Diseases of the liver and pancreas

Renal Dysplasia

• 
  MOST COMMON cystic disease in children-associated with Potter’s syndrome
  
• 
  Disturbed differentiation-failure of differentiation of metanephric tissue
  

• 
  Whole kidney or just one segment
  
• 
  Unilateral or bilateral-incompatible with life in severe form
  
• 
  Solid or cystic masses with predominant cartilage
  

• 
  Oligohydramnios and abnormalities of urinary tract, lungs, and CNS
  

• 
  Disorganized architecture
  
• 
  Dilated tubules
  
• 
  Islands of immature cartilage
  

Autosomal Recessive Polycystic Kidney Disease
(Infantile Polycystic Kidney Disease)

• 
  Autosomal recessive
  
• 
  Massive enlargement of the kidneys at birth
  
• 
  Common cause of a palpable abdominal mass in a newborn-may impede delivery
  
• 
  The kidneys are thought to develop normally during most of the fetal period but some unidentified stimulus causes dilatation of the collecting ducts
  
• 
  Bilateral; also cysts of liver, proliferation of bile-ducts and congenital hepatic fibrosis
  
• 
  Potter’s facies
  
• 
  Death in infancy or childhood
  

Autosomal Recessive Polycystic Kidney Disease

• 
  Hypoplastic lungs Note the massive enlargement Small but evenly distributed
  
• 
  Enlarged kidneys of both kidneys in this infant cysts in the renal parenchyma
  

• 
  Cysts fill most of the parenchyma
  
• 
  Hard to find glomeruli
  
• 
  Many of the cysts are elongated and radially arranged
  

from the center of the kidney (on the right) –

like spokes on a wagon wheel


Autosomal Dominant Polycystic Kidney Disease (Adult Polycystic Kidney Disease)

• 
  MOST COMMON INHERITED RENAL DISEASE
  
• 
  Autosomal dominant; bilateral
  
• 
  Aberrant gene on chromosome 16
  
• 
  Bilateral-kidneys greatly enlarged
  
• 
  Cysts not manifest at birth
  
• 
  Usually presents in 4th decade with hypertension and hematuria-renal failure within a decade
  
• 
  Berry aneurysms may present with subarachnoid hemorrhage (10-15%)
  
• 
  Cysts in liver (30%)
  
• 
  Approximately 30% of patients die of renal failure; Another 30% die of complications relating to hypertension
  

Medullary Cystic Disease

• 
  Two major types of medullary cystic disease:
  

• 
  Medullary sponge kidney - a relatively common and usually innocuous structural change
  
• 
  Nephronophthisis - uremic medullary cystic disease complex, almost always associated with renal dysfunction.
  

Medullary Sponge Kidney

• 
  Lesions consist of multiple cystic dilatations of the collecting ducts in the medulla.
  
• 
  Occurs in adults
  
• 
  Is usually discovered radiographically incidentally or sometimes in relation to secondary complications.
  

• 
  Calcifications within the dilated ducts
  
• 
  Hematuria
  
• 
  Infection
  
• 
  Urinary calculi
  

• 
  Renal function is usually normal
  

Nephronophthisis—Uremic Medullary Cystic Disease (UMCD) Complex

• 
  Onset in childhood
  
• 
  Presence of a variable number of cysts in the medulla associated with significant cortical tubular atrophy and interstitial fibrosis - is the cause of the eventual renal insufficiency
  
• 
  Accounts for about 20% of cases of chronic renal failure in children and adolescents.
  
• 
  Affected children present first with polyuria and polydipsia
  
• 
  Reflect a marked tubular defect in concentrating ability
  
• 
  Sodium wasting and tubular acidosis
  
• 
  Consistent with initial injury to the distal tubules and collecting ducts
  
• 
  Progresses to terminal renal failure in 5 to 10 years
  
• 
  High index of suspicion in children or adolescents with otherwise unexplained chronic renal failure, a positive family history, and chronic tubulointerstitial nephritis on biopsy.
  

