Colchicine therapy of the renal amyloidosis of ulcerative colitis

GASTROENTEROLOGY

1988;94:1503-7

Colchicine Therapy of the Renal Amyloidosis of Ulcerative Colitis SAMUEL MEYERS, HENRY D. JANOWITZ, VIVEK V. GUMASTE, RUTH G. ABRAMSON, LAURENCE J. BERMAN, V. S. VENKATASESHAN, and STEVEN H. DICKMAN Departments of Medicine and Pathology, Mount Sinai School of Medicine of the City University of New York, New York, New York, and the Barnert Memorial Hospital Center, Paterson, New Jersey

Two patients with severe proteinuria, due to renal amyloidosis complicating chronic ulcerative colitis, improved remarkably with colchicine therapy. One patient with an initial daily urine protein excretion of 13.70 g had a reduction within 2 mo to 6.50 g and to 0.37 g after 9 yr. The other patient’s daily urine protein excretion was 9.00 g. This was reduced to 5.10 g/day within 3 mo and was 0.53 g/day by 8 mo. Renal function remained stable or improved during the period of therapy. Colchicine resulted in rapid and prolonged benefit for these patients, despite their amyloid-induced nephrotic syndrome.

R

enal involvement bowel

with amyloid

disease,

usually

of the

in inflammatory Crohn’s

disease

variety, has a very poor prognosis. Death due to renal failure occurs in many cases within a year after the diagnosis ports

is established

of the

colchicine familial

on colitis

amyloidosis senior

the

were

enced a marked proteinuria.

Materials Clinical

fever

treated

(Z),

with Both

and continued

effects

of

complicating 2 patients

proteinuria

(H.D.J.).

by the re-

protective

amyloidosis

and severe

investigator

Stimulated

and

renal

Mediterranean

ulcerative

(1).

therapeutic

with

due to renal

colchicine

by

the

patients

experi-

improvement

of their

and Methods Diagnosis

The diagnosis and extent of ulcerative colitis was established in each case by the presence of characteristic radiographic, endoscopic, and histopathological criteria (3-5). Crohn’s disease was excluded by the guidelines elaborated by Lockhart-Mummery and Morson (6). Urine

Protein

Laboratories, Inc., Elkbart, Ind.). A quantitative measure of the urinary protein was obtained by collecting all of the urine voided during a 24-h period in a plastic, covered container stored on ice. The urine protein was then determined by the sulfosalicylic acid turbidity method. Morphologic

Analysis

Colonic mucosa obtained by colonoscopic biopsy was fixed in buffered formalin. Tissue obtained by a percutaneous renal biopsy guided by intravenous pyelography was divided into three parts for light, electron, and immunofluorescence microscopy. The tissue for light microscopy was fixed in 4% paraformaldehyde. The specimens for light microscopy were processed in the routine manner and embedded in paraffin. Sections were stained with hematoxylin and eosin, periodic acid-Schiff, and crystal violet. Special stains for amyloid such as Congo red and Thioflavine-T were used and the tissue was examined under polarized light and ultraviolet light, respectively, to detect the presence of amyloid. Further, to characterize the type of amyloid, paraffin sections were stained with (a) Congo red after reaction with potassium permanganate and (b) immunoperoxidase stain using antibody to amyloid A protein (7,8). For electron microscopy, small blocks of tissue fixed in 4% paraformaldehyde were postfixed in osmic acid, dehydrated in graded alcohols, and embedded in Epon. Ultrathin sections were cut and stained with lead citrate and uranyl acetate and viewed under a Philips 300 electron microscope (Philips Electronic Instruments, Mohawk, N.J.). Fresh renal tissue was snap frozen in isopentane wiih dry ice. This was serially sectioned and stained with fluorescein isothiocyanate-conjugated antibodies to human immunoglobulins (immunoglobulin G, A, and M), complement components ((3, Clq), and fibrinogen (Calbiochem-Behring, La Jolla, Calif.) and examined by direct immunofluorescence.

