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.

Pathophysiology: The link between ANCA and the pathogenesis of ANCA-associated disease is unknown, but it is postulated that neutrophils and mononuclear phagocytes are directly activated by ANCA, and these activated cells in turn attack vessel walls, producing injury similar to that produced by anti-GBM antibodies or immune complexes.

ANCAs react with antigens in the primary granules in the cytoplasm of neutrophils (antiproteinase-3 [PR3]) and in lysosomes of monocytes (myeloperoxidase [MPO]). ANCA demonstrates 2 major types of staining patterns. Cytoplasmic ANCA (cANCA) produces a cytoplasmic staining pattern with central accentuation in alcohol-fixed neutrophils. Perinuclear ANCA (pANCA) demonstrates a perinuclear staining pattern of alcohol-fixed neutrophils, which is actually an artifact of the fixation process. ANCA specificity is determined by enzyme-linked immunosorbent assay (ELISA), with cANCA most commonly an antibody directed against PR3 and pANCA most commonly an antibody directed against MPO.

A nonspecific pANCA can occur in association with other autoimmune or inflammatory diseases, but they do not have the MPO specificity. The most common occurrence is in systemic lupus erythematosus. Other associated diseases include inflammatory bowel disease, sclerosing cholangitis, autoimmune hepatitis, rheumatoid arthritis, and Felty syndrome.

The ANCA-associated diseases are closely related and are distinguished by only a few clinical and pathologic criteria.

Wegener granulomatosis

WG is characterized by the presence of upper airway lesions, pulmonary infiltrates, and RPGN. Patients often present with pulmonary hemorrhage and renal failure. Pathologically, the lung, and sometimes the upper airway lesions, shows granulomatous inflammation. Eighty to ninety percent of patients with WG are ANCA positive, and almost all have a cANCA (anti-PR3). A negative ANCA test does not rule out the presence of WG.

Churg–Strauss disease

This condition is characterized by allergic asthma and eosinophilia. Seventy to ninety percent of patients with Churg-Strauss are positive for ANCA, and these are primarily pANCAs.

Microscopic polyangiitis

MPA is characterized by pulmonary infiltrates and RPGN, often coupled with musculoskeletal systems or with neuropathy or central nervous system abnormalities. The term polyangiitis is used in preference to arteritis because vessels other than arteries normally are involved in the disease. Eighty to ninety percent of patients with MPA are ANCA positive, and almost all have a pANCA (anti-MPO). A negative ANCA test does not rule out the presence of MPA. Isolated necrotizing crescentic glomerulonephritis is the renal limited form of MPA

The most common prodrome of ANCA-associated vasculitis is flulike symptoms, characterized by malaise, fever, arthralgias, myalgias, anorexia, and weight loss. This occurs in over 90% of patients and can occur within days to months of the onset of nephritis or other manifestations of vasculitis.

Physical: Hypertension can be present but is not commonly found. Unless there are specific findings such as those listed below, the physical examination results are usually normal. Organ systems affected by ANCA-associated disease are listed below.

Causes: The cause of ANCA-associated disease is unknown. It is thought that there may be a genetic predisposition to development of this disease. Patients with WG are more likely to have abnormal alpha1-antitrypsin phenotypes. Patients who have the Z phenotype are more likely to have aggressive disease. Multiple studies have demonstrated that ANCA-activated neutrophils attack vascular endothelial cells. Given that 97% of patients have a flulike prodrome, it is possible that there is a viral etiology, but thus far no evidence exists to support this postulate

Histologic Findings: Renal biopsy specimens show a diffuse, proliferative, necrotizing glomerulonephritis with crescent formation.

 

Case Presentation

A 58-year-old man, an international business consultant, presented to his primary care physician complaining of fever, cough, and weight loss. The patient reported that he had been healthy until about a month earlier, when a low-grade fever developed along with a cough productive of whitish sputum that was occasionally streaked with blood. His weight had dropped by about 6.8 kg, and he felt weak and tired.

Ten years ago, he had received a blood transfusion in a foreign country after an automobile accident that had resulted in a fractured leg and a lung contusion. The patient smoked two packs of cigarettes a day and drank alcohol moderately. There was no family history of cancer, tuberculosis, or kidney disease.

