Hereditary amyloidosis with progressive peripheral neuropathy associated with apolipoprotein AI Gly26Arg: outcome of hepatorenal transplantation.

Liver transplantation (LT) has been reported in only 1 patient with hereditary variant apolipoprotein AI (apoAI) amyloidosis and was associated with a 50% decrease in production of variant apoAI. The potential for this to benefit clinical manifestations of apoAI amyloidosis such as peripheral neuropathy has not been determined. A 59-yr-old Irish-born male with hereditary systemic amyloidosis associated with apoAI Gly26Arg, which was suspected to be the cause of a progressive peripheral neuropathy, along with end-stage renal failure and hepatic dysfunction, underwent hepatorenal transplantation. Evaluation of his clinical outcome included serial neurological examinations and nerve conduction studies. The proportion of variant apoAI in the plasma was estimated before and after LT. Hepatorenal transplantation was successful, with the plasma concentration of variant apoAI decreasing by over 50% after transplantation and this was associated with progressive resolution of the patient's neuropathic symptoms and a significant and sustained improvement in electrophysiological parameters. In conclusion, liver transplantation reduces production of the amyloid fibril precursor protein to a degree that can facilitate net regression of amyloid deposits, which may aid recovery of end-organ damage such as that seen in peripheral neuropathy.     

Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg

Hereditary systemic amyloidosis associated with a new apolipoprotein AII stop codon mutation Stop78Arg. BACKGROUND: Mutations in the gene for apolipoprotein AII (apoAII) have recently been found to cause hereditary renal amyloidosis. In each case amyloid deposition has been associated with a peptide extension at the carboxyl-terminus of apoAII, the result of mutations in the normal stop codon. METHODS: A Caucasian man who has had progressive renal dysfunction since age of 34 was found to have amyloidosis on renal biopsy at age 56. Echocardiogram showed mild intraventricular septal thickness and technetium-99m (99mTc)-pyrophosphate scintigraphy demonstrated uptake by cardiac muscle consistent with amyloid deposition in the myocardium. His father died of renal failure and his paternal half brother has renal dysfunction. RESULTS: DNA sequencing of the apoAII gene in the proband showed a T to C transition at the first position of the stop codon indicating replacement of the stop codon by l-arginine (Arg) at residue 78. Western analysis of the proband's plasma under reducing conditions using anti-apoAII revealed an extra band at approximately 10 kD in addition to the normal apoAII band at 8 kD. Western analysis of solubilized amyloid fibrils isolated from rectal biopsy tissue contained only the variant apoAII. CONCLUSION: These results indicate that the proband's amyloid fibrils are derived from apoAII and the amyloidogenesis is linked to the peptide extension at the carboxyl-terminus of variant apoAII. Of particular interest is that this novel apoAII variant may cause amyloid cardiomyopathy in addition to renal amyloid.     

Infertility and hypergonadotropic hypogonadism as first evidence of hereditary apolipoprotein A-I amyloidosis

PURPOSE: We report that primary infertility and hypergonadotropic hypogonadism in young patients may be caused by testicular amyloidosis and it is associated with the presence of a mutation in the apoA-I gene, resulting in the replacement of proline for leucine at residue 75 of the protein. MATERIALS AND METHODS: Ten patients presenting with infertility, gynecomastia, decreased libido, erectile dysfunction or a family history of amyloidosis underwent clinical evaluation, hormone assays, semen analysis, ultrasonographic investigation of the testicles, testicular biopsy and DNA sequencing of the apoA-I gene. RESULTS: All patients showed azoospermia and 9 had increased testicular volume. Massive amyloid deposition was observed in all testicular biopsies and the apoA-I mutation of replacement of proline for leucine at residue 75 of the protein was noted. Five patients showed hypergonadotropic hypogonadism and 5 had normal testosterone values with high gonadotropin levels. CONCLUSIONS: Nonobstructive azoospermia and macro-orchidism with or without hypogonadism may be caused by hereditary apoA-I amyloidosis in young patients. Testicular amyloidosis can be the first manifestation of this systemic disease. Specific staining for amyloid deposits and genetic analysis of apoA-I mutations are recommended in young, infertile patients with macro-orchidism. Finally, surveillance in asymptomatic mutation carriers is suggested to evaluate the opportunity to implement sperm retrieval and start androgen replacement therapy when necessary.     

