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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2018  |  Volume : 29  |  Issue : 2  |  Page : 456-461
Complete remission of nephrotic syndrome secondary to amyloid a amyloidosis in patient with inactive Crohn's disease after treatment by infliximab

Department of Nephrology, Dialysis and Renal Transplantation, Military Training Hospital Mohammed V, Rabat, Morocco

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Date of Web Publication10-Apr-2018


Secondary amyloidosis Amyloid A (AA) is an infrequent but a severe complication of Crohn's disease (CD). This complication results from the activity of the underlying inflammation disease to form amyloid fibril deposits in tissues. We present a case of a 34-year-old female patient with CD treated by azathioprine with inactive disease for three years and who developed a nephrotic syndrome secondary to AA amyloidosis. The treatment by infliximab for one year leads to a complete remission of the nephrotic syndrome. In this case, this complication occurred while the patient was clinically well, with biological and endoscopic markers showing an inactive or only mildly active disease. Infliximab could be a useful tool for a successful treatment of amyloidosis secondary to CD.

How to cite this article:
Hassani K, Hamzi MA, El Kabbaj D. Complete remission of nephrotic syndrome secondary to amyloid a amyloidosis in patient with inactive Crohn's disease after treatment by infliximab. Saudi J Kidney Dis Transpl 2018;29:456-61

How to cite this URL:
Hassani K, Hamzi MA, El Kabbaj D. Complete remission of nephrotic syndrome secondary to amyloid a amyloidosis in patient with inactive Crohn's disease after treatment by infliximab. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2020 Jun 2];29:456-61. Available from: http://www.sjkdt.org/text.asp?2018/29/2/456/229282

   Introduction Top

Secondary amyloidosis Amyloid A (AA) is a rare but severe complication of Crohn's disease (CD) as well as any other condition that is associated with a sustained inflammatory acute-phase response such as rheumatoid arthritis or chronic sepsis. Irrespective of the underlying disease, the general opinion is that AA amyloidosis occurs after a long period of an ongoing inflammatory and infectious process. Amyloidosis is rarely seen in the early course of a possibly chronic or recurrent inflammatory disease.

The deposition of amyloid material mainly affects the kidneys with varying degrees of proteinuria and renal failure as major clinical manifestations. The progression to end-stage kidney disease of AA renal amyloidosis associated with CD in the absence of an effective treatment is frequent.[1],[2],[3]

However, infliximab, an antitumor necrosis factor-alpha (anti-TNFα) agent, has been successfully used in recent years to treat AA amyloidosis in some inflammatory rheumatic diseases and also in rare cases of CD.[4],[5],[6],[7],[8],[9]

We report the case of a patient diagnosed with oligosymptomatic CD who developed AA renal amyloidosis and successfully treated with infliximab over one year with a complete remission of her nephrotic syndrome. No complications or relapse was observed during the follow-up.

   Case Report Top

A 33-year-old female patient was referred to our nephrology unit due to lower limb edema and proteinuria. She had no history or clinical manifestations of any kidney disease in the past. Four years previously, she has been diagnosed with oligosymptomatic CD of the small bowel based on clinical, endoscopic, and histological criteria. Her digestive symptoms have responded well to azathioprine (only the 1st year after CD diagnosis) and 5-amino-salicylates (mesalazine 1500 mg/day). Since the CD diagnosis, the patient remained well, with a good nutritional status (body mass index: 22 kg/m2). Her disease activity was well controlled with a C-reactive protein (CRP) level <10 mg/L and the patient has not experienced any CD complications.

During the past few weeks before her admission, she reported suffering from swelling of the two lower limbs and a weight gain of 7 kg. She also complained postprandial heaviness, without any other gastrointestinal manifestations. She had no febrile episodes, joint inflammation, skin lesions, ocular manifestation, or problems with any other organs or systems. Physical examination showed lower limbs’ edema and a blood pressure of 130/79 mm Hg. The rest of the examination was unremarkable.

The most relevant laboratory data are summarized in [Table 1]. Urine dipstick revealed proteinuria +++ but no blood. The urinary sediment was acellular and urine culture was negative. Proteinogram, immunoglobulins, and complement were normal. Rheumatoid factor, antinuclear antibodies, anti-DNA antibodies, and anti-neutrophil cytoplasmic antibodies were negative. Complement component was normal. Serology for hepatitis B and C viruses and human immunodeficiency virus was negative.
Table 1: Patient most relevant laboratory data.

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Chest X-ray, electrocardiography, and echo-cardiography were normal. Ultrasound scans of the abdomen, kidneys, and urinary passages were normal with increased kidneys cortical echogenicity. Abdominal computerized tomography imaging showed no CD complication.

