nephrin).

Secondary: HIV, Heroin, other nephropathies IgA nephropathy

Focal Segmental Glomerulosclerosis

Histology: The affected glomeruli exhibit increased mesangial matrix, obliterated capillary lumen, and deposition of hyaline masses (hyalinosis) and lipid droplets.

• Occasionally, glomeruli are completely sclerosed (global sclerosis).

.


• Electron microscopy: effacement of foot processes as in MCD.

• progression =>to global sclerosis of the glomeruli with pronounced tubular atrophy and interstitial fibrosis.


Clinical disease• Commonest cause of nephrotic syndrome in

adults the U.S(Hispanics, blacks)• Presents with non selective

proteinuria• Hypertension and hematuria may be

present (i.e may also give nephritic picture)

• Prognosis: end stage renal disease in 50% within 10 years. Worse in adults.

Focal segmental glomerulosclerosis




• Minimal change disease• Focal segmental glomerulosclerosis• Membranous nephropathy

Membranous NephropathySummary:• Peak age 30 and 50 years of age,

Idiopathic in about 85% of cases• Auto immune antibodies against a yet to

be identified renal antigen.• Slowly progressing disease

Membranous Nephropathy• Morphology: sub epithelial deposits (that

contains immunoglobulin's) along the GBM.• Little or no inflammation• Spike and dome• Immunoflourescence: Granular pattern• Glomeruli may appear normal by light

microscopy initially => diffuse thickening with disease progression.

• Podocyte effacement may also be seen

Membranous nephropathy

Membranous Nephropathysecondary membranous nephropathy:• Infections (chronic hepatitis B, syphilis,

schistosomiasis, malaria)• Malignant tumors, carcinoma of the lung ,

colon and melanoma• SLE and other autoimmune conditions• Exposure to inorganic salts (gold, mercury)• Drugs (penicillamine, captopril,

nonsteroidal NSAIDS).

Membranous Nephropathy

Pathogenesis: • Idiopathic forms are induced by

antibodies reacting in situ to endogenous or planted glomerular antigens.

• Circulating immune complexes are responsible for secondary diseases.

Membranous Nephropathy

Pathogenesis:• Immune complex deposition activate the

c5b-9 (MAC)=>direct podocyte and mesangial cell injury=>Proteases and Oxidant production.

• Spike and dome: Sub-epithelial deposits that are separated from each other by small, spike-like protrusions of GBM matrix that form in reaction to the deposits.

Membranous NephropathyClinical course:• Slowly developing disease• Non selective proteinuria/contrast

with MCD(globulins as well as albumin lost)

• Poor steroid response• Variable course, remission in 10-

30%• End stage renal disease in up to

40% within 2-20 years

Membranous nephropathy

Membranoproliferative GN (MPGN)• Characterized by alterations in the GBM and

mesangium and proliferation of glomerular cells. • 5% to 10% of cases of idiopathic nephrotic syndrome

in children and adults. • Some present only with hematuria or proteinuria in

the non-nephrotic range(nephritic); others have a combined nephrotic-nephritic picture.

• Two major types of MPGN (I and II) Type I accounts for 80% of cases)

• Different pathogenetic mechanisms responsible for the two types of MPGN

Membranoproliferative GN

Type 1.• Circulating immune complexes

responsible for most cases.• Inciting antigen is not yet known. Occurs in association with :• Hepatitis B ,Hepatitis C and SLE

Membranoproliferative GN (MPGN)Type II• Also known as dense deposit disease• Pathogenesis unclear• Excessive complement activation• Some patients possess C3 nephritic

factor which is an autoantibody against C3 convertase.

-It stabilizes the enzyme and prolong its activity=>extensive alternative pathway complement activation.

Membranoproliferative GN (MPGN)

Type II• Mutations affecting regulatory

protein such as factor H has also been described.=>excessive complement activation.

• Low complement level is a feature of type 2 disease. Due to excessive consumption of complements as well as reduced synthesis of factor 3 by the liver.

Type II• How complement activation leads

to glomerular injury is still not very clear.

Membranoproliferative GN (MPGN)Morphology:

Similar appearance on light microscopy• Large glomeruli ,lobular appearance with

proliferation of mesangial and endothelial cells. There is increased cellularity(leucocytes,mesangial cells,)

• Mesangial proliferation and interposition causes apparent split in basement membrane

=> thickened basement membrane with tram track appearance

Membranoproliferative GN (MPGN)

• Electron microscopy and immunoflourescence studies would demonstrate the differences in the two conditions.