The patient was mildly hypertensive with a blood pressure of 160/92 mm Hg. He weighed 70 kg. The physical examination was otherwise unremarkable.

The results of urinalysis were protein 3+; 10 to 15 red blood cells, most of them dysmorphic; 5 to 10 white blood cells; no bacteria; and occasional cellular casts, but no red blood cell casts. A complete blood count showed a slightly decreased hematocrit level of 34% and a hemoglobin level of 11 gm/dL. The white blood cell count was elevated at 12,000/mm3, with a normal differential except for 6% eosinophils. The red blood cell indices were normal. The serum creatinine level was 1.5 mg/dL (normal, 0.7-1.4); blood urea nitrogen, 30 mg/dL (normal, 10-20); serum electrolytes, normal; and serum albumin, slightly decreased at 3.4 gm/dL.

A chest x-ray showed small infiltrates in the left mid-lung and right lower lung, with possible mediastinal adenopathy. The physician referred the patient to a nephrologist for further evaluation.

This case offers several diagnostic possibilities. The patient is an older man, a heavy smoker, who presented with cough, fever, and a pulmonary infiltrate: Does he have lung cancer? He travels abroad regularly: Does he have tuberculosis, and perhaps hepatitis as well? He had had a blood transfusion in a foreign country: Does he have HIV infection? He has impaired renal function and slight anemia, and his urine contains protein and abnormal red blood cells: Does he have glomerulonephritis? He has fever, pulmonary infiltrates, weight loss, and abnormal urine: Does he have systemic vasculitis?

In fact, the primary care physician in this case thought that the patient had tuberculosis, but he referred him because of the abnormal renal function and urinalysis. The nephrologist's first task was to narrow the differential diagnosis by appropriate testing.


Referral to a Nephrologist

The nephrologist confirmed the primary care physician's findings. In addition, he noted a few raised, nontender, erythematous lesions on the lower legs suggestive of a leukocytoclastic cutaneous vasculitis.

A tuberculin skin test was negative. No acid-fast bacilli were seen on sputum smears and sputum culture was pending. A computed tomographic chest scan confirmed the presence of infiltrates in both lungs, without mediastinal adenopathy. There were no pleural effusions and the apical areas of the lungs were free of infiltrates or scarring.

Ultrasound showed normal-sized kidneys; however, there was increased echogenicity. The serum creatinine level, taken one week after the first measurement, had risen from 1.5 to 2.0 mg/dL. The urinalysis was essentially unchanged. The erythrocyte sedimentation rate (ESR) by the Westergren method was greatly elevated at 90 mm/hr.

HIV antibody tests were negative, as were tests for hepatitis B and C. Complement testing showed C3 levels at the upper limit of normal and normal C4 levels. Immunofluorescence and specific testing for antineutrophil cytoplasmic autoantibodies (ANCA) confirmed the presence of p-ANCA at a titer of 1:320 (normal, <1:20). The antibody was confirmed to be an anti-myeloperoxidase. Tests for antiglomerular basement membrane antibody, c-ANCA, and antiproteinase-3 anti-body were negative.

In the context of this patient's differential diagnosis, the erythematous lesions on the lower legs could have been (among other things) Kaposi's sarcoma, complications of HIV disease, or a skin manifestation of vasculitis. However, further laboratory studies ruled out HIV infection, along with tuberculosis and hepatitis, and established the diagnosis as a systemic vasculitis.

Our understanding of vasculitis has been transformed during the past decade. Initial work in this field, conducted by German pathologists in the early 20th century, identified a number of diseases that involve inflammation of the blood vessels. By the 1950s, these heterogeneous disorders had been divided into two groups, large- and small-vessel vasculitis.

In the 1990s, it was discovered that some of these vasculitides were associated with circulating ANCA. This led very quickly to the recognition that vasculitides could also be categorized serologically, rather than simply on the basis of pathology or clinical expression, into ANCA-positive and ANCA-negative varieties.

