Case 2 -

Focal Glomerular Fibrinoid Necrosis, Most Consistent with Atheroembolic Disease Serena M. Bagnasco Johns Hopkins University School of Medicine Baltimore, MD

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Clinical History At the time of biopsy the patient was a 72 year old white male with past medical history of hypertension, and achalasia, found to have renal failure with serum creatinine 9 mg/dl, during hospitalization for chest pain. Case 2 - Figure 1 Case 2 - Figure 2 Case 2 - Figure 3 Case 2 - Figure 4 Case 2 - Figure 5 Case 2 - Figure 6 Case 2 - Figure 7 Case 2 - Figure 8 Case 2 - Figure 9 Case 2 - Figure 10 Case 2 - Figure 11 Case 2 - Figure 12 A native kidney biopsy showed "Necrotizing crescentic GN, c/w anti-GBM disease" with positive anti-GBM titer: 7.7 U/ml (NV:<3 U/ml). He underwent transplant from deceased donor followed by DGF with slow serum creatinine stabilization to baseline ~1.3 mg/dl. The post transplant course included: Repair of anterior wall hernia, and recurrent esophageal stricture. At 2.7 years post transplant: a severe stenosis of right and left coronary arteries was diagnosed, and was followed by CABG x3. At 2 weeks post CABG he developed internal jugular vein thrombosis (started on anticoagulant), pleural effusions, had an episode of altered mental status, and his serum creatinine increased up to 2.6-3 mg/dl. At ~1.5 months post CABG his creatinine had reached 7 mg/dl, he was hospitalized, and underwent bladder decompression with incomplete recovery of renal function, and serum creatinine of 4.9 mg/ml at discharge. At ~2.9 years post transplant, due to persistence of elevated serum creatinine a graft biopsy was performed At the time of biopsy laboratory tests were as shown below (serology was pending) Renal Biopsy Findings Light Microscopy Immunofluorescence Electron microscopy Serologic results were received few days later and showed: Anti-GBM <3 U/ml (Negative) PR3 3 Units (Negative) MPO 4.5 Units (Negative) The time-course of declining renal function is illustrated below: Final Diagnosis Focal glomerular fibrinoid necrosis, most consistent with atheroembolic disease. No diagnostic evidence of acute rejection. Summary and Discussion The possibility of focal necrotizing glomerulonephritis associated with anti-GBM antibodies, although supported by immunofluorescence findings of positive linear IgG staining along the glomerular capillary wall, was inconsistent with serology, which demonstrated undetectable anti-GBM antibodies at time of biopsy. Positive IgG staining in the GBM can be seen in renal allograft, but recurrence of anti-GBM disease is very rare in transplanted kidneys, and in most cases the recipient had Alport's disease as the original cause of ESRD (Daly C et al., Ren. Fail. 18:105, 1996; Deegens JK et al., Clin. Nephrol. 59:1, 2003; Cameron JS, Curr. Opin. Nephrol. Hypert. 3:602, 1994). The possibility of focal necrotizing glomerulonephritis as manifestation of ANCA-associated microscopic polyangiitis/Wegener's disease, was inconsistent with serology, which demonstrated undetectable ANCAs, PR3, and MPO at time of biopsy. ANCA-associated renal disease can recur in about 17-19% of patients, and is usually accompanied by elevated ANCA titer, but rarely leads to graft loss (Nachman PH et al. Kidney Int. 56:1544, 1999, Elmedhem A et al. Nephrol. Dial. Transplant. 18:1001, 2003). Glomerular fibrin can be seen in antibody-mediated rejection (AMR), which in this case was ruled out for lack of detectable donor-specific-antibodies, and negative C4d in the peritubular capillaries. The possibility that the glomerular findings could result from endothelial injury associated with tacrolimus toxicity was inconsistent with Tacrolimus levels, which were within therapeutic range at time of biopsy. In support of the diagnosis of Atheroembolic disease, the deterioration of the renal function in this patient occurred following coronary artery arteriogram, and coronary artery by-pass, which are known triggers of atheroembolism. There was evidence of cholesterol emboli in small caliber arteries and within glomerular capillary loops, with segmental breaks in the glomerular basement membrane, resulting in sparse microscopic fibrin accumulation and reactive changes detectable in the affected glomeruli. Atheroembolic disease can have protean manifestations, mimicking systemic diseases. Its incidence in native kidney biopsy is reported as 1.1-2.7%, even rarer in renal allograft (0.30%). The small size renal arteries and glomeruli are major targets of embolization. Focal necrotizing glomerulonephrits, and vasculitis look-alike have been described in association with atheroemboli (Modi KS et al., J. Am. Soc. Nephrol. 12:1781, 2001; Lai CK et al., Am.J. Surg.Pathol 31:536, 2007; Ballestreros et al., Nephrol. Dial. Transplant. 4:430, 1999; Aviles et al., Am. J. Kid. Dis. 40:847-851, 2002)