Morphology:E/M and Immunoflourescence

Type IE.M• Subendothelial

electron dense deposit

Immunoflouresence:

• Granular pattern of C3.IgG, c1q-c4 seen.

Type IIE.M• Intramembranous

very electron dense deposit.

• Immunoflouresence:• Linear pattern of

C3,IgG, C1q-c4 absent• C3 nephritic factor

may be seen

PAS showing tram track

Membrano-proliferative GN

Type II MPGNIntramembranous dense deposit

Membranoproliferative GN (MPGN)Clinical Disease• 50% as nephrotic syndrome• Mixed presentation also possible• Progression to end stage

disease in 40% of cases in 10 years

• Prognosis worse for dense deposit disease.





– Nephritic syndrome

Symptoms of Nephritic Syndrome

Again,• Hematuria• Oliguria, azotemia• Hypertension• Non Nephrotic proteinuria < 3.5g/day Characterized by proliferative changes

and inflammation

Causes of Nephritic Syndrome

• Post-infectious GN,• IgA nephropathy• Immunologically-mediated




– Nephritic syndrome• Postinfectious GN

Post-Infectious Glomerulonephritis

• Child ,1-4 weeks after strep throat• Immune complexes• Hypercellular glomeruli• Subepithelial humps• Hypo complementemia• Increased ASO titres


• Glomerular deposition of immune complexes

• Caused by certain "nephritogenic" strains of β-hemolytic streptococci

• Other exogenous antigens such as staph aureus,pneumococcus,mumps measles,chicken pox.

• Endogenous antigens from SLE may also cause it(but more likely to give a membranous pattern)


“Sore throat, swollen face , pee coke with hypertension”

Increased cellularity

Sub-epithelial hump

PSGN -IF

The immune deposits are distributed in the capillary loops in a

granular, bumpy pattern


• Introduction



glomerulosclerosis• Membranous nephropathy

– Nephritic syndrome• Postinfectious GN• IgA nephropathy

A 25-years-old woman presented with 10 days history of facial edema and no other symptoms. She relates that one-year ago she saw the doctor because of hematuria. She does not have fever, weight loss.

There was no personal or family history of major medical problems.

Physical examination : blood pressure: 190/100, t Otherwise normal.

Urinalysis revealed 60 erythrocytes HPF, proteins 4.27 g/24 h; a complete blood count was normal.

What are your differentials?

Renal biopsy, shows mesangial proliferation and matrix increase

Silver staining showing increase mesangial matrix.

IgA Nephropathy/Berger Disease• Commonest cause of nephritic syndrome• Child with hematuria after URI,UTI or GI

infection• Typically recurrent hematuria even years

after the primary episode• IgA in mesangium• Variable prognosis• May also cause nephrotic range

proteinuria(less common)

IgA Nephropathy• Abnormality in IgA production and

clearance. • IgA, is at low levels in normal serum

but increased in 50% of patients with IgA nephropathy due to increased production in the marrow.

• In addition, circulating IgA-containing immune complexes are present in some individuals.

•

IgA Nephropathy• The prominent mesangial deposition of

IgA suggests entrapment of IgA immune complexes in the mesangium,

• increased frequency in celiac disease and in liver disease

• Clinical Course. Common in children and young adults.

• Nephritic-Nephrotic picture or typical nephritic syndrome

• Slow progression to chronic renal failure in 25% to 50% of cases over 20 years.

IgA nephropathy- E/M

Electron dense deposits in the mesangial area

IgA nephropathy

Immunofloursecence IGA shows mesangial deposits

Alport Syndrome (Hereditary Nephritis)• Hereditary nephritis• Caused by mutations in GBM proteins. • X linked disorder• Along with nephritis, Alport syndrome is

associated with nerve deafness, lens dislocation, cataract, and corneal defects

• Mutations in any one of the alpha chains of collagen type IV result in defective assembly of these chains

Alport Syndrome

• Clinical findings in a female carrier will result in asyptomatic hematuria.

