Pbl Exam 11 Case 2

Front 1

1. What are three main implications of the anatomy of renal vessels?

Back 1

1. B/c the arteries are largely end-arteries, occlusion of any branch usually results in infarction of the specific area it supplies.
2. All tubular capillary beds are derived from the efferent arterioles and thus glomerular disease that interferes w/blood flow thru the glomerular capillaries has profound effects on the tubules
3. The peculiarities of the blood supply to the renal medulla render them especially vulnerable to ischemia; the medulla does not have its own arterial blood supply but is dependent on the blood emanating from the glomerular efferent arterioles. Thus, minor interference w/the blood supply of the medulla may result in medullary necrosis from ischemia.

Front 2

2. What are glomeruli and what are the major characteristics of their filtration?

Back 2

The glomerulus consists of an anastomosing network of capillaries lined by fenestrated endothelium invested by two layers of epithelium.

The major characteristics of normal glomerular filtration are an extraordinarily high permeability to water and small solutes, b/c of the highly fenestrated nature of the endothelium, and impermeability to proteins, such as molecules the size of albumin or larger.

Front 3

3. What is the glomerular barrier function?

Back 3

This function discriminates among various protein molecules depending on their size (the larger, the less permeable) and charge (the more cationic, the more permeable).

This size and charge dependent barrier function is accounted for by the complex structure of the capillary wall, the collagenous porous and charged structure of the BGM, and the many anionic moieties present within the wall, including the acidic proteoglycans of the GBM and the sialoglycoproteins of epithelial and epithelial cell coats.

The charge-dependent restriction is important in the virtually complete exclusion of albumin from the filtrate, b/c albumin in an anionic molecule of pI 4.5.

Front 4

4. What is the visceral epithelial cell AKA podocyte important for?

Back 4

The podocyte is important for the maintenance of glomerular barrier function; its slit diaphragm presents a size selective distal diffusion barrier to the filtration of proteins, and it is the cell type that is largely responsible for synthesis of GBM components.

Proteins located in the slit diaphragm control glomerular permeability.

Front 5

5. What are the important proteins have been identified in the slit diaphragm?

Back 5

Nephrin; a transmembrane protein w/a large EC portion made up of Ig like domains.

Nephrin then forms molecular connections w/podocin, CD2-associated protein, and ultimately the actin skeleton.

Mutations in the genes that encode for these proteins give rise to nephrotic syndrome.

Front 6

6. What is the structure and function of the tubules?

Back 6

The structure of the tubule is correlated with its function; for ex: the highly developed structure of the proximal tubular cells, with their abundant long microvilli, numerous mitochondria, apical canaliculi, and extensive intercellular interdigitations is correlated w/their major functions: reabsorption of 2/3's of filtered sodium and water as well as glucose, potassium, phosphate, AAs, and proteins.

The proximal tubule is particularly vulnerable to ischemic damage. Furthermore, toxins are freq reabsorbed by the proximal tubule, rendering it also susceptible to chemical injury.

Front 7

7. What is the juxtaglomerular apparatus?

Back 7

It lies against the glomerulus where the afferent arteriole enters it. It consists of:
1. The JG cells, modified granulated smooth muscle cells that contain renin
2. The macula densa
3. The lacis cells or nongranular cells.

The JG apparatus is a small endocrine organ, and the JG cells are the principal sources of renin production in the kidney.

Front 8

8. What are the four categories of renal diseases?

Back 8

Renal diseases are divided into four categories based on the four basic anatomic compartments affected:

1. Glomeruli
2. Tubules
3. Intersitium
4. Blood vessels

Whatever the origin, there is a tendency for all forms of chronic renal disease ultimately to destroy all four components of the kidney, culminating in chronic renal failure.

Front 9

9. What is azotemia?

Back 9

Azotemia is a biochemical abnormality that refers to an elevation of the blood urea nitrogen (BUN) and creatinine levels and is related largely to a decreased glomerular filtration rate (GFR).

Azotemia is produced by many renal disorders but also arises from extrarenal disorders.

Front 10

10. What is prerenal azotemia?

Back 10

This is encountered when there is hypoperfusion of the kidneys (e.g. in hemorrhage or shock) that impairs renal function in the absence of parenchymal damage.

Front 11

11. What is postrenal azotemia?

Back 11

This is seen whenever urine flow is obstructed below the level of the kidney. Relief of the obstruction is followed by correction of the azotemia.

Front 12

12. What is uremia?

Back 12

When azotemia becomes associated w/a constellation of clinical signs and symptoms and biochemical abnormalities, it is termed uremia.

Uremia is characterized no only by failure of renal excretory function but also by a host of metabolic and endocrine alterations resulting from renal damage. There is, in addition, secondary involvement of the GI system, peripheral nerves, and heart, which is usually necessary for the Dx of uremia.

Front 13

13. What is acute nephrotic syndrome?

Back 13

ANS is a glomerular syndrome dominated by the acute onset of usually grossly visible hematuria, mild to moderate proteinuria, and hypertension; it is the classic presentation of acute poststreptococcal glomerulonephritis.

Front 14

14. What is nephrotic syndrome?

Back 14

Nephrotic syndrome is characterized by heavy proteinuria, hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria (lipids in the urine).

Front 15

15. What is acute renal failure?

What is chronic renal failure?

Back 15

Acute renal failure is dominated by oliguria or anuria, with recent onset of azotemia. It can result from glomerular, interstitial, or vascular injury or tubular necrosis.

Chronic renal failure is characterized by prolonged symptoms and signs of uremia, and is the end result of all chronic renal parenchymal diseases.

Front 16

16. What are the 4 stages of chronic renal failure?

Back 16

1. Diminished renal reserve (GFR = 50% of normal)
2. Renal insufficiency (GFR = 20-50% of normal with azotemia, anemia, and hypertension)
3. Renal failure (GFR < 20-25% of normal; with edema, metabolic acidosis, and hypocelcemia)
4. End-stage renal disease (GFR < 5% of normal; this is the terminal stage of uremia)

Front 17

17. What are renal tubular defects?

Back 17

Renal tubular defects are dominated by polyuria, nocturia, and electrolyte disorders. They are the result of either diseases that directly affect tubular structure (e.g. medullary cystic disease) or defects in specific tubular functions. The latter can be inherited (e.g. familial nephrogenic diabetes, cystinuria, renal tubular acidosis) or acquired (e.g. lead nephropathy).

Front 18

18. What are the characteristics of UTIs?

Back 18

UTI is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may affect the kidney or the bladder.

Front 19

19. What is renal agenesis?

Back 19

Total bilateral agenesis of the kidney is incompatible w/life and is usually encountered in stillborn infants. It is often associated w/many other congenital disorders (e.g. limb defects, hypoplastic lungs) and leads to early death.

Unilateral agenesis is an uncommon anomaly that is compatible w/normal life if no other abnormalities exist. The opposite kidney is usually enlarged as a result of compensatory hypertrophy. Progressive glomerular sclerosis sometimes develops in the remaining kidney.

Front 20

20. What is renal hypoplasia?

Back 20

Refers to failure of the kidneys to develop to a normal size. This may occur bilaterally, resulting in renal failure in early childhood, but it is more commonly encountered as a unilateral defect.

True renal hypoplasia is extremely rare. ***A truly hypoplastic kidney shows no scars and has a reduced number of renal lobes and pyramids, usually 6 or less.

In one form of hypoplastic kidney, oligomeganephronia, the kidney is small but the nephrons are markedly hypertrophied.

Front 21

21. What is an ectopic kidney?

Back 21

Ectopic kidneys lie either just above the pelvic brim or sometimes within the pelvis.

Because of their abnormal position, kinking or tortuosity of the ureters may cause urinary obstruction, predisposing to bacterial infection.

Front 22

22. What are horseshoe kidneys?

Back 22

Fusion of the upper (10%) or lower (90%) poles produces a horseshoe-shaped structure continuous across the midline anterior to the aorta and inferior vena cava.

This anomaly is quite common and is found in about 1 in 500-1,000 autopsies.

Front 23

23. Why are cystic diseases of the kidney important?

Three reasons...

Back 23

1. They are reasonably common and often represent diagnostic problems for clinicians, radiologists, and pathologists
2. Some forms, such as AKPD, are major causes of chronic renal failure
3. They can occasionally be confused w/malignant tumors.

Front 24

24. What are the classifications of renal cysts?

Back 24

1. Cystic renal dysplasia
2. Polycystic kidney disease
3. Medullary cystic disease
4. Acquired cystic disease
5. Simple renal cysts
6. Glomerulocytic disease
7. Extraparenchymal renal cysts
8. Renal cysts in hereditary malformation syndromes

Front 25

25. What is cystic renal dysplasia?

Back 25

Cystic renal dysplasia refers to sporadic, nonfamilial disease resulting from abnormal metanephric differentiation. It is frequently associated w/obstructive abnormalities of the ureter and lower urinary tract and may be uni- or bilateral.

Histologically, it is characterized by the persistence in the kidney of abnormal structures- cartilage, undifferentiated mesenchyme, and immature collecting ductules, and by abnormal lobar organization.

Front 26

26. What are the gross and morphological characteristics of cystic renal dysplasia?

Back 26

Dysplasia can be unilateral or bilateral and is almost always cystic. In gross appearance, the kidney is usually enlarged, extremely irregular, and multicystic. The cysts vary in size from microscopic structures to some that are several cm in diameter.

On histologic exam, they are lined by flattened epithelium. Although normal nephrons are present, many have immature ducts.

*The characteristic histologic feature is the present of islands of undifferentiated mesenchyme, often w/cartilage, and immature collecting ducts.

Front 27

27. What are the clinical features of cystic renal dysplasia?

Back 27

When unilateral, the dysplasia is discovered by the appearance of a flank mass that leads to surgical exploration and nephrectomy.

The function of the opposite kidney is normal, and such patients have an excellent prognosis after surgical removal of the affected kidney. In bilateral renal dysplasia, renal failure may ultimately result.

Front 28

28. What is autosomal dominant adult polycystic kidney disease?

Back 28

ADPKD is a hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately destroy the renal parenchyma and cause renal failure.

It is a common condition affecting roughly 1/400 - 1,000 live births and accounting for about 5-10% of cases of chronic renal failure requiring transplantation or dialysis.

The disease is universally bilateral; reported unilateral cases probably represent multicystic dysplasia. The cysts initially involve only portions of the nephrons, so renal function is retained until the 4th or 5th decade of life.

Front 29

29. What are the genetic causes of ADPKD?

Back 29

ADPKD is autosomal dominant, with high penetrance. Family studies show that the disease is caused by mutations in genes located on chromosome 16p13.3 (PKD1) and 4q21 (PKD2).

Mutations of PKD1 account for about 85% of cases and are associated w/a more severe disease, ESRD or death occurring at an average of 53 years, compared to 69 years for PKD2.