A few years later, researchers found that ANCA occurred in two major groups--cytoplasmic (c-ANCA) and peripheral (p-ANCA)--based on the antibody pattern seen on indirect immunofluorescence testing. Soon after that, p-ANCA and c-ANCA were associated with very specific antibodies to antigens in the granules of leukocytes. The c-ANCA pattern is strongly associated with antibodies to proteinase-3 (PR3), whereas the p-ANCA pattern is strongly associated with antibodies to myeloperoxidase (MPO). This permitted the further categorization of ANCA-positive vasculitis into anti-MPO and anti-PR3 varieties.

When it was found that these antibodies are associated with clinical and morphologic patterns of disease, the previous clinical and pathologic classification of vasculitis was reexamined. It turned out that anti-PR3 is associated with Wegener's granulomatosis, a clinical category of vasculitis first recognized in the 1940s. Anti-MPO is associated with what we now call microscopic polyangiitis. These associations are strong but not perfect.

The next major advance was the recognition that when measured serially, these antibodies also have prognostic significance. Falling titers are strongly associated with clinical improvement, whereas rising titers are often associated with worsening. With their clinical utility proven, assays for these antibodies quickly spread from research to commercial laboratories, and they are now widely available in clinical practice.

The management of vasculitis has become heavily dependent on these serologic assays. In fact, they form the basis for decisions about biopsies and treatment and, if treatment is indicated, with what kinds of drugs and for how long.

Other tests that may be ordered in these cases include complement assays. Low levels indicate a hypocomplementemic form of glomerulonephritis, such as acute postinfectious glomerulonephritis or systemic lupus erythematosus (SLE). Complement testing was not absolutely necessary in this patient, but there are rare examples of patients who present with fever and pulmonary and renal disease that are caused by SLE. Normal levels of complement, as in this patient, exclude that category of illnesses.

Antiglomerular basement membrane (GBM) antibody testing was performed in this case because the patient had hemoptysis and pulmonary infiltrates, which could represent intrapulmonary hemorrhage. Concomitant pulmonary hemorrhage and glomerulonephritis suggest Goodpasture's disease. The anti-GBM antibody assay has high sensitivity and specificity for Goodpasture's disease, so the negative result permitted the physician to exclude that condition, which requires a different therapeutic approach. Goodpasture's disease is rare; a busy general hospital may see one case every two years, compared with two cases of vasculitis every month.

In this patient, the positive p-ANCA and anti-MPO tests, his age, the systemic features, the renal involvement, and the rate of progression attested to a classic case of microscopic polyangiitis (58 years is the median age for this disorder). Less commonly, microscopic polyangiitis maybe limited to the kidneys--patients present without pulmonary manifestations, weight loss, or fever, just with abnormal urine and a rising serum creatinine level.

Note that I did not call this Wegener's granulomatosis disease. Although that condition is characterized by upper and lower airway disease, renal involvement, and granulomas, the autoantibody in Wegener's granulomatosis disease is more often of the c-ANCA, anti-PR3 variety. In the strictest sense, Wegener's disease is a pathologic diagnosis; granulomas must be identified on tissue biopsy. The granulomas in patients with Wegener's disease often occur in the lung. This patient had lung involvement; however, x-rays cannot distinguish granulomatous from nongranulomatous lesions. Wegener's syndrome, in contrast to Wegener's disease, can be diagnosed if upper and lower airway disease coexist with glomerulonephritis and ANCA (especially c-ANCA and anti-PR3) even if granulomas cannot be found.

The primary care physician who encounters a case such as this should be able to quickly assemble a differential diagnosis that includes vasculitis. Prompt referral to a nephrologist is appropriate because a renal biopsy may be needed, and the elevated serum creatinine level renders delay potentially dangerous. If too much time elapses, systemic disease may worsen and the kidney may be irreversible damaged.


Treatment and Renal Biopsy

Treatment was begun with 500 mg of IV methylprednisolone for three days, followed by oral prednisone, 60 mg a day. Oral cyclophosphamide was started at a dose of 2 mg/kg/day. Renal biopsy was performed.

During the next two weeks the patient's fever abated and the cough disappeared. Malaise and weakness resolved and the patient began to regain weight.

Renal biopsy results, obtained five days after treatment was begun, indicated a necrotizing, crescentic glomerulonephritis involving 90% of the glomeruli in the specimen, with extensive interstitial and periglomerular inflammation. The immunofluorescence study showed only scanty immunoglobulin deposition in the glomeruli and extensive fibrin deposits in Bowman's space.