• Male with the disease would present with hematuria, proteinuria and eventual renal failure

• Microscopy : foam cells, which are due to accumulation of fat and mucopolysaccharides in interstitial cells.

• E/M: The GBM develops irregular foci of thickening or attenuation with pronounced splitting and lamination of the lamina densa, yielding a "basket-weave" appearance.

Rapidly Progressive (Crescentic) GN (RPGN)• Rapid decrease in GFR and loss of renal function

in weeks to several months • Major pathologic finding :extensive glomerular

crescent formation within Bowman’s space• due to proliferation of the parietal epithelial cells

of Bowman’s capsule• These crescents are composed of parietal

epithelial cells, macrophages, monocytes, and fibrin

• It may be associated with other diseases or it may be idiopathic

RPGN

• Three main types of RPGN, based upon the immunological process: 1)Type I- Anti-GBM Ab- Goodpasture syndrome2)Type II-Immune complex-poststreptococcal, SLE, HSP, IgA nephropathy3)Type III- Pauci immune –ANCA associated- Wegener granulomatosis, microscopic angiitis

• On immunofluorescence, granular or linear deposits of immunoglobulins may be present +/- complement

• Electron microscopy may show GBM disruption

RPGN

Clinical findings includes: • nephritic syndrome• severe oliguria• Poor prognosis with rapid

progression to renal failure• Long term dialysis or

transplantation may be required

RPGN – M/E

There are epithelial crescents squashing the glomerular tufts from all sides.

Type I RPGN

• This is characterized deposits of IgG and C3 on the GBM .

• Note: anti-GBM Ab’s also deposit on the pulmonary alveolar basement membrane => pulmonary hemorrhage and renal failure- known as Goodpasture syndrome

• In idiopathic cases, there is only renal involvement.

• Treatment: plasmapheresis

Type I RPGN- Goodpasture syndrome- IF

There is strong linear reactivity for IgG along the glomerular basement membranes.

Type II RPGN

• These are characterized by the presence of immune complexes

• An underlying cause i.e. poststreptococcal GN, IgA nephropathy,etc. may be present

• Immunofluorescence reveals a granular (“lumpy bumpy”) pattern on the GBM or mesangium

Type III RPGN• This is also known as pauci immune RPGN• No significant immune complex or anti-GBM Ab

deposition seen on immunofluorescence or electron microscopy

• There is the presence of ANCA in the serum of these individuals

• Vasculitides i.e. Wegener granulomatosis and microscopic angiitis play a role in the pathogenesis of renal disease

• Severe segmental necrosis may be seen in the glomeruli

Chronic GNImportant cause of end stage renal disease (ESRD)

characterized by chronic renal failure and uremiaClinical features: • Hypertension, • Proteinuria, • Azotemia,• Anemia, • Nephritic or Nephrotic syndrome• The glomeruli get obliterated and the degree of

proteinuria decreases with disease progression. • Treatment with renal dialysis and transplantation . • Prognosis is poor .

Chronic GN-gross

In ESRD, the kidneys are small and shrunken bilaterally, as shown here.

Chronic GN- micro

There is interstial fibrosis, the glomeruli are sclerotic, and there are scattered chronic inflammatory cell infiltrates

Diabetes Nephropathy

• Glomerular lesions are the commonest cause of end stage renal disease in Diabetes

Three major patterns of Glomerular disease:• -Non Nephrotic Proteinuria• -Nephrotic syndrome• Chronic renal failure Diabetes also affects the arterioles.

Characteristically involving both the afferent and efferent arterioles. Efferent arterioles are not affected in non diabetics.

Diabetes Glomerulonephritis

• Pathogenesis• D/M Microangiopathy (small vessel

disease)is responsible.1.Metabolic effect=>Hyperglycemia=> None

enzymatic glycosylation of proteins=>AGE.=> Increased type IV collagen in the GBM

and decreased Heparan sulfate=>thickened GBM, increased mesangial matrix.

2.Hemodynamic effects. Initial GFR increase=>glomerular hypertrophy=>glomeruloscleorsosis

Diabetes GlomerulonephritisMorphology:3 main lesions1. Capillary Basement Membrane

Thickening:Thickening of basement membrane occurs in all diabetics.

• Starts from 2 – 5 years of D/M onset• Detectible only by E/M.2. Diffuse Mesangial Sclerosis:• Diffuse progressive increase in mesangial

matrix• The mesangial depositions are PAS positive• May also be seen in old age and

hypertension.