Front 30

30. What is the role of the PKD1 gene?

Back 30

The PKD1 gene accounts for 85% of cases.

It encodes a large protein named polycystin1. Although the precise function is unknown, polycystin 1 normally localizes to tubular epithelial cells and has homology to proteins involved in cell-cell and cell-matrix interactions.

It also servers a suppressor function; its loss leads to hyperplasia of epithelial cells.

Front 31

31. What is the role of the PKD2 gene?

Back 31

The PKD2 gene product polycystin-2 is an integral membrane protein. Polycystin-2 may act as a calcium-permeable cation channel and that a basic defect in ADPKD is a disruption in the regulation of intracellular calcium levels.

Front 32

32. What is the general theory as to how these mutations cause the pathogenesis of ADPKD?

Back 32

*These mutations alter cell-cell and cell-matrix interactions that are important for tubular epithelial growth and differentiation.

Epithelial cells lining the cysts of ADPKD have a high proliferation rate. Cysts are freq detached from adjacent tubules and enlarge by active fluid secretion from the lining epithelial cells. In addition, the ECM produced by cyst-lining cells is abnormal. These findings have led to the scenario that cysts develop as a result of abnormality in cell differentiation, associated w/sustained cellular proliferation and some degree of apoptosis, transeptihelial fluid secretion, and remodeling of the ECM.

Front 33

33. What is the morphology of ADPKD?

1/2

Back 33

In gross appearance, the kidneys are usually bilaterally enlarged and may achieve enormous sizes. The external surface appears to be composed solely of a mass of cysts, up to 304 cm in diameter, w/no intervening parenchyma. However, microscopic exam reveals functioning nephrons dispersed between the cysts.

The cysts may be filled w/a clear, serous fluid or, more usually w/turbid, red to brown, sometimes hemorrhagic fluid.

Front 34

34. What is the morphology of ADPKD?

2/2

Back 34

As these cysts enlarge, they may encroach on the calyces and pelvis to produce pressure defects. The cysts arise from the tubules throughout the nephron and therefore have variable lining epithelia.

On occasion, papillary epithelial formations and polyps project into the lumen. Bowman capsules are occasionally involved in cyst formation, and glomerular tufts may be seen w/in the cystic space.

Front 35

35. What are the clinical features of ADPKD?

Back 35

Patients have flank pain from hemorrhage into cysts, hematuria, hypertension, proteinuria, progressive renal failure, and bilateral abdominal masses inducing a dragging sensation.

Progression is accentuated in the presence of hypertension, in blacks (w/sickle cell trait), and in males.

Patients w/PKD2 mutations tend to have an older age at onset and later development of renal failure.

Front 36

36. What are the extrarenal anomalies associated with ADPKD?

Back 36

1. About 40% have one to several cysts in the livers (polycystic liver disease) that are usually asymptomatic
2. Intracranial berry aneurysms, presumably from altered expression of polycystin in vascular smooth muscle, arise in the Circle of Willis, and subarachnoid hemorrhages from these account for death in about 4-10% of those with ADPKD
3. Mitral valve prolapse and other cardiac valvular anomalies occur in 20-25% of patients, but most are asymptomatic.

Front 37

37. What is autosomal-recessive (childhood) polycystic kidney disease?

Back 37

ARPKD is a rare developmental anomaly presenting from the perinatal through juvenile periods. Infants often succumb rapidly to renal failure.

Kidneys are enlarged by multiple, cylindrically dilated collecting ducts, oriented at right angels to the cortex and filling both the cortex and medulla.

Front 38

38. What are the genetic causes of ARPKD?

Back 38

The disease appears to be genetically homogenous, with a gene, PKHD1. The PKHD1 gene encodes a large novel protein, fibrocystin. This gene is highly expressed in adult and fetal kidney and also in liver and pancreas.

Fibrocystin is a protein that may function in cell surface receptors with a role in collecting-duct and biliary differentiation.

Front 39

39. What is the morphology of ARPKD?

Back 39

The kidneys are enlarged and have a smooth external appearance. On cut section, numerous small cysts in the cortex and medulla give the kidney a spongelike appearance.

Dilated elongated channels are present at right angles to the cortical surface, completely replacing the medulla and cortex.

On microscopic exam, there is 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 tubules.

The disease is bilateral; in almost all cases, the liver has cysts with portal fibrosis as well as proliferation of portal bile ducts.

Front 40

40. What is the clinical course in ARPKD?

Back 40

Patients who survive infancy may develop a peculiar type of hepatic fibrosis characterized by bland periportal fibrosis and proliferation of well-differentiated biliary ductules, a condition now termed congenital hepatic fibrosis. In older children, the hepatic picture in fact predominates.

Such patients may develop portal hypertension with splenomegaly.

Front 41

41. What is medullary sponge kidney?

Back 41

This disease should be restricted to lesions consisting of multiple cystic dilations of the collecting ducts in the medulla, usually presenting in adults.

Although it is typically an innocuous lesion discovered incidentally by radiographic studies, it can predispose to renal calculi, hematuria, infection, and dilated ducts.

On gross inspection, the papillary ducts in the medulla are dilated, and small cysts may be present. The cysts are lined by cuboidal epithelium or occasionally be transitional epithelium.

Front 42

42. What with nephronophthisis-medullary cystic disease complex?

Back 42

This complex is actually a family of progressive renal disorders, usually w/onset in childhood.

*The common characteristic is the presence of a variable number of cysts in the medulla, usually concentrated at the corticomedullary junction.

Although the presence of medullary cysts is important, the cortical tubulointerstitial damage is the cause of the eventual renal insufficiency.

Front 43

43. What are the four variants of nephronophthisis-medullary cystic disease complex?

Back 43

1. Sporadic; non-familial (20%)
2. *Familial juvenile nephronophthisis (50%)
3. *Renal-retinal dysplasia (15%)
4. **Adult onset medullary cystic disease (15%)

*Autosomal recessive
**Autosomal dominant

Front 44

44. What are the clinical features of nephronophthisis-medullary cystic disease complex?

Back 44

Affected children present first with polyuria and polydipsia, which reflect a marked defect in the concentrating ability of renal tubules. Sodium wasting and tubular acidosis are also prominent.

Some variants of juvenile nephronophthisis can have extrarenal associations, including ocular motor abnormalities, retinitis pigmentosa, liver fibrosis, and cerebellar abnormalities.

The expected course is progression to terminal renal failure in 5-10 years.

Front 45

45. What are the genes involved in the pathogenesis of nephronophthisis-medullary cystic disease complex?

Back 45

Thee genes, NPH1, NPH2, and NPH3, define the juvenile forms of the nephronophthisis and cause autosomal recessive disease.

The protein product of NPH1 is nephrocystin but its function is unknown.

Two genes (MCKD1 and MCKD2) with autosomal dominant transmission, have been identified as causing medullary cystic disease that is characterized by progression to endstage kidney disease in adult life.

Front 46

46. What is the morphology of nephronophthisis-medullary cystic disease complex?

Back 46

In gross appearance, the kidneys are small, have contracted granular surfaces, and show cysts in the medulla, most prominently at the corticomedullary junction. Small cysts are also seen in the cortex.

The cysts are lined by flattened or cuboidal epithelium and are usually surrounded by either inflammatory cells or fibrous tissues. In the cortex, there is widespread atrophy and thickening of the basement membranes of the proximal and distal tubules, together w/interstitial fibrosis.

Front 47

47. What is acquired (dialysis-associated) cystic disease?

Back 47

End-stage kidneys of patients undergoing dialysis can develop multiple cortical and medullary cysts.

They are often lined by atypical, hyperplastic epithelium that can undergo malignant transformation to renal cell carcinoma.

These cysts often contain calcium oxalate crystals.

Front 48

48. What are simple renal cysts?

How do they differ radiologically from renal tumors?

Back 48

These occur as multiple, single, usually cortical cystic spaces that vary widely. They are lined by low cuboidal epithelium and usually are 2-5 cm in diameter but can measure up to 10 cm. They have smooth walls and are filled w/clear serous fluid.

On occasion, they hemorrhage and calcification of the hemorrhage can cause flank pain and irregular contours, thus mimicking renal carcinoma.

Radiologic studies show that in contrast to renal tumors, renal cysts have smooth contours, are almost always avascular, and give fluid rather that solid signals on ultrasonography.

Front 49

49. What is the most common cause of chronic renal failure in humans?

Back 49

Chronic glomerulonephritis is one of the most common causes of chronic renal failure in humans.

Front 50

50. What is the difference between primary and secondary glomerular diseases?

Back 50

Primary glomerular diseases are ones in which the kidney is the only or predominant organ involved. These include: poststreptococcal glomerulonephritis, minimal change disease, IgA nephropathy, etc...

Secondary glomerular diseases include systemic immunologic diseases such as SLE, vascular disorders such as hypertension and polyarteritis nodosa, DM, etc...

Front 51

51. What are the 4 main histologic alterations in the various types of glomerulonephritis?

Back 51

1. Hypercellularity
2. Basement membrane thickening
3. Hyalinization
4. Sclerosis

Front 52

52. What causes the hypercellularity in glomerulonephritis?

What are the 3 characteristics of hypercellularity?

Back 52

Some inflammatory diseases of the glomerulus are characterized by an increase in the number of cells in the glomerular tufts. This is characterized by one or more combos of the following:
1. Cellular proliferation of mesangial or endothelial cells
2. Leukocytic infiltration, consisting of neutrophils, monocytes, and lymphocytes
3. Formation of crescents. These are accumulations of cells composed of proliferating parietal epithelial cells and infiltrating leukocytes.

Front 53

53. What is the molecule that is mainly responsible for eliciting the crescentic response?

Back 53

Fibrin, which leaks into the urinary space, often thru ruptured basement membranes, has been long thought to be the molecule that elicits the crescentic response.

In support of this, fibrin can be demonstrated immunohistochemically in the glomerular tufts and urinary spaces of glomeruli that contain crescents.

Front 54

54. What causes the basement membrane thickening in glomerulonephritis?

Back 54

Such thickening can be resolved as one of two alterations:

1. Deposition of amorphous electron-dense material, most often immune complexes, on the endothelial or epithelial side of the basement membrane or w/in the GBM itself. Fribrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also deposit in the GBM.
2. Thickening of the basement membrane proper, as occurs in diabetic glomerulosclerosis.

Front 55

55. What causes the hyalinization and sclerosis in glomerulonephritis?

Back 55

Hyalinization denotes the accumulation of material that is homogeneous and eosinophilic by light microscopy. By electron microscopy, the hyalin is extracellular and consists of amorphous substance. This change contributes to obliteration of capillary lumina of the glomerular tuft (a feature of sclerosis).

Hyalinosis is usually a consequence of endothelial or capillary wall injury and typically is the end result of various forms of glomerular damage.

