Recurrent AA Amyloidosis in a Kidney Transplant

Kidney Biopsy Teaching Case Recurrent AA Amyloidosis in a Kidney Transplant Sanjeev Sethi, MD, PhD,1 Mireille El Ters, MD,2 Srividya Vootukuru, MD,2 and Qi Qian, MD2 Recurrent AA amyloidosis in a kidney transplant is rare, especially when the underlying inflammatory condition is controlled. We present a 59-year-old man who underwent a living donor kidney transplant 17 years ago for kidney failure due to AA amyloid nephropathy in the setting of long-standing Crohn disease. His Crohn disease was quiescent before and after the kidney transplant. Transplant function had been stable until a month before presentation, when he developed worsening proteinuria and decreased kidney function. A transplant biopsy showed recurrent AA amyloidosis despite excellent clinical and histologic control of Crohn disease. Am J Kidney Dis. 57(6):941-944. © 2011 by the National Kidney Foundation, Inc. INDEX WORDS: AA amyloidosis; kidney transplant; Crohn disease; proteinuria; recurrence; decreased kidney function.

INTRODUCTION Kidney transplant is an accepted treatment for patients with end-stage kidney failure due to AA amyloidosis. Recurrent AA amyloidosis in the kidney transplant is rare, especially when the underlying inflammatory condition is controlled. We present a case of AA amyloidosis associated with long-standing Crohn disease that recurred in the kidney transplant 17 years after transplant despite excellent control of Crohn disease. CASE REPORT Clinical History and Initial Laboratory Data A 59-year-old man presented in September 2010 with progressive weakness, fatigue, and hypotension. Crohn disease was diagnosed when he was 20 years old, and he underwent multiple small-bowel resections in 1982-1989, resulting in ⬃120 cm of small bowel remaining. After the bowel resections, Crohn disease was well controlled and he was taken off medications for Crohn disease in 1990. He had symptoms of short gut syndrome, which he controlled through dietary modification; he ate small meals 8 times a day and on average had 2-3 soft to firm stools daily. In 1992, he developed heavy proteinuria and decreased kidney function, and AA amyloid nephropathy was diagnosed by means of kidney biopsy. In 1993, shortly after he developed kidney failure, he underwent a living donor kidney transplant at the age of 42; the kidney was donated by his brother. Apart from an episode of acute cellular rejection that resolved with steroid treatment, during the next 17 years, transplant function was stable with serum creatinine concentrations of 1.4-1.7 mg/dL (123.7150.3 ␮mol/L) and estimated glomerular filtration rate (eGFR) of 45-60 mL/min/1.73 m2 (0.75-1 mL/s/1.73 m2; calculated using the 4-variable MDRD [Modification of Diet in Renal Disease] Study equation1). He was maintained on a stable regimen of azathioprine and low-dose prednisone. A kidney transplant biopsy was performed in April 2009 for evaluation of proteinuria with protein excretion of 283 mg/24 h (predicted from a spot urine protein to osmolality ratio). Serum creatinine concentration was stable at 1.5 mg/dL (132.6 ␮mol/L), and eGFR was 51 mL/min/1.73 m2 (0.85 mL/s/ 1.73 m2) at that time. The biopsy specimen showed that 4 of 10 glomeruli were globally sclerotic. Glomeruli showed no mesangial matrix expansion or hypercellularity, no segmental scar, and no Am J Kidney Dis. 2011;57(6):941-944