Diabetes Glomerulonephritis

3.Nodular sclerosis otherwise known as Kimmelstiel-Wilson Disease

• Ball like deposits of PAS positive laminated matrix located in the periphery of the glomerulus.

• Usually contained trapped mesangial cells.

• Seen in 15-30% of long term diabetics• More Pathognomonic of D/m than

diffuse sclerosis.

Exudative lesions in D/m Fibrin Cap.Hyaline deposits in the peripheral tufts of capillaries.

Exudative Lesions of D/M. capsular drop.Hyalin deposits in bowmans capsule.




• Tubular and interstitial diseases– Tubulo-interstitial Nephritis

• pyelonephritis• drug-induced interstitial nephritis

– Toxic/ischemic lesions• Acute tubular necrosis

Tubulointerstitial nephritis

• Kidney diseases that involve structures in the kidney apart from the glomerulus.

Two main categories:• Pyelonephritis• Interstitial Nephritis




• Tubular and interstitial diseases– Inflammatory lesions

• pyelonephritis

Pyelonephritis• Invasive suppurative infection of the kidneys and the

renal pelvis.• Usually ascends from UTI• Fever, flank pain• Hematogenous spread is also possible in the

immuno-compromised, severe sepsis and debilitated patients.

Organisms:• E. coli, Proteus, enterobacter ,Pseudomonas• Urinary tract mainipulations, anomalies of the lower

urinary tract

Acute Pyelonephritis

Pathogenesis

• Bacteria can reach the kidneys via two pathways: the bloodstream or the lower urinary tract (ascending infection)

• Ascending infection from the lower urinary tract (most important route) :bacteria adhere to the mucosa colonize distal urethra (introitus in females) gain bladder accessmove upstream against flow of urine ascend ureters and enter pelvis of kidney

Acute PyelonephritisPathogenesis Predisposing factors for infection include: VUR (vesicoureteral reflux)- most important.Others• access to bladder via instrumentation i.e.

catheterization and cystoscopy • females :short urethra, urethral trauma during

intercourse,• outflow obstruction or bladder dysfunction may

lead to stasis and lead to multiplication of bacteria

• congenital or acquired-

Acute Pyelonephritis

Pathogenesis• Congenital- defective

ureterovesical valve • Acquired-- Bladder atony due to spinal cord

injury and neurogenic bladder in diabetics.

Acute Pyelonephritis- gross

There is a variable number of small , yellowish abscesses scattered over the renal surface

The kidney may be normal sized or enlarged

Acute Pyelonephritis• Clinical findings: fever, chills, malaise

costovertebral tendernessurinary symptoms: dysuria,

frequency, and urgencyurinalysis: pyuria and WBC

casts

Complications: chronic pyelonephritis papillary necrosis perinephric abscess

Acute pyelonephritis-micro

Numerous PMN's are seen filling renal tubules

Acute pyelonephritis

WBC cast

• White cell cast differentiates between pyelonephritis and a mere UTI.

Chronic pyelonephritis• Renal injury induced by recurrent or

persistent renal infection.• Associated with progressive renal scarring,

which can lead to end-stage renal disease (ESRD)

• Continuous damage and scarring of renal parenchyma=>ESRD

• There are two types:1) chronic obstructive pyelonephritis- recurrent infections, due to obstruction, lead to renal failure

2) reflux nephropathy- this is due to VUR, which causes chronic renal damage

Chronic Pyelonephritis con’t

• Hallmark of chronic pyelonephritis is scarring of pelvis or calyces, which leads to papillary blunting and an asymmetrically contracted kidney

• Clinical findings and diagnosis: hypertension ultrasound-looks at size and shape of kidney

Chronic pyelonephritis

Drug-Induced Interstitial Nephritis

• Antibiotics, NSAIDS• IgE and T-cell-mediated immune

reaction• Fever, eosinophilia, hematuria• Patient usually recovers

• Analgesic nephritis is different (bad)

Drug Induced Nephritis• Injury to the kidney can be caused by a number

of drugs, which include: penicillin (ampicillin, methicillin) rifampin NSAIDS

Pathogenesis: - Type I (eosinophilia and rash) and Type IV hypersensitivity reactions ( granulomatous reaction)

-drugs act as haptens, which bind tubular cells and become immunogenicMicroscopically, there is infiltration by lymphocytes, neutrophils and eosinophils. Granulomas may be present.