Assay

Proteinuria was detected in a lo-mm random sample of urine by a dipstick method (Ames Division, Miles

0 1988 by the American

Gastroenterological 0018-5085/88/$3.50

Association

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Blood

ET AL.

Mononuclear

GASTROENTEROLOGY

Cell Studies

Peripheral blood monocytes from patient 1 were isolated and cultured. They were then incubated in a serum-free medium with purified serum amyloid A protein to determine the pathways of the protein degradation (9).

Case Reports Patient

3

This 29-yr-old woman had developed left-sided ulcerative colitis at the age of 8 yr in 1957. She was treated with intermittent oral prednisone, chronic sulfathalidine, and a low residue diet. At the age of 20 yr (July 1977) she was found to have proteinuria on urinalysis. At that time her blood pressure was 120/90 mmHg. There was bilateral pedal edema, but no lymphadenopathy, macroglossia, or hepatosplenomegaly. There was no evidence of congestive heart failure or pericardial effusion. Microscopic examination of the urine sediment showed no casts, red blood cells, white blood cells, or lipiduria. Laboratory studies disclosed the following values: 24-h protein excretion, 13.70 g with a urine volume of 1800 ml and a creatinine clearance of 115 ml/min (1.92 ml/s); serum creatinine, 0.6 mg/dl (53 pmol/L); blood urea nitrogen, 8 mg/dl(2.9 mmol/L); serum albumin, 3.9 g/d1 (39 g/L); and serum cholesterol 301 mg/dl (7.78 mmol/L). A rectal biopsy showed a homogeneous eosinophilic material in the mucosa and submucosa and around the vascular structures. Congo red stain identified the material as amyloid. Immunoperoxidase staining with specific antibody and the characteristic abolishment of Congo red staining by prior treatment with potassium permanganate confirmed the presence of amyloid A protein. The mononuclear cells of this patient were similar to those ,of all patients with acquired systemic amyloidosis. They degraded serum amyloid A protein through an intermediate that seemed to be siinilar to the amyloid A prbtein (9). Although we could not definitively reject the possibility of some form of minimal change glomerulonephritis or membranous nephropathy, the proteinuria was ascribed to amyloidosis in the absence of any other identifiable etiology and in the presence of rectal amyloid. Treatment was initiated with colchicine (0.6 mg/day orally for 3 mo and then increased to 0.6 mg b.i.d.). During the first 2 mo the proteinuria decreased to 6.50 g/day and then continued to decline progressively over the next 9 yr to a level of 0.37 g/day. Her renal function and serum albumin level remained normal. A recent renal radionuacid elide scan using ggmTc-diethyltriaminopentaacetic demonstrated normal blood flow and function. Her ulcerative colitis was complicated by bilateral sacroiliitis demonstrated incidentally on x-rays. At the age of 21 yr, 8 mo after the initial diagnosis of amyloidosis, she was diagnosed as having Takayasu’s arteritis, which was manifested by an increased blood pressure and absent arterial pulses in the left arm. It was confirmed by angiography and has been successfully treated with continued oral prednisone, warfarin sodium, and dipyridamole.

Patient

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2

A young woman with congenital Turner’s syndrome was diagnosed as having universal ulcerative colitis at the age of 10 yr. It was complicated by bilateral uveitis and peripheral arthralgias. She was treated with intermittent oral prednisone, sulfasalazine, and a low residue diet. At the age of 20 yr she developed bilateral pedal edema and was found to have proteinuria. At that time her blood pressure was 120170 mmHg. Pitting pedal edema was present bilaterally and there was mild hepatosplenomegaly but no lymphadenopathy or macroglossia. Urinalysis showed no red blood cells, casts, white blood cells, or lipiduria. Laboratory studies disclosed the following values: 24-h protein excretion, 9 g, with a urine volume of 1.5 L and a creatinine clearance of 29 ml/min (0.48 ml/s); serum creatinine, 1.3 mg/dl (115 pmol/L); and serum albumin, 3.3 g/d1 (33 g/L). A rectal biopsy specimen showed no evidence of amyloid deposition after staining with hematoxylin and eosin and Congo red. A percutaneous renal biopsy was performed. There were up to 20 glomeruli in the renal cortex by light microscopy. Deposits of variable amounts of homogeneous, pale eosinophilic material were found in the glomeruli, mainly in

Figure

1. Patient 2. Glomerulus showing focal mesangial deposition of amyloid. Some capillary walls also contain amyloid. (Hematoxylin and eosin, x250.)

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COLCHICINE THERAPY OF RENAL AMYLOIDOSIS

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creatinine level fell to 1.0 mg/dl (88 PmoliL) during this period. Additional

Information

A variety of laboratory studies were normal in both patients. These included serum rheumatoid factor, antinuclear antibody, antistreptolysin,O, uric acid, glucose, protein electrophoresis, and immunoelectrophoresis. Bence Jones protein could not be demonstrated in the urine. Chest x-rays were normal. There was no evidence of prior chronic infection or inflammatory disorder other than the known ulcerative colitis. Neither patient had ever selfinjected drugs or other foreign bodies. There was no personal or family history of familial Mediterranean fever, amyloidosis, hypertension, or diabetes mellitus. There was no exposure to potentially nephrotoxic chemicals.

Discussion

Figure

2. Patient 2. Peritubular and perivascular its. (Hematoxylin and eosin, x250.)

amyloid depos-

the mesangium and extending onto portions of the capillary walls (Figure 1). Similar deposits were also observed in the interstitium, along tubular basement membranes, and within blood vessel walls (Figure 2). Crystal violet, Congo red, and Thioflavine-T demonstrated positive staining for amyloid. The potassium permanganate reaction abolished Congo red affinity, suggesting the presence of amyloid A protein in the same distribution. This was confirmed by immunoperoxidase stain. Electron microscopy showed focal nodular deposition of amyloid fibrils in a haphazard manner within the mesangium, with occasional extension into the subendothelial space and the capillary walls. They ranged from 8 to 12 nm in width. The epithelial foot processes were partly effaced. Immunofluorescence studies revealed minimal nonspecific deposits of immunoglobulin A, immunoglobulin M, and C3 along the glomerular capillary walls. Complement C3 only was present in the tubular basement membranes, small arteries, arterioles, and Bowman’s capsule. The renal amyloidosis was treated with oral colchicine (0.6 mg b.i.d.). Her 24-h protein excretion decreased to 5.10 g within 3 mo and was 0.53 g by 8 mo. The creatinine clearance rose to 49 ml/min (0.82 ml/s) and the serum

The results of therapy in our patients are encouraging in view of the poor prognosis associated with renal involvement due to acquired systemic amyloidosis complicating inflammatory bowel disease. Overall, surgical therapy in these patients has had dismal results (l,lO,ll). However, excision of the diseased bowel alone in 1 patient with Crohn’s disease has been reported to result in improvement (12). In 2 other patients, it was suggested that combined surgical and medical therapy of their Crohn’s disease may have delayed or even halted the progression of renal amyloidosis (13). Colchicine, dimethylsulfoxide, and ascorbic acid have been shown to successfully influence amyloidosis in both animal and human studies (2,14-17). There is some fragmentary experience with medical therapy in the management of renal amyloidosis complicating Crohn’s disease. One patient showed resolution of the nephrotic syndrome due to renal amyloidosis when surgical resection of all diseased bowel was followed by colchicine therapy for a period of 5 yr (18). Azathioprine and sulfasalazine were used to treat another such patient. Three years of continuous therapy resulted in clinical remission of the Crohn’s disease and a decrease in the proteinuria from ~5 g/day to normal 7 yr later (19). The reduction of the proteinuria in these cases may have been due to the direct effect of the drugs or of remission or resection of the primary intestinal disease, or both. Both our patients with nephrotic syndrome were treated with colchicine, Patient 1 experienced a 5096 reduction in he? daily protein excretion withili 2 mo, from 13.70 to 6.50 g. This trend continued, reaching a level of 0.37 g 9 yr later. Her renal function remained normal during this period. The second patient also responded quickly. Within several months there was a marked decrease in the protein-

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uria. This decrease continued during the 8 mo of therapy and reached a level of 0.53 g/day from a pretreatment level of S/day. There was a marginal increase in creatinine clearance from 29 to 49 ml/min (0.48to 0.82 ml/s). During the period of colchicine therapy both patients were treated medically for their ulcerative colitis. As complete intestinal remissions were not obtained, it appears unlikely that the reduced proteinuria could be ascribed to any significant reduction in the underlying colitis of these patients. Whether the reduction of the proteinuria could be due to a spontaneous improvement of the amyloidosis is difficult to establish. However, such an occurrence is unusual (20-22). The mechanism of action of colchicine in the therapy of amyloidosis is unclear. Experimentally, it diminishes and may even prevent the usually reliable induction of amyloidosis by casein (14,151. In vitro, colchicine has been shown to inhibit the secretion or synthesis of serum amyloid A protein by Tissue deposition may be aided by hepatocytes (23). a serum amyloid-enhancing factor that. may also be blocked by colchicine (24,25). We are aware of 17 cases reported in the literature of amyloidosis caused by ulcerative colitis (10, 26-39).However, careful review of these cases revealed that 15 of them had features more typical of Crohn’s disease (10,27-32,34239). One other patient had chronic osteomyelitis, which may have contributed to the amyloidosis (33). In the 1 remaining case (26)the diagnosis of ulcerative ‘colitis appears well established. Both our patients had colonic disease characteristic of ulcerative colitis and we propose that it resulted in the amyloidosis in each. No other potential etiologic factor could be demonstrated, although the first patient developed the rare complication of Takayasu’s arteritis which itself can be complicated by amyloidosis (40-42). As the arteritis was diagnosed 8 mo after the onset of the amyloidosis, it was not likely to be an important factor. Whatever its contribution, it did not prevent the therapeutic response to colchicine. Although steroids have been implicated in the pathogenesis of amyloidosis on the basis of animal experiments (43), there is no conclusive evidence that they lead to amyloid deposition in humans. Both patients also received other drugs that may have theoretically contributed to their proteinuria. However, this adverse effect is extremely rare with sulfonamides (44) and has not been reported due to sulfasalazine or its 5-aminosalicylic acid moiety (45,46). In addition, the amyloidosis improved, despite continuing these drugs. Amyloid A protein deposition was demonstrated in both our patients. This is the characteristic finding in acquired systemic amyloidosis associated with

GASTROENTEROLOGY

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other chronic inflammatory disorders and is the form of amyloid found in patients with familial Mediterranean fever (47). The successful use of colchicine therapy may not only be limited to this type of amyloid. In primary systemic amyloidosis melphalan and prednisone (48), as well as colchicine, have improved the survival (49). It seems likely that the initiation of colchicine therapy for even asymptomatic systemic amyloidosis in patients suffering from ulcemtive colitis may be worthwhile. The excellent results obtained with colchicine in preventing or reversing the amyloidosis in familial Mediterranean fever and Crohn’s disease have been attributed to the early stage of the disease at the time therapy was started (2,12). The improvement of our patients also supports the use of colchicine alone or as adjunctive therapy despite more advanced amyloid-induced nephrotic syndrome (18,19,50). The number of patients with inflammatory bowel disease and amyloidosis who could benefit from this therapy remains unknown. From the larger experience with familial Mediterranean fever, the majority of patients treated prophylactically or when they have only proteinuria might be expected to improve or stabilize, compared with only an occasional case with amyloid-induced nephrotic syndrome (50,51).

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Received August 28, 1987. Accepted January 11, 1988. Address requests for reprints to: Samuel Meyers, M.D., Division of Gastroenterology, Annenberg 23-02. Mount Sinai Hospital, 1 Gustave L. Levy Place, New York, New York 10029.