Front 56

56. What are the two patterns of antibody associated glomerular injury?

Back 56

1. Injury by antibodies reacting in situ w/in the glomerulus, either with insoluble fixed (intrinsic) glomerular antigens or w/molecules planted w/in the glomerulus

2. Injury resulting from deposition of circulating antigen-antibody complexes in the glomerus

Front 57

57. What is in situ immune complex deposition?

Back 57

In this form of injury, antibodies react directly w/intrinsic tissue antigen, or antigens "planted" in the glomerulus from the circulation.

These include Anti-GBM antibody induced nephritis and Heymann nephritis.

Front 58

58. What is anti-GBM antibody-induced nephritis?

Back 58

In this type of injury, antibodies are directed against intrinsic fixed antigens that are normal components of the GBM proper.

It results in a diffuse linear pattern of staining of the antibodies by immunofluorescent techniques.

Front 59

59. What is the GBM antigen responsible for classic anti-GBM antibody induced nephritis and Goodpasture syndrome?

Back 59

The GBM antigen responsible for classic anti-GBM antibody induced nephritis and Goodpasture syndrome is a component of the noncollagenous domain (NC1) of the α₃-chain of collagen Type IV, which is critical for maintenance of the GBM superstructure.

Most instances of anti-GBM antibody induced nephritis are characterized by severe crescentic glomerular damage and the clinical syndrome of rapidly progressive glomerulonephritis.

Front 60

60. What is Heymann nephritis?

Back 60

The Heymann model of rat glomerulonephritis is induced by immunizing animals w/an antigen contained w/in preparations of proximal tubular brush border. The disease results from the reaction of antibody w/an antigen complex located on the basal surface of visceral epithelial cells and cross-reacting w/the brush border antigen.

The rats develop antibodies to this antigen, and a membranous glomerulopathy develops, resembling human membranous glomerulopathy.

On electron microscopy, the glomerulopathy is characterized by the presence of numerous eletron-dense deposits along the subepithelial aspect of the basement membrane. This pattern of immune deposition by immunofluorescence microscopy is granular rather than linear.

Front 61

61. What are "antibodies against planted antigens" diseases?

Back 61

Antibodies can react in situ w/antigens that are not normally present in the glomerulus but are "planted" there.

These include exogenous and endogenous antigens. Planted antigens include cationic molecules that bind to glomerular capillary anionic sites; DNA, nucleosomes, and other proteins; bacterial products; and immune complexes themselves.

Antibodies that bind to most of these planted antigens induce a discrete pattern of immunoglobulin deposition detected as granular staining by immunofluorescence microscopy similar to the pattern found in circulating immune complex nephritis.

Front 62

62. What is circulating immune complex nephritis?

Back 62

In this type of nephritis, glomerular injury is caused by the trapping of circulating antigen-antibody complexes w/in glomeruli. The antibodies have no immunologic specificity of glomerular constituents, and the complexes localize w/in the glomeruli b/c of their physicochemical properties and the hemodynamic factors peculiar to the glomerulus.

Front 63

63. What factors affect glomerular localization of antigens, antibody, or complexes?

Back 63

The molecular charge and size of these reactants are clearly important.

Highly cationic immunogens tend to cross the GBM, and the resultant complexes achieve a subepithleial location.

Highly anionic macromolecules are excluded from the GBM and either are trapped subendothelially or may not be nephrogenic at all.

Neutral molecules tend to accumulate in the mesangium.

*Large circulating complexes are not usually nephritogenic b/c they are cleared by the mononuclear phagocyte system and do not enter the GBM in sufficient quantities.

Front 64

64. What is the pattern of immune deposition in most of the cases of glomerulonephritis?

Back 64

In the largest proportion of cases of human glomerulonephritis, the pattern of immune deposition is granular and along the basement membrane or in the mesangium.

Front 65

65. In sum, what is the summary of immune mechanisms of glomerular injury?

Back 65

Antigen-antibody deposition in the glomerulus is a major pathway of glomerular injury and that in situ immune reactions, trapping of circulating complexes, interactions between these two events, and local hemodynamic and structural determinants in the glomerulus all contribute to the diverse morphologic and functional alterations in glomerulonephritis.

Front 66

66. When does activation of alternative complement pathway occur in glomerulonephritis?

Back 66

Alternative complement pathway activation occurs in the clinicopathologic entity called dense-deposit disease, AKA membranoproliferative glomerulonephritis.

Front 67

67. What causes the detachment of visceral epithelial cells from the GBM?

Back 67

It is hypothesized that the detachment of visceral epithelial cells is caused by loss of adhesive interactions w/the basement membrane and that this detachment contributes to protein leakage.

Front 68

68. What are the nine mediators of glomerular injury?

Back 68

1. Neutrophils
2. Monocytes, macrophages, lymphocytes, and NK cells
3. Platelets
4. Resident glomerular cells, particularly mesangial cells
5. C5b-C9
6. Coagulation proteins, especially fibrin
7. Hemodynamic regulators
8. Cytokines (IL-1 and TNF)
9. Growth factors (TGF-β, MCP-1, RANTES)

Front 69

69. What happens when a renal disease, glomerular or otherwise, destroys functioning nephrons and reduces the GFR to about 30-50% of normal?

Back 69

Progression to ESRD proceeds at a relatively constant rate, independent of the original stimulus or activity of the underlying disease.

Front 70

70. What are the 2 major histologic characteristics of such progressive renal damage?

Back 70

1. Glomerulosclerosis (both segmental and focal)
2. Tubulointerstitial fibrosis

Front 71

71. What is focal segmental glomerulosclerosis (FSGS)?

Back 71

Patients w/this secondary change develop proteinuria, even is the primary disease was nonglomerular. The glomerulosclerosis appears to be initiated by the adaptive change that occurs in the relatively unaffected glomeruli of diseased kidneys. Compensatory hypertrophy of the remaining glomeruli serves to maintain renal function, but proteinuria and glomerulosclerosis soon develop, leading eventually to total glomerular sclerosis and uremia. Most of the mediators of chronic inflammation and fibrosis, particularly TGF-β, play a role in the induction of sclerosis.

Treatment w/inhibitors of the renin-angiotensin system can be successful interventions to interrupt these mechanisms of progressive glomerulosclerosis.

Front 72

72. What else contributes to the progressive injury of focal and segmental glomerulosclerosis?

Back 72

The inability of mature visceral epithelial cells (podocytes) to proliferate after injury. This can lead to a decrease in glomerular podocyte number after a severe injury resulting in loss of some of these cells, leading structural alterations. These alterations lead to abnormal protein filtration as well as loss of structural support for the glomerular capillary walls.

This latter alteration in turn may lead to segmental loop dilatation b/c of now incompletely opposed intracapillary pressures, w/subsequent formation of a fibrous attachment to Bowman capsule by the bulging capillary segment, and eventual sclerosis of this segment.

Front 73

73. What is tubulointerstitial fibrosis?

Back 73

Tubulointerstitial injury, manifested by tubular damage and interstitial inflammation, is a component of many acute and chronic glomerulonephrides.

Tubulointerstitial fibrosis contributes to progression in both immune and nonimmune glomerular diseases, for example, diabetic nephropathy. Indeed, there is often a much better correlation of decline in renal function w/the extent of tubulointerstitial damage than w/the severity of glomerular injury.

Front 74

74. What factors lead to tubulointerstitial fibrosis?

Back 74

Many factors, including ischemia distal to sclerotic glomeruli, concomitant immune reactions to shared tubular and glomerular antigens, phosphate or ammonia retention leading to interstitial fibrosis, and the effects of proteinuria on tubular cell structure and function.

Proteinuria, in particular, causes direct injury to an activation of tubular cells. In turn, activated tubular cells elaborate proinflammatory cytokines and growth factors that drive interstitial fibrosis.

Front 75

75. What is acute glomerulonephritis?

Back 75

This group of glomerular diseases is characterized anatomically by inflammatory alterations in the glomeruli and clinically by the syndrome of acute nephritis.

The nephritis patient usually presents w/hematuria, red cell casts in the urine, azotemia, oliguria, and mild to moderate hypertension. The patient also commonly has proteinuria and edema.

This syndrome may occur in SLE and microscopic polyarteritis. Typically, however, it is characteristic of acute proliferative glomerulonephritis and is an important component of crescentic glomerulonephritis.

Front 76

76. What is acute proliferative glomerulonephritis?

Back 76

AKA post-streptococcal, postinfectious glomerulonephritis.

This cluster of diseases is characterized histologically by diffuse proliferation of glomerular cells, associated w/influx of leukocytes. These lesions are typically caused by immune complexes, and the inciting antigens may be endogenous or exogenous.

Front 77

77. What is post-streptococcal glomerulonephritis?

Back 77

This glomerular disease usually appears 1-4 weeks after a streptococcal infection of the pharynx or skin. It occurs most freq in children 6-10 years of age, but adults of any age can be affected.

Front 78

78. What is the pathogenesis of post-streptococcal glomerulonephritis?

Back 78

Only certain strains of group A β-hemolytic streptococci are nephritogenic.

Post-streptococcal glomerulonephritis is an immunologically mediated disease. The period between infection and onset of nephritis is compatible w/the time required for the production of antibodies and the formation of immune complexes. The presence of granular immune deposits in the glomeruli demonstrates and immune complex-mediated mechanism.

*Endostreptosin and several cationic antigens related to streptokinase can be present in affected glomeruli.

Front 79

79. What is the morphology of post-streptococcal glomerulonephritis?

Back 79

The classic diagnostic picture is one of enlarged, hypercellular glomeruli. The hypercellularity is caused by (1) infiltration by leukocytes, both neutrophils and monocytes; (2) proliferation of endothelial and mesangial cells; and (3) in severe cases by crescent formation.

By immunofluorescence microscopy, there are granular deposits of IgG, IgM, and C3 in the mesangium and along the basement membrane.

*The characteristic electron microscopic findings are discrete, amorphous, electron dense deposits on the epithelial side of the membrane, often having the appearance of "humps".

Front 80

80. What is the clinical course of post-streptococcal glomerulonephritis?

Back 80

In the classic case, a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria 1-2 weeks after recovery from a sore throat. The patients has red cell casts in the urine, mild proteinuria, periorbital edema, and mild to moderate hypertension. In adults, the onset is atypical, w/the sudden appearance of hypertension or edema, freq w/elevation of BUN.

More than 95% of children recover. In adults, the epidemic form has a good prognosis, although only 60%% recover after the sporadic form; the remainder develop rapidly progressive disease, chronic renal failure, or delayed, but eventual resolution.

Front 81

81. What are the lab finding in post-streptococcal glomerulonephritis?

Back 81

*Important lab findings include elevations of antistreptococcal antibody (ASO) titers and a decline in the serum concentration of C3 and other components of the complement cascade and the presence of cryoglobulins in the serum.