AA systemic amyloidosis secondary to CD was considered. A subcutaneous fat aspiration biopsy was performed, but no amyloid deposits were detected. Thus, a percutaneous renal biopsy was performed. Histopathological examination of the biopsy specimen showed eosinophilic deposits in the mesangial areas of glomeruli and in the walls of the blood vessels [Figure 1]. The deposits tested positive for Congo red with green birefringence under polarized light. Immunohistochemical staining detected the presence of AA protein.
Figure 1: Congo red staining of kidney biopsy showing mesangial depositions of amyloid.

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The patient had no symptoms or clinical signs suggestive of any other type of inflammatory or infectious disease. We concluded that AA was due to CD and we decided to start treatment based on intravenous infliximab (5 mg/kg) at weeks 0, 2, and 6 then every two months. This treatment was given along with valsartan (80 mg/day) and diuretics.

Serum creatinine was maintained in a normal range, serum albumin increased to 3.5 g/dL, and proteinuria decreased to 0.35 g/day one year after the treatment by infliximab has been started [Figure 2]. Afterward, infliximab was discontinued and the patient was put on maintenance treatment with azathioprine (1.5 mg/Kg).
Figure 2: Progression of serum creatinine, albuminemia, and urinary protein excretion after treatment by infliximab.

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After two years of follow-up, complete remission of nephrotic syndrome is still sustained. There have been no complications of the CD or side effects from the medications. Serum levels of SAA were not investigated in this particular case. Kidney biopsy after treatment has not been performed.

   Discussion Top

The association between secondary amyloidosis and inflammatory bowel disease is well known, and although rare, with only very few cases reported mostly among CD patients. Retrospective studies showed a prevalence of AA ranging from 0.9% to 3% among CD patients.[1],[2],[3] The time lapse between the onset of CD and the diagnosis of amyloidosis has been reported to range from one to 21 years but can also occur as an early CD complication.[10],[11],[12] In exceptional cases, both clinical entities can occur simultaneously.[9]

Unlike this case, patients are usually male with extensive, persistent, and long-lasting disease with uncontrolled inflammatory activity.[2] In our patient, CD was diagnosed four years ago and at this time was oligosymptomatic with only minor digestive manifestations.

As it occurs in other types of secondary amyloidosis, the kidney is the main target organ. Clinical presentation as renal impairment with proteinuria and nephrotic syndrome accounts for 90% of cases. The onset of renal insufficiency is the most important predictor of mortality in these patients, and amyloidosis is frequently described as a major cause of death in patients with CD, with long-term mortality between 40% and 60%.[1],[2],[3],[13]

It has been reported that the activity of the underlying inflammation is an important factor in the development and progression of secondary amyloidosis and AA amyloidosis develops only after a sustained or recurrent acute phase response.[14],[15] Mahmud et al evaluated serum amyloid-A in inflammatory bowel disease patients. In this study, serum amyloid- A was significantly increased in active disease compared with inactive disease.[16] At the opposite, Lovat et al reported four patients with CD who, despite having only low-grade clinical activity, developed progressive AA amyloidosis and renal failure.[17]

Our case raises the question of how the usual markers of inflammation may underestimate the inflammatory activity of CD as CRP had been below 10 mg/L and routine endoscopic evaluation had shown mild inflammatory activity in the past years. In this case, the time of exposure to a subclinically active CD before the diagnosis of AA amyloidosis is unknown and the time of occurrence of the very first deposits remains obscure. We can deduce that AA amyloidosis in CD can also develop in the absence of chronic infections or extraintestinal complications and not necessarily be associated with a clinically manifest, extensive, and aggressive disease.

There is no definite treatment for secondary amyloidosis with CD. The control of the underlying inflammatory process can lead to the reduction of serum AA, the precursor protein avoiding new amyloid tissue deposits, and hence curb the progression of disease. Mandelstam et al[18] reported a case of amyloid regression after bowel resection in a CD patient, but the effectiveness of intestinal resection to prevent or treat renal amyloidosis in CD has not been established.[1],[3] The effects of drugs such as colchicine and dimethyl sulfoxide on slow downing the progression of amyloid nephropathy is controversial.[3] Eprodisate, a promising molecule that inhibits amyloid protein polymerization and deposition in tissues, has small effect on proteinuria and survival.[19]

Recent biochemical research revealed that synthesis of serum AA is regulated by certain pro-inflammatory cytokines such as TNF-α. It has been reported that the use of anti-TNF-α may improve the clinical course of AA amyloidosis in rheumatologic and also in some[4],[5],[6],[7],[8],[9],[20],[21],[22]

Although the detailed mechanism is unknown, it has been suggested that infliximab might not only reduce serum AA synthesis but also slow amyloid deposition.[20] The other possible mechanisms that can explain the therapeutic action of infliximab in secondary amyloid nephropathy are the reduction of glomerular inflammation and permeability to albumin induced by TNFa cytokines and interleukin-6.

Only a few case reports, including our case, have shown the therapeutic effects of infliximab on CD-associated amyloidosis.[4],[5],[6],[7],[8],[9],[21] In most reported cases, treatment with infliximab followed by improvement of renal function and rapid decrease in proteinuria with no complications associated with the medication.