Drug Induced Nephritis

• Clinical findings include: fever eosinophila rash hematuria proteinuria +/-

Note: complete recovery of renal function is the rule following cessation of drug intake

Drug-induced interstitial nephritis

Analgesic Nephropathy Chronic usage of analgesic mixtures leads to papillary necrosis. Drugs implicated include:

Aspirin inhibits the vasodilatory action of PGE2 and causes ischemia Acetaminophen causes free radical formation that damage renal

tubules.• Pathogenesis: papillary necrosis followed by interstitial nephritis• Clinical findings: gross hematuria , proteinuria • Increased risk of transitional cell carcinoma of the renal pelvis in

survivors

Acute Tubular Necrosis

• The most common cause of ARF!• Reversible tubular injury• Many causes: ischemic (shock),

toxic (drugs)• Most patients recover

Acute Tubular Necrosis (ATN)

• ATN is a renal disorder involving damage to the tubular epithelial cells.

• It is the most common causes of acute renal failure, which is manifested by anuria or oliguria( < 400 ml/24hrs)

• ATN usually occurs after an acute ischemic or toxic event. Examples include: septicemia, acute pancreatitis, hemorrhage, trauma, etc.

ATN

• There are two types of patterns seen in ATN:1. Ischemic ATN2. Nephrotoxic ATN

• Ischemic ATN Hypovolemia and shock are the most

common causes of ischemic ATN Ischemia damages endothelial cells.

Causes decrease in vasodilators i.e. nitric oxide, PGI2

Increase in vasoconstrictors i.e endothelin These effects lead to vasoconstriction of afferent

arterioles, which decrease GFR.

ATN

• Nephrotoxic type Causes include:

Aminoglycosides i.e. gentamicin Radiographic contrast agents Heavy metals (i.e. lead and mercury)Organic solvents ( carbon tetrachloride)

ATN Pathogenesis: Toxins or anoxia causes shedding of

tubular cells into the urine continual injury leads to further damage of tubules tubular debris (casts) accumulates leads to increased intra-tubular pressure fluid is pushed into interstitium GFR is reduced

Final result: oliguriaNote: necrosis of tubular segments leads to

the production of proteinaceous casts- brown colored granular casts

ATN

Clinical findings: • Well-defined sequence of events. Initiation phase- (first 36 hours) • Acute decrease in GFR (and oliguria)• Sudden increase in serum creatinine and

blood urea nitrogen (BUN) concentrations. The maintenance phase (first week) • Sustained severe reduction in GFR,• continues for a variable length of time(about

1-2 weeks.) • Oliguria and increased BUN/creatinine persists

ATN The recovery phase, • Tubular function is restored, • Increase in urine volume (up to a few

liters a day) • there is an increased susceptibility to

infection thus, a higher mortality rate • Renal function is restored and urine

output returns to normal. • Some kidney abnormalities may persist

for several months. With appropriate therapy, there is a good

prognosis

Acute tubular necrosis

Urinary Tract Infection

• Women, elderly• Patients with catheters or malformations• Dysuria, frequency• Organisms: E. coli, Proteus

E. coli

uncomplicated complicated

UTI: Common Bugs

Urinary catheter colonized by Proteus


• Introduction


• Tubular and interstitial diseases

• Diseases involving blood vessels– Benign nephrosclerosis

– Malignant nephrosclerosis

Benign Nephrosclerosis

• Found in patients with benign hypertension

• Hyaline thickening of arterial walls• Leads to mild functional impairment• Rarely fatal• Affects only afferent arterioles• When seen in diabetes affects both

afferent and efferent arterioles

Benign nephrosclerosis

Malignant Nephrosclerosis

• Arises in malignant hypertension• Hyperplastic vessels• Ischemia of kidney• “Flea beaten”kidney on gross

appearance• Medical emergency

Malignant Hypertension

• 5% of cases of hypertension• Super-high blood pressure, encephalopathy,

heart abnormalities• First sign often headache, scotomas• Decreased blood flow to kidney leads to

increased renin, which leads to increased BP!• 5y survival: 50%• Histology:Necrotising arteriolitis, onion

skinning,

Malignant nephrosclerosis





• Diseases involving blood vessels

• Cystic diseases– Adult polycystic kidney disease

– Childhood polycystic kidney disease

Adult Polycystic Kidney Disease

• Autosomal dominant• Huge kidneys full of cysts• Usually no symptoms until 30s• Associated with berry aneurysms and

Hypertension,hematuria• Germline mutation affecting PKD1

gene on chromosome 16(85-90%). or PKD2 gene on chromosome 4(15%)

ADPKD

• Cysts can be formed anywhere in the kidney i.e. tubules, collecting ducts, bowman’s space, etc.