Front 82

82. What is nonstreptococcal acute glomerulonephritis (postinfectious glomerulonephritis)?

Back 82

A similar form of glomerulonephritis occurs sporadically in associated w/other bacterial infections, viral disease, and parasitic infections.

In this setting, granular immunofluorescent deposits and subepithelial humps characteristic of immune complex nephritis are present.

Front 83

83. What is rapidly progressive (crescentic) glomerulonephritis?

Back 83

Rapidly progressive glomerulonephritis (RPGN) is a syndrome associated w/severe glomerular injury and does not denote a specific etiologic form of glomerulonephritis.

It is characterized clinically by rapid and progressive loss of renal function associated w/severe oliguria and (if untreated) death from renal failure w/in weeks to months.

***Regardless of the cause, the classic histologic picture is characterized by the presence of crescents in most of the glomeruli.

Front 84

84. What are the three types of RPGN?

Back 84

Type I RPGN (Anti-GBM antibody)

Type II RPGN (Immune complex)

Type III RPGN (Pauci-immune)

Front 85

85. What is Type I RPGN (Anti-GBM antibody)?

Back 85

This is characterized by linear deposits of IgG, and in many cases, C3 in the GBM.

In some patients, the anti GBM antibodies cross-react w/pulmonary alveolar basement membranes to produce the clinical picture of pulmonary hemorrhage associated w/renal failure (Goodpasture syndrome).

Plasmapheresis to remove the pathogenic circulating antibodies is usually part of treatment.

Front 86

86. What are the environmental and genetic risk factors for Goodpasture syndrome?

Back 86

Exposure to viruses or hydrocarbon solvents has been implicated in some patients, as have various drugs and cancers. There is a high prevalence of certain HLA subtypes and haplotypes (e.g., HLA-DRB1) in affected patients.

Front 87

87. What is Type II RPGN (Immune complex)?

Back 87

The second type of RPGN is the result of immune complex-mediated disease. It can be a complication of any of the immune complex nephritides, indcluding postinfectious glomerulonephritis, SLE, IgA nephropathy, and Henoch-Schonlein purpura.

In all of these cases, immunofluorescence studies reveal the granular pattern of staining characteristic of immune complex deposition.

These patients cannot usually be helped by plasmapheresis, and they require treatment for the underlying disease.

Front 88

88. What is Type III RPGN (Pauci-immune)?

Back 88

The third type of RPGN, AKA pauci-immune type, is defined by the lack of anti-GBM antibodies or immune complexes by immunofluorescence and electron microscopy. Most patients w/this type of RPGN have antineutrophil cytoplasmic antibodies (ANCA).

In some cases, this type of RPGN is a component of a systemic vasculitis such as Wegener granulomatosis or microscopic polyarteritis. In many cases, however, pauci-immune crescentic glomerulonephritis is isolated and hence idiopathic. More than 90% of such idiopathic cases have c-ANCA or p-ANCA in the sera. The presence of circulating ANCAs in both idiopathic RPGN and cases of RPGN that occur as a component of systemic vasculitis, and the similar pathologic features in either setting, have led to the idea that these disorders are pathogenetically related.

Front 89

89. What is the morphology in RPGN?

Back 89

The common denominator in all types of RPGN is severe glomerular injury.

The kidneys are enlarged and pale, often w/petechial hemorrhages on the cortical surfaces. Depending on the underlying cause, the glomeruli may show focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation. The histologic picture, however, is dominated by the formation of distinctive crescents.

Fibrin strands are prominent between the cellular layers in the crescents; indeed, the escape of fibrin into Bowman space is an important contributor to crescent formation.

EM shows distinct ruptures in the GBM. By immunofluorescence microscopy, postinfectious cases exhibit granular immune deposits; Goodpasture syndrome cases show linear fluorescence for Ig and complement, and pauci-immune cases have little or no deposition of immune reactants.

Front 90

90. What is the clinical course in RPGN?

Back 90

All forms include hematuria w/urinary RBC 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 helpful in Dx subtyping.

Renal involvement is usually progressive over the course of a few weeks, culminating in severe oliguria. Functional recovery may occur w/intensive plasmapheresis combined w/steroids and cytotoxic agents (e.g., in Goodpasture syndrome).

Front 91

91. What are the 4 manifestations of nephrotic syndrome?

Back 91

1. Massive proteinuria, w/the daily loss of 3.5 gm or more of protein
2. Hypoalbuminemia, w/plasma albumin levels less than 3 gm/dL
3. Generalized edema
4. Hyperlipidemia and lipiduria

Front 92

92. What is nephrotic syndrome?

Back 92

Nephrotic syndrome is characterized by excessive permeability of the glomerular capillary wall to plasma proteins. Depending on the lesions, the proteinuria may be highly selective, such as LMW proteins (chiefly albumin). W/more severe injury, relatively nonselective proteinuria leads to loss of HMW proteins in addition to albumin.

Heavy proteinuria leads to hypoalbuminemia, decreased colloid osmotic pressure, and systemic edema. There are also sodium and water retention, hyperlipidemia, lipiduria (oval fat bodies), vulnerability to infection, and thrombotic complications.

Front 93

93. What is the pathogenesis of nephrotic syndrome?

Back 93

In children < 17 y/o in the US, the nephrotic syndrome is almost always caused by a lesion primary to the kidney; whereas among adults, it may often be associated w/a systemic disease.

The most frequent systemic causes of nephrotic syndrome are diabetes, amyloidosis, and SLE.

The most important of the primary glomerular lesions are minimal change disease, membranous glomerulopathy, and focal segmental glomerulosclerosis. The first is most common in children, the second is most common in older adults, but focal glomerulosclerosis occurs in all ages.

Front 94

94. What is membranous glomerulopathy?

Back 94

Membranous glomerulopathy is the most common cause of the nephrotic syndrome in adults. It is characterized by diffuse thickening of the glomerular capillary wall and the accumulation of electron-dense, Ig containing deposits along the subepithelial side of the basement membrane.

Front 95

95. What are the 5 main causes of membranous glomerulopathy?

Back 95

1. Drugs (penicillamine, captopril, gold, NSAIDs)
2. Underlying malignant tumors, particularly CA of the lung and colon and melanoma
3. SLE; about 15% of glomerulonephritis in SLE is of the membranous type
4. Infections (chronic HBV, HCV, syphilis, schistosomiasis, malaria)
5. Other autoimmune disorders, such as thyroiditis

*In about 85% of patients, however, no associated condition can be uncovered, and the disease is considered idiopathic.

Front 96

96. What is the pathogenesis of membranous glomerulonephropathy?

Back 96

Membranous glomerulopathy is a form of chronic immune complex-mediated disease. The lesions bear a striking resemblance to those of experimental Heymann nephritis, which is induced by antibodies to a megalin antigenic complex. Thus, idiopathic membranous glomerulopathy, like Heymann nephritis, is considered an autoimmune disease linked to susceptibility genes and caused by antibodies to a renal autoantigen.

Front 97

97. How does the glomerular capillary wall become leaky in membranous glomerulopathy?

Back 97

There is a paucity of neutrophils, monocytes or platelets in glomeruli and the virtually uniform presence of complement, and experimental work suggests a direct action of C5b-C9, the pathway leading to the formation of the MAC.

C5b-C9 causes activation of glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage.

Front 98

98. What is the morphology of membranous glomerulopathy?

Back 98

By light microscopy, the glomeruli either appear normal in the early stages of the disease or *exhibit uniform, diffuse thickening of the glomerular capillary wall.* By EM, the thickening is seen to be caused by irregular dense deposits btw the basement membrane and the overlying epithelial cells, the latter having effaced foot processes.

Basement membrane material is laid down between these deposits, appearing as irregular spikes protruding from the GBM. These spikes are best seen by silver stains, which color the basement membrane black.

Immunofluorescence microscopy demonstrates that the granular deposits on the subepithelial side of the basement membrane contain both Igs and various amts of complement.

Front 99

99. What is the clinical course of membranous glomerulopathy?

Back 99

This condition usually starts w/the insidious onset of nephrotic syndrome or subnephrotic-range proteinuria. Progression is associated w/increasing sclerosis of the glomeruli, rising BUN, and development of hypertension. Some 40% of cases progress to renal insufficiency over an unpredictable time span of 2-20 years.

Secondary causes of membranous GN should be excluded in any new case.

Front 100

100. What is minimal change disease (lipoid nephrosis)?

Back 100

This relatively benign disorder is the most freq cause of nephrotic syndrome in children, but is less common in adults.

It is characterized by diffuse effacement of foot processes of epithelial cells in glomeruli that appear virtually normal by light microscopy. The peak incidence is btw 2-6 years of age.

The disease sometimes follows a respiratory infection or routine prophylactic immunization.

*Its most characteristic feature is its usually dramatic response to corticosteroid therapy.

Front 101

101. What are 6 reasons for the immunologic basis of minimal change disease?

Back 101

1. The clinical association w/respiratory infections and prophylactic immunization
2. The response to corticosteroids and/or other immunosuppressive therapy
3. The association w/other atopic disorders (e.g., eczema, rhinitis)
4. The increased prevalence of certain HLA haplotypes in patients w/minimal change disease associated w/atopy
5. The increased incidence of minimal change disease in patients w/Hodgkin disease, in whom T cell-mediated defected are well recognized
6. Reports of proteinuria inducing factors in the plasma or lymphocyte supernatants of patients w/minimal change disease and focal glomerulosclerosis

Front 102

102. What is the current hypothesis on the pathogenesis of minimal change disease?

Back 102

That minimal change disease involves some immune dysfunction, evutally resutling in the elaboration fo a cytokien that damages visceral epithelial cells and causes proteinuria.

The ultrastructural changes point to a primary visceral epithelial cell injury, and this suggests a loss of glomerular polyanions. This leads to defects in the charge barrier, which may contribute to the proteinuria.

Front 103

103. Mutations in _____ causes a hereditary form of congenital nephrotic syndrome w/minimal change glomerular morphology?

Back 103

Nephrin.

Such mutations and the proteinuria they engender demonstrate that at least some cases of nephrotic syndrome w/minimal change disease morphology can occur in the absence of abnormal responses of the immune system.

Front 104

104. What is the morphology in minimal change disease?

Back 104

The glomeruli are normal by light microscopy. By EM, the basement membrane appears normal, and no dense material is deposited.

*The principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes. It is only when effacement is associated w/normal glomeruli by light microscopy that the Dx of minimal change disease can be made.

The cells of the proximal tubules are often laden w/lipid and protein, reflecting tubular reabsorption of lipoproteins passing thru diseased glomeruli (lipoid nephrosis).

Front 105

105. What is the clinical course in minimal change disease?

Back 105

Despite massive proteinuria, renal function remains good, and there is commonly no hypertension or hematuria.

The proteinuria usually is highly selective, most of the protein consisting of albumin. Most children respond to corticosteroid therapy. However, the nephrotic phase may recur, and some pts may become steroid dependent or resistant.

