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Renal Pathology
Sunday, March 25, 2007, 7:30 PM
Elizabeth HDrug-Induced Renal Disease
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Moderator:
ROBERT B. COLVIN
Massachusetts General Hospital
Boston, MA
Disclosure: The speakers have indicated they have nothing to disclose.
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for Text and References
Submitted by: Stephen Bonsib - LSU Health Sciences Center, Shreveport, LA
The patient is a 19-year old white female. She was first seen by her family physician because of acute onset of peripheral edema with swelling of feet and lower extremities. Two days before the patient received vaccinations (hepatitis B and meningococcal) in preparation for college. She was treated with a prednisone Dosepak pack with transient resolution of the edema. The edema recurred 1 week later and was still present at a follow up visit 1 month later. 3+ proteinuria was detected and she was referred to a nephrologist.
The initial nephrology evaluation occurred 2 months after the first onset of edema. By that time she had gained 8 kg. Physical examination was essentially unremarkable aside from significant edema. She was afebrile, with blood pressure of 110/60 mm Hg, and weight of 72.4 kg.
Family history: No family history of renal disease.
Past medical history: Recurrent upper respiratory infections characterized by tonsillitis
Laboratory findings:
Creatitine - 0.5 mg/dl
Urinalysis:
4+ proteinuria
No rbcs or cellular casts
24-hr urine protein - 6.5 gm
Serum albumin - 2.4 gm/dl
Cholesterol - 280 mg/dl / Triglycerides - 216 mg/dl
C3/C4 - normal
ANA - negative
Case 1 - Slide 1 - H&E
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Case 1 - Slide 2 - PAS
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Case 1 - Figure 7 - Direct immunofluorescence shows prominent mesangial deposition of IgA.
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Case 1 - Figure 8 - This electron micrograph shows loss of podocyte foot processes. The mesangial matrix is not expanded and no electron dense deposits are present.
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Case 1 - Figure 9 - This electron micrograph shows loss of podocyte foot processes. The mesangial matrix is not expanded and no electron dense deposits are present.
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for Text and References
Submitted by: Arthur H. Cohen - Cedars-Sinai Medical Center, Los Angeles, CA
A 58 year old Caucasian man with 22 year history of HIV infection developed heavy proteinuria (6.4 grams/24 hr) with renal insufficiency (creatinine clearance 78 ml/min with serum creatinine 1.6 mg/dl) one year prior to renal biopsy. Kidneys were of normal size by ultrasound (11.2 and 11.0 cm). He was started on an aggressive regimen of antiretroviral therapy; this led to a decrease in viral count to 50 and a dramatic reduction in protein excretion to 836 mg/24 hrs. The serum creatinine remained at 1.6 mg/dl. Two months prior to biopsy, renal function began to deteriorate and Scr was 2.0 mg/dl and clearance 59 ml/min. In addition, hypouricemia, hypophosphatemia and increased urinary acid excretion were noted. Protein excretion also increased. He was normotensive; urine analysis was "bland." Because of these developments he was referred to a nephrologist for renal biopsy.
Past medical history was pertinent for HIV infection and hepatitis B infection. Liver biopsy in the past disclosed increased iron stores and no evidence of cirrhosis. Recent CD4 - 260/ cu mm, and HIV RNA by PCR was 73 copies/ml. He was hypertensive for two years.
Medications included kaletra (lopinavir, ritonivir), epivir (lavimudine), viread (tenofovir), among many.
Physical exam disclosed a chronically ill appearing man of stated age and in no distress and with BP 120/70. There were no abnormal findings.
Laboratory data on admission:
Hgb/Hct - 17.4 gm/50.5; WBC 5,900 with normal differential; platelets 173,000.
Na 139; K 5.4; Cl 101; CO2 23.
BUN/Cr - 223/2.3.
Urine analysis protein 2+; 0 rbc; 26 granular casts.
A biopsy was performed.
Case 2 - Slide 1 - Jones
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Case 2 - Slide 2 - PAS
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Case 2 - Slide 3 - Trichrome
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Case 2 - Slide 4
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Case 2 - Figure 1 - General overview to indicate mild tubular atrophy and interstitial fibrosis. (periodic acid-Schiff)
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Case 2 - Figure 2 - Glomeruli with no significant changes. (periodic acid-methenamine silver)
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Case 2 - Figure 3 - Glomeruli with no significant changes. (periodic acid-methenamine silver)
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Case 2 - Figure 4 - Some proximal tubular cells are enlarged with prominent nuclei while others are irregularly flattened. (periodic acid-Schiff)
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Case 2 - Figure 5 - Some proximal tubular cells are enlarged with prominent nuclei while others are irregularly flattened. (periodic acid-Schiff)
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Case 2 - Figure 6 - C3-weak granular staining in mesangial regions and possibly capillary walls.
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Case 2 - Figure 7 - Portion of glomerulus with segmental foot process effacement and no deposits.
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Case 2 - Figure 8 - Proximal tubular cells with abnormal mitochondria: enlarged, with increase in number and loss of cristae.
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Case 2 - Figure 9 - Proximal tubular cells with abnormal mitochondria: enlarged, with increase in number and loss of cristae.
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for Text and References
Submitted by: Agnes Fogo - Vanderbilt University Medical Center, Nashville, TN
This 64-year-old white retired man with a kidney transplant for end-stage renal disease (ESRD) secondary to diabetes, presented in August 2006 for evaluation of recent weakness, muscle pain and diarrhea. He had received a living non-related 0 antigen match kidney in June 2005, and had been in stable health, with controlled glucose and moderately controlled blood pressure, but persistent hyperlipidemia. He had one episode of acute cellular rejection, biopsy proven, in January 2006. Serum creatinine stabilized after this at 2.6-2.7 mg/dl. His medications included mycophenolate, cyclosporine, diuretics, prednisone, aspirin, simvastatin and insulin. His prescription for an angiotensin receptor-blocker (ARB) had not been filled as it was not on his hospital's formulary. An ARB was added to his medications in mid-July 2006, when he presented with edema and increased weight of 8-10lbs. His dose of diuretic was also increased. Serum creatinine remained stable at this time. Approximately one month later, he had muscle aches and weakness that started in the lower legs and then involved the anterior thigh and calf. The pain rendered him unable to walk. He also had diarrhea for three days, and noticed red/brown urine, but maintained normal urine output.
On admission, his blood pressure was 152/78 mmHg, he was afebrile, pulse was 88 beats/min and weight 259 lbs. He had tenderness of the posterior calves and anterior thighs and 1+ edema of the lower extremities, but otherwise normal neurological and musculoskeletal exam. Admission laboratories showed sodium 130 mmol/L, potassium 7.0 mmol/L, chloride 95 mmol/L, CO2 19 mmol/L, serum creatinine 8.3 mg/dl, glucose 242 mg/dl, phosphorus 8.8 mg/dl, AST 503 U/L, ALT 204 U/L, alkaline phosphatase 80 U/L, total bilirubin 0.6 mg/dl, direct bilirubin 0.4 mg/dl. His CBC showed a decreased hematocrit at 31.5%, with platelets 209,000/mm3, white blood cells 8,900/mm3, with lymphocytes 5.3%, PMNs 88.5%, monocytes 5.6%, eosinophils 0.5%, and basophil 0.1%. PT and PTT were normal. CPK was 16,393 U/L, with CPK-MB 123.9 ng/mL (normal 0-3.6). Urinalysis showed positive dipstick for protein, large blood and urobilinogen, with negative glucose and bilirubin.
He had a smoking history of 60-70 pack yrs, but had quit five years ago. He did not use alcohol. His past history was significant for coronary artery disease with four vessel bypass in 2000, ICD placement in March 2005 and elective cholecystectomy in 2005.
He was treated with fluids, and cyclosporin, ARB and simvastatin were discontinued, and the patient was given Imuran. On day four, with creatinine remaining high, a renal biopsy was performed.
Case 3 - Slide 1
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Case 3 - Figure 1 - Low power, PAS stain shows widespread acute tubular injury with thinning of cytoplasm and loss of brush borders. Several mixed cellular and proteinaceous casts are present. The interstitium has a mild mononuclear infiltrate and edema. A small artery and two glomeruli are unremarkable.
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Case 3 - Figure 2 - Similar features are present, but with even more casts are shown, sometimes with little PAS positivity.
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Case 3 - Figure 3 - Similar features are present, but with even more casts are shown, sometimes with little PAS positivity.
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Case 3 - Figure 4 - Higher power PAS stain shows granular pattern of casts and loss of brush borders from proximal tubular cells.
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Case 3 - Figure 5 - Granular and weakly PAS positive pattern of casts is illustrated.
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Case 3 - Figure 6 - Granular and dense redish brown ball-like cast material is present, typical of myoglobin.
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Case 3 - Figure 7 - A normal glomerulus at high power (PAS).
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for Text and References
Submitted by: Glen S. Markowitz - Columbia Presbyterian Medical Center, New York, NY
A 64-year-old Caucasian female presented with unexplained renal failure, a creatinine of 2.6 mg/dl, malaise, and weight loss. Four months prior, the patient had a creatinine of 0.9 mg/dl. Past medical history was significant for hypertension for 6 months and a remote history of chronic urethritis and cystitis requiring urethrotomy (40 years prior). At the time of evaluation the patient's medications included amlodipine, metoprolol, and esomeprazole (as needed), although she had recently been switched from lisinopril to amlodipine and metoprolol due to poor blood pressure control. Physical examination revealed a blood pressure of 194/74 and no edema. Urinalysis revealed rare WBC's, no RBC's, and no proteinuria. There was no evidence of a monoclonal serum spike. The patient had an albumin of 4.3 g/dl, calcium 9.9 mg/dl, hematocrit 27.3%, platelet count 301,000, normal C3 and C4, negative ANCA, and negative anti-GBM antibody. The kidneys measured 9.5 and 8.8 cm in length by ultrasound. During the following 2 months the patient's creatinine declined to 2.3 mg/dl, at which time renal biopsy was performed.
Biopsy materials:
Single glass slide (stained with H&E)
Immunofluorescence: negative
Electron microscopy: not provided (no significant glomerular abnormalities noted)
Case 4 - Slide 1
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Case 4 - Figure 1 - A low magnification view displays disproportionate tubulointerstitial scarring. There is mild to moderate interstitial chronic inflammation. Prominent tubular calcifications are seen in the upper left and lower right portions of the field.
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Case 4 - Figure 2 - A glomerulus appears histologically unremarkable.
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Case 4 - Figure 3 - An intermediate magnification view shows abundant tubular calcifications. The calcifications do not polarize and are mainly confined to distal tubules.
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Case 4 - Figure 4 - A high power view shows that the calcifications have an intra-cellular (within tubular epithelia), intra-luminal, and interstitial distribution.
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Case 4 - Figure 5 - The tubular calcifications stain intensely with the von Kossa stain, consistent with calcium phosphate.
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Case 4 - Figure 6 - A periodic acid Schiff stain demonstrates the prominent tubular atrophy and interstitial fibrosis. Glomeruli appear unremarkable. There is no significant tubulitis.
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for Text and References
Submitted by: Helmut Rennke - Brigham & Women's Hospital, Boston, MA
61-year-old man was diagnosed Stage IIIB non-small-cell carcinoma of the lung (T2, N3) in 2002. He received carboplatin and Taxol chemotherapy followed by concurrent chemoradiotherapy. In April 2003 a right supraclavicular node was noted and treated with radiation. At the time he had received Taxotere with ZD6474, Iressa, Navelbine, and beginning February 2004, gemcitabine was started. He tolerated the treatment well, and on 2 subsequent scans he showed improvement.
On July 5, 2004 he was admitted to Brigham and Women’s Hospital with increasing dyspnea, edema, pleural effusions, which showed no malignant cells. He was discharged, the edema got worse, and he developed systemic hypertension. He was re-admitted to the renal service. His PE remained unchanged with marked edema, his UA showed 4+ protein, and a 24-hour collection revealed 10 g of protein. The sediment was bland. His serum creatinine was 1.6 mg/dl.
Biopsy materials: Images of LM, IF, and EM
Case 5 - Slide 1 - H&E
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Case 5 - Slide 2 - Jones
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Case 5 - Slide 3 - PAS
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Case 5 - Slide 4
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Case 5 - Figure 1 - This low power image of the renal cortex shows well-preserved parenchyma without signs of glomerulosclerosis or tubular atrophy. Two small arteries on the right show prominent walls. PAS.
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Case 5 - Figure 2 - The glomerulus depicted on this H&E reveals capillaries largely occluded by swollen cells, although with this stain it is difficult to know if there are also changes of the capillary wall that are contributing to this appearance. Significant hypercellularity of the tuft is not present.
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Case 5 - Figure 3 - This PAS-stained section of a glomerulus reveals thickening of the capillary walls with numerous irregular "double contours", especially noticeable in the center and on the right side of the image. Swollen cells appear to occlude several capillaries. The tuft shows mild mesangial expansion and slight increase of cells at these sites.
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Case 5 - Figure 4 - This glomerulus reveals changes similar to those seen in Figure 3. One arteriole at the vascular pole of the glomerulus is occluded by foamy material. The wall of the arteriole also reveals indistinct cell borders. PAS
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Case 5 - Figure 5 - This image depicts kidney cortex with few tubules showing necrotic debris in the lumen and one small artery with a moderately thickened vascular wall. PAS.
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Case 5 - Figure 6 - The immunofluorescence microscopy reveals diffuse and irregularly distributed granular deposits reactive predominantly for IgM (and C3, not illustrated). Direct immunofluorescence microscopy with anti-IgM
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Case 5 - Figure 7 - There is also dull reactivity for fibrin-related antigens along the glomerular capillary walls. Direct immunofluorescence microscopy with antibodies against fibrin-related antigens.
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Case 5 - Figure 8 - This low power electron micrograph shows three glomerular capillary loops with prominent thickening of the wall. Small fragments of cells in the urinary space include prominent lysosomes.
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Case 5 - Figure 9 - This electron micrograph shows the details of the thickened capillary wall. The endothelial cells show marked loss of fenestrations. There is prominent expansion of the subendothelial space by electron-lucent debris and interposition of cells and cell projections. There is also widespread effacement and simplification of foot processes. The epithelial cells show microvillous degeneration of the cell surface. Several small and ill-defined aggregates of electron dense material is also present in the markedly expanded subendothelial space.
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Case 5 - Figure 10 - This high power electron micrograph shows the details of the glomerular capillary wall changes. Notice the multi-layered basement membrane under the endothelium, the cell projections in the expanded subendothelial space, and the aggregates of ill-defined dense material. The lamina densa proper is maintained, and the foot processes of the epithelium are well preserved in this capillary.
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