• Expanding cysts cause pressure on the surrounding tissues and lead to ischemic changes

Adult polycystic kidney disease

ADPKD

• Clinical findings: - Most patients remain asymptomatic until middle age - Abdominal mass – massive bilateral kidney

enlargement- Flank pain- Hypertension- Gross hematuria - Berry aneurysms, liver cysts are extrarenal findings

• Diagnosis: ultrasound

• Most patients develop end stage renal failure

Childhood Polycystic Kidney Disease

• Autosomal recessive• Numerous small cortical

cysts• Associated with liver cysts• Patients often die in

infancy

Autosomal Recessive (Childhood) Polycystic Kidney disease

• This rare disease has a autosomal recessive pattern, which result from a mutation in the PKHD1 gene-codes for the fibrocystin gene on chromosome 6

• It presents bilaterally as small cysts, which are usually found in the cortex and medulla and give a sponge-like appearance

• Cysts may be found in the liver

• There is a high mortality rate associated with

neonates or young infants. In the surviving patient, liver cirrhosis will ensue

Childhood polycystic kidney disease

Urinary Outflow ObstructionRenal stones

-passage of a urinary stone is a frequent cause of obstruction to urinary tract

-calculus (stone formation) can occur anywhere along the urinary tractThe first phenomenon is supersaturation of the urine by stone-forming constituents, including calcium, oxalate, and uric acid.

Crystals or foreign bodies can act as nidi, upon which the supersaturated urine form microscopic crystalline structures

-

Urinary Outflow Obstruction • Composition of renal stones:

1. calcium oxalate or calcium oxalate + calcium phosphate (approximately 80 %)

2. magnesium ammonium phosphate (struvite stones) (approximately 10 %)

3. Uric acid (approximately 6 -7%)

4. Cystine stones (approximately 1-2%)

Urinary Outflow Obstruction • PathogenesisCalcium containing stones (calcium oxalate,

calcium phosphate) - Idiopathic hypercalciuria occurs in more than one

half of patients with calcium oxalate stones. Most causes of hypercalciuria are absorptive

-Increased absorption in individuals after a normal diet causes an elevation of serum calcium levels

-Hypercalcemia due to hyperparathyroidism, sarcoidosis, vitamin D intoxication

-The presence of uric acid , oxalates, and citrates in the urine provide a conducive environment for calcium deposition

- Crystallization of calcium phosphate stones occurs in a high pH

Urinary Outflow Obstruction con’t Magnesium ammonium phosphate (struvite stones)- Urinary tract infections provide an alkaline environment, which naturally cause urea splitting bacteria i.e. Proteus vulgaris to flourish-deposition in the kidney creates a cast in the renal pelvis and calyces, which is known as staghorn calculi

Uric acid stones• Hyperuricemia due to gout or leukemias • The most important determining factor in uric

stone production the presence of acidic urine-

Urinary Outflow Obstruction

Cystine stones-there is a defect in renal transport of cystine

- Inborn errors of cystine metabolism

Clinical findings in renal Stones-The patient may remain asymptomatic until a small stone passes out into the ureter. This typically causes a colicky pain, which radiates to the groin-Gross hematuria -Obstruction caused by stones leads to infection- Xray shows radiopaque calcium stones

Urolithiasis-CXR

Radiopaque stones can be seen in this xray

These are are composed of calcium

Staghorn calculi

This is an x-ray of staghorn calculi

Hydronephrosis• Hydronephrosis is defined as a dilation of

the renal pelvis and calyces, due to the interruption of urine outflow

• The obstruction can be anywhere along the urinary tract

• Causes include:congenital- urethral atresia, kinked ureter, etc.acquired- stones, carcinoma prostate, BPH, spinal cord damage, prostatitis, ureteritis

Hydronephrosis

• Can be unilateral or bilateral. It is bilateral if the obstruction is below the level of the urethra; and, it is unilateral if it is above the bladder.

• Pathogenesis: If the flow of urine is obstructed, urine backs up behind the point of blockage, eventually reaching the small tubes of the kidney and renal pelvis

Continued filtration (GFR) and back pressure (due to the obstruction) cause compression of the renal vasculature

Obstruction leads to tubular dysfunction and reduction in GFR

Hydronephrosis • Bilateral hydronephrosis leads to renal

failure. In contrast, unilateral hydronephrosis causes an enlarged kidney

• There is atrophy and compression of renal parenchyma, along with loss of papillae and flattening of the pyramids

• Hydroureter may result depending upon the level of obstruction

• On M/E: tubular dilation/ atrophy and fibrosis of tubular epithelium/ loss of glomeruli (late finding), papillary necrosis eventually, cortical atrophy progresses to the point at which only a thin rim of parenchyma is present

Hydronephrosis

• Clinical findings:-obstruction bilaterally leads to anuria-obstruction unilaterally may be

asymptomatic -with acute obstruction, patients may

present with pain, which is usually described as severe, intermittent, and dull

Hydronephrosis- gross

The cut surface shows a very thin rim of cortex

The area of the pelvis and calyx are distended, and large cystic spaces occupy the pyramids.

The ureter is dilated.





• Diseases involving blood vessels

• Cystic diseases

• Tumors– Renal cell carcinoma

– Bladder carcinoma

Renal Cell Carcinoma

Renal cell carcinoma accounts for 3 % of all malignancies.Most of these cancers arise from the proximal renal tubular epithelium

Risk factors include: smoking, hypertension, cadmium exposure, and obesity.

The classification of the three most common types of tumors is based upon genetic predisposition.

RCC con’t

• The three most common types of RCC :

1. Clear cell carcinoma 2. Papillary renal cell

carcinoma3. Chromophobe renal

carcinoma

RCC Clear cell carcinoma

-This is the most common type ( 70-80%)-As the name suggests, it is made up of cells with clear or granular cytoplasm-There may be an association with von Hippel Lindau (VHL) disease-VHL is an autosomal dominant disease that is characterized by cerebellar or retinal hemangioblastomas- Presents as bilateral multiple cysts

RCC Clear cell carcinoma

-VHL gene (tumor suppressor gene) is present on chromosome 3 (3p25) and an individual inherits the germ line mutation. -Somatic “hit” or somatic mutation causes the loss of the second allele. This leads to clear cell mutation, by uncontrolled tumor growth and angiogenesis-The tumor invades the renal vein, as it enlarges and extends through the kidney to reach other parts of the body- IVC penetration and invade the heart-they can metastasize to lungs (most frequent) and bone (causes lytic lesions)

RCC

• Papillary Renal Cell Carcinoma- They make up 10-15 % of all renal cancers- These tumors are multifocal and bilateral with a papillary growth pattern-Associated with the MET- proto-oncogene, which is located on chromosome 7 (7q31) - Grossly, they appear as a yellow mass, but to a lesser degree than clear cell carcinoma (due to lower lipid content)

RCC

• Chromophobe Renal Carcinoma- These tumors represent 5 % of all renal cell carcinomas-They are made up of intercalated cells of the collecting duct. -Grossly, the tumor appears tan brown. Microscopically, nuclei are surrounded by clear cytoplasm- Missing chromosomes ( chromosomes 1,2 6, 10, 13, 17, and 21)=> hypodiploidy

-This tumor has a good prognosis

This photograph shows the cut surface of a kidney

There is a large renal cell carcinoma in the upper pole with bright yellow areas, areas of hemorrhage, and tan and white areas

They appear as spherical masses

RCC (clear cell carcinoma)- M/E

The malignant cells have abundant clear or empty appearing cytoplasm

The tumor may appear vacuolated or solid

RCC

Clinical findings:-triad of :

painless hematuria, palpable abdominal mass, and dull flank pain -fever-polycythemia-erythropoiesis-paraneoplastic syndrome:

hypertension, hypercalcemia, Cushing syndrome

Renal cell carcinoma

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