Regardless, the prognosis for adults and children is quite good.

Front 106

106. What is focal segmental glomerulosclerosis?

Back 106

This lesion is characterized by sclerosis of some, but not all, glomeruli (thus, it is focal); and in the affected glomeruli, only a portion of the capillary tuft is involved (thus it is segmental).

Focal segmental glomerulosclerosis is freq accompanied clinically by the nephrotic syndrome or heavy proteinuria.

Front 107

107. What are the 5 types of focal segmental glomerulosclerosis?

Back 107

1. Idiopathic
2. A secondary event, reflecting glomerular scarring, consequent to another primary glomerular disease (e.g. IgA nephropathy)
3. Associated w/loss of renal mass as the result of chronic reflex, analgesic abuse, or unilateral renal agenesis
4. Secondary to other known disorders (e.g. heroin abuse, HIV, obesity).
5. The result of inherited mutations of proteins present in the podocytes (podocin, α-actinin 4) or in the slit diaphragm between podocytes (nephrin).

Front 108

108. What is the most common cause of nephrotic syndrome in adults in the US?

Back 108

Focal segmental glomerulosclerosis, both primary and secondary, is the most common cause of nephrotic syndrome in adults in the US, especially in Hispanics and Blacks.

Front 109

109. The clinical signs in FSGS differ from minimal change disease in what five ways?

Back 109

1. There is a higher incidence of hematuria, reduced GFR, and hypertension
2. Proteinuria is more often nonselective
3. There is poor response to corticosteroid therapy
4. There is progression to chronic glomerulosclerosis, w/at least 50% developing ESRD w/in 10 years
5. Immunofluorescence microscopy may show nonspecific deposition of IgM and C3 in the sclerotic segment

Front 110

110. What is the morphology of focal segmental glomerulosclerosis?

Back 110

The lesions tend to initially involve the juxtamedullary glomeruli.

***In the sclerotic segments, there is collapse of basement membranes, increase in matrix, and segmental insudation of plasma proteins along the capillary wall (hyalinosis), which may extend to aggregates w/in glomerular capillaries that occlude the lumen.*** Lipid droplets and foam cells are often present.

By immunofluorescence microscopy, IgM and C3 may be present in the sclerotic areas and/or in the mesangium. In addition to the focal sclerosis, there may be pronounced hyalinosis and thickening of the afferent arterioles.

Front 111

111. What is collapsing glomerulopathy?

Back 111

A morphologic variant of FSGS, called collapsing glomerulopathy, is characterized by collapse and scelerosis of the entire glomerular tuft in addition to the usual focal segmental glomerulosclerosis lesions. **A characteristic feature is proliferation and hypertrophy of glomerular visceral epithelial cells.

*This lesion may be seen in idiopathic situations, but it is the most characteristic lesion of HIV-associated nephropathy.*

In both cases, there is associated prominent tubular injury w/formation of microcysts. It has a particularly poor prognosis.

Front 112

112. What is the hallmark of focal segmental glomerulosclerosis?

Back 112

The characteristic degeneration and focal disruption of visceral epithelial cells are thought to represent an accentuation of the diffuse epithelial cell change typical of minimal change disease.

It is this epithelial damage that is the hallmark of FSGS.

Front 113

113. Mutations in what gene is thought to be related to FSGS?

Back 113

NPHS1; several mutations in this gene have been identified - it encodes nephrin, and they give rise to congenital nephrotic syndrome of the Finnish type.

A distinctive pattern of autosomal recessive FSGS results from mutations in the NPHS2 gene - it encodes podocin.

Also, α-actinin 4 mutations can also underlie cases of autosomal dominant FSGS.

Front 114

114. What is renal ablation focal segmental glomerulosclerosis?

Back 114

Renal ablation focal segmental glomerulosclerosis occurs as a complication of glomerular and nonglomerular diseases causing reduction in functioning renal tissue, particularly reflex nephropathy and unilateral agenesis.

These may lead to progressive glomerulosclerosis and renal failure.

Front 115

115. What is the clinical course of FSGS?

Back 115

There is little tendency for spontaneous remission in idiopathic FSGS and responses to corticosteroid therapy are variable.

In general, children have a better prognosis than adults do. Progression of renal failure occurs at variable rates. About 20% of patients follow an unusually rapid course, w/intractable massive proteinuria ending in renal failure w/in 2 years.

Front 116

116. What is HIV-associated nephropathy?

Back 116

HIV infection can result directly or indirectly in a number of renal complications, including acute renal failure, and/or acute interstitial nephritis induced by drugs, infection, thrombotic microangiopathies, postinfectious glomerulonephritis, and most commonly, *a severe form of the collapsing variant of focal segmental glomerulosclerosis.

Front 117

117. What are the three main morphologic features of HIV-associated nephropathy?

Back 117

1. A high frequency of the collapsing variant of focal segmental glomerulosclerosis, with global involvement of the tuft
2. A striking focal cystic dilation of tubule segments, which are filled with proteinaceous material, and inflammation and fibrosis
3. The presence of large numbers of tubuloreticular inclusions in endothelial cells, detected by electron microscopy. Such inclusions, also present in SLE, have been shown to be induced by circulating interferon-α. They are not present in idiopathic focal segmental glomerulosclerosis and therefore may have diagnostic value in a biopsy specimen.

Front 118

118. What is membranoproliferative glomerulonephritis?

Back 118

MPGN is characterized histologically by alterations in the basement membrane, proliferation of glomerular cells, and leukocyte infiltration.

B/c the proliferation is predominantly in the mesangium, a frequently used synonym is mesangiocapillary glomerulonephritis. MPGN accounts for 10-20% of cases of nephrotic syndrome in children and young adults. Some patients present only w/hematuria or proteinuria in the non-nephrotic range, and others have a combined nephrotic-nephritic picture.

Like many other glomerunephritides, MPGN either can be associated w/other systemic disorders and known etiologic agents or may be idiopathic.

Front 119

119. What are the two types of MPGN?

Back 119

Primary MPGN is divided intwo two major types on teh basis of distinct ultrastructural, immunofluorescent, and pathologic findings: type I and typeII MPGN (dense-deposit disease).

Front 120

120. What is the morphology of MPGN?

Back 120

Both types are similar via light microscopy. The glomeruli are large and hypercellular. The glomerui have a "lobular" appearance accentuated by the proliferating mesangial cells and increased mesangial matrix.

The GBM is clearly thickened, often focally, this is most evident in the peripheral capillary loops. The glomerular capillary wall often shows a "double contour" or "tram-track" appearance, especially evident in silver or PAS stains. This is caused by duplication of the basement membrane. W/in the basement membrane there is inclusion or interposition of cellular elements; such interposition gives rise to the appearance of "split" basement membranes.

Front 121

121. What is the morphology of Type I MPGN?

Back 121

Most of the cases are this type. It is characterized by the presence of subendothelial electron-dense deposits. Mesangial and occasional subepithelial deposits may also be present.

By immunofluorescence, C3 is deposited in a granular pattern, and IgG and early complement components (C1q and C4) are often also present.

Front 122

122. What is the morphology of Type II MPGN?

Back 122

In dense-deposit disease (type II MPGN), a relatively rare entity, the lamina densa of the GBM is transformed into an irregular, ribbon-like, extremely electron-dense structure b/c of the deposition of dense material of unknown composition in the GBM proper, giving rise to the term dense-deposit disease.

C3 is present in irregular granular or linear foci in the basement membranes on either side. C3 is also present in the mesangium in characteristic circular aggregates (mesangial rings). IgG is usually absent, as are the early-acting complement components (C1q and C4).

Front 123

123. What is the pathogenesis of Type I MPGN?

Back 123

In most cases of type I MPGN there is evidence of immune complexes in the glomerulus and activation of both classical and alternative complement pathways.

The antigens are believed to be proteins derived from infectious agents such as HCV and HBV viruses.

Front 124

124. What is the pathogenesis of Type II MPGN?

Back 124

Most patients w/dense-deposit disease (Type II) have abnormalities that suggest activation of the alternative complement pathway.

These patients have a consistently decreased serum C3 but normal C1 and C4. They also have diminished serum levels of factor B and properdin, parts of the alternative complement pathway.

*More than 70% of patients w/dense-deposit disease have a circulating antibody termed C3 nephritic factor (C3NeF), which is an autoantibody that binds to the alternative pathway C3 convertase. Binding of the antibody stabilizes the convertases, protecting it from degradation and thus favoring persistent C3 degradation and hypocomplementemia.

Front 125

125. What is the clinical course of primary MPGN?

Back 125

Although steroids may slow the progression of MPGN, about 50% of patients develop chronic renal failure w/in 10 years. There is a high recurrence rate in transplant recipients, particularly in patients w/type II disease.

Front 126

126. What is secondary MPGN?

Back 126

Secondary MPGN (invariably type I) is more common in adults and arises in the following settings:
1. Chronic immune complex disorders, i.e. SLE, HBV, HCV
2. α1-antitrypsin deficiency
3. Malignant diseases (chronic lymphocytic leukemia and lymphoma)
4. Hereditary deficiencies of complement regulatory proteins

Front 127

127. What is IgA nephropathy (Berger disease)?

Back 127

This form of glomerulonephritis is characterized by the presence of prominent IgA deposits in the mesangial regions, detected by imunofluorescence microscopy. The disease can be suspected by light microscopy, but Dx is made only by immunocytochemical techniques.

IgA nephropathy is a freq cause of recurrent gross or microscopic hematuria and is probably the most common type of glomerulonephritis worldwide. Mild proteinuria is usually present, and the nephrotic syndrome may occasionally develop.

Front 128

128. What is the pathogenesis of IgA nephropathy?

Back 128

In aptients w/IgA nephropathy, serum polymeric IgA is increased, and circulating IgA-containing immune complexes are present in some patients.

*Only IgA1 forms the nephritogenic deposits of IgA nephropathy. The prominent mesangial deposition of IgA suggests entrapment of IgA immune complexes in the mesangium, and the presence of C3 combined w/the absence of C1q and C4 in glomeruli points to activation of the alternative complement pathway.

This is supported by the fact that IgA nephropathy occurs w/increased freq in pts with celiac disease.

Front 129

129. What is the morphology of IgA nephropathy?

Back 129

On histologic exam, the glomeruli may be normal or may show mesangioproliferative GN, focal proliferative GN, or rarely, overt crecentic GN. The presence of leukocytes w/in glomerular capillaries is a variable feature.

The characteristic immunofluorescent picture is of mesangial deposition of IgA, often w/C3 and properdin and lesser amts of IgG or IgM. EM confirms the presence of electron-dense deposits in the mesangium.

Front 130

130. What is the clinical course of IgA nephropathy?

Back 130

The hematuria typically lasts for several days, then subsides only to recur. Although most patients have an initially benign course, chronic renal failure develops in 50% over a period of 20 years. Recurrence occurs in 20-60% of grafts.

