Case 1

KELLY D. SMITH
University of Washington
Seattle, WA

Clinical Summary:

A 52-year-old female, who is status post cadaveric renal transplant for polycystic kidney disease and end stage renal disease (one and a half years status post bilateral nephrectomies). Total ischemic time was 13 hours and 32 minutes, and cold ischemic time was 12 hours and 58 minutes. The patient put out a small amount of urine immediately postoperatively, but soon became anuric. Several renal ultrasounds obtained in the post-operative period demonstrated excellent perfusion of the kidney.

She has been followed in transplant clinic for her delayed graft function, and is now 8 weeks status post cadaveric kidney transplant. She continues to complain of marked fatigue and weakness. She has been receiving intermittent transfusions of packed red blood cells, and regular hemodialysis. She has very minimal urine output, and the urine has been relatively dark. Today, she has made 6 cc, and her typical urine output ranges from 10-50 cc per day. She has not experienced dysuria, or noted any change in her urine. She denies any fevers or chills, and has not had any headaches.

Her medications are tacrolimus (2 mg bid), sirolimus (5 mg per day), ganciclovir (500 mg per day), clotrimazole (10 mg qid), Zantac (150 mg per day), Docusate (250 mg bid), Multivitamin (one per day), Temazepam (30 mg hs), Trazodone (12.5 mg per day), Dilaudid (2 mg q 2-4 h prn), Fentanyl (patch 50 mcg every 3 days), and PhosLo (two tablets tid).

On physical exam the patient is afebrile with a blood pressure of 110/80 mmHg. Her abdomen is markedly distended with pain in several areas (secondary to her polycystic liver disease), but her graft is relatively nontender. Her ankles show symmetrical edema without any effusion in the joints or erythema.

Laboratory studies are notable for a tacrolimus level of 4.4 (target 10), BUN 30, creatinine 3.8, and glucose 154, white blood cell count 3.77, hematocrit 33, and platelet count 106,000. Sirolimus level 8.9 (target 10-15).

Clinical impression: Primary graft nonfunction. The patient's immunosuppressive levels have been kept relatively low over the last several weeks with tacrolimus levels between 2.1 and 10, but mostly in the 2-3 range. Sirolimus levels have been under the goal of 10-15, often times 8.9 to 9.1. She has not had any evidence of obstruction. She is being dialyzed.

Case 1 - Figure 1 - SU-01-430 LM1 - PAS stain at 2 weeks - PAS stain of the 2 week biopsy demonstrates features of acute tubular injury/"acute tubular necrosis," characterized by tubular epithelial cell loss of brush border, accumulation of debris in tubular lumina, and the additional feature of prominent intratubular cast formation. Many casts have irregular sharply demarcated contours, and occasional apparent fracture lines.

Case 1 - Figure 2 - SU-01-430 LM2 - PAS stain at 2 weeks - PAS stain of the 2 week biopsy demonstrates findings similar to those seen in Figure 1.

Case 1 - Figure 3 - SU-01-430 EM1 - electron micrograph at 2 weeks - Electron micrograph of the 2 week biopsy demonstrates tubular epithelial cell injury, with loss of brush border, simplification of basolateral membrane interdigitations, and prominent accumulation of heterogenous lysosomes (tertiary lysosomes).

Case 1 - Figure 4 - SU-01-430 EM2 - electron micrograph at 2 weeks - Electron micrograph of the 2 week biopsy demonstrates tubular epithelial cell injury and cast material within the tubular lumen. The central portion of the lumen contains cells that have accumulated osmiophilic material along membranes and on organelles. These cells are surrounded by a dense ring of osmiophilic cast material, which in some fields is associated with organoid cellular debris.

Case 1 - Figure 5 - SU-01-1808 LM1 - Jones stain at 5 weeks - Jones stain of the 5 week biopsy demonstrates persistent intratubular cast formation, as seen in the 2 week biopsy. At this time there is also an apparent increase in interstitial collagen.

Case 1 - Figure 6 - SU-01-1808 LM2 - Jones stain at 5 weeks - Jones stain of the 5 week biopsy demonstrates persistent tubular injury and intratubular cast formation. Some tubules contain eosinophilic bodies and membranous rings, which correspond to the degenerating cells laden with osmiophilic material, as detected by electron microscopy.

Case 1 - Figure 7 - SU-01-3502 LM1 - Jones stain at 8 weeks - Jones stain of the 8 week biopsy demonstrates persistent tubular injury and atypical intratubular casts. In this biopsy, there is also a further increase in interstitial collagen and tubular atrophy.

Case 1 - Figure 8 - SU-01-3502 LM2 - Jones stain at 8 weeks - Jones stain of the 8 week biopsy demonstrates focal multinucleate giant cell formation within the tubular lumen.

Case 2

SEYMOUR ROSEN
Beth Israel Deaconess Medical Center
Boston, MA

Clinical Summary:

A19-year old college freshman running in a 400 m race (no prior training) fell just before the end, sustained abrasions, but completed the race. He had not eaten all day, drank minimally on the nine-hour bus ride home, and vomited once. In the Emergency Room, he vomited again, and physical examination was significant for mild hypotension and abrasions. Urinalysis revealed proteinuria (3+), many RBC's, and no casts. He was admitted 3/28; biopsied 3/29.

	CREATININE		CREATINE KINASE
3/28	2: 41 AM	3.0	320
3/28	7:10 AM	3.9
3/28	3:00 PM	4.3
3/29	7:00 AM	5.1	468
3/30	8:00 AM	3.6	1104
3/31	6:35 AM	2.4	1135
4/07	3:42 PM	1.2	118

Case 2 - Figure 1 - Cortex. Labyrinth containing an unremarkable glomerular tuft. The proximal tubular brush borders are fairly well maintained as documented by electron microscopic studies (inset). The latter shows vacuolar change likely related to endocytosis. PAS

Case 2 - Figure 2 - Cortex. Labyrinth containing two unremarkable somewhat distorted glomerular tufts. A medullary ray is seen in the upper left. The proximal tubular brush borders seemed to be at least in part maintained, but are not clearly delineated as in figure 1. PAS

Case 2 - Figure 3 - Inner stripe of outer medulla. The photograph depicts vasa recta , the vessels of which contain cells which seem to be, at least in part, of hematopoietic origin, i.e. erythroblasts and granulocytic precursors. H&E

Case 2 - Figure 4 - Inner medulla, towards the papillary tip. The collecting ducts show necrosis and regenerative changes. Very focal acute inflammation was noted in the stroma (lower right). H&E

Case 2 - Figure 5 - Inner medulla, towards the papillary tip. The collecting ducts show regenerative changes. PAS

Case 2 - Figure 6 - Inner medulla, towards the papillary tip. There appears to be stromal edema and collecting duct injury. Masson trichrome

Case 2 - Figure 7 - Inner medulla, towards the papillary tip. The collecting ducts show regeneration with focal denudation of basement membranes which is best seen in the right hand photograph. Limited stromal acute inflammation is noted as well (left) . Masson trichrome

Case 3

CYNTHIA C. NAST
Cedars-Sinai/UCLA
Los Angeles, CA

Clinical Summary:

The patient is a 29 year old Vietnamese woman who initially presented an elevated serum creatinine level of 2.3 mg/dl and hypertension. At that time she had normal size kidneys by ultrasound and a normal serologic profile. She was treated with atenolol. One month later she developed nausea, vomiting and generalized fatigue and was admitted. She had developed hematuria and dysuria 2 days prior to admission. She denied arthralgias, hemoptysis and rash.

Physical Exam
BP 120/92     Pulse 88     Temp 99
HEENT:	no retinopathy, malar rash or pharyngitis
Chest:	clear
Cardiac:	normal
Abdomen:	soft, no organomegaly
Extremities:	no C,C, E

Laboratory Studies

WBC 7.4, Hct 19, Plt 189,000

Na 128, K 6.1, Cl 100, CO2, Glu 129, Cr 7.3, BUN 75

ANA < 1:40, Anti-ds DNA < 1:5, C3 170, C4 42

Urine analysis: Ph 5.0, 3+ protein, large occult blood, TNTC RBCs and WBCs, no casts

A renal biopsy was performed.

Case 3 - Figure 1 - The interstitium contains a diffuse infiltrate of large polygonal cell. There is acute tubular injury with cellular debris within tubular lumina. (Periodic acid-Schiff x 10)

Case 3 - Figure 2 - The infiltrating interstitial cells have PAS + cytoplasm and replace the renal parenchyma in this field. A tubule is ruptured with degenerating cellular material in the disrupted lumen. (Periodic acid-Schiff x 20)

Case 3 - Figure 3 - There is a heterogeneous interstitial infiltrate composed of histiocytes, lymphocytes and scattered neutrophils. (Hematoxylin and eosin x 20)

Case 3 - Figure 4 - The interstitial histiocytes have abundant cytoplasm with PAS + fine granules. A portion of a completely sclerotic glomerulus is present. (Periodic acid-Schiff x 40)

Case 3 - Figure 5 - The glomerulus is intact and shows mesangial expansion with mild segmental hypercellularity. The surrounding interstitium has a heterogeneous inflammatory infiltrate. (Periodic acid-Schiff x 20)

Case 3 - Figure 6 - Granular mesangial staining for IgA. (x 20)

Case 3 - Figure 7 - Transmission EM of an interstitial histiocyte. There are few cytoplasmic lipid vacuoles and electron dense lysosome-like structures. (x 5000)

Case 3 - Figure 8 - Transmission EM of a glomerulus. There are electron dense deposits in the mesangium beneath the paramesangial basement membrane. (x 5000)

Case 4

XOCHI J. GEIGER
Mayo Clinic
Jacksonville, FL

Clinical Summary:

A 44 year-old African-American female presented with worsening renal function over a several month period. Her serum creatinine had steadily increased from baseline of 1.9-2.0 mg/dL to 2.2, 2.7 and a current value of 2.9 mg/dL over the past two months. At her previous visit she was noted to have left maxillary sinusitis, for which she received antibiotics, but currently was without complaints, feeling well and denied shortness of breath, lower extremity edema, hematuria or rash. Her past medical history was significant for recurrent urinary tract infections, granulomatous hepatitis, sarcoidosis and Crohn's disease. She was afebrile with blood pressure 118/80 mm Hg and weight 111 kg. Physical exam revealed clear lungs, no hepatosplenomegaly and and no extremity edema. Laboratory examination revealed serum creatinine 2.9 mg/dL, urine protein /creatinine ratio 0.15, platelets 258,000/uL and hemoglobin and hematocrit 11.6 and 33.9 g/dL, respectively. Urinalysis showed trace protein and moderate blood. Renal biopsy was performed.

Case 4 - Figure 1 - Granulomatous interstitial nephritis with several noncaseating granulomas, interstitial edema and inflammation. (Jones silver stain; x 100)

Case 4 - Figure 2 - Well-formed noncaseating granulomas and scattered giant cells, tubulitis and tubular injury. One globally sclerosed glomerulus is present, upper left. (Jones silver stain; x 200)

Case 4 - Figure 3 - Granulomatous inflammation infiltrating tubules with tubular basement membrane breaks. (Jones silver stain; x 400)

Case 4 - Figure 4 - Granulomatous arteritis with fibrinous exudates. Note infiltration of vessel wall by epithelioid granulomata and vessel wall injury. (Jones silver stain, x 200).

Case 4 - Figure 5 - Small artery with arteritis and surrounding granulomatous inflammation. (Jones silver stain; x 400)

Case 4 - Figure 6 - Glomerulus with ischemic change and periglomerular fibrosis. There are no proliferative or necrotizing lesions. Interstitial nephritis with tubulitis is also present. (PAS stain; x 400)

Case 5

VIVETTE D. D'AGATI
Columbia University
New York, NY

Clinical Summary:

A 3 year-old African-American male (date of birth 4/2/94) was referred to a pediatric nephrologist in May l997 for work-up of polydipsia, renal glycosuria and proteinuria. The child's height was in the 50th percentile and his weight was in the 25th percentile for age. Physical examination was unremarkable, with BP 96/56. Urinalysis disclosed pH 7.0, 1+ protein, 3+ glucose (quantitated urine glucose 500 mg/dl with simultaneous blood glucose 91 mg/dl), 3-4 rbc/hpf, 0 wbc. Blood chemistries included Na 139 mEq/L, K 5.0 mEq/L, HCO3 18 mEq/L, BUN 14 mg/dl, and creatinine 0.8 mg/dl. By ultrasound, the kidneys were normal sized with increased echogenicity. Further work-up disclosed creatinine clearance 79 ml/min/1.73 m2, Uprot/Ucreat ratio of 0.8, serum albumin 4.8 g/dL, cholesterol 168 mg/dL, calcium 10.0 mg/dL, phosphorus 5.1 mg/dL (fractional excretion of PO4 17%), uric acid 2.7 mg/dL, amylase 195 (normal <80). The following were all negative or normal: liver function tests, pyruvate, lactate, CH50, C3, C4, C5, C2, C1q, ANA, RF, anti-DNA, SSA, SSB, ENA, anti-Smith, anti-RNP, lead (Pb) levels, sickle prep, slit lamp examination. A renal biopsy was performed at an outside institution in October 1997. Because of inadequate tissue for immunofluorescence, a second renal biopsy was performed in February 1998. The following slides are from this second biopsy.

Case 5 - Figure 1 - Low-power view showing patchy tubular atrophy and interstitial fibrosis with a mild interstitial inflammatory infiltrate of mononuclear leukocytes. (Masson's trichrome)

Case 5 - Figure 2 - High-power view of the atrophic tubules shows inconspicuous tubular basement membranes and dense intervening interstitial fibrosis. (Masson's trichrome)

Case 5 - Figure 3 - A representative glomerulus has internal vacuolizations of the glomerular basement membranes typical of membranous glomerulopathy. (Jones methenamine silver)

Case 5 - Figure 4 - Immunofluorescence staining for IgG reveals 2+ finely granular staining of the glomerular basement membranes in an apparently subepithelial distribution. By contrast linear staining can be seen in Bowman's capsule and the adjacent tubular basement membranes.

Case 5 - Figure 5 - Immunofluorescence staining for IgG shows diffuse intense (3+) linear staining of all the tubular basement membranes, including those of atrophic and non-atrophic tubules.

Case 5 - Figure 6 - Indirect immunofluorescence was performed by application of patient serum to cryostat sections of normal kidney, followed by FITC-rabbit antihuman IgG. There is linear staining of tubular basement membranes and Bowman's capsule, but not the glomerular basement membranes or mesangium. These findings provide conclusive evidence of the presence of circulating anti-TBM antibody.

Case 5 - Figure 7 - Electron micrograph showing electron dense subepithelial and intramembranous deposits embedded in the glomerular basement membranes, consistent with stage 1-3 membranous alterations.

Case 5 - Figure 8 - Electron micrograph showing the absence of any electron dense deposits involving the tubular basement membranes, which appear thinned.