Case 1

submitted by:
Robert B. Colvin
Massachusetts General Hospital
Boston, Massachusetts

Clinical Summary:

33 year old man presents with mild proteinuria (0.9 gm/d) and normal creatinine (0.8 gm/d). Since adolescence had paresthesias of hands and feet, most severe when febrile. He also has longstanding purple papules on flanks and groin area. No family history of renal disease. A renal biopsy (Biopsy A) was performed and he was entered into a clinical trial. At the end of the trial, 11 months later a second biopsy was performed (Biopsy B). Both biopsies were processed in epon for one micron sections and EM. What was the disease and treatment and how did the pathology change?

Case 1 - Figure 1 - Biopsy A: Low power view showing lipid deposits in the podocytes, (toluidine blue).

Case 1 - Figure 2 - Biopsy A: The glomerulus shown here has lipid deposits in podocytes, endothelial cells, and mesangial cells (toluidine blue).

Case 1 - Figure 3 - Biopsy A: Peritubular capillaries show lipid within their endothelium (insert) (toluidine blue).

Case 1 - Figure 4 - Biopsy A: Electron microscopy of a peritubular capillary and arteriole show endothelial cell and smooth muscle lipid deposits.

Case 1 - Figure 5 - Biopsy B: Low power view showing lipid deposits in the podocytes, (toluidine blue).

Case 1 - Figure 6 - Biopsy B: On high power view the glomerulus shows little or no lipid in endothelium or mesangium. Podocytes still have lipid, (toluidine blue).

Case 1 - Figure 7 - Biopsy B: Electron micrograph of peritubular capillaries shows no lipid deposits remaining in the endothelium.

Case 2

submitted by:
Laura Finn
Children's Hospital
Seattle, Washington

Clinical Summary:

This AGA male infant (XY karyotype) was delivered at 36 weeks to a 31-year-old G3P3 mother who received no prenatal care. The placenta was large and the infant had widely spaced cranial sutures, large anterior and posterior fontanelles, mild periorbital and moderate peripheral edema. He developed respiratory distress and an infectious etiology was excluded. Evaluation revealed low serum albumin (<1.0 g/dl) and protein (2.6 g/dl) with nephrotic-range proteinuria; BUN and Cr were 12 mg/dl and 0.2 mg/dl, respectively. Renal sonogram showed enlarged kidneys with diffuse bilateral echogenicity. An open biopsy was performed. The infant failed to thrive and several bouts of sepsis followed. His proteinuria was unresponsive to drug management but his renal function remained intact. A unilateral nephrectomy was performed at 4 months of age; persistent heavy proteinuria prompted removal of the second kidney at 7.5 months.

Case 2 - Figure 1 - At 4 months, there is patchy interstitial fibrosis and moderate tubular dilatation. Subcapsular glomeruli resemble those in the deeper cortex.

Case 2 - Figure 2 - Representative glomeruli adjacent to dilated proximal tubules have minimal mesangial hypercellularity without mesangial sclerosis.

Case 2 - Figure 3 - A prior biopsy at 6 weeks of age showed minimal fibrosis, mildly thickened arteries and mild mesangial matrix and cell increase. Only a few tubules are dilated.

Case 2 - Figure 4 - Podocyte foot process fusion is obvious by electron microscopy. Electron dense deposits are not identified. The basement membrane is appropriately thin for age.

Case 3

submitted by:
Mark Haas
Johns Hopkins Hospital
Baltimore, Maryland

Clinical Summary:

A 4 year old African-American girl was admitted to the hospital with a one week history of vomiting, anorexia, and lethargy. There was a history of polydipsia without reported polyuria or dysuria. Physical exam was remarkable for height 93 cm (<5th percentile, height age 2.75 years), weight 11.5 kg (<5th percentile), hypotonia, and evidence of dehydration. There was no edema. Blood pressure was 100/60. Family history was positive for hypertension, but otherwise negative for renal disease.