Onset in old age, heavy proteinuria, hypertension, crescents, and vascular sclerosis portend a poorer prognosis.

Front 131

131. What is hereditary nephritis?

Back 131

Hereditary nephritis refers to a group of heterogeneous familial renal diseases associated primarily w/glomerular injury. These include Alport syndrome, and thin basement membrane disease, the most common cause of benign familial hematuria.

Front 132

132. What is Alport syndrome?

Back 132

Alport syndrome, when fully developed, is manifest by nephritis progressing to chronic renal failure, accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy.

In the most common X-linked form, males express the full syndrome, and females are carriers in whom manifestations of disease are typically limited to hematuria.

Front 133

133. What is the pathogenesis of Alport syndrome?

Back 133

Defective GBM synthesis b/c of the production of abnormal collagen type IV underlies the renal lesions. In patients w/X-linked disease, the defect is caused by mutations in the gene encoding the α5-chain of collagen type IV (COL4A5), a component of the GBM. This is though to interfere w/the assembly and architecture of collagen type IV and thus the structure and function of the GBM.

Front 134

134. What is the morphology of Alport syndrome?

Back 134

On histologic exam, the glomeruli are always involved. The early lesion is detectable only by EM and consists of diffuse glomerular basement membrane thinning. In some kidneys, interstitial cells acquire a foamy appearance owing to accumulation of neutral fats and mucopolysaccharides (foam cells).

*The characteristic features seen w/EM on the GBM are irregular foci of thickening alternating w/attenuation (thinning) with pronounced splitting and lamination of the lamina densa, often w/a distinctive basket-weave appearance.

*There is also absence of α5-chain of collagen type IV in skin biopsies.

Front 135

135. What is the clinical course of Alport syndrome?

Back 135

The most common presenting sign is gross or microscopic hematuria, freq accomapnied by erythrocyte casts. Proteinuria may occur, and rarely, the nephrotic syndrome develops. Symptoms appear at ages 5-20 years, and the onset of overt renal failure is between ages 20 and 50 years in men.

The auditory defects may be subtle, requiring sensitive testing.

Front 136

136. What is thin basement membrane disease (benign familial hematuria)?

Back 136

This a fairly common entity manifested clinically by familial asymptomatic hematuria, usually uncovered on routine urinalsysis and morphologically by diffuse thinning of the GBM to between 150 and 250 nm (compared to the normal 300-400 nm).

Although mild or moderate proteinuria may also be present, renal function is normal and prognosis is excellent.

In contrast to Alport syndrome, hearing loss, ocular abnormalities, and a family history of renal failure are absent, and skin biopsy specimens show presence of the α5-chain of collagen type IV.

Front 137

137. What is chronic glomerulonephritis?

Back 137

Chronic glomerulonephritis is best considered a pool of end-stage glomerular disease fed by a number of streams of specific types of glomerulonephritis.

Nevertheless, in any series of patients w/chronic glomerulonephritis, a variable percentage of cases arise mysteriously w/no antecedent history of any of the well recognized forms of acute glomerulonephritis.

Front 138

138. What is the morphology of chronic glomerulonephritis?

1/3

Back 138

The kidneys are symmetrically contracted and have diffusely granular, cortical surfaces. On section, the cortex is thinned and there is an increase in peripelvic fat. There eventually ensues hyaline obliteration of glomeruli, transforming them into acellular eosinophilic masses.

B/c hypertension is an accompaniment, arterial and arteriolar sclerosis may be conspicuous. Marked atrophy of associated tubules also occur.

Front 139

139. What is the morphology of chronic glomerulonephritis?

(Dialysis changes) 2/3

Back 139

Dialysis changes: kidneys from patients w/ESRD on long term dialysis show arterial intimal thickening, extensive deposition of calcium oxalate crystals in tubules and interstitium, acquired cystic disease, and increased numbers of renal adenomas and adenocarcinomas.

Front 140

140. What is the morphology of chronic glomerulonephritis?

(Uremic complications) 3/3

Back 140

Uremic complications: patients dying w/chronic GN also exhibit changes outside the kidney related to the uremic state. Often clinically important, these include uremic pericarditis, uremic gastroenteritis, secondary hyperparathyroidism with nephocalcinosis and renal osteodystrophy, LV hypertrophy due to hypertension, and pulmonary changes of diffuse alveolar damage often ascribed to uremia (uremic pneumonitis).

Front 141

141. What is the clinical course of chronic GN?

Back 141

In most patients, chronic GN develops insidiously and slowly progresses to renal insufficiency or death from uremia.

Most patients are hypertensive, and sometimes the dominant clinical manifestations are cerebral or cardiovascular. In all, the disease is relentlessly progressive.

Front 142

142. What are the renal involvements in SLE?

Back 142

SLE gives rise to a heterogeneous group of lesions and clinical presentations. The clinical manifestations can include recurrent microscopic or gross hematuria, acute nephritis, the nephrotic syndrome, chronic renal failure, and hypertension.

Front 143

143. What is Henoch-Schonlein purpura?

Back 143

This syndrome consists of purpuric skin lesions characteristically involving the extensor surfaces of arms and legs as well as buttocks; abdominal manifestations including pain, vomiting, and intestinal bleed; nonmigratory arthralgia, and renal abnormalities.

Renal involvement occurs in 1/3 of pts and include gross or microscopic hematuria, proteinuria, and nephrotic syndrome.

*IgA is deposited in the glomerular mesangium in a distribution similar to that of IgA nephropathy.

Front 144

144. What is the morphology of Henoch-Schonlein purpura?

Back 144

On histologic exam, the renal lesions vary from mild focal mesangial proliferation to diffuse mesangial proliferation to crescentic GN.

Whatever the histologic lesions, the prominent feature by fluorescence is the deposition of IgA, sometimes with IgG and C3 in the mesangial region.

The skin lesions consist of subepidermal hemorrhages and a necrotizing vasculitis in the small vessels of the dermis. IgA is also present in these vessels.

Front 145

145. What are the renal complications in bacterial endocarditis?

Back 145

Glomerular lesions in the course of bacterial endocarditis represent a type of immune complex nephritis initiated by complexes of bacterial antigen and antibody.

Hematuria and proteinuria of various degrees can occur, but an acute nephritic presentation is not uncommon.

The histologic lesions, when present, generally reflect these clinical manifestations. Milder forms have a more focal and segmental necrotizing glomerulonephritis, whereas more severe ones exhibit a diffuse proliferative glomerulonephritis, and the rapidly progressive forms show large numbers of crescents.

Front 146

146. What is diabetic glomerulosclerosis?

Back 146

DM is a major cause of renal morbidity. By far the most common lesions involve the glomeruli and are associated clinically w/three glomerular syndromes: non-nephrotic proteinuria, nephrotic syndrome, and chronic renal failure.

Also, DM causes hyalinizing arteriolar sclerosis, papillary necrosis, and a variety of tubular lesions. Thus, diabetic nephropathy is used.

Front 147

147. What are the 3 morphologic changes in the glomeruli in diabetic nephropathy?

Back 147

1. Capillary basement membrane thickening
2. Diffuse mesangial sclerosis
3. Nodular glomerulosclerosis

Front 148

148. What is the pathogenesis of diabetic nephropathy?

Back 148

Two processes seem to play a role in the fully developed diabetic glomerular lesions: a metabolic defect, possibly linked to advanced glycosylation end products, that accounts for the thickened GBM and increased mesangial matrix that occur in patients; and hemodynamic effects, associated w/glomerular hypertrophy, which also contributes to the development of glomerulosclerosis.

Front 149

149. What is the morphology of the capillary basement membrane thickening in diabetic nephropathy?

Back 149

Widespread thickening of the glomerular capillary basement membrane (GBM) occurs in virtually all diabetics.

This thickening begins as early as 2 years after the onset of type I diabetes and by 5 years amts to about 30% increase. The thickening continues progressively and usually concurrently w/mesangial widening. Simultaneously, there is thickening of the tubular basement membranes.

Front 150

150. What is the morphology of diffuse mesangial sclerosis in diabetic nephropathy?

Back 150

This lesion consists of diffuse increase in mesangial matrix. There can be mild proliferation of mesangial cells early in the disease process, but cell proliferation is not a prominent part of this injury.

The mesangial increase is typically associated w/the overall thickening of the GBM. The matrix depositions are PAS positive.

Front 151

151. What is nodular glomerulosclerosis?

Back 151

AKA intercapillary glomerulosclerosis or Kimmelsteil-Wilson disease.

The glomerular lesions take on the form of ovoid or spherical, often laminated, nodules of matrix situated in the periphery of the glomerulus. The nodules are PAS-positive.

These nodular lesions are freq accompanied by prominent accumulations of hyaline material in capillary loops ("fibrin caps") or adherent to Bowman's capsules ("capsular drops"). As a consequence of the glomerular and arteriolar lesions, the kidney suffers from ischemia, develops tubular atrophy and interstitial fibrosis, and usually undergoes contraction in size.

*Approx 15-30% of patients w/long term DM develop nodular glomerulosclerosis, and it most instances it is associated w/renal failure.

Front 152

152.What is the clinical course of diabetic glomerulosclerosis?

Back 152

Depends on the type of diabetes.

The increased GFR typical of early-onset type 1 DM is associated w/microalbuminuria. Microalbuminuria and increased GFR are important predictors of future overt diabetic nephropathy in these patients.

Systemic hypertension may precede the development of proteinuria and renal insufficiency.

*Most exciting is the fact that good glycemic homeostassi by pancreatic transplantation in patients w/diabetic nephropathy can actually reverse the nephropathy. ACE inhibitors or ARBs can also have a beneficial effect by reversing the increased intraglomerular capillary pressure.

Front 153

153. What is amyloidosis?

Back 153

Most types of disseminated amyloidosis may be associated w/deposits of amyloid w/in the glomeruli; most commonly renal amyloid is of light-chain AL or AA type.

The typical Congo red amyloid-positive fibrillary deposits are present w/in the mesangium and capillary walls and rarely are localized to the subepithelial space. Eventually, they obliterate the glomerulus completely.

Pts w/glomerular amyloid may present w/the nephrotic syndrome and later die of uremia. Characteristically, kidney size tends to be either normal or increased.

Front 154

154. What is fibrillary glomerulonephritis?

Back 154

Fibrillary GN is a morphologic variant of GN associated w/characteristic fibrillar deposits in the mesangium and glomerular capillary walls that resemble amyloid fibrils in appears but differ from amyloid fibrils when measured ultrastructurally and in that they do not stain w/Congo red.

The fibrils are typically 18-24 nm and hence are larger than the 10-12 nm characteristic of amyloid. There is usually selective deposition of IgG, often of IgG4 subclass, w/complement C3 and Ig kappa and delta light chains also present.

Clinically, pts develop nephrotic syndrome, hematuria, and progressive renal insufficiency.