Denis et al reported a cohort of 16 patients with renal AA amyloidosis complicating CD.[23] Six patients were treated with anti-TNF-α agents. Treatment was interrupted in two patients (anaphylactic reaction and death from septic shock). Reduction of nephrotic syn- drome and stabilization of renal insufficiency were observed in three patients. A complete remission was obtained in only one patient. These findings suggest that, in some cases, once renal damage from systemic amyloidosis occurs, anti-TNF-α cannot restore the previous damage, although it may prevent further progression of renal failure.

In our case, azathioprine was introduced only one year after initiation of infliximab treatment and complete remission of nephrotic syndrome. This drug was successfully used in the treatment of renal amyloidosis secondary to Familial Mediterranean fever or rheumatoid arthritis, but there is a lack of evidence of its real benefit in AA amyloidosis due to CD.[24],[25],[26],[27] In a retrospective study of five cases of systemic amyloidosis in CD, there was no beneficial effect of azathioprine on amyloid nephropathy and most patients have developed secondary amyloidosis when they were already treated by azathioprine.[3]

Based on the results of the GAIN trial, in case of intolerance or loss of effectiveness of infliximab, adalimumab, another anti-TNFα, seems to be a potential alternative drug.[28] In a reported clinical case of secondary amyloidosis to CD, the switch from infliximab to adalimumab failed to obtain remission of nephrotic syndrome.[29] Renal transplantation may offer the best prospect for patients with CD who developed amyloidosis and end-stage renal failure.

   Conclusion Top

Secondary renal amyloidosis can appear as an early complication in patients with CD, even in cases with mild clinical symptoms. Monitoring of patients with CD requires measurement of urinary protein excretion and renal function at regular intervals even if they are considered to be in remission: regular urinary dipstick testing for proteinuria is an important aid to early diagnosis, and it is almost impossible to determine the insidious onset of AA amyloidosis in clinical practice unless patients at risk are identified in advance and screened routinely. Amyloidosis should be suspected and ruled out in CD patients whenever clinical symptoms of renal impairment appear.

Infliximab is a useful tool in the early treatment of amyloidosis secondary to CD that can lead to a complete and sustained remission of renal symptoms.

   Acknowledgment Top

We acknowledge Dr. Mahtat El Mehdi for his invaluable help in drafting this case report.

Conflict of interest: None declared.

   References Top

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Serra I, Oller B, Mañosa M, et al. Systemic amyloidosis in inflammatory bowel disease: Retrospective study on its prevalence, clinical presentation, and outcome. J Crohns Colitis 2010;4:269-74.  Back to cited text no. 3
Fernández-Nebro A, Tomero E, Ortiz- Santamaría V, et al. Treatment of rheumatic inflammatory disease in 25 patients with secondary amyloidosis using tumor necrosis factor alpha antagonists. Am J Med 2005; 118:552-6.  Back to cited text no. 4
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Rashid H, Blake D, Gokal R, Gooptu D, Kerr DN. The association of renal amyloidosis with regional enteritis (Crohn's disease) – report of two cases and review of the literature. Clin Nephrol 1980;14:154-7.  Back to cited text no. 10
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Dember LM, Hawkins PH, Hazenberg BPC, et al. Eprodisate for the treatment of renal disease in AA amyloidosis. N Engl J Med 2007; 356:2349-60.  Back to cited text no. 19
Verschueren P, Lensen F, Lerut E, et al. Benefit of anti-TNFalpha treatment for nephrotic syndrome in a patient with juvenile inflammatory bowel disease associated spon-dyloarthropathy complicated with amyloidosis and glomerulonephritis. Ann Rheum Dis 2003; 62:368-9.  Back to cited text no. 20
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Denis MA, Cosyns JP, Persu A, et al. Control of AA amyloidosis complicating Crohn's disease: A clinico-pathological study. Eur J Clin Invest 2013;43:292-301.  Back to cited text no. 23
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Sayarlioglu H, Erkoc R, Sayarlioglu M, Dogan E, Soyoral Y. Successful treatment of nephrotic syndrome due to FMF amyloidosis with azathioprine: Report of three Turkish cases. Rheumatol Int 2006;27:197-9.  Back to cited text no. 26
Shapiro DL, Spiera H. Regression of the nephrotic syndrome in rheumatoid arthritis and amyloidosis treated with azathioprine. A case report. Arthritis Rheum 1995;38:1851-4.  Back to cited text no. 27
Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn disease previously treated with infliximab: A randomized trial. Ann Intern Med 2007;146: 829-38.  Back to cited text no. 28
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Correspondence Address:
Dr. Mohamed Amine Hamzi
Department of Nephrology, Dialysis and Renal Transplantation, Military Training Hospital Mohammed V, Rabat
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DOI: 10.4103/1319-2442.229282

PMID: 29657220

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