By four weeks, the serum creatinine level had fallen to 1.1 mg/dL. The proteinuria decreased to 1+ and the hematuria resolved. The chest x-ray was normal; the lung infiltrates had disappeared. The ANCA titer decreased to 1:20, slightly above normal.

Once the serologic diagnosis of microscopic polyangiitis has been established, the physician is faced with an important clinical decision: Do you treat on the basis of the serology, or do you wait until a renal biopsy can be performed--and if the latter, how long should you wait? Is it safe to let this patient go without treatment for another week--or longer, if you have difficulty scheduling him for the biopsy? In this case, in view of the patient's systemic manifestation and the rapidly rising serum creatinine level, immediate treatment was required.

Moreover, a recent study has shown that renal biopsy results do not contribute to clinical decisions in cases such as this. Serologic testing is extremely accurate--the combination of a positive p-ANCA and anti-MPO test has approximately an 85% sensitivity and about a 98% specificity for microscopic polyangiitis. Hence, this patient's overall probability of having the disease is in the vicinity of 95%. A biopsy would contribute little to the diagnostic certainty.

However, many nephrologists still think that a renal biopsy should be performed, not only to confirm the diagnosis but also to obtain other information that may have prognostic significance. Serologic studies do not reliably indicate disease extent or severity. Are all the glomeruli involved, or only a portion? How severe is the involvement? These questions cannot be answered with any degree of accuracy by noninvasive testing. The biopsy results help to guide the intensity and duration of therapy.

In this case, the biopsy showed extensive involvement of the glomeruli with necrosis of the tufts. In particular, it showed crescent formation, which is an exuberant proliferation of cells in Bowman's space. As expected, the immunofluorescence study showed scanty immunoglobulin deposits in the glomeruli (pauci-immune necrotizing and crescentic glomerulonephritis). Severe necrotizing crescentic glomerulonephritis requires intensive treatment.

Fortunately, the diagnosis was made relatively early, when the serum creatinine level had risen to only 2.0 mg/dL, and the patient received aggressive therapy. More than 85% of patients who are diagnosed this early and receive this type of therapy show a good initial response. If the serum creatinine been had been greater than 8 mg/dL at the time that treatment was instituted and the patient had required dialysis, remission would have been much less likely.

The Therapeutic Regimen

Treatment begins with a glucocorticoid. In a patient such as this, who has a rapidly rising serum creatinine level and extrarenal manifestations of disease, I would start with intravenous rather than oral steroids. Because of the positive ANCA test, I would add cyclophosphamide. I administer cyclophosphamide orally because studies have shown no evidence that the intravenous route is more efficacious than the oral route. In addition, because the IV dose is given in a bolus, it requires very precise calculation. In patients with rapidly declining renal function, there is the risk of administering an overdose and causing serious leukopenia (some of the myelosuppressive metabolites of cyclophosphamide are excreted by the kidney).


Complications

After two months of treatment, the patient continued to feel well and remain stable. ANCA titers, which were measured every month, remained at 1:20, slightly above normal. The ESR decreased to 20 mm/hr and the urine sediment showed only 1 to 3 red cells per high-power field.

Prednisone tapering was begun. Cyclophosphamide was continued, however. The patient complained of some hair loss and the white blood cell count dropped to the lower limit of normal. Trimethoprim-sulfamethoxazole, one double-strength tablet a day, was begun. After four months, cyclophosphamide was discontinued and azathioprine, 2 mg/kg a day, was started.

For the next two months the patient remained well and renal function remained normal (serum creatinine level, 0.9 mg/dL), although low-grade proteinuria (1+) persisted. Then his course changed as cough, yellow sputum, and fever developed. A chest x-ray showed an infiltrate in the right lower lung. Sputum culture was positive for Streptococcus pneumoniae, and treatment with erythromycin was begun. Within three days, the fever was gone and the infiltrate was diminishing. Within a week, pneumonia had completely resolved.

At the same time, however, serum creatinine level rose to 2.0 mg/dL, microscopic hematuria recurred, and proteinuria increased to 4+. The ANCA titer rose to 1:320.

