normal kidneyThis is a normal glomerulus by light microscopy. The glomerular capillary loops are thin and delicate. Endothelial and mesangial cells are normal in number. The surrounding tubules are normal. Life is good.

This normal glomerulus is stained with PAS to highlight basement membranes. The capillary loops of the glomerulus are well-defined and thin.

kidney
glomerulus
PAS-Hematoxylin

Endothelial basement membrane is stained to pink with PAS

# End: endothelial cells
# Pod: podocytes
# Mes: mesangial cells

# juxtaglomerular apparatus
macula densa (MD)
juxtaglomerular cells (JG cells)
extraglomerular mesangium

kidney
glomerulus
toluidine blue (epoxy resin embedding)

JG cells have granules stained with toluidine blue.

kidney
proximal and distal tubules
PAS-Hematoxylin

Brush border of proximal tubules is well stained with PAS. The proximal tubules can be divide into two group (PT1, PT2). There are PAS positive granules in cytoplasm of the proximal tubules, of which brush border is strongly stained.
Nucleus of distal tubules is arranged near its free surface. Basal striations of the distal tubules are well observed.

 

 

 

A normal glomerulus is shown diagramatically. Note the relationship of the capillary loops to the mesangium. About 15% of glomerular filtration occurs through the mesangium, with the remainder through the fenestrated epithelium. The normal anionic charge barrier prevents protein molecules such as albumin from passing through the endothelium. The normal mesangium contains about 2 to 4 mesangial cells, which have a macrophage-like function.

This is minimal change disease (MCD) which is characterized by effacement of the epithelial cell (podocyte) foot processes and loss of the normal charge barrier such that albumin selectively leaks out and proteinuria ensues. By light microscopy, the glomerulus is normal with MCD. In this electron micrograph, the capillary loop in the lower half contains two electron dense RBC's. Fenestrated endothelium is present, and the basement membrane is normal. However, overlying epithelial cell foot processes are effaced (giving the appearance of fusion) and run together.

 

 

 

 

 

 

 

This is a section from a fetal cat kidney. It's been stained with Masson's method for CT. The capsule is highlighted as a green band running around the outside of the organ, indicated by the arrow.

The collagen fibers of the capsule run in and out of the plane of the section, as well as parallel to it, and are tightly packed together. Some texts will refer to organ capsules as dense regular CT; I'd have to disagee because the orientation of the fibers isn't parallel to each other (as it is, say, in a tendon). They run in and out of the section plane, so in my opinion, "irregular" is a preferable description

 

 

 

 

 

 

Glomerulosclerosis, diffuse: Thickening of the basement membrane as a result of diabetes mellitus.

Glomerulosclerosis, focal/segmental: A pattern of injury with foot process fusion and hyalinization of some lobules in some glomeruli. It has nothing to do with diabetes mellitus.

Glomerulosclerosis, nodular: Diabetes mellitus with Kimmelstiel-Wilson disease. Always superimposed on diffuse glomerulosclerosis.

*Hyalinosis: A distinctive, homogeneous pink blob seen in certain sick glomeruli, notably those damaged by FSGS, diabetes, or other causes of hyperfiltration.

Hyalinized glomeruli: A term which can mean collagenized or sclerotic glomeruli.

 

Nephrotic syndrome: The sequelae of heavy protein leakage at the glomerular capillaries.

Nephrosclerosis: Disease of the renal arteries and/or arterioles.

Nephrosclerosis, arterial: Multiple small infarcts destroying scattered groups of glomeruli. Causes V-shaped cortical scars. Usually caused by atheroembolization.

Nephrosclerosis, arteriolar: Vascular disease that destroys scattered individual nephrons. Causes sandpaper-surface kidney. "Benign nephrosclerosis". Caused by high blood pressure and/or diabetes.

Nephrosclerosis, benign: Arteriolar nephrosclerosis due to "benign essential hypertension

 

The collecting duct is site of anti-diuretic hormone (hADH) action.

·        This neuropeptide is produced when osmoreceptors in the hypothalamus determine the need for the body to retain water. It opens little pores in the walls of the collecting ducts, allowing water to flow back into the hypertonic renal interstitium.

·        Inability of the collecting duct to respond to hADH produces nephrogenic diabetes insipidus.

·        "Atrial natriuretic factor" (hANF, atriopeptins, etc.), the most important of several natriuretic peptides (NEJM 399: 321, 1998). It comes from the atria, cause loss of water and sodium by several mechanisms. It's released when the right atrium is stretched. This is probably the overriding way in which we regulate our volume in health.

ANF...