During the first week of hospitalization, laboratory work-up showed (normal range for age listed in parentheses for abnormal values only): serum sodium 125-135 (138-145), potassium 1.8-2.8 (3.4-4.9), chloride 82-92 (97-110), and bicarbonate 27-32 (21-28) mmol/L. BUN was 7 mg/dl and serum creatinine 0.4 mg/dl. Total serum calcium was 9.4 mg/dl and magnesium 2.1 mg/dl. Total serum protein was 7.3 g/dl and albumin 4.4 g/dl. Urinalysis showed 3+ protein, with no glucose, RBC, or WBC. A 24 hour urine collection showed specific gravity 1.010 (1.015-1.025), osmolality 224 mosmol/kg (300-900), protein 290 mg (50-80), protein/creatinine ratio 1.1 (<0.2), sodium 54 mmol, potassium 25 mmol, chloride 50 mmol (15-40), calcium 71 mg. Renal ultrasound showed low-normal kidney sizes with increased echogenicity but no apparent nephrocalcinosis. ANA, anti-double-stranded DNA, and Sjogren's SS-A and SS-B antibodies were negative, and serum C3 and C4 were normal. Serum aldosterone was 167 ng/dl (normal <40), plasma renin activity 1542 mU/ml (normal <100), and serum 6-keto-prostaglandin F1a (a product of renal prostaglandin metabolism) 13 pg/ml (normal <10).

The clinical impression was probable Bartter's syndrome, although this did not explain the proteinuria. Largely for this reason, an open renal biopsy was performed.

Case 3 - Figure 1 - Photomicrograph of two glomeruli from the mid-portion of the cortex. The juxtaglomerular apparati appear hyperplastic. PAS stain, x 200.

Case 3 - Figure 2 - Photomicrograph of two additional glomeruli. The glomerulus at the upper left is near, but not directly beneath, the renal capsule. The deeper glomerulus appears enlarged with mild to moderate mesangial hypercellularity accompanied by mild increase in mesangial matrix. H&E stain, x200.

Case 3 - Figure 3 - Direct immunofluorescence for C1q. Glomerulus shown is representative of non-sclerotic glomeruli within the specimen. Staining for C1q is present in the mesangial regions. FITC-conjugated anti-human C1q on cryostat section, x400.

Case 3 - Figure 4 - There is irregular effacement of the podocytes. Glomerular basement membranes appear normal in thickness. An electron dense deposit is identified in the mesangium, subjacent to the glomerular basement reflection.

Case 3 - Figure 5 - Electron micrograph of a cell within the juxtaglomerular apparatus. The JGA cells contain prominent rough endoplasmic reticulum and Golgi complexes. Rounded or rhomboidal secretory granules are located adjacent to Golgi complexes. Uranyl acetate and lead citrate stain, total magnification x78, 750 (original magnification x35, 000, print x2.25).

Case 4

submitted by:
M. Barry Stokes
New York University Medical Center
New York, New York

Clinical Summary:

A 28-year old American-born Chinese man presented with bilateral ankle edema, foamy urine, sore throat, and new-onset of hypertension (blood pressure 164/114 mm Hg). Urinalysis showed 16 to 20 RBCs/HPF and 24 hour urine collection protein contained 3.9 g protein. Laboratory investigations revealed blood urea nitrogen 34 mg/dL, serum creatinine 2.6 mg/dL, serum albumin 2.5 g/dL, total serum protein 5.0 g/dL, cholesterol 499 mg/dL, triglycerides 485 mg /dL, low-density lipoprotein (LDL) 275 mg/dL and glucose 112 mg/dL. Urine electrophoresis revealed predominantly albumin. Serologic tests for antinuclear antigen, cryoglobulin, paraproteins, and hepatitis B surface antigen were all negative. Anti-streptolysin-O titer, serum C3 and serum C4 levels were within normal limits. Renal ultrasound revealed normal sized kidneys with diffusely increased echogenicity of the renal parenchyma. The patient had no significant past medical history and neither his parents nor his two sisters had a known history of renal disease. A renal biopsy was performed.

Case 4 - Figure 1 - Glomerular capillary lumens are markedly dilated and contain pale-staining, weakly eosinophilic thrombus-like material. This material has a finely lamellar pattern. There is marked thickening of the peripheral capillary wall, with duplication of glomerular basement membranes and focal cellular interposition (Jones' methenamine silver stain, 40x).

