Organ Transplantation in Hereditary Apolipoprotein AI Amyloidosis

Transcription

1 American Journal of Transplantation 2006; 6: Blackwell Munksgaard C 2006 The Authors Journal compilation C 2006 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Organ Transplantation in Hereditary Apolipoprotein AI Amyloidosis J. D. Gillmore a,, A. J. Stangou b, H. J. Lachmann a, H. J. Goodman a, A. D. Wechalekar a, J. Acheson c, G. A. Tennent a, A. Bybee a, J. Gilbertson a, D. Rowczenio a, J. O Grady b, N. D. Heaton b, M. B. Pepys a and P. N. Hawkins a a National Amyloidosis Centre, Centre for Amyloidosis and Acute Phase Proteins, Department of Medicine, Hampstead Campus, Royal Free and University College Medical School, b Institute of Liver Studies and Liver Transplant Services, King s College Hospital and c Department of Neuro-ophthalmology, Moorfields Eye Hospital, London, UK Corresponding author: Julian D. Gillmore, j.gillmore@medsch.ucl.ac.uk Patients with hereditary apolipoprotein AI (apoai) amyloidosis often have extensive visceral amyloid deposits, and many develop end-stage renal failure as young adults. Solid organ transplantation to replace failing organ function in systemic amyloidosis is controversial due to the multisystem and progressive nature of the disease and the risk of recurrence of amyloid in the graft. We report the outcome of solid organ transplantation, including dual transplants in 4 cases, among 10 patients with apoai amyloidosis who were followed for a median (range) of 16 (4 28) and 9 (0.2 27) years from diagnosis of amyloidosis and transplantation, respectively. Eight of 10 patients were alive, seven with a functioning graft at censor. Two patients died, one of disseminated cytomegalovirus infection 2 months after renal transplantation and the other of multisystem failure following severe trauma more than 13 years after renal transplantation. The renal transplant of one patient failed due to recurrence of amyloid after 25 years. Amyloid disease progression was very slow and the natural history of the condition was favorably altered in both cases in which the liver was transplanted. Failing organs in hereditary apoai amyloidosis should be replaced since graft survival is excellent and confers substantial survival benefit. Key words: Amyloid, amyloidosis, apolipoprotein AI, cardiac transplantation, kidney transplantation, liver transplantation Received 21 March 2006, revised 9 June 2006 and accepted for publication 27 June 2006 Introduction Systemic amyloidosis is a clinical disorder caused by extracellular deposition of abnormal insoluble fibrils derived from aggregation of misfolded, normally soluble protein (1). Most forms of systemic amyloidosis are inexorably progressive and fatal. Hereditary nonneuropathic systemic amyloidosis, first described by Ostertag in 1932 (2), is a rare autosomal dominant condition in which progressive amyloid deposition in the viscera, especially the kidneys, frequently leads to organ failure. Mutations in the genes encoding apolipoprotein AI (apoai) (3 13), apolipoprotein AII (apoaii) (14,15), fibrinogen Aa-chain (16 19) and lysozyme (20) have been identified as the cause of the disease in different kindreds. The clinical amyloidosis syndromes that accompany the various mutations in these different genes are diverse with respect to age of onset, mode of presentation, pattern of organ distribution, rate of progression and prognosis. ApoAI is secreted by the liver and intestine, catabolized in the liver and kidneys, and is the main protein in high-density lipoprotein (21). It is a cofactor for lecithin cholesterol acyltransferase, playing a key role in reverse cholesterol transport (22). Twelve different causative apoai variants have been reported in patients with hereditary apoai amyloidosis. The phenotype among patients with six such variants (Gly26Arg, Trp50Arg, Leu60Arg, Del70-72, Leu75Pro and Leu64Pro) is characterized by renal manifestations in association with extensive visceral amyloid deposits and hepatosplenomegaly. Clinical presentation in such cases is typically with hypertension and proteinuria between 18 and 55 years of age, although there is considerable variability between and even within families; patients with the Leu75Pro variant have reportedly presented as late as their seventh decade and survived into their 90s (13,23). In contrast to renal failure associated with systemic AL amyloidosis (24,25), progression of renal impairment is often remarkably slow in hereditary apoai amyloidosis, although death in end-stage renal failure between the ages of 40 and 60 years is typical. Certain apoai variants (Leu90Pro, Arg173Pro, Leu174Ser and Leu178His) are associated with skin and cardiac amyloid deposits with death usually occurring due to progressive cardiomyopathy within 10 years of diagnosis (8 11). The Spanish deletion/insertion and the Del107 variants have been reported to cause fatal hepatic amyloidosis in the absence of renal disease (6,26) and aortic intimal amyloid deposits (27), respectively. 2342

2 Transplantation in Hereditary ApoAI Amyloidosis The replacement of failing organs in systemic amyloidosis is controversial due to concerns regarding accumulation of amyloid in the graft and progressive amyloid accumulation in other organs (28,29). Patient survival after cardiac transplantation for AL amyloid cardiomyopathy is reduced compared to survival following cardiac transplantation for other causes (29). Our experience of orthotopic liver transplantation for liver failure due to progressive systemic AL amyloidosis has been similarly disappointing with survival of less than 1 year from transplantation in the majority of patients (data unpublished). Although favorable outcomes following organ transplantation have been reported in isolated cases of hereditary apoai amyloidosis, there have not previously been any sizeable patient series (7,30). We present here the outcome of solid organ transplantation in 10 patients with failing organ function due to hereditary apoai amyloidosis evaluated at the UK National Amyloidosis Centre (NAC), demonstrating remarkable longterm graft and patient survival despite the absence, in most cases, of measures to reduce ongoing amyloid deposition. Materials and Methods Patients Twenty-four out of 6000 patients evaluated at the UK NAC were discovered to have hereditary apoai amyloidosis, among whom 10 underwent single or dual solid organ transplantation at several different transplant centers between 1978 and Three patients are currently listed for transplant surgery, two awaiting a combined liver and kidney graft and one a combined heart and kidney transplant. The novel medical care described here was performed with informed consent from each patient in accordance with the Declaration of Helsinki. Diagnosis and evaluation of amyloidosis at the NAC All patients had a family history of amyloidosis, were heterozygous for a known or novel mutation of the apoai gene, and had histological proof of amyloid by Congo red staining. Specific immunohistochemical staining of their amyloid deposits with antibodies to apoai confirmed apoai as the amyloid fibril protein. No staining of amyloid deposits was seen using antisera to any of the other known amyloid fibril proteins. Assessment at each visit to the NAC included clinical evaluation, electrocardiographic and echocardiographic studies, and measurements of hepatic and renal function including 24-h urinary protein excretion. All patients underwent whole body anterior and posterior scintigraphic imaging 24 h after administration of 123 I-labeled SAP using an Elscint Superhelix gamma camera, as previously described (31). Serial scans were performed in six patients and changes in amyloid load defined as follows: regression, reduction of abnormal tracer uptake into target organs and/or an increase in the blood-pool background signal; accumulation when the opposite changes occurred; stable when no change in tracer localization could be identified (32). Initial SAP scintigraphy was performed after organ transplantation in five cases, and was undertaken a median (range) of 5.4 (0 23) years after amyloidosis had been diagnosed. Labeled SAP studies were interpreted by a single physician (PNH) with experience of over 4000 SAP scans. Preoperative transplant assessments and postoperative immunosuppression regimens were according to the local protocol in each case. Eight patients underwent deceased donor transplantation, one received a transplant from a living related donor (patient 2) and another from a living unrelated donor (patient 8). There were no alterations in immunosuppression regimens or immunosuppressant drug doses as a result of the diagnosis of amyloid and drug tolerability was normal. Eight patients received triple therapy with a calcineurin inhibitor (cyclosporine A or tacrolimus), steroids and either mycophenolate mofetil or azathioprine; two patients received prednisolone and azathioprine in combination. The dual hepatorenal transplant was performed using the piggy back technique and was uncomplicated. The combined cardiac and renal transplants were performed sequentially by two surgical teams, and were both complicated by primary nonfunction of the renal allograft which recovered. There were no acute rejection episodes in any of the dual transplants. The rationale for transplantation of the liver as well as kidney in two cases with extensive and progressive hepatic amyloid deposits was not only to restore normal liver function but also to remove the liver-derived supply of the fibril precursor protein, variant apoai, and thereby slow the rate of new amyloid formation. The aim was to reduce the rate of amyloid formation with resulting clinical benefit. Results Ten patients from eight different families with six different apoai mutations underwent solid organ transplantation. The characteristics of all 10 patients are shown in Table 1. Interestingly, among three English patients with the Leu60Arg apoai variant, the organ distribution of amyloid deposits and clinical phenotype were very similar in patients 5 and 7 who were brother and sister and differed markedly from that of patient 6 who was apparently unrelated. Renal manifestations predominated; proteinuria and/or renal impairment was detected in nine patients at presentation, and the diagnosis of amyloidosis was confirmed by renal biopsy in eight cases. All 10 patients received kidney transplants with two patients receiving both heart and kidney grafts and two cases receiving both liver and kidney transplants. The median (range) time to end-stage renal failure from presentation was 8 (1 20) years and from diagnosis of amyloid was 6 (1 13) years. The initial SAP scintigraphs of eight patients showed extensive visceral amyloid deposits in the liver, spleen and kidneys; however, two patients, both of whom had predominant involvement of the heart by amyloid, had only minor extracardiac amyloid deposits. Eight of 10 patients transplanted were alive, seven with functioning grafts, at the time of censor with median (range) follow-up from diagnosis of amyloidosis for the whole cohort of 16 (4 28) years and from organ transplantation of 9 (0.2 27) years (Table 2). Patient 3 died 2 months after renal transplantation due to disseminated CMV infection including severe pneumonitis. Patient 7 died with a functioning graft more than 13 years after renal transplantation following accidental trauma that led to decompensation of her amyloid-related liver disease and multisystem collapse. She had biochemical and scintigraphic evidence American Journal of Transplantation 2006; 6:

3 Gillmore et al. Table 1: Clinical characteristics of patients undergoing solid organ transplantation for hereditary apolipoprotein AI amyloidosis SAP Organ Time from Geographic Presenting Age at scintigraphy at biopsied Predominant End-stage presentation area of ApoAI clinical presentation/ diagnosis for clinical organ to end-stage Organ(s) No Sex origin variant feature(s) diagnosis (load/organ) diagnosis manifestations failure failure (years) transplanted 1 M Irish Gly26Arg HTN/CKD 38/44 Large L,S,K Liver CKD/Hepatomegaly ESRF 19 Liver/Kidney 2 F Welsh Del70-72 HTN/Proteinuria 18/18 Mod L,S,K Renal CKD/Hepatomegaly ESRF 5 Kidney 3 M Polish Jewish Trp50Arg HTN/Proteinuria 34/36 Large L,S,K Renal CKD/Hepatomegaly ESRF 10 Kidney 4 F Welsh Del70-72 HTN/ Proteinuria 21/21 Large L,S,K Renal CKD/Hepatomegaly ESRF 6 Kidney 5 M English Leu60Arg HTN/ Proteinuria 30/40 Large L,S,K Renal CKD/Hepatomegaly ESRF 20 Liver/Kidney 1 6 F English Leu60Arg CHF/CKD 31/31 Small K Renal CHF/CKD Heart 1 Heart/Kidney 2 7 F English Leu60Arg HTN/ Proteinuria 22/35 Large L,S,K Renal CKD/Hepatomegaly ESRF 13 Kidney 8 M Italian Leu64Pro Proteinuria 56/56 Large L,S,K Renal CKD/Hepatomegaly ESRF 1 Kidney 9 M English Arg173Pro Hoarseness 44/46 Normal Cardiac CHF/CKD Heart 10 Heart/Kidney 2 10 M Irish Gly26Arg CKD 29/29 Mod L,S,K Renal CKD/Hepatomegaly ESRF 6 Kidney 1 Renal transplant performed 3 years after liver transplant. 2 Pre-emptive renal transplantation for CKD. HTN = hypertension; CKD = chronic kidney disease; L = liver; S = spleen; K = kidney; CHF = congestive heart failure; ESRF = end-stage renal failure. Table 2: Outcome of solid organ transplantation for hereditary apolipoprotein AI amyloidosis Time from Renal function Liver Amyloid by SAP Recurrence Tx to Cause at censor function scan at death of graft Patient death/censor of (creatinine, lmol/l/24 h at censor Echo at or censor/change amyloid at No status (years) death protein loss, g) (ALP, IU/PT, s) censor since transplant censor/death 1 Alive /0.3 77/13.4 No amyloid None/Regressed No 2 Alive / /14.1 No amyloid Large/Accumulated 1 Yes 3 Dead 0.2 CMV disease NA NA No amyloid NA No 4 Alive 25.3 D/NA 350/13.5 No amyloid Not known Yes 5 Alive 3.8 (0.8 2 ) 99/ /13.6 No amyloid Small/Regressed No 6 Alive / /13.6 No amyloid Small/Accumulated Yes 7 Dead 13.1 Liver failure 181/ / No amyloid 3 Large/Accumulated 3 Yes 8 Alive / /14.1 No amyloid Large/Not known No 9 Alive /0.3 86/14.4 No amyloid None/Stable No 10 Alive / /12.2 No amyloid Moderate/Not known Yes Tx = transplantation; CMV = cytomegalovirus; GI = gastrointestinal; D = dialysis dependent; NA = not applicable. 1 Accumulation in the graft only, no accumulation of amyloid in the other major viscera. 2 Time since renal transplantation. 3 Results at last amyloid evaluation American Journal of Transplantation 2006; 6:

4 Transplantation in Hereditary ApoAI Amyloidosis of gradually progressive liver amyloid with a rising alkaline phosphatase concentration and evidence of amyloid in the renal graft (despite stable function) at her last visit to the NAC 6 months prior to her death. Although, the requirement for orthotopic liver transplantation was considered at that time, referral for this was postponed because renal transplant function was stable and she did not have liver failure. Although not systematically sought in all patients, recurrence of amyloid was detected in five grafts, either by routine serial SAP scintigraphy (two cases) or following transplant biopsies performed routinely or to investigate graft dysfunction (Table 3). Amyloid recurrence caused failure of the renal transplant in patient 4, 25 years after transplantation and 6.5 years after its discovery in the graft. The allografts of three patients were functioning at the time of censor 8, 6.2 and 5.3 years after discovery of recurrent amyloid and was functioning in patient 7 at her death 3.1 years after discovery of recurrent amyloid. Progressive hepatic amyloid deposition was detected in patients 6 and 7. Patients 2 and 4 (who are cousins) developed slowly progressive visual impairment. Detailed ophthalmological assessment showed obliteration of the choriocapillaris with resultant atrophy of retinal pigment epithelium consistent with amyloid deposition in both cases. This has not previously been described in apoai amyloidosis but neither patient has had a choroid biopsy to confirm the clinical diagnosis. Progressive amyloid did not occur in any nontransplanted organs among the remaining evaluable patients (Table 2). Importantly, no patient has developed clinically significant cardiac or neuropathic amyloid post-transplant. Two patients (patient 1 and patient 5) received combined liver and kidney transplants. Liver transplantation was followed by marked regression of existing extra-hepatic amyloid deposits in both cases. Patient 5 had been dialysisdependent with extensive but stable liver amyloid and preserved liver synthetic function (bilirubin 14 lmol/l (5 17), ALP 220 IU/L (42 128), AST 39 IU/L (5 40), PT 16.6 s (12 16)) for over 2 years prior to a planned simultaneous renal and liver transplant procedure. He received an orthotopic liver transplant but did not receive the intended renal allograft due to discovery of a clear cell carcinoma in the donor kidney during surgery. Interestingly, isolated liver transplantation was not only followed by marked regression of existing splenic amyloid deposits by SAP scintigraphy (Figure 1), but also by a remarkable improvement in the patient s general wellbeing. Three years later he underwent renal transplantation and both grafts were functioning well at the time of censor. Recurrence of amyloid has not been detected in the grafts of either patient 1 or patient 5 after 7 and 3.5 years, respectively. Table 3: Patients identified to have recurrence of amyloid in the transplant organ Time from Method of Time from transplant diagnosis discovery of Transplanted to discovery of graft of graft graft amyloid to Patient organ(s) amyloid (years) amyloid censor/death (years) Outcome 2 Kidney 22.0 SAP scintigraphy 5.3 Functioning allograft at censor 4 Kidney 18.5 Renal transplant biopsy Allograft failed due to progressive amyloidosis 25 years after transplant, now dialysis dependent 6 Kidney/Heart 5 Heart transplant biopsy 2 8 Stable, functioning allografts at censor 7 Kidney 10 SAP scintigraphy 3.1 Died with stable, functioning allograft 13.1 years after transplantation 10 Kidney 4.1 Renal transplant biopsy Stable, functioning allograft at censor 1 Biopsy performed to investigate allograft dysfunction. 2 Routine transplant biopsy. American Journal of Transplantation 2006; 6:

5 Gillmore et al. Figure 1: Serial anterior whole body 123 I- SAP scintigraphy in a patient with hereditary apoai amyloidosis. Prior to liver transplantation (left) there was extensive amyloid in the liver and spleen obscuring the kidneys and adrenal glands. One year after liver transplantation (middle), there was regression of amyloid from the spleen. Three and a half years after liver transplantation and 8 months after deceased donor renal transplantation (right) there had been further substantial regression of splenic amyloid without evidence of amyloid in either graft; the normal transplant kidney is apparent in the right iliac fossa. Discussion This is the first series reporting long-term outcome after solid organ transplantation for hereditary systemic amyloidosis due to variant apoai, and highlights the excellent graft and patient survival with this approach for treatment of the disease. Patients with 6 of the 12 reported amyloidogenic apoai mutations were included in this series and 8 of 10 patients were alive at censor, seven with functioning grafts, with a median (range) follow-up from diagnosis of 16 (4 28) years and from transplantation of 9 (0.2 27) years. In contrast to systemic AL amyloidosis, which is usually inexorably progressive and rapidly fatal (24,25), progression of renal impairment was generally slow among the patients reported here with a median time from presentation to ESRF of 8 years and as long as 20 years in one patient. The slowly progressive natural history of this form of hereditary amyloidosis was further illustrated by serial biochemical tests of native liver and renal transplant function, by serial SAP scintigraphy and by the longevity of the transplanted organs among the eight patients in whom no measures were undertaken to reduce production of variant apoai. We previously reported the first case of regression of apoai amyloid deposits following combined liver and kidney transplantation in an individual (patient 1) from this series and demonstrated that approximately 50% of plasma apoai is derived from liver synthesis (30). Here, with a second case of amyloid regression after liver transplantation, we strengthen our original hypothesis that by reducing the supply of the amyloidogenic variant apoai and thereby slowing amyloidogenesis we have altered the balance between accumulation and regression of amyloid in favor of regression (Figure 1). A third patient with hereditary apoai Gly26Arg amyloidosis who underwent combined liver and kidney transplantation in Australia experienced improvement in amyloid-related peripheral neuropathy within 1 year of surgery (Peter Angus, Australia, personal communication, December 2005). Given the prolonged graft and patient survival with isolated renal transplantation observed in this series, routine liver transplantation to prevent amyloid progression or recurrence in the kidney cannot be justified. However, liver transplantation should clearly be considered when, as in both cases in this series, there is extensive liver amyloidosis and/or when there is clinically significant amyloidotic functional impairment in nontransplantable organs, such as peripheral nerves. It is noteworthy that patient 5, who underwent liver transplantation before renal transplantation due to unforeseen circumstances, and thus remained dialysis-dependent, showed remarkable symptomatic benefit immediately after receiving the new liver which persisted after steroid withdrawal. The improvement in general wellbeing, appetite and energy levels occurred despite normal tests of liver synthetic function and only mild elevation of the alkaline phosphatase and gamma gluteryl transferase prior to liver transplantation, uniquely illustrating the limitation of standard biochemical measures of liver function. In conclusion, the excellent outcome of solid organ transplantation presented in this report underscores the importance of accurate typing of all cases of amyloidosis so that each is appropriately managed. Hereditary apoai amyloidosis generally has a slowly progressive natural history, contrasting with that of systemic AL amyloidosis, and failing organs can be replaced with prolonged clinical benefit despite the extensive multisystem nature of the disease American Journal of Transplantation 2006; 6:

6 Transplantation in Hereditary ApoAI Amyloidosis Acknowledgments We would like to acknowledge all the physicians and surgeons who were involved in the clinical care of the patients reported in this study and Beth Jones for expert preparation of the article. MRC Programme Grant G (M.B.P. & P.N.H.), Wolfson Foundation, UCL Amyloidosis Research Fund and NHS Research and Development Funds. References 1. Pepys MB. Amyloidosis. Annu Rev Med 2006; 57: Ostertag B. Demonstration einer eigenartigen familiaren paraamyloidose. Zentralbl Aug Pathol 1932; 56: Nichols WC, Dwulet FE, Liepnieks J, Benson MD. Variant apolipoprotein AI as a major constituent of a human hereditary amyloid. Biochem Biophys Res Commun 1988; 156: Soutar AK, Hawkins PN, Vigushin DM et al. Apolipoprotein AI mutation Arg-60 causes autosomal dominant amyloidosis. Proc Natl Acad Sci USA 1992; 89: Booth DR, Tan SY, Booth SE et al. A new apolipoprotein AI variant, Trp50Arg, causes hereditary amyloidosis. 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