Tubular diseases which prevent reabsorption of water (or a non-resorbable substance in the filtrate) will produce polyuria (urine volume more than 1500 mL/day). Plugged or leaky tubules (or low GFR) will cause oliguria (urine volume less than 500 mL/day.)

-Casts in the urinary sediment are cylinders of congealed Tamm-Horsfall protein produced by the tubular cells.

-They may contain other formed elements which aid in the diagnosis of kidney disease.

·        Hyaline casts do not contain formed elements, and are a normal finding.

·        Epithelial casts contain renal tubular cells and suggest interstitial disease or acute tubular damage.

·        Fatty casts are epithelial casts in which the cells contain abundant lipid (i.e., the patient has the nephrotic syndrome.)

·        Red cell casts (* "active sediment") indicate bleeding into the nephron (i.e., glomerular disease). Hemoglobin casts usually mean the red cells have hemolyzed, often in the bloodstream.

·        White cell casts contain polys and indicate acute inflammation in the renal interstitium.

·        Granular casts are cellular casts in which the cells have undergone necrosis and fragmentation.

·        Casts that contain a lot of lipid mean nephrotic syndrome (which you should already be aware is present.)

·        Broad and waxy casts are very large casts that indicate a low rate of flow through the tubules and hence serious disease.

 

 

 

Immune Deposits

Here is a list of the more important entities that are likely to be caused by a particular pattern:

Subepithelial, large, irregularly-spaced ("coarse granules")

Diffuse proliferative GN (especially post-streptococcal)
Membranoproliferative GN type I
Lupus, class IV

 

Subepithelial, uniform, evenly-spaced ("fine granules evenly spaced")

Membranous glomerulopathy (any cause) Lupus, class V

 

Anti-GBM diseases ("smooth linear" -- don't expect to see these on EM)

Goodpasture's, others

 

 

Subendothelial (various descriptions, you will only need to recognize on EM)

Membranoproliferative GN type I
Lupus, especially class IV ("wire loops")
Cryoglobulinemia
Hemolytic-uremic syndrome ("fluff")

Also look here for amyloid deposits.

 

Intramembranous (various descriptions, depends on the disease)

Dense deposit disease (membranoproliferative GN type II)
Late membranous glomerulopathy
Late stages of any other progressive immune complex disease

 

Mesangial ("mesangial pattern")

IgA nephropathy
IgM mesangial-proliferative glomerulopathy
Membranoproliferative GN type I
Lupus, any class

Also look here for amyloid deposits.

Glomerulonephritis Causes

  1. Primary Glomerular Disease
    1. IgA Nephropathy
    2. Mesangial proliferative disease
    3. Membranoproliferative disease
    4. Antiglomerular basement membrane
  2. Infectious Causes
    1. Bacterial
      1. Acute Poststreptococcal Glomerulonephritis
      2. Infective endocarditis
      3. Staphylococcus bacteremia
      4. Pneumococcal bacteremia
      5. Syphilis
      6. Leptospirosis
      7. Meningococcemia
      8. Mycoplasma
      9. Typhoid fever
      10. Visceral sepsis
    2. Viral
      1. Hepatitis B
      2. Influenza A and Influenza B
      3. Adenovirus
      4. Epstein-Barr Virus (EBV)
      5. Cytomegalovirus
      6. Measles
      7. Mumps
      8. Parasitic
      9. Malaria
      10. Toxoplasmosis
      11. Schistosomiasis
      12. Filariasis
  3. Multisystem Disease Causes
    1. Systemic Lupus Erythematosus
    2. Henoch-Schoenlein Purpura
    3. Necrotizing Fasciitis
    4. Goodpasture's Syndrome
    5. Wegener's granulomatosis
    6. Thrombotic Thrombocytopenic Purpura
    7. Postpartum Renal Failure
    8. Hemolytic Uremic Syndrome
    9. Hereditary nephritis
    10. Cryoglobulinemia
  4. Medications (primarily cause RPGN)
    1. Penicillamine
    2. Hydralazine
    3. Allopurinol
    4. Rifampin
  5. Causes of Rapidly Progressive Glomerulonephritis
    1. IgA Nephropathy
    2. Membranoproliferative disease
    3. Antiglomerular basement membrane
    4. Acute Poststreptococcal Glomerulonephritis
    5. Infective endocarditis
    6. Visceral sepsis
    7. Hepatitis B
    8. Systemic Lupus Erythematosus
    9. Necrotizing Fasciitis
    10. Goodpasture's Syndrome
    11. Wegener's granulomatosis
    12. Hemolytic Uremic Syndrome
    13. Cryoglobulinemia
    14. Penicillamine
    15. Hydralazine
    16. Allopurinol
    17. Rifampin

