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Glomerular Dz Lab

CASE 1

Clinical History:

A 10 year old caucasian girl was brought by her parents to their family physician. History revealed that the child had a sore throat for about 10 days prior to the office visit. Initial laboratory tests ordered by the family physician revealed an elevated BUN and creatinine. A urinalysis showed hematuria with dysmorphic RBC's. The patient is referred to a nephrologist. The nephrologist, based upon the usual course of this illness, elects to follow the patient. However, two weeks later, the C3 is still decreased.

Pathologic Findings:

A renal biopsy was performed next.

Slide 1.1At medium power, a glomerulus is shown here with H&E stain.

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Slide 1.2At higher power, a glomerulus is shown here with H&E stain.What are the light microscopic findings?

Slide 1.3The pattern of immunofluorescence of the glomerulus is shown here with antibody to human complement (C3).What does the immunofluorescence staining show in slide 1.3 for C3 (staining was negative with C1q, IgM, and IgA)? Staining for IgG is +/-.

Slide 1.4: The electron micrograph of the glomerulus is shown here. Note the electron dense subepithelial "humps" above the basement membrane and below the epithelial cell. The capillary lumen is filled with a leukocyte demonstrating cytoplasmic granules.

What does the electron microscopy show?

Questions:

1. What tests should be ordered?

Antistreptolysin O (ASO) - elevated; Complement C3 - decreased.

2. What diagnosis is suggested at this point?

Post-streptococcal glomerulonephritis.

3. What is the differential diagnosis? o post-streptococcal glomerulonephritis o IgA nephropathy o membranoproliferative glomerulonephritis (I or II) o SLE

4. What additional laboratory tests should be ordered?

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C3 nephritic factor - negative (tends to rule out MPGN II); ANA - negative (tends to rule out SLE).

CASE 2

Clinical History:

A 25 year old male works in a military fuel depot. He began having respiratory difficulty along with red-tinged sputum. Two months later, he had increasing malaise and flank pain. He went to see the base physician. The patient then developed very rapid onset of renal failure with hematuria within three days.

Pathologic Findings:

A renal biopsy was performed.

Slide 2.1At medium power, a glomerulus is shown here with H&E stain.

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Slide 2.2At medium power, another glomerulus is shown here with H&E stain. Most of the glomeruli had this appearance.

What does the light microscopy show?

Slide 2.3The immunofluorescence pattern is seen here with antibody to fibrinogen.

What does the immunofluorescence show with staining for fibrinogen?

Slide 2.4The immunofluorescence pattern is seen here with antibody to IgG.

What does the immunofluorescence show with staining for IgG?

Questions:

1. What tests and procedures would you order? o Chest x-ray - infiltrates are present, but no cavitary lesions or mass

lesions o Sputum culture - negative for pathogens o PPD - negative

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o Urinalysis - many RBC's 2. What is the differential diagnosis?

o Goodpasture's syndrome o Vasculitis (Wegener's granulomatosis, SLE, polyarteritis nodosa) o IgA nephropathy

3. What additional laboratory tests can be ordered? o Anti-neutrophil cytoplasmic antibody (ANCA) - negative (tends to

exclude Wegener's) o anti-GBM antibody - positive

CASE 3

Clinical History:

A young male in his early 20's had a routine checkup by his family physician, which included a urinalysis. The urinalysis revealed a few RBC's. Physical examination was non-contributory. A repeat urinalysis shows dysmorphic RBC's and RBC casts, but no WBC's.

Pathologic findings:

Though one diagnosis in particular is most strongly suspected and has no specific treatment, a renal biopsy was performed for confirmation of the diagnosis.

Slide 3.1At medium power, a glomerulus is shown here with H&E stain. The arrow points to one mesangial region.

What does the light microscopy show?

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Slide 3.2The immunofluorescence pattern is shown here. This would be the same whether the antibody was to IgA or complement C3.

What does the immunofluorescence show that represents the pattern seen with staining for both IgA and C3? What does the urinalysis microscopic examination show?

Slide 3.3The microscopic appearance of the urine sediment is shown here. Note the appearance of many of these RBC's, compared to two relatively normal RBC's at the center left of the right panel.

Questions:

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1. What additional history do you want to know?

There was no history of trauma. He had no dysuria. He had a recent "flu-like" illness. There is no family history of renal disease. One maternal uncle is deaf.

2. What is the differential diagnosis? o IgA nephropathy o Alport's syndrome o Vasculitis (Wegener's granulomatosis, SLE, polyarteritis nodosa) o Urinary tract infection

3. What additional laboratory tests could be ordered? o ANA - negative o ANCA - negative o Urine culture - negative

4. What diagnosis would you consider if the patient had presented with petechiae and purpura of the skin?

Henoch-Schonlein purpura

CASE 4

Clinical History:

A 15 year old female seen by her family physician because of increasing lethargy. She had a recent history of the "flu". The child's condition does not improve after several weeks, so a renal biopsy is then done.

Pathologic Findings:

Slide 4.1At medium power, a glomerulus is shown here with H&E stain.

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Slide 4.2At medium power, a glomerulus is shown here with Masson's trichrome stain.

What does the light microscopy show (Slide 4.2 is stained with a trichrome stain)? What diagnosis would you consider if the patient had been a 1 year old child with a history of failure to thrive and edema, urinalysis showing hyaline casts and oval fat bodies, proteinuria of 3.7 gm/day, and hypoalbuminemia with increased serum cholesterol?