• 
  Cysts at cortico-medullary junction
  

Simple Retention Cysts

• 
  MOST COMMON FORM OF RENAL CYSTIC DISEASES (not inherited)
  

• 
  50% incidence in patients > 50
  

• 
  Usually cysts are large and solitary
  
• 
  May be confused with renal cell carcinoma
  
• 
  Note the smooth lining to this large retention cyst
  

Acquired Cysts (Dialysis-associated) Disease

• 
  Seen in kidneys of patients who are treated by dialysis or transplantation
  
• 
  Associated with renal cell carcinoma
  

Table: exam: proteinuria (<3.5 g/day)

Severe proteinuria (>3.5 g/day)

Generalized edema

Hyperlipidemia

lipiduria

Glomerular Diseases

• 
  Nephritic Syndrome
  

• 
  Post-Streptococcal Glomerulonephritis
  
• 
  Goodpasture’s Syndrome
  
• 
  Rapidly Progressing Glomerulonephritis (RPGN)
  
• 
  IgA Nephropathy (Buerger’s Disease)
  
• 
  Membrano-proliferative Glomerulonephritis (MPGN)
  

• 
  Nephrotic Syndrome
  

• 
  Membranous Glomerulonephritis
  
• 
  Minimal Change Disease
  
• 
  Focal Segmental Glomerulosclerosis
  

GLOMERULAR DISEASES

RENAL BIOPSY

• 
  Light microscopy
  
• 
  Immuno-fluorescence
  
• 
  Electron-microscopy
  

PRIMARY GLOMERULOPATHIES


Acute Post-Streptococcal Glomerulonephritis

• 
  Also called as acute proliferative / Post infectious glomerulonephritis
  
• 
  Children
  
• 
  2-4 weeks after a Streptococcus infection
  
• 
  Smoky urine
  
• 
  Organism: β- hemolytic group A streptococcus
  
• 
  Can be associated with other bacteria, viruses and systemic infections
  
• 
  Nephritic syndrome
  

• 
  Normal colored urine
  
• 
  Urine with frank blood
  
• 
  Smoky urine – typical of Nephritic Syndrome
  

Laboratory Findings:

• 
  Elevated ASO titers – evidence of streptococcal infection
  
• 
  Low complement (immune complexes are being formed, activating complement and lowering its levels)
  

Light Microscopy:

• 
  Not very specific
  
• 
  Hypercellular glomeruli
  
• 
  Red cell casts
  

ImmunoFluorescence: IMPORTANT

• 
  Granular deposits within the glomeruli
  
• 
  Highlighted by IgG or IgM antibodies
  

Electron Microscopy:

• 
  Immune complexes
  
• 
  Occur in subepithelial locations in 2 sizes (small and large)
  
• 
  Large deposits called as subepithelial humps.
  

• 
  Subepithelial hump
  

• 
  Glomerular hypercellularity
  
• 
  Red cell casts in tubules
  

Acute Post-Streptococcal Glomerulonephritis

Treatment:

• 
  Conservative
  
• 
  Most children do well
  

• 
  95% recover completely
  
• 
  1% develop aggressive RPGN or chronic glomerulonephritis
  

Prognosis:

• 
  Children - excellent
  
• 
  Adults- worse
  

GOODPASTURE’S SYNDROME

• 
  Also known as anti-GBM disease
  

Pathogenesis :

• 
  Autoantibodies against type IV collagen of basement membrane
  
• 
  Damage to the lungs + kidneys
  

Clinical features :

• 
  Males
  
• 
  20-40 years of age
  
• 
  Hemoptysis presents earlier → renal manifestations
  

Light Microscopic:

• 
  Non specific
  
• 
  Some crescents
  

ElectronMicroscopy:

• 
  Non specific - GBM disruption
  

ImmunoFluorescence: IMPORTANT

• 
  “Neon sign” (smooth and linear)
  
• 
  Stain positive for IgG and C3 complement component
  
• 
  Linear pattern of immune-complex deposition seen by
  

immunofluorescence microscopy
Treatment :

• 
  Plasma exchange
  
• 
  Steroids
  

Prognosis :