glomerular basement membrane thickening. Approximately 5%10% focal interstitial fibrosis and tubular atrophy were present. One artery was present and had minimum fibrotic intimal thickening and no evidence of endothelialitis. No amyloid fibrils were detected on electron microscopy. In July 2010, the patient developed bacterial bronchitis requiring intravenous antimicrobials administered through an upper-arm peripherally inserted central catheter. In the course of the treatment, he developed deep vein thrombosis in the arm and anticoagulation therapy was started. In August, he noted lower-extremity fluid retention, and evaluation showed proteinuria with a urine protein to osmolality ratio of 2.9, sharply increased from baseline. Proteinuria was confirmed using a 24-hour urine collection that showed 2.13 g of protein excretion. Serum creatinine level subsequently increased to 2.6 mg/dL (229.8 ␮mol/L; eGFR, 27 mL/min/1.73 m2 [0.45 mL/s/ 1.73 m2]) from 1.5 mg/dL (132.6 ␮mol/L; eGFR, 51 mL/min/1.73 m2 [0.85 mL/s/1.73 m2]) 2 months prior, and serum albumin level decreased to 2.4 g/dL (24 g/L) from 3.7 g/dL (37 g/L) 3 months prior. The following month, serum creatinine level increased further to 3.2 mg/dL (282.8 ␮mol/L; eGFR, 21 mL/min/1.73 m2 [0.35 mL/s/1.73 m2]), urine protein excretion increased to 4.3 g/24 h, and serum albumin level decreased to 1.8 g/dL (18 g/L; Fig 1). In light of these changes, anticoagulation therapy was withheld temporarily and a transplant kidney biopsy was performed.

Kidney Biopsy The sample submitted for light microscopy contained 20 glomeruli, of which 3 were globally sclerosed. Glomeruli showed mild mesangial expansion with periodic acid–Schiff–negative acellular material. Proliferative features were not present. Glomerular base-

From the 1Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, and 2Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN. Received November 14, 2010. Accepted in revised form February 7, 2011. Originally published online April 18, 2011. Address correspondence to Qi Qian, MD, Department of Medicine, Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55902. E-mail: [email protected] © 2011 by the National Kidney Foundation, Inc. 0272-6386/$36.00 doi:10.1053/j.ajkd.2011.02.383 941

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Figure 1. Time course of the patient’s urine protein to osmolality ratio, serum creatinine (mg/dL), estimated glomerular filtration rate (eGFR; mL/min/1.73 m2), and serum albumin (S. Alb; g/dL) values after kidney transplant is shown. Arrows indicate the time of transplant biopsies. Conversion factor for units: serum creatinine concentration in mg/dL to ␮mol/L, ⫻88.4; eGFR in mL/min/1.73 m2 to mL/s/1.73 m2, ⫻0.01667; serum albumin in g/dL to g/L, ⫻10.

ment membranes were slightly thickened with acellular material along the capillary walls; basement membrane spikes or pinholes were not present along the capillary walls. Significant interstitial inflammation was not present, and there was mild tubular atrophy and interstitial fibrosis. Arteries and arterioles showed moderate thickening of vessel walls with periodic acid–Schiff–negative acellular material. Congo Red stain was positive, showing reddishbrown material in glomeruli, interstitium, and vessels. The material showed apple-green birefringence under polarized light. Immunoperoxidase staining for serum amyloid A was strongly positive, and serum amyloid A was present predominantly in the vessels and focally in the interstitium and glomeruli. Immunofluorescence microscopy was negative for all immunoglobulins, including ␬ and ␭ light chains. Electron microscopy showed small collections of amyloid fibrils in the mesangium and along the basement membranes; vascular amyloid fibrils also were noted. Mean fibril thickness was 9.3 nm (Fig 2).

Diagnosis AA amyloidosis in the kidney transplant involving vessels, interstitium, and glomeruli.

Clinical Follow-up The patient was evaluated by pulmonology and gastroenterology. Bronchoscopy was positive for Pneumocystis jirovecii. Esophageal gastroscopy and colonoscopy showed no evidence of active Crohn disease. He was treated with concomitant prednisone and trimethoprim-sulfamethoxazole for P jirovecii infection and responded well. However, he subsequently developed pneumonia caused by Pseudomonas aeruginosa, and ertapenem therapy was started. At the 2-month follow-up, the bronchitis had resolved, but serum creatinine level remained at 3.6-3.8 mg/dL (318.2-335.9 ␮mol/L; eGFR, 16-18 mL/min/1.73 m2 [0.26-0.3 mL/s/1.73 m2]) off renal replacement therapy.