 

Clinical Presentations of Glomerular Diseases

Clinical Manifestations of Glomerular Disease

  • asymptomatic proteinuria
  • nephrotic syndrome
    (proteinuria, hypoproteinemia, lyperlipidemia, edema)
  • asymptomatic hematuria
  • glomerulonephritis
    (hematuria, proteinuria, hypertension, renal failure)
  • acute glomerulonephritis
    (neprhitis with short term renal failure)
  • crescentic glomerulonephritis
    (nephritis with rapidly progressive renal failure)
  • chronic glomerulonephritis
    (chronic progression of renal failure)
  • End Stage Renal Disease
    (irreversible renal failure)

The Nephrotic Syndrome

The nephrotic syndrome is characterized by massive proteinuria, which leads to hypoproteinemia/hypoalbunemia, hyperlipidemia with elevated cholesterols, triglicerides and other lipids, and edema. The edema results not only from the hypoosmolar state caused by the loss of plasma proteins, but also from abnormal salt and water retention.

demonstrates the relative frequency with which certain glomerular diseases present as either the nephrotic syndrome or the nephritic syndrome. Some diseases, for example, minimal change glomerulopathy and membranous glomerulopathy, very frequently cause nephrotic syndrome without substantial nephritic features. Other diseases, especially the so-called proliferative glomerulonephritides, which usually have a lot of leukocyte infiltration and lots of inflammatory injury to the integrity of the glomerulus, usually cause the nephritic (glomerulonephritic) syndrome.

 

shows a histologic feature that is found in any patient with nephrotic range proteinuria no matter what the cause, i.e., substantial resorption into the proximal tubular epithelial cells of proteins and lipoproteins that are spilled into the urine. In this trichrome-stained section the droplets are red. They would be black with a silver stain, and purple with a PAS stain. The cytoplasm of these engorged epithelial cells sometimes sloughs into the lumen as little chunks of cytoplasm containing droplets of lipoproteins and proteins

 

(standard light microscopy and polarized light microscopy) shows the appearance of these in the urine as so-called oval fat bodies. Oval fat bodies can be seen quite nicely with polarized microscopy because of the birefringence of the lipid, which produces maltese cross configurations. Oval fat bodies are markers for nephrotic range proteinuria but not for any particular disease. These lipid droplets also can become incorporated into casts

 

i.e., fatty casts. In summary, fatty casts and oval fat bodies are characteristic of the nephrotic syndrome and derived from epithelial cells that have engorged themselves with the lipoproteins and proteins spilled during nephrosis.

 

Minimal Change Glomerulopathy

There are many synonyms for minimal change glomerulopathy, e.g., minimal change disease, lipoid nephrosis, nill disease. The histologic section of an H&E stained glomerulus in shows the characteristic light microscopic finding, i.e., no abnormality. Sometimes there may be a little bit of mesangial hypercellularity in a few segments. Otherwise, any scarring, any infiltration of leukocytes, any necrosis, or any other substantial structural changes in glomeruli rule out a diagnosis of minimal change glomerulopathy.

is a representative immunofluorescence micrograph of the immunohistology of minimal change glomerulopathy, i.e., background staining. There are occasional specimens that will have small amounts of exclusively mesangial immunoglobulin (especially IgM) or complement accumulation that can still be designated minimal change glomerulopathy. A little bit of mesangial IgM and/or C3 without ultrastructural evidence for electron dense deposits is tolerable for a diagnosis of minimal change glomerulopathy. When groups of patients with absolutely no immunofluorescence findings have been compared to those that have low levels of IgM dominant mesangial deposits without electron dense deposits, they act no differently with respect to their clinical response to steroids and long term outcomes. Well defined mesangial electron dense deposits, however, worsen the prognosis for response to steroids or spontaneous remission. Thus, if there are electron dense deposits, minimal change glomerulopathy is not an appropriate diagnoses.

The ultrastructural finding diagramed in are effacement of visceral epithelial foot processes and epithelial microvillous transformation. Microvillous transformation of epithelial cytoplasm often accompanies effacement. The effacement of foot processes and microvillous transformation are not specific for minimal change glomerulopathy. Foot process effacement is characteristic for minimal change glomerulopathy and is required for the pathologic diagnosis of this disease; however, this same change is present in any patient with substantial proteinuria of any cause. Therefore, the diagnosis of minimal change glomerulopathy is one of exclusion, i.e., these ultrastructural changes should be present in the absence of light microscopic, immunohistologic or other ultrastructural features of any other cause of proteinuria.