Prednisone, which had been tapered to 10 mg a day, was increased to 60 mg. Azathioprine was discontinued, and cyclophosphamide reinstituted at the original dose of 2 mg/kg/day.

Because of its immunosuppressive effect, cyclophosphamide may promote the development of infection or malignancy. This patient's low-normal white blood cell count raised concerns about that, particularly since he was a heavy smoker. On the other hand, many investigators have suggested that induction of long-term remission in patients with microscopic polyangiitis requires at least 12 months of treatment with cyclophosphamide. Especially in a patient such as this, whose ANCA titer remains positive, discontinuation of cyclophosphamide therapy before then risks relapse.

Trimethoprim-sulfamethoxazole may be given in these cases, not necessarily for its antimicrobial effect but because it has been empirically demonstrated to lower the risk of relapse. The mechanism of action is unknown.

Patients with systemic microscopic polyangiitis in whom remission has been achieved still have a 50% risk of at least one relapse. For that reason, the physician must be very vigilant about follow-up. Relapses often occur in association with intercurrent infection, such as bacterial pneumonia. Thus, it is worthwhile to test for nasal carriage of coagulase-negative Staphylococcus aureus, which also increases the risk of recurrence. Staphylococcal carriage can be eradicated with topical mupirocin ointment, provided that the strain is sensitive to the antibiotic.

Cigarette smoking increased this patient's risk of pneumonia. In retrospect, it would have been wise to give him the pneumococcal vaccine before vasculitis developed and immunosuppressive therapy was begun.

One would expect properly treated pneumococcal pneumonia to improve quickly, as this patient's did. Nevertheless, there was sufficient time for it to trigger a relapse of the vasculitis, at least in terms of serologic studies and renal function.


Chronic Management

During the next two to three weeks, the patient's serum creatinine level decreased but remained slightly above normal at 1.5 mg/dL. Urinalysis showed only 1 to 4 red blood cells. Proteinuria continued at 3+ to 4+. However, for the first time since the onset of vasculitis, however, the ANCA titer was negative.

A 24-hour urine collection showed a protein excretion of 3.4 gm/day. Blood pressure was also modestly elevated, at 165/100 mm Hg.

Treatment with enalapril, 10 mg a day, was begun. After two weeks, the blood pressure fell to 130/85 mm Hg, and the serum creatinine level rose slightly. Proteinuria decreased to 2+ qualitatively; quantitatively it decreased to 0.9 gm/day.

The treatment plan was to continue the cyclophosphamide for a full six-month course, measure the ANCA titers monthly, and continue angiotensin converting-enzyme (ACE) inhibitor therapy.

Although the vasculitis in this patient became serologically inactive with resumption of cyclophosphamide therapy, proteinuria and mildly impaired kidney function remained. A 24-hour urine collection was indicated to quantitate the proteinuria.

If the vasculitis remains serologically negative, the risk of another relapse is decreased but not eliminated. The patient has a systemic disease, and the available drugs are more palliative than curative.

The persistence of the elevated serum creatinine level and high-grade proteinuria after serologic remission had been achieved implies that, either during the initial illness or the relapse, there was sufficient damage to the glomeruli to cause some permanent scarring. Thus there is almost no chance that this patient's kidneys will ever return to completely normal function. Moreover, as in almost all renal disease, persistent heavy proteinuria and impaired renal function are predictive of future progression.

For this reason, ACE inhibitor therapy was begun. There is abundant evidence that ACE inhibitors retard the rate of disease progression considerably when proteinuria falls to less than 2.0 gm/day. This patient may eventually require dialysis, but perhaps in five to 10 years rather than one to two years.

From this point on, the case can be managed as a chronic rather than an acutely life-threatening disase. The physician can focus on preventive aspects; for example, smoking cessation. In addition to its other harmful effects, smoking may accelerate the progression of this patient's renal disease.

Hyperlipidemia may be a feature of late-stage crescentic glomerulonephritis. This patient's lipid levels should be measured, and if they are elevated he would benefit from treatment with an HMG-CoA reductase inhibitor. Considering his age and smoking history, a low-density lipoprotein level greater than 130 mg/dL would be grounds for treatment, especially if he also has a family history of coronary artery disease.