DISCUSSION Recurrent AA amyloidosis in a kidney transplant typically presents as proteinuria and decreased trans942

plant function, which clinically may resemble allograft nephropathy. However, transplant loss related to this entity is uncommon. We describe a patient with recurrent AA amyloidosis in the kidney transplant related to Crohn disease presenting as worsening proteinuria and decreased transplant function 17 years after the kidney transplant. AA amyloidosis is caused by extracellular deposition of amyloid A protein formed from the precursor serum amyloid A, an acute-phase protein produced and secreted by hepatocytes in response to inflammation. AA amyloidosis occurs in up to 6% of patients with any condition associated with a sustained acutephase response or chronic inflammatory disorders, including familial Mediterranean fever, rheumatoid arthritis, ankylosing spondylitis, chronic infection (eg, tuberculosis, osteomyelitis, and bronchiectasis), and inflammatory bowel disease. The incidence of AA amyloidosis due to long-standing Crohn disease varies widely depending on geographic areas. In the United States, ⬃0.5%-0.9% of patients with Crohn disease develop AA amyloidosis.2,3 The kidney is the major organ affected by AA amyloidosis: ⬎80% of patients with AA amyloid show kidney involvement. The clinical features of AA amyloid nephropathy are proteinuria and kidney failure. End-stage renal failure is the cause of death in 40%-60% of cases.4 Kidney transplant has been accepted as a treatment for patients with kidney failure due to AA amyloidosis.5 These patients show a lower rate of transplant rejection compared with patients without amyloidoAm J Kidney Dis. 2011;57(6):941-944

AA Amyloidosis in Kidney Transplant

Figure 2. (A) Periodic acid–Schiff–stained section shows mild or no mesangial expansion. (B) Congo Red stain shows positive staining along the artery and mild mesangial staining. (C) Positive serum amyloid A stain in an artery, interstitium, and glomerulus (A-C: original magnification, ⫻20). (D) Electron microscopy shows amyloid fibrils in a glomerulus (original magnification, ⫻46,000).

sis, but experience more perioperative complications and death primarily from cardiac abnormalities (eg, arrhythmias) and infection. Death with a functioning transplant is relatively common.6,7 Only a few case series of recurrent AA amyloidosis in kidney transplant recipients were described, primarily in patients with familial Mediterranean fever, ankylosing spondylitis, and rheumatoid arthritis.6,8 To our knowledge, there has not been a report of kidney transplant AA amyloid recurrence in the setting of Crohn disease. In this case, AA amyloid recurrence in the transplant was not strongly suspected because the Crohn disease was quiescent and the transplant biopsy 1.5 years prior showed no evidence of amyloid fibrils. Urine protein excretion was screened throughout the posttransplant period using spot urine protein to osmolality ratio (Fig 1), a ratio equivalent to protein-creatinine ratio in estimating urine protein excretion when an adult is on a steady diet and has a relatively stable GFR.9 Repeated transplant biopsy in this case was critical for the diagnosis of amyloid recurrence. On a closer look at the literature, there are reports describing persistent tissue deposition of amyloid fibrils despite good control and the absence of suppurative complications of Crohn disease.3,10,11 Our patient’s active amyloid deposition in the transplant in the absence of active Crohn disease appears consistent with these previous observations. He had had infective bronchitis for about 3 months, which might have contribAm J Kidney Dis. 2011;57(6):941-944

