Efficacy of haemodiafiltration treatment with PEPA dialysis membranes in plasma free light chain removal in a patient with primary amyloidosis
Toshihiko Machiguchi*,,
Tadao Tamura and
Haruyoshi Yoshida*
Department of Internal Medicine, Himeji National Hospital, Himeji, Japan
Keywords: dimethyl sulfoxide; free light-chain; haemodiafiltration; high performance membrane; polyester-polymer alloy membrane; primary amyloidosis
 |
Introduction
|
---|
Primary amyloidosis is a disease that causes intractable nephrotic syndrome, with continuous progression to end-stage renal failure (ESRF) [1,2]. Furthermore, it causes fatal cardiac conditions such as conduction disturbance and restrictive heart failure [3]. Although regular haemodialysis (HD) therapy has been attempted for ESRF in primary amyloidosis, a successful therapy has not been established yet [1,3]. In this study of a patient with primary amyloidosis, we estimated the removal ratio of free light (L)-chaina precursor of amyloid fibrilby various blood purification methods. In addition, we examined the usefulness of dimethyl sulfoxide (DMSO).
 |
Case
|
---|
A 58-year-old woman was admitted to Himeji National Hospital because of systemic oedema. Moderate proteinuria had been noted 6 months earlier. On admission, her blood pressure (BP) was 132/84 mmHg, controlled with a Ca2+-antagonist, manidipine (10 mg/day), and her pulse was regular at 76/min. Urinalysis demonstrated severe proteinuria at 5.1 g/day and slight occult blood. Blood urea nitrogen and creatinine (Cr) were 31 and 1.7 mg/dl, respectively, and the creatinine clearance rate (Ccr) was 48 ml/min. Total serum protein/albumin was 4.2/2.0 g/dl without M-protein or liver dysfunction. Abdominal ultrasonography demonstrated oedematous kidneys with sizes 11.4x5.1 (right) and 12.0x5.4 cm (left), but liver, gall bladder, spleen, and pancreas were normal. Cardiac examinations showed mild cardiomegaly [cardiothoracic ratio (CTR) 0.56] on chest X-ray, low voltage and 1° atrioventricular block on electrocardiogram (ECG), and 432 single ventricular premature contractions (VPCs) on 24-h Holter monitoring. Although left ventricular ejection fraction (LVEF) was normal at 69%, the intraventricular septum (IVS) and the left ventricular posterior wall (LVPW) were moderately to severely thickened at 17 and 16 mm without granular sparkling images on the ultrasonogram. Cardio-angiography showed intact coronary arteries. Biopsies of the kidney and the heart showed the accumulation of homogeneous materials that were positive to Congo red staining even after KMnO4 treatment in the mesangial matrix and cardiac connective tissue. Electron microscopy demonstrated amyloid fibrils in both organs. Although Bence Jones protein (
type) was found in the urine sample, a level of plasma cells of 7% by myelogram was not compatible with multiple myeloma. The patient was prescribed with a diagnosis of primary amyloidosis. She was administered an immunosuppressant, mizoribine (150 mg/day) and DMSO (5 g/day).
Six months later, she was re-admitted because her renal function deteriorated8.7 mg/dl of serum Cr and 9.0 ml/min of Ccr. On the second admission, her BP was at 140/82 mmHg without use of anti-hypertensive drugs. CTR was up to 0.61 and she had mild bilateral pleural effusions. IVS/LVPW also were thickened to 20/16 mm and LVEF was decreased to 49%. The plasma level of free L-chain (
type) (p/f L-chain) was 42 mg/dl.
We first examined the change in the levels of p/f L-chain (
type) using DMSO (12 g) i.v. injection in two trials. As shown in Figure 1
, there were no remarkable differences in the p/f L-chain between samples obtained 0, 3, 6, 9, 12 and 24 h after DMSO injection.

View larger version (16K):
[in this window]
[in a new window]
|
Fig. 1. Timed changes in the levels of p/f L-chain ( type) after DMSO (200 mg/kg body weight) injection in two trials. There were no remarkable changes in the p/f L-chain after either trial, measured between 3 and 24 h after the injections.
|
|
Next, we measured and compared the removal ratios of p/f L-chain (
type) with various methods such as HD with a cuprophane membrane dialyzer (HD-Cu) (ALF-100G, Nikkiso Co., Japan), HD with a polysulfone membrane dialyzer (HD-PS) (PS-1.6UW, Kawasumi Co., Japan), HD with a polyester-polymer alloy membrane dialyzer (HD-PEPA) (FLX-15GW, Nikkiso Co., Japan), haemodiafiltration (HDF) with the same PEPA dialyzer (HDF-PEPA) as utilized in HD (replacement liquid 6 l), haemofiltration (HF) with a PEPA dialyzer (HF-PEPA) (FLX-15GW) (replacement liquid 20 l) and direct plasma exchange (PE) (fresh frozen plasma 3.2 l). HD and HDF methods were all performed for 4 h with a fluid removal volume of 3 l, and HF was performed for 6 h without fluid removal. Blood samples were obtained from the pre-dialyzer line of blood circuit at the beginning and the end of each clearance method. The removal ratios of p/f L-chain (
type) were as follows: 6.9% in HD-Cu, -3.3% in HD-PS, 13.1% in HD-PEPA, 26.0% in HDF-PEPA, 18.7% in HF-PEPA, and 25.3% in PE (Table 1
).
Based on these findings, HDF was performed three times a week with a PEPA dialyzer. The administration of DMSO and mizoribine was discontinued. Serum Cr concentration was maintained at 5.27.4 mg/dl before HDF treatment. After the initiation of HDF, the p/f L-chain remained at 2530 mg/dl throughout the course of treatment. Single VPC count decreased to 50150/24 h. The thickness of IVS/LVPW remained at about 20/15 mm. However, LVEF gradually decreased to 47, 42 and 38% after 4, 12 and 24 months of HDF treatment, respectively. Systolic BP also decreased to 90, 70 and 50 mmHg after 10, 18 and 30 months, respectively. The patient died of restrictive heart failure with hypotension 37 months after the initiation of HDF. Permission for autopsy was denied.
 |
Discussion
|
---|
Primary amyloidosis is a fatal disease with the median survival of 12 years [1,2,4]. Arrhythmia and heart failure with hypotension due to restrictive cardiomyopathy are the most frequent causes of the death [3]. Blood purification therapies such as HD, peritoneal dialysis (PD) and plasmapheresis (PP), in addition to melphalan and prednisolone (MP) therapy and autologous stem-cell transplantation have been attempted, but effective treatment methods have not yet been established [14]. In previous studies, DMSO was reported to be effective in improving clinical symptoms or renal function in patients with AA- and AL-type amyloidosis [5,6]. We first examined the effect of DMSO in the removal of amyloid fibrils from tissues. Significant changes in the p/f L-chain level were not observed after DMSO injections (200 mg/kg body weight). We concluded that DMSO treatment might not reduce the accumulated amyloid fibrils in tissues, and stopped using DMSO.
We next measured the removal ratios of p/f L-chain by various blood purification methods, and concluded that HDF with a PEPA dialyzer, as well as PE, was more effective than HD with a Cu, PA or PEPA dialyzer and HF with a PEPA dialyzer. Although a PS membrane is considered a high performance membrane (HPM) like PEPA, HD with a PS dialyzer did not remove free L-chain with a molecular weight of 23 000 in the monomeric form. This may be because the PS membrane has a pore size equal to or slightly larger than ß2-microglobulin (molecular weight 11 500). We hypothesize that a PEPA membrane may have an uneven pore size that can remove free L-chain with molecular weights more than 23 000, and that the hydrophobic property of the PEPA membrane may favour the adsorption of free L-chain by molecular interaction.
It is uncertain if controlling the free L-chain level prolonged the survival of this patient. Her highest level of p/f L-chain was 42 mg/dl and the level was maintained at 2530 mg/dl after the initiation of HDF. Despite the rapid progression of renal and heart failures in the first 6 months of treatment with DMSO and mizoribine, she survived 37 months after the initiation of HDF. Although long-lasting survivals of patients with diffuse primary amyloidosis have occasionally been described, Gertz et al. [2] in a study of 38 dialysis patients with primary amyloidosis reported that the median time from diagnosis to initiation of dialysis was 13.8 months and the median patient survival after the start of dialysis was 8.2 months. We suppose that the removal of p/f L-chain contributed to prolonging the survival of this patient. As we have not shown a reduction in amyloid deposits in the heart, additional experience of HDF treatment would help understand the increased survival of our patient.
We did not attempt PD to remove free L-chain in this patient, because the patient did not consent to such treatment. In this regard, Gertz et al. [2] have reported that there was no survival difference between HD (n=27) and PD (n=10).
Finally, we regret that we did not treat her with a combination of intense chemotherapy including MP therapy, despite the rapid progression of her disease, and that we did not start HDF or PP earlier before she reached end-stage renal disease.
In summary, we present a patient with primary amyloidosis who survived 3 years and 1 month after the initiation of HDF with a PEPA dialyzer, a treatment that appears capable of removing substantial amounts of p/f L-chain.
 |
Acknowledgments
|
---|
We gratefully thank Dr Eiichi Matsuyama, Dr Masaki Kawanami and Dr Tetsuya Haruna, Department of Cardiovascular Medicine, Himeji National Hospital, for performing ultrasonic cardiography, cardioangiography and cardiac biopsy.
 |
Notes
|
---|
Correspondence and offprint requests to: Toshihiko Machiguchi, MD, Department of Clinical Laboratory Medicine and Nephrology, Fukui Medical University, Matsuoka, Fukui 910-1193, Japan. Email: tmachi{at}fmsrsa.fukui\|[hyphen]\|med.ac.jp 
*Present address: Department of Clinical Laboratory Medicine and Nephrology, Fukui Medical University, Fukui, Japan. 
 |
References
|
---|
- Appel GB, Radhakrishnan J, D'Agati V. Amyloidosis. In: Brenner BM, ed. The Kidney. W.B. Saunders, Philadelphia, 2000; 13861390
- Gertz MA, Kyle RA, O'Fallon WM. Dialysis support of patients with primary systemic amyloidosis. A study of 211 patients. Arch Intern Med1992; 152: 22452250[Abstract]
- Wynne J, Braunwald E. Amyloidosis. In: Braunwald E, ed. Heart Disease. W.B. Saunders, Philadelphia, 1997; 14271429
- Sezer O, Niemoller K, Jakob C, Langelotz C, Eucker J, Possinger K. Novel approaches to the treatment of primary amyloidosis. Exp Opinion Inv Drug2000; 9: 23432350
- Scheinberg MA, Pernambuco JC, Benson MD. DMSO and colchicine therapy in amyloid disease. Ann Rheum Dis1984; 43: 421423[Abstract]
- Shibuya T, Murakawa M, Tsuda Y, Harada M. Successful treatment of primary amyloidosis with dimethylsulfoxide and cytoreductive chemotherapy. Intern Med1992; 31: 544548[ISI][Medline]
Received for publication: 28.11.01
Accepted in revised form: 3. 4.02