• 
  Poor
  

• 
  Death from pulmonary hemorrhage / RPGN
  

RAPIDLY PROGRESSING GLOMERULONEPHRITIS

Clinical Features:

• 
  Also known as Crescentic Glomerulonephritis
  
• 
  Rapid progression → renal failure
  

• 
  Span of weeks to months
  

• 
  Several settings that will arise into this glomerulonephritis
  

• 
  Following Goodpasture’s Syndrome
  
• 
  Vasculitis (eg Wegener’s )
  
• 
  Idiopathic (50%)
  

Light Microscopic:

• 
  Crescent formation in glomeruli
  
• 
  Composed of → fibrin, proliferation of parietal epithelial
  

cells and an influx of Monocytes/ macrophages

Prognosis:

• 
  Poor
  

IgA NEPHROPATHY (Berger’s disease)

Clinical

• 
  Most common glomerulonephritis in the world
  
• 
  France, Japan, Italy
  
• 
  Male, young adults
  
• 
  Gross hematuria
  
• 
  Associated with respiratory infection and other IgA diseases like celiac sprue, Henoch-Schönlein purpura
  

Light Microscopy

• 
  Mesangial proliferation
  

ImmunoFluorescence: IMPORTANT

• 
  Mesangial deposition of IgA
  

ElectronMicroscopy:

• 
  Immune complexes
  

Prognosis

• 
  Slowly progress → renal failure
  

MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS

Types of MPGN:

• 
  Type I
  
• 
  Type II (dense deposit disease)
  

Clinical features:

• 
  Nephrotic +/or nephritic
  

Lab findings:

• 
  Type II produce an antibody called C3 nephritic factor is produced
  

Light Microscopy:

• 
  Lobulated glomeruli
  
• 
  Mesangial proliferation
  
• 
  “Tram-tracking” (splitting of basement membrane due to mesangial proliferation)
  

ImmunoFluorescence:

• 
  Granular pattern (not specific)
  

ElectronMicroscopy:

• 
  Type I- subendothelial immune complexes
  
• 
  Type II- deposits within GBM
  

Prognosis:

• 
  Slowly progressive course – renal failure in 10-15 years
  

Top- Lobulated glomeruli ,Mesangial proliferation

Bottom- Silver stain demonstrates "tram-tracking“ - double contour to many basement membranes that results from basement membrane reduplication

Middle- Bright deposits scattered along capillary walls and in the mesangium with antibody to C3 are typical for membranoproliferative glomerulonephritis, type II (Dense deposit disease). Most patients have detectable circulating C3 nephritic factor, an IgG autoantibody

Glomerular Diseases

• 
  Nephrotic Syndrome
  

• 
  Membranous Glomerulonephritis
  
• 
  Minimal Change Disease
  
• 
  Focal Segmental Glomerulosclerosis
  

Membranous Glomerulonephritis

• 
  Most common cause of adult nephrotic syndrome
  

Etiology

• 
  Idiopathic
  
• 
  Drugs
  
• 
  Hepatitis
  
• 
  SLE
  
• 
  Diabetes
  
• 
  Genetic predisposition
  

Light Microscopy:

• 
  Diffuse thickening of capillary walls
  
• 
  “Spiking” of basement membrane (on silver stain)
  

ImmunoFluorescence:

• 
  Granular and linear pattern
  

ElectronMicroscopy:

• 
  Subepithelial deposits
  

Prognosis:

• 
  Variable – spontaneous remission / persistence Diffuse thickening of
  

of proteinuria / end stage renal disease glomerular capillary walls

1. 
   Electron Dense Sub-epithelial Deposits in Glomerular Basement Membrane
   
2. 
   Diagrammatic Representation showing deposits and spike formation
   

MINIMAL CHANGE DISEASE

Clinical features:

• 
  Also known as Lipoid Nephrosis or Nil’s Disease
  
• 
  Most common cause in children 2-6 years old
  
• 
  Diagnosis of exclusion
  

Light Microscopy+ImmunoFluorescence:

• 
  Normal
  

ElectronMicroscopy:

• 
  No immune complexes
  
• 
  Effacement of foot processes
  

Treatment:

• 
  Steroids
  

Prognosis:

• 
  Excellent
  

Thin Basement Membrane

Absence of proliferation

FOCAL SEGMENTAL GLOMERULOSCLEROSIS

Clinical:

• 
  African American- all ages
  
• 
  Nephrotic
  

Etiology:

• 
  Idiopathic
  
• 
  Sickle cell anemia
  
• 
  Heroin abuse
  
• 
  AIDS
  

Light Microscopy: IMPORTANT

• 
  Segmental sclerosis
  
• 
  Glomerular hyalinization
  

ImmunoFluorescence +ElectronMicroscopy:

• 
  Nonspecific
  

Treatment:

• 
  Poor response to steroids
  
• 
  Recur in renal transplants
  

Prognosis:

• 
  Children better than adults
  
• 
  → chronic renal failure
  

Low Power view showing segmental

sclerosis in one out of three glomeruli
High-power view showing hyalime

mass and lipid in sclerotic areas

SECONDARY DISEASES OF THE KIDNEY

Diabetes Mellitus

• 
  Kimmelstein- Wilson disease
  

• 
  Nephrotic
  

• 
  Amyloidosis
  

• 
  Nephrotic syndrome
  
• 
  Congo red stain
  

CHRONIC GLOMERULONEPHRITIS

Definition

3. 
   End stage renal disease
   
4. 
   Uremia
   

Clinical

5. 
   Anemia
   
6. 
   HTN
   
7. 
   Azotemia
   

Gross

8. 
   Small kidneys
   

Micro

9. 
   Hyalinization of glomeruli
   

Treatment

10. 
    Dialysis
    
11. 
    Transplant
    

Diseases Affecting Tubules and Interstitium

• 
  Diseases characterized by
  

• 
  Ischemic or toxic tubular injury, leading to acute tubular necrosis and acute renal failure
  
• 
  Inflammatory involvement of the tubules and interstitium (tubulointerstitial nephritis)
  

Acute Tubular Necrosis

• 
  Is a clinicopathologic entity characterized:
  

• 
  Morphologically by destruction of tubular epithelial cells
  
• 
  Clinically by acute suppression of renal function
  

• 
  Is a reversible renal lesion that arises in a variety of clinical settings
  
• 
  It is the most common cause of acute renal failure (ARF)
  

• 
  Acute suppression of renal function and urine flow (<400ml/24 hours)
  

Acute Renal Failure

ARF can be caused by the following conditions:

12. 
    Organic vascular obstruction
    

• 
  Polyarteritis nodosa
  
• 
  Malignant hypertension
  
• 
  Hemolytic-uremic syndrome
  

13. 
    Severe glomerular disease - rapidly progressive glomerulonephritis
    
14. 
    Acute tubulointerstitial nephritis - hypersensitivity to drugs
    
15. 
    Pyelonephritis - especially when accompanied by papillary necrosis
    
16. 
    Disseminated intravascular renal coagulation
    
17. 
    Urinary obstruction
    

• 
  Tumors
  
• 
  Prostatic hypertrophy
  
• 
  Blood clots (so-called postrenal ARF)
  

18. 
    Acute tubular necrosis (ATN)
    

Acute Tubular Necrosis

• 
  Types of ATN
  

• 
  Ischemic ATN
  
• 
  Nephrotoxic ATN
  

• 
  The critical event in both ischemic and nephrotoxic ATN is tubular damage
  

Patterns of Tubular Damage

19. 
    Ischemic type: Patchy involvement of tubules specially PCT and HL (ascending part)
    
20. 
    Toxic type: Extensive necrosis of PCT + some HL
    
21. 
    Lumina of DCT and CD contain casts in both
    

Acute Tubular Necrosis

22. 
    Ischemic ATN is characterized by
    

• 
  Focal tubular necrosis at multiple points along the nephron
  
• 
  Large skip areas in between
  
• 
  Rupture of basement membranes (tubulorrhexis)
  