Front 155

155. What is immunotactoid GN?

Back 155

A much rare condition in which the deposits are microtubular in structure and 30-50 nm in width.

Patients often have circulating paraproteins and/or monoclonal Ig deposition in glomeruli.

Front 156

156. What about Goodpasture syndrome, microscopic polyarteritis, and Wegener granulomatosis?

Back 156

These diseases are commonly associated with similar forms of GN ranging from focal segmental necrotizing GN to crescentic GN.

Front 157

157. What is essential mixed cryoglobulinemia?

Back 157

This is another systemic condition in which deposits of cryoglobulins composed principally of IgG-IgM complexes induce cutaneous vascultitis, synovitis, and a proliferative GN.

Most cases of essential mixed cryoglobulinemia have been associated w/infection w/HCV, and this condition in particular is associated w/GN usually of the MPGN type.

Front 158

158. What about plasma cell dyscrasias and multiple myelomas?

Back 158

These are associated w/:
1. Amyloidosis, in which the fibrils are usually composed of monoclonal lambda light chains
2. Deposition of monoclonal Ig or light chains in glomerular basement membranes
3. Distinctive nodular glomerular lesions resulting form the deposition of nonfibrillar light chains

*These patients usually present w/proteinuria or the nephrotic syndrome, hypertension, and progressive azotemia.

Front 159

159. What is acute tubular necrosis?

Back 159

ATN is a clinicopathologic entity characterized morphologically by destruction of tubular epithelial cells and clinically by acute diminution or loss of renal function.

*It is the most common cause of acute renal failure, which signifies rapid reduction of renal function and urine flow, falling w/in 24 hours to less than 400 mL per day.

Front 160

160. What are the five conditions that can cause ATN?

Back 160

1. Ischemia, due to decreased or interrupted blood flow (polyarteritis nodosa, malignant hypertension, HUS, etc...)
2. Direct toxic injury to the tubules via drugs, radiocontrast, HGB, radiation
3. Acute tubulointerstitial nephritis, most commonly occurring as a hypersensitivity reaction to drugs
4. DIC
5. Urinary obstruction by tumors, BPH, or blood clots

Front 161

161. What is ischemic ATN?

Back 161

Most ATN lesions arise in a variety of clinical settings. Most of these, ranging from severe trauma to acute pancreatitis, have in common a period of inadequate blood flow, usually accompanied by marked hypotension and shock.

This pattern of ATN is called ischemic ATN.

Also, mismatched blood transfusions and other hemolytic crises cuasing hemoglobinuria and skeletal muscle injuries causing myoglobinuria also produce a picture resembling ischemic ATN

Front 162

162. What is nephrotoxic ATN?

Back 162

Nephrotoxic ATN is caused by a multitude of drugs, such as gentamicin and other antibiotics; radiographic contrast agents; poisons, including heavy metals, and organic solvents.

Front 163

163. What are the 2 critical events in both ischemic and nephrotoxic ATN?

Back 163

1. Tubular injury
2. Persistent and severe disturbances in blood flow.

Front 164

164. What does tubular injury result in?

Back 164

Results in loss of polarity due to redistribution in membranes and increased sodium delivery to distal tubules. The latter incites tubuloglomerular feedback. There is also increased expression of ICAM-1.

In time, injured cells detach from the basement membranes and cause limited tubule obstruction, increased intratubular pressure, and decreased GFR.

Front 165

165. What are the 4 main events leading to diminished renal function?

Back 165

1. Arteriolar vasoconstriction (w/tubuloglomerular feedback involving the renin-angiotensin system and endothelial dysfunction) leading to increased endothelin and decreased NO and PGI₂
2. Tubular obstruction by casts derived from necrotic and apoptotic epithelial cells and proteinaceous material
3. Back-leak of tubular fluids
4. Altered glomerular ultrafiltration

Front 166

166. What is the morphology of ischemic ATN?

Back 166

Ischemic ATN is characterized by focal tubular epithelial necrosis at multiple points along the nephron, with large skip areas in between, often accomapnied by rupture of basement membranes (tubulorrhexis) and occlusion of tubular lumens by casts. Tubular cell injury typically involve the proximal tubular straight segments and thick ascending loop of Henle.

Paradoxically, the clinical syndrome of ATN is not manifest by overt tubular necrosis, but often lesser degrees of tubular injury.

Front 167

167. What type of casts are present in the distal tubules and collecting ducts in ischemic ATN?

Back 167

Eosinophilic hyaline casts, as well as pigmented granular casts, are common, particularly in the distal tubules and collecting ducts.

These casts consist principally of Tamm-Horsfall protein (a urinary glycoprotein normally secreted by the cells of ascending thick limb and distal tubules) in conjunction with other plasma proteins.

Also, flattened epithelial cells w/hyperchromatic nuclei and mitotic figures are often present.

Front 168

168. What is the morphology of nephrotoxic ATN?

Back 168

Toxic ATN is manifested by acute tubular injury most obvious in the proximal convoluted tubules.

The type of injury may be distinctive in poisoning with certain agents.

Front 169

169. What is the injury like with mercuric chloride?

Back 169

With mercuric chloride, severely injured cells that are not yet dead might contain large acidophilic inclusions. Later these cells become totally necrotic, are desquamated into the lumen, and may undergo calcification.

Front 170

170. What is the injury like with CCl₄?

Back 170

With CCl₄ poisoning, there is an accumulation of neutral lipids in injured cells, and such fatty change is followed by necrosis.

Front 171

171. What is the injury like with ethylene glycol poisoning?

Back 171

Ethylene glycol produces marked ballooning and hydropic or vacuolar degeneration of proximal convoluted tubules.

Calcium oxalate crystals are often found in the tubular lumens in such poisoning.

Front 172

172. What are the 3 clinical phases of ATN?

Back 172

1. Initiation
2. Maintenance
3. Recovery

Front 173

173. What occurs in the initiation phase?

Back 173

The initiation phase, lasting for about 36 hrs, is dominated by the inciting medical, surgical, or obstetric event in the ischemic form of ATN. The only indication of renal involvement is a slight decline in urine output w/a rise in BUN.

At this point, oliguria could be explained on the basis of a transient decrease in blood flow to the kidneys.

Front 174

174. What occurs in the maintenance phase?

Back 174

The maintenance phase is characterized by sustained decreases in urine output to btwn 40 and 400 mL/day with salt and water overload, rising BUN concentrations, hyperkalemia, metabolic acidosis, and other manifestations of uremia.

With appropriate attention to the balance of water and blood electrolytes, including dialysis, the pt can be carried over this oliguric crisis.

Front 175

175. What occurs in the recovery phase?

Back 175

The recovery phase is ushered in by a steady increase in urine volume that may reach up to 3 L/day. The tubules are still damaged, so large amts of water, sodium, and potassium are lost in the urinary flood.

*Hypokalemia, rather than hyperkalemia, becomes a clinical problem.

There is also an increased vulnerability to infection at this stage. Eventually renal tubular function is restored and BUN and creatinine levels begin to return to normal.

Front 176

176. What is the clinical course of ATN?

Back 176

It depends on the type of ATN. With modern methods of care, 95% of those who do not succumb to the precipitating cause have a chance of recovery. Conversely, in shock related to sepsis, extensive burns, or other causes of multiorgan failure, the mortality rate can rise to more than 50%.

*Up to 50% of patients with ATN might not have oliguria and might in fact have increased urine volumes. This so-called nonoliguric ATN occurs particularly often with nephrotoxins, and it generally follows a more benign clinical course.

Front 177

177. What is acute tubulointerstitial nephritis?

Back 177

Can be acute or chronic. Acute TIN has a rapid clinical onset and is characterized by interstitial edema, often accompanied by leukocytic infiltration of the interstitium and tubules, and focal tubular necrosis.

Front 178

178. What is chronic tubulointerstitial nephritis

Back 178

In chronic TIN, there is infiltration with predominantly mononuclear leukocytes, prominent interstitial fibrosis, and widespread tubular atrophy.

Front 179

179. What are the morphologic differences btwn acute and chronic tubulointerstitial nephritis?

Back 179

Edema, and when present, eosinophils and neutrophils occur in the acute form.

Fibrosis and tubular atrophy are in the chronic form.

Front 180

180. How are tubulointerstitial diseases distinguished from glomerular diseases on clinical grounds?

Back 180

The conditions are distinguished from glomerular disease by the absence, in early stages, of such hallmarks of glomerular injury as nephritic or nephrotic syndromes and by the presence of defects in tubular function.

The latter may be subtle and include impaired ability to concentrate urine, evidenced clinically by polyuria or nocturia; salt wasting; diminished ability to excrete acids (metabolic acidosis), and isolated defects in tubular reabsorption or secretion.

Front 181

181. What are the most common agents in UTIs?

Back 181

By far the most common are the gram-negative bacilli that are normal inhabitants of the intestinal tract. These are E.coli, followed by Proteus, Klebsiella, and Enterobacter.

Streptococcus faecalis, also of enteric origin, staphylococci, and virtually every other bacterial and fungal agent can also cause lower UTI and renal infection.

Front 182

182. What is the most common cause of clinical pyelonephritis?

Back 182

Ascending infection is the most common cause of clinical pyelonephritis.

This requires:
1. Colonization of the distal urethra and introitus (in the female ) by coliform bacteria).
2. Spread from the urethra to the bladder
3. Multiplication in the bladder
4. Vesicoureteral reflux; it is incompetence of the vesicoureteral valve that allows bacteria to ascend into the renal pelvis
5. Intrarenal reflux

Front 183

183. What causes incompetence of the vesicoureteral valve?

Back 183

Reflux is most often due to congenital absence or shortening of the intravesical portion of the ureter.

In addition, bladder infection can cause or accentuate vesicoureteral reflux, esp in children.

Acquired vesicoureteral reflux in adults can result from persistent bladder atony caused by spinal cord injury.

Front 184

184. Where is intrarenal reflux most common?

Back 184

Vesicoureteral reflux can propel urine up to the renal pelvis and deep into the renal parenchyma thru open ducts at the tips of the papillae.

Intrarenal reflux is most common in the upper and lower poles of the kidney, where papillae tend to have flattened or concave tips rather than the convex pointed type present in the midzones of the kidney.

Front 185

185. What are the hallmarks of acute pyelonephritis?

Back 185

Patchy interstitial suppurative inflammation, intratubular aggregates of neutrophils, and tubular necrosis.

In pyelonephritis associates w/reflux, damage occurs most commonly in the lower and upper poles.

Front 186

186. What are 3 potential complications of acute pyelonephritis?

Back 186

1. Papillary necrosis (seen mainly in diabetics and those w/urinary tract obstruction) - the necrotic tissue shows characteristic coagulative necrosis with preservation of outlines of tubules.