The electron micrograph in is from a patient with minimal change glomerulopathy and shows almost complete effacement of the visceral epithelial foot processes. There is condensation of the epithelial cytoskeleton near the basement membrane. If you don't know what this is, you can mistake it for subepithelial electron dense deposits, suggesting membranous glomerulopathy. It is actin condensation that takes place inside of visceral epithelial cytoplasm when there is effacement of foot processes, suggesting that there is movement of cytoplasmic structures during the effacement event.

 

Glomerulonephritis, Rapidly Progressive

 

Acute glomerulonephritis marked by a rapid progression to end-stage renal failure and, histologically, by profuse epithetical proliferation. The principal signs are anuria, proteinuria, hematuria, and anemia. Usual course - progressive.

Rapidly progressive glomerulonephritis (RPGN) is a disease of the kidney that results in a rapid loss of glomerular filtration rate (GFR) of at least 50% over a short period (a few days to 3 months). The main pathologic finding is fibrinoid necrosis in more than 90% of biopsy specimens; extensive crescent formation is present in at least 50% of the glomeruli.

Rapidly progressive glomerulonephritis (RPGN)

  • diffuse crescentic glomerulonephritis
  • massive proliferation of cells (crescent formation) in Bowman's space, affecting a high percentage of glomeruli, & quickly develop renal failure.
  • glomeruli:
    1. crescent on the inside of Bowman's capsule, from a focal & segmental accumulation of a few cells lining Bowman's capsule to extensively circumferential involvement.
    2. cellular, fibrocellular or fibrotic crescent.
    3. minimal change in tuft & tubules in early stage, then tubular atrophy, fibrosis & scarring in progressive patient.
    4. edematous interstitium with mononuclear cells infiltration.

　

L-00 125x

crescent (arrow) in glomeruli with focal atrophic change of tubules.

　

L-0 625x

fibrotic crescent on the inside of Bowman‘s; note cast in the atrophic tubule, and edematous interstitium (right lower) with separate tubules.

　L-01 625x

cellular crescent on the Bowman‘s capsule; note a hyalinized glomerulus (left) with global sclerosis.

　

L-02 125x

IgG linear deposition - rapidly progressive glomerulonephritis - Goodpasture's syndrome

GOODPASTURE'S SYNDROME, MICRO, KIDNEY - Linear IgG deposition along glomerular basement membrane by immunofluorescence. This type of linear deposits may also be seen along alveolar septa in the lung.

Rapidly Progressive Glomerulonephritis (Pathogenesis)

·         RPGN is divided into three groups on the basis of immunofluorescence

·         Type I RPGN - anti-GBM disease

·         Type II RPGN - immune complex mediated disease

·         Type III RPGN - pauci-immune RPGN

 

 

 

The term RPGN was first used to describe a group of patients who had an unusually fulminant poststreptococcal glomerulonephritis and a poor clinical outcome. Several years later, it was discovered that antiglomerular basement membrane (anti-GBM) antibody produced a crescentic glomerulonephritis in sheep, and following this the role of anti-GBM antibody in Goodpasture syndrome was elucidated. Soon afterwards the antibody’s role in RPGN associated with Goodpasture disease was established.

In the mid 1970s, a group of patients was described who fit the clinical criteria for RPGN, but in whom no cause could be established. Many of these cases were associated with systemic signs of vascular inflammation (systemic vasculitis), but some were characterized only by renal disease. A distinct feature of these patients' cases was the virtual absence of antibody deposition on immunofluorescence staining of the biopsy specimens, which led to the label pauci-immune RPGN. Over 80% of patients with pauci-immune RPGN were subsequently found to have circulating antineutrophil cytoplasmic antibodies (ANCA), and thus this form of RPGN is now termed ANCA-associated vasculitis.

RPGN is classified pathologically into 3 categories: (1) anti-GBM antibody disease (composing about 3% of cases), (2) immune-complex disease (45% of cases), and (3) pauci-immune disease (50% of cases). The disorders also are classified by their clinical presentation, and finally they are classified immunologically, by the presence or absence of ANCA. Below is a classification based on pathology, with the clinical syndromes and ANCA status subsumed under each pathological description.

Anti-GBM antibody

Immune complex

Pauci-immune

The conditions listed under the Anti-GBM antibody and Immune complex headings are discussed in other articles. The remainder of this chapter will address the ANCA-associated diseases.

In 1982, Davies et al first noted the presence of ANCA in 8 patients with pauci-immune RPGN and systemic vasculitis. Hall et al noted this again in 1984, in 4 patients with a small-vessel vasculitis. Subsequently, ANCA positivity was found to correlate closely with the clinical syndromes of WG, Churg-Strauss syndrome, and MPA.