Case 4 - Figure 2 - Numerous fat droplets (red) in capillary lumens, capillary walls, and Bowman's capsule cells and in some tubular epithelial cells (Oil Red O stain of cryosections; 40x).

Case 4 - Figure 3 - Electron micrograph: large aggregates of finely vacuolated osmiophilic material with a concentric lamellated appearance in a capillary lumen.

Case 4 - Figure 4 - Electron micrograph: similar finely vacuolated osmiophilic material in the subendothelial region of a capillary wall and in the adjacent Bowman's capsule.

Case 5

submitted by:
Agnes Fogo
Vanderbilt University Medical Center
Nashville, Tennessee

Clinical Summary:

A three-year-old white boy presented to the emergency room department after he developed "tea-colored" urine. He was given antibiotics (not specified) in the emergency department and referred to his primary physician. There was no periorbital or extremity swelling, petechiae, purpura, rashes, joint swelling or pain. He had upper respiratory symptoms with low-grade fever and a "croupy cough". The past medical history was significant for a normal vaginal delivery induced four weeks before term secondary to recurrent "UTI's" in the mother. The family history was significant for approximately 40 episodes of "UTI's" not further characterized in the mother, as well as a history of one episode of nephrolithiasis in the mother. The father also had a history of UTI's and mild vesicoureteral reflux as a child. The father had a history of persistent microscopic hematuria with onset in childhood, and many episodes of gross hematuria between the ages of five and seven years. He had been followed by a pediatric nephrologist. The father currently at age 36 still had positive dipstick for blood with occasional RBCs, no RBC casts. He had normal renal function (Screat 0.9) and no proteinuria, blood pressure 100/64 mm Hg on no meds. The father's mother at some point had "kidney trouble" but no details were known. Both the father's parents were alive and well.

On examination, the child was afebrile, with blood pressure 86/59 mm Hg. He weighed 13 kg (25%), and was 93 cm tall (25%). He appeared alert and playful and was in no apparent distress. The physical exam was unremarkable, and further review of system was noncontributory. Laboratory examination showed WBC 7000/mm3, PCV 36%, platelets 316,000 mm3. The differential showed 31% neutrophils, 54% lymphocytes and 6% atypical lymphocytes. Electrolytes were normal, BUN was 9 mg/dl, serum creatinine 0.3 mg/dl, Ca 2+ 8.8 mg/dl, phosphorus 4.5 mg/dl, glucose 69 mg/dl, albumin 3.3 g/dl, total biliubin 0.5 mg/dl, alkaline phosphatase 154 U/L, SGOT 55 U/l. An ASO titer was <58 (<125 is neg), and streptozyme was <1:100. C3 was slightly decreased at 84 units mg/dl (88-201 normal), C4 was 38 mg/dl (15/45), IgA level was 52 mg/dl (25-154 mg/dl normal), and ANA and ANCA tests were negative. Urinalysis showed a specific gravity of 1.020, pH 7, 2+ protein and large blood positivity, with negative leukocyte esterase and nitrogen tests. The microscopic exam showed 5 to 10 WBCs and numerous dysmorphic RBCs and occasional RBC casts. Renal ultrasound showed normal kidneys with normal shape and size (7 cm), without cysts, stones or masses. The urine protein/creatinine ratio was 0.4.

The patient was followed up in the Pediatric Renal Clinic with close monitoring of renal function and hematuria. The hematuria persisted over the next six months, and diagnostic procedures were performed.

Case 5 - Figure 1 - Light microscopic appearance of a representative glomerulus from the 3-year-old patient, revealing mild increase in mesangial matrix. (Jones' silver stain, X400).

Case 5 - Figure 2 - Diffuse thinning of glomerular basement membrane with intact foot processes and no deposits. (Transmission electron microscopy, X4,000)

Case 5 - Figure 3 - Some glomerular capillary walls have lamellated basement membranes. (Transmission electron microscopy, x5000).

Case 5 - Figure 4 - Research immunostaining with antibody to a5 type IV collagen in control normal tissue and in the 3-year-old patient.(X200)

Case 5 - Figure 5 - Research immunostaining with antibody to a5 type IV collagen in control normal tissue and in the father.(X200)