2. Pyonephrosis - suppurative exudate is unable to drain and thus fills the renal pelvis, calyces, and ureter.

3. Perinephric abscess (extension of suppurative inflammation thru the renal capsule into the peripnephric tissue.

Front 187

187. What happens after the acute phase of pyelonephritis?

Back 187

After the acute phase, healing occurs. The neutrophilic infiltrate is replaced by one that is predominantly mononuclear, with macrophages, plasma cells, and lymphocytes.

The inflammatory foci are replaced by scars that can be seen on the cortical surface as fibrous depressions.

***However, the pyelonephritic scar is almost always associated w/inflammation, fibrosis, and deformation of the underlying calyx and pelvis, reflecting the role of ascending infection and vesicoureteral reflux in the pathogenesis of the disease.

Front 188

188. What are the eight conditions that predispose to acute pyelonephritis?

Back 188

1. Urinary tract obstruction
2. Instrumentation of the urinary tract (catheterization)
3. Vesicoureteral reflux
4. Pregnancy
5. Patients' sex and age (more freq in females until after 40 - then it becomes equal between males and females)
6. Preexisting renal lesions
7. DM
8. Immunosuppression

Front 189

189. What is the clinical course of acute pyelonephritis?

Back 189

When clinically apparent, the onset is usually sudden, w/pain at the costovertebral angle and systemic evidence of infection, such as fever and malaise. There are usually indications of bladder and urethral irritation, such as dysuria, frequency, and urgency. The urine contains many leukocytes (pyuria) derived from the inflammatory infiltrate, but pyuria does not differentiate upper from lower UTI.

The finding of leukocyte casts, typically filled w/neutrophils (pus casts) indicates renal involvement, b/c casts are formed only in tubules.

Front 190

190. What is an emerging viral pathogen causing pyelonephritis in kidney allografts?

Back 190

Polyoma virus - latent infection w/polyoma virus is widespread in the general population, but immunosuppression of the allograft recipient can lead to reactivation of the latent infection and the development of a nephropathy resulting in allograft failure in up to 1-5% of kidney transplant recipients.

Front 191

191. What is the morphology of polyoma virus pyelonephritis?

Back 191

This form is characterized by viral infection of tubular epithelial cell nuclei, leading to nuclear enlargement and intranuclear inclusions visible by light microscopy (viral cytopathic effect).

The inclusions are composed of viral structures arrayed in distinctive crystalline-like lattices when visualized by electron microscopy.

Front 192

192. What is chronic pyelonephritis?

Back 192

Chronic pyelonephritis is a chronic tubulointerstitial renal disorder in which chronic tubulointerstitial inflammation and renal scarring are associated w/pathologic involvement of the calyces and pelvis.

Chronic pyelonephritis is an important cause of end-stage kidney disease.

It has two forms : chronic reflux associated and chronic obstructive

Front 193

193. What is chronic reflux pyelonephritis?

Back 193

This is the more common form of chronic pyelonephritis scarring.

It begins in childhood, as a result of infections superimposed on congenital vesicoureteral reflux and intrarenal reflux. Reflux nephropathy may have a silent, insidious onset, sometimes presenting w/hypertension or evidence of renal dysfunction in the absence of persisting infection.

Front 194

194. What is chronic obstructive pyelonephritis?

Back 194

In obstructive chronic pyelonephritis, chronic obstruction predisposes the kidney to infections, and multiple recurrences over time produce chronic pyelonephritis. It is usually caused by enteric bacteria.

Front 195

195. What is the morphology of chronic pyelonephritis?

Back 195

The kidneys are usually scarred; if bilateral, the involvement is asymmetric.

The hallmark of chronic pyelonephritis is the coarse, discrete, corticomedullary scar overlying a dilated, blunted, or deformed calyx. Most are in the upper and lower poles, consistent w/the freq of reflux in these sites.

There is often fibrosis around the calyceal epithelium as well as a marked chronic inflammatory infiltrate.

Front 196

196. What is xanthogranulomatous pyelonephritis?

Back 196

Xanthogranulomatous pyelonephritis is an unusual and relatively rare form of chronic pyelonephritis characterized by accumulation of foamy macrophages intermingled w/plasma cells, lymphocytes, polymorphonuclear leukocytes, and occasional giant cells.

Often associated w/Proteus infections and obstruction, the lesions sometimes produce large, yellowish orange nodules that may be confused w/renal cell CA.

Front 197

197. hat is the clinical course of chronic pyelonephritis?

Back 197

May be insidious in onset or may present w/clinical manifestations of acute recurrent pyelonephritis w/back pain, fever, frequent pyuria, and bacteriuria. Chronic pyelonephritis associated w/reflux may have a silent onset. These pts come to clinical attention b/c of renal insufficiency and hypertension or the discovery of pyuria or bacteriuria on routine exam.

Front 198

198. What does focal segmental glomerulosclerosis have to do with chronic pyelonephritis?

Back 198

Some patients w/pyelonephritic scars develop focal segmental glomerulosclerosis with significant proteinuria, even in the nephrotic range, usually several years after the scarring has occurred and often in the absence of continued infection or persistent vesicoureteral reflux.

The appearance of proteinuria and FSGS is a poor prognostic sign.

Front 199

199. What are the 3 ways in which toxins and drugs can produce renal injury?

Back 199

1. They may trigger an interstitial immunologic reaction (methicillin)
2. They may cause acute renal failure
3. They may cause subtle but cumulative injury to tubules that takes years to become manifest, resulting in chronic renal insufficiency

Front 200

200. What is acute drug-induced interstitial nephritis?

Back 200

Acute drug-induced interstitial nephritis is an adverse hypersensitivity reaction to a variety of drugs. It begins 2 to 40 days after exposure. The disorder is immune-mediate; the offending agents act as immunizing haptens.

During tubular secretion, the drugs covalently bind to cytoplasmic or extracellular matrix components, become immunogenic, and induce antibody (IgE) (Type I Hypersensitivity reaction) and T cell-mediated immune reactions (Type IV Hypersensitivity reaction).

Front 201

201. What are the clinical features of acute drug-induced interstitial nephritis?

Back 201

Fever, eosinophilia, skin rash, hematuria, mild proteinuria, sterile pyuria, azotemia, and acute renal failure can all be variably present.

Drug withdrawal usually leads to full recovery.

Front 202

202. What is the morphology of acute drug-induced interstitial nephritis?

Back 202

On histologic exam, the abnormalities are in the interstitium, which shows variable but freq pronounced edema and infiltration by mononuclear cells, principally lymphocytes and macrophages.

With some drugs (e.g., methicillin, thiazides), interstitial granulomas w/giant cells may be seen. "Tubulitis", the infiltration of tubules by lymphocytes, is common.

Front 203

203. What is analgesic nephropathy?

Back 203

This is a form of chronic renal disease caused by excessive intake of analgesic mixtures and characterized morphologically by chronic tubulointerstitial nephritis w/renal papillary necrosis.

Most pts with this disease usually ingest at least two antipyretic analgesics (phenacetin-containing mixtures).

*The drugs act synergistically to cause papillary necrosis first, and then cortical tubulointerstitial nephritis is a secondary phenomenon.

Front 204

204. How do the analgesics cause this shitstorm?

Back 204

The phenacetin metabolite acetaminophen injures cells by both covalent binding and oxidative damage.

Aspirin induces its potentiating effect by inhibiting the vasodilatory effects of prostaglandin, predisposing the papillae to ischemia.

Thus, the papillary damage may be due to a combo of direct toxic effects and ischemic injury to both tubular cells and vessels.

Front 205

205. What is the morphology of analgesic nephropathy?

1/2

Back 205

In gross appearance, the kidneys are either normal or slightly reduced in size, and the cortex exhibits depressed and raised areas; the depressed areas represent cortical atrophy overlying necrotic papillae.

The papillae show various stages of necrosis, calcification, fragmentation, and sloughing.

Front 206

206. What is the morphology of analgesic nephropathy?

2/2

Back 206

On microscopic exam, the papillary changes may take one of several forms.

In early cases, there is patchy necrosis; but in the advanced form, the entire papilla is necrotic, often remaining in place as a structureless mass w/ghosts of tubules and foci of dystrophic calcification. Segments of entire portions of the papilla may then be sloughed and excreted into the urine.

Cortical changes consist of loss and atrophy of tubules and interstitial fibrosis and inflammation.

Front 207

207. What is the clinical course of analgesic nephropathy?

Back 207

Patients may have polyuria, headaches, anemia, GI symptoms, pyuria, UTIs, and hypertension. *The anemia, in particular, is out of proportion to the renal insufficiency, owing to damage to RBCs by the phenacetin metabolites.

These pts have an increased incidence of transitional cell CA of the renal pelvis. Chronic renal failure can result, but drug withdrawal often stabilizes renal function.

Renal papillary necrosis can be Dx radiologically, although it is not specific for analgesic nephropathy.

Front 208

208. What are some NSAID associated renal syndrome?

Back 208

1. Hemodynamically induced acute renal failure, due to the inhibition of vasodilatory prostaglandin synthesis by NSAIDs
2. Acute hypersensitivity interstitial nephritis
3. Acute interstitial nephritis and minimal change disease
4. Membranous glomerulonephritis, w/the nephrotic syndrome

Front 209

209. What is acute uric acid nephropathy?

Back 209

Caused by the precipitation of uric acid crystals in the renal tubules, principally in the collecting ducts, lead into obstruction of nephrons and the development of acute renal failure.

This type is particularly likely to occur in pts w/leukemias and lymphomas who are undergoing chemo.

Front 210

210. What is chronic urate nephropathy?

Back 210

AKA gouty nephropathy, this occurs in patients w/more protracted forms of hyperuricemia.

The lesions are ascribed to the deposition of monosodium urate crystals in the acidic milieu of the distal tubules and collecting ducts as well as in the interstitium.

These deposits have a distinct histologic appearance and may form birefringent needle-like crystals either in the tubular lumina or in the interstitium.

Front 211

211. What is the earliest functional defect in the kidney?

Back 211

The inability to elaborate a concentrated urine.

Other tubular defects, such as tubular acidosis and salt-losing nephritis may also occur.

Front 212

212. What is multiple myeloma?

Back 212

Renal involvement is a sometimes ominous manifestation of multiple myeloma; overt renal insufficiency occurs in half of patients w/this disease.

Front 213

213. What is the main cause of renal dysfunction in multiple myeloma?

What is Bence Jones proteinuria?

Back 213

Bence Jones proteinuria and cast nephropathy - some light chains are directly toxic to epithelial cells. In addition, Bence Jones proteins combine with the urinary glycoproteins (Tamm-Horsfall protein) under acidic conditions to form large, histologically distinct tubular casts that obstruct the tubular lumens and induce a peritubular inflammatory reaction (cast nephropathy).

Front 214

214. How is amyloidosis associated with myelomas?

Back 214

Amyloidosis, formed by accumulations of light chains w/a predisposition to form amyloid fibrils, which occurs in 6-24% of pts w/myelomas.