A case of systemic amyloidosis associated with cyclic neutropenia

Reactive AA amyloidosis is caused by the accumulation of the acute phase reactant, serum amyloid A (SAA), as a complication of chronic inflammatory conditions. Cyclic neutropenia is a rare hereditary disorder characterized by repeated episodes of neutropenia at regular intervals, with or without concurrent infection, and is known to be a rare cause of AA amyloidosis. Here, we report a case of a patient who developed systemic AA amyloidosis following a prolonged course of undiagnosed cyclic neutropenia. The patient had a history of recurrent infections since infancy and developed goiter, proteinuria, and azotemia at age 14 years. Her SAA level was markedly increased (601.8 μg/mL, normal range <8 μg/mL), and a thyroid and kidney biopsy revealed typical lesions of AA amyloidosis. Amyloid deposits were also detected in the myocardium, colon, and gallbladder. She had repeated episodes of neutropenia regularly at 3-week intervals and a pathogenic mutation in the ELA2 gene. After 10 months of treatment with recombinant human granulocyte colony-stimulating factor, her SAA level normalized (<2.5 μg/mL), but her renal function did not recover. This case clearly shows that cyclic neutropenia can be complicated by AA amyloidosis unless it is detected early and treated adequately.     

自身免疫病患者肾移植术后的临床研究

目的　探讨自身免疫病患者肾移植术后原发病复发的高危因素。方法　回顾分析25例接受肾移植的自身免疫病患者的临床资料。结果　25例自身免疫病患者肾移植术后人/肾1、3、5年存活率与同期因其它原因所致的终末期肾功能衰竭而接受肾移植者相比,差异不显著;4例原发病复发者术前平均血液透析时间为（23.6±17.5）个月,21例未复发者的平均血液透析时间为（25.8±20.1）个月（P>0.05）;原发病复发者从发病至肾功能衰竭的时间较未复发者短,发病年龄明显高于未复发者。结论　自身免疫病患者可以接受肾移植术,但应注意原发病的复发。     

Renal apolipoprotein A-I amyloidosis: a rare and usually ignored cause of hereditary tubulointerstitial nephritis

Apolipoprotein A-I amyloidosis is a rare, late-onset, autosomal dominant condition characterized by systemic deposition of amyloid in tissues, the major clinical problems being related to renal, hepatic, and cardiac involvement. Described is the clinical and histologic picture of renal involvement as a result of apolipoprotein A-I amyloidosis in five families of Italian ancestry. In all of the affected family members, the disease was caused by the Leu75Pro heterozygous mutation in exon 4 of apolipoprotein A-I gene, as demonstrated by direct sequencing and RFLP analysis. Immunohistochemistry confirmed that amyloid deposits were specifically stained with an anti-apolipoprotein A-I antibody. The clinical phenotype was mainly characterized by a variable combination of kidney and liver disturbance. The occurrence of renal involvement seemed to be almost universal, although its severity varied greatly ranging from subclinical organ damage to overt, slowly progressive renal dysfunction. The renal presentation was consistent with a tubulointerstitial disease, as suggested by the findings of defective urine-concentrating capacity, moderate polyuria, negative urinalysis, and mild tubular proteinuria. Histology confirmed tubulointerstitial nephritis. Surprising, amyloid was restricted to nonglomerular regions and limited to the renal medulla. This location of apolipoprotein A-I amyloid differs sharply from other systemic amyloidoses that are mainly characterized by glomerular and vascular deposits. The tubulointerstitial nephritis as a result of hereditary apolipoprotein A-I amyloidosis is a rare disease and a challenging diagnosis to recognize. Patients who present with familial tubulointerstitial nephritis associated with liver disease require a high index of suspicion for apolipoprotein A-I amyloidosis.     

Study of live donor kidney transplantation outcome in recipients with renal amyloidosis

We studied the results of renal transplanta tion in 16 patientswith renal amyloidosis and in 46 controls with primary glomerulonephritis.Amyloidosis was primary in five and secondary to familial Mediterraneanfever (FMF) in 11. All patients received live related donorkidneys and the majority had onehaplotype HLA match. One- and5-year graft and patient survival rates were comparable in bothgroups. Moreover, the frequency of acute rejection episodesand the mean serum creatinine values were not signi ficantlydifferent between members of the two groups. Significant gastrointestinalsymptoms in the form of nausea, vomiting, abdominal pains, anddiarrhoea occurred in seven of the patients with amyloidosis(43.7%) and in only one of the controls (2%) (P=0.001). Allseven recipients with amyloidosis who developed the gastrointestinalmanifestations were receiving cyclosporin and six had FMF. Maintenancecolchicine treatment prevented recurrence of FMF symptoms. Inone patient discontinuation of colchicine was followed by recurrenceof FMF symptoms. Recurrence of renal amyloidosis was not observedin five patients subjected to Trucut graft biopsies 1, 2, 3,18 and 72 months post-transplantation. It is concluded that live-related donor kidney transplantationis a safe procedure in patients with amyloidosis and followsa course similar to glomerulo nephritis patients.     