Slide 4.3At medium power, a glomerulus that appears normal with H&E stain is shown here.

What does the H&E appearance of the glomerulus show?

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Slide 4.4An electron micrograph is shown here.

What is the essential feature seen in the electron micrograph?

Questions:

1. What additional history should be obtained?

There is no family history of congenital diseases, including sickle cell disease. The child is being fed well.

2. What laboratory tests should be ordered?

Urinalysis - 3+ protein, everything else negative; it is a "selective proteinuria" with just albumin present; 24 hr urine protein is 1.5 gm.

3. What is the differential diagnosis? o Minimal change disease o Focal segmental glomerulosclerosis o Membranoproliferative glomerulonephritis o SLE (rare)

4. What additional laboratory tests could be ordered? o C3 is normal o C1q is negative o ANA is negative

5. What do you do next?

Treat with corticosteroids and see if the child improves.

CASE 5

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Clinical History:

A 41 year old male is found to have proteinuria on urinalysis performed as part of a yearly checkup by his physician. The dipstick urinalysis showed no blood, glucose, or ketones. The microscopic urinalysis revealed only 1 RBC/hpf and no WBC/hpf. Physical examination findings include 1+ pitting edema of the lower extremities to the knees. His blood pressure is 130/80. The rectal examination reveals no masses, but the stool guaiac is positive. The lungs are clear to auscultation and percussion. Palpation of the abdomen reveals no masses, and bowel sounds are present. Additional laboratory testing revealed a 24 hour urine protein of 4.1 gm. His serum creatinine was 4.2 with BUN of 40. He was referred to a nephrologist, and a renal biopsy was performed.

Pathologic Findings:

Slide 5.1At high power, a glomerulus is shown here with H&E stain.

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Slide 5.2At high power, a glomerulus is shown here with the Jones silver stain.

What does the light microscopic appearance demonstrate (Slide 5.2 is a Jones silver stain) in all glomeruli?

Slide 5.3The immunofluorescence pattern is seen here with antibody to IgG.

What is the pattern seen on immunofluorescence with antibody to IgG?

Slide 5.4 The electron micrograph of the glomerulus is seen here.

What are the features demonstrated by electron microscopy?

Questions:

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1. What is the differential diagnosis?

This is nephrotic syndrome in an adult. The most common cause is membranous glomerulonephritis, but minimal change disease, focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis can also occur. Nephrotic syndrome can also occur with systemic diseases such as diabetes mellitus, infections such as hepatitis B, malignancies, and amyloidosis. SLE would be uncommon in this setting, but could occur. About 85% of cases of membranous GN are idiopathic.

2. What additional laboratory testing would be useful?

An ANA was negative. The serum IgG was slightly decreased, and serum complement levels were normal. His serum glucose was 110 mg/dl. He is HbsAg negative.

3. What additional workup is necessary in this case?

The positive stool guaiac suggests gastrointestinal hemorrhage. A colonoscopy was performed, and a 5 cm irregular exophytic mass found in the cecum. The most common malignancies associated with adult membranous GN are melanomas, lung cancers, and colon cancers.

4. What is the pathogenesis of the disease seen here?

MGN is a chronic antigen-antibody mediated disease in which the immune complexes are deposited in the glomerular capillaries. The antigen may be within the glomerular capillary (in idiopathic cases) or extrinsic to the kidney (in secondary causes).

CASE 6

Clinical History:

A 34 year old male is found to have 1+ proteinuria on urinalysis performed as part of a pre-employment physical examination. The dipstick urinalysis showed no blood or ketones, but the glucose was 2+. Physical examination was unremarkable. His blood pressure was 135/85.

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Slide 6.1At high power, a glomerulus is shown here with H&E stain.

Slide 6.2At high power, a glomerulus is shown here with PAS stain.

What light microscopic appearance is shown in Slides 6.1 and 6.2 (Slide 6.2 is a PAS stain) that was present in many glomeruli?

Questions:

1. What underlying disease process is suggested by these findings?

Diabetes mellitus. Proteinuria occurs in about half of patients with either type I or type II diabetes mellitus, usually about 1 to 2 decades after initial appearance of clinical diabetes mellitus, and suggests a greater likelihood for progression to chronic renal failure in 5 years.

2. What additional laboratory testing would be helpful?

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A fasting blood glucose greater than 140 mg/dl as measured on two occasions will document the hyperglycemia indicative of diabetes mellitus. The presence of ketonuria would suggest type I diabetes mellitus, but the lack of ketones is not specifically indicative of type II diabetes mellitus. If he were overweight, then type II is more likely.

3. What other complications could be present, given his underlying disease? Examples of additional complications are shown in Slides 6.3 and 6.4.

Slide 6.3 demonstrates numerous neutrophils in and around renal tubules, indicative of acute pyelonephritis. Slide 6.4 shows many round cells, including lymphocytes, and more significantly, plasma cells, that can be found with chronic pyelonephritis. Urinary tract infections are more common and severe in patients with diabetes mellitus. Diabetics can also develop papillary necrosis. Accelerated atherosclerosis can lead to marked nephrosclerosis, either arterial or arteriolar. The term diabetic nephropathy is often used to denote the spectrum of pathologic lesions that can be found in kidneys in patients with diabetes mellitus types I and II.

Examples of additional complications are shown in Slides 6.3 and 6.4.

Slide 6.3A complication of diabetes mellitus is shown here with H&E stain.