• 
  Occlusion of tubular lumina by casts
  

23. 
    Especially vulnerable
    

• 
  Straight portion of the proximal tubule
  
• 
  Ascending thick limb in the renal medulla
  

24. 
    Common casts found are:
    

• 
  Eosinophilic hyaline casts
  
• 
  Pigmented granular casts
  

25. 
    These casts consist principally of Tamm-Horsfall protein + hemoglobin, myoglobin, and other plasma protein
    

• 
  Tamm-Horsfall protein: A specific urinary glycoprotein normally secreted by the cells of ascending thick limb and distal tubules
  

• 
  Toxic ATN is characterized by
  

• 
  Acute tubular injury most obvious in the proximal convoluted tubules
  

• 
  Histologically the tubular necrosis may be:
  

• 
  Nonspecific
  
• 
  Distinctive in poisoning with certain agents
  

26. 
    Mercuric chloride – severely injured cells contain large acidophilic inclusions.
    
27. 
    Carbon tetrachloride poisoning - accumulation of neutral lipids in injured cells followed by necrosis.
    
28. 
    Ethylene glycol - marked ballooning and hydropic or vacuolar degeneration of proximal convoluted tubules
    

Clinical Course

• 
  Divided into initiating, maintenance, and recovery stages:
  
• 
  Initiating phase:
  
• 
  Lasting for about 36 hours
  
• 
  Dominated by the inciting medical, surgical, or obstetric event in the ischemic form of ATN
  
• 
  Indication of renal involvement: Slight decline in urine output+rise in BUN
  
• 
  Maintenance phase:
  
• 
  Sustained decreases in urine output to 40 - 400 ml / day (oliguria)
  
• 
  Salt and water overload
  
• 
  Rising blood urea nitrogens, hyperkalemia, metabolic acidosis, and other manifestations of uremia dominating this phase.
  
• 
  Treatment:
  

• 
  Maintenance of water and blood electrolytes
  
• 
  Dialysis
  

• 
  Recovery phase:
  
• 
  A steady increase in urine volume that may reach up to 3 liters per day
  
• 
  The tubules are still damaged, so that large amounts of water, sodium, and potassium are lost in the urinary flood.
  
• 
  Hypokalemia, rather than hyperkalemia, becomes a clinical problem
  

Prognosis:

• 
  Depends on the clinical setting surrounding its development
  
• 
  Recovery is expected with nephrotoxic ATN when the toxin has not caused serious damage to other organs, such as the liver or heart.
  
• 
  Conversely, in shock related to sepsis or extensive burns, the mortality rate may rise to over 50%.
  
• 
  Nonoliguric ATN:
  

29. 
    Up to 50% of patients with ATN may not have oliguria, and may in fact have increased urine volumes.
    
30. 
    Occurs particularly often with nephrotoxins
    
31. 
    Generally tends to follow a more benign clinical course.
    

Tubulointerstitial Nephritis

32. 
    Group of renal diseases characterized by histologic and functional alterations that involve predominantly the tubules and interstitium
    
33. 
    Have diverse causes and different pathogenetic mechanisms
    
34. 
    Tubulointerstitial nephritis (TIN) can be acute or chronic
    
35. 
    Acute TIN:
    

• 
  An acute clinical onset
  
• 
  Characterized histologically by
  

• 
  Interstitial edema
  
• 
  Leukocytic infiltration
  
• 
  Focal tubular necrosis
  

36. 
    Chronic interstitial nephritis (CIN):
    

• 
  Infiltration with mononuclear cells
  
• 
  Prominent interstitial fibrosis
  
• 
  Widespread tubular atrophy
  

• 
  Clinically distinguished from glomerular diseases by:
  

Early stages:

• 
  Absence of nephritic or nephrotic syndromes
  
• 
  Presence of defects in tubular function
  

• 
  Impaired ability to concentrate urine - polyuria or nocturia
  
• 
  Salt wasting
  
• 
  MM.Diminished ability to excrete acids (metabolic acidosis)
  

Advanced stages:

• 
  Difficult to distinguish clinically from other causes of renal
  

insufficiency