Clinical outcome and genotype in patients with hereditary multiple exostoses

Hereditary multiple exostoses (HME) is an autosomal dominant skeletal disorder with a wide spectrum of clinical manifestations. In 52 out of 60 individuals from HME+ families, exostoses became clinically apparent. In this study, the clinical and radiological outcome of these 52 HME patients (19 families) was investigated by medical history, clinical examination, and radiographs. In addition to correlating phenotype with genotype, a linkage/exclusion analysis was performed in 35 HME patients. We found several correlations between HME genes (EXT1, EXT2) and phenotype. Compared to EXT2‐linkage, female individuals with EXT1‐linkage were smaller in stature. Patients with EXT1‐linkage and patients with undetermined linkage (EXT?) were more severely affected, underwent more surgeries, and showed a higher number of exostoses at follow‐up. Moreover, we found an increased phenotype risk for limb shortening for EXT1‐ and EXT?‐linkage. This study corresponds to data of other investigators who showed that EXT1 mutations are associated with a more severe phenotype than other EXT forms. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:1541–1551, 2007     

Fatal disseminated aspergillosis following sequential heart and stem cell transplantation for systemic amyloidosis.

Infectious complications are a major cause of morbidity and mortality in transplant recipients. We describe a case of fatal disseminated aspergillosis immediately following autologous peripheral stem cell reconstitution in a patient who had undergone orthotopic heart transplantation for systemic amyloidosis. The case described suggests that the infectious risks in patients undergoing these sequential procedures may be distinct from those occurring in patients undergoing either procedure independently. Potential prophylactic and therapeutic interventions are discussed. Since this experimental and evolving approach for the management of systemic amyloidosis is potentially applicable to a limited number of patients, multicenter collaboration may be needed to further define the infectious risks in this unique subset of transplant recipients.     

原发性淀粉样变性患者行自体外周血干细胞移植术后护理

对13例原发性淀粉样变性患者行自体外周血干细胞移植.结果患者均获得外周血重建,完全缓解5例,部分缓解3例,疾病稳定3例,进展2例.提出术后做好口腔黏膜炎及胃肠道反应的护理,观察并及时处理术后出血,加强心律失常的监护及时调节容量平衡,有助于提高移植成功率.     

Incidence and outcome of acute renal failure complicating autologous stem cell transplantation for AL amyloidosis

BACKGROUND: High-dose intravenous melphalan and autologous peripheral blood stem cell transplantation (HDM/SCT) is an effective treatment for AL amyloidosis but is associated with significant toxicity, including the development of acute renal failure (ARF). The incidence and outcome of ARF as a complication of such treatment is not known. METHODS: All AL amyloidosis patients treated with HDM/SCT at a single institution between July 1, 1994 and May 31, 2000 were included in the analysis unless they were dialysis-dependent prior to treatment. Baseline data were collected prospectively. Treatment-related data were obtained from a prospectively maintained database and medical record review. ARF was defined as either a >/=1 mg/dL increase in serum creatinine or a doubling of serum creatinine to >/=1.5 mg/dL for at least 2 days. Recovery of renal function was defined as a return of serum creatinine to less than or within 0.5 mg/dL of the pretreatment value or the ability to discontinue dialysis initiated as a result of ARF. RESULTS: ARF occurred in 37 of 173 patients (21%). Initiation of dialysis was required in nine patients (5%). Forty-six percent of patients with ARF, including four of nine who required dialysis, had recovery of renal function. Baseline clinical variables that were independent predictors of transplant-associated ARF included creatinine clearance, proteinuria, and cardiac amyloidosis. Treatment-related variables associated with ARF included melphalan dose and bacteremia. ARF was associated with reduced survival at 90 days but did not have an impact on overall survival at a median follow-up of 2.9 years. CONCLUSION: ARF is a frequent but often reversible complication of HDM/SCT for AL amyloidosis. Specific clinical and treatment-related factors are associated with the development of this complication.