uted to the overall inflammatory state in the circulation, facilitating the progression of amyloidosis. The current treatment approach for recurrent amyloidosis mirrors native kidney amyloidosis, focusing solely on suppressing the underlying inflammatory condition. Suppression of inflammation is expected to limit hepatic production of amyloidogenic precursor proteins, thereby slowing disease progression.12 Efficient anti-inflammatory treatments have delayed or halted the development of AA amyloidosis and preserved organ function in some patients with rheumatoid arthritis,13 chronic infection,14-17 Castleman disease,15 and familial Mediterranean fever.8,16,17 Although these modalities seem effective, they are not directly applicable to our patient because his underlying Crohn disease was quiescent for more than 20 years, and from a gastroenterology standpoint, there was no clinical indication to treat. Recently, new treatment modalities directly targeting amyloid formation, such as eprodisate, are emerging and have shown great promise. Eprodisate disrupts the interaction between amyloidogenic proteins and glycosaminoglycans (which promotes tissue amyloid fibril deposition18) and has halted the progression of AA amyloidosis–associated kidney disease in humans in a phase 2/3 trial.19 Although more clinical trials are needed to confirm these exciting initial findings, such treatment likely would benefit our patient. 943

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In summary, despite clinical and histologic control of the underlying inflammatory condition (Crohn disease in this case), AA amyloidosis can still recur in the kidney transplant. Recurrence should be suspected when patients show worsening proteinuria and decreased kidney function. Moreover, conventional therapy for AA amyloidosis with controlling the underlying inflammation may not always be sufficient. Therapy directly targeting amyloid fibril formation, such as eprodisate, represents a promising future treatment addition for patients with AA amyloidosis.

ACKNOWLEDGEMENTS Support: None. Financial Disclosure: The authors declare that they have no relevant financial interests.

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8. Keven K, Sengul S, Kutlay S, et al. Long-term outcome of renal transplantation in patients with familial Mediterranean fever amyloidosis: a single-center experience. Transplant Proc. 2004; 36(9):2632-2634. 9. Wilson DM, Anderson RL. Protein-osmolality ratio for the quantitative assessment of proteinuria from a random urinalysis sample. Am J Clin Pathol. 1993;100(4):419-424. 10. Werther JL, Schapira A, Rubinstein O, Janowitz HD. Amyloidosis in regional enteritis. A report of five cases. Am J Med. 1960;29:416-423. 11. Fernandez-Castroagudin J, Brage Varela A, Lens Neo XM, Martinez Castro J, Abdulkader I. [Renal amyloidosis as initial clinical manifestation of Crohn’s disease]. Gastroenterol Hepatol. 2002;25(6):395-397. 12. Gillmore JD, Lovat LB, Persey MR, Pepys MB, Hawkins PN. Amyloid load and clinical outcome in AA amyloidosis in relation to circulating concentration of serum amyloid A protein. Lancet. 2001;358(9275):24-29. 13. Deschenes G, Prieur AM, Hayem F, Broyer M, Gubler MC. Renal amyloidosis in juvenile chronic arthritis: evolution after chlorambucil treatment. Pediatr Nephrol. 1990;4(5):463-469. 14. Costero O, Rinon C, Gil F, et al. [Recurrence and spontaneous remission of nephrotic syndrome in secondary renal amyloidosis]. Nefrologia. 2002;22(5):482-485. 15. Perfetti V, Bellotti V, Maggi A, et al. Reversal of nephrotic syndrome due to reactive amyloidosis (AA-type) after excision of localized Castleman’s disease. Am J Hematol. 1994;46(3):189193. 16. Moser C, Pohl G, Haslinger I, et al. Successful treatment of familial Mediterranean fever with anakinra and outcome after renal transplantation. Nephrol Dial Transplant. 2009;24(2):676678. 17. Alpay N, Sumnu A, Caliskan Y, Yazici H, Turkmen A, Gul A. Efficacy of anakinra treatment in a patient with colchicineresistant familial Mediterranean fever [published online ahead of print April 13, 2010]. Rheumatol Int. doi:10.1007/s00296-0101474-6. 18. Kisilevsky R. The relation of proteoglycans, serum amyloid P and apo E to amyloidosis current status, 2000. Amyloid. 2000;7(1): 23-25. 19. Dember LM, Hawkins PN, Hazenberg BP, et al. Eprodisate for the treatment of renal disease in AA amyloidosis. N Engl J Med. 2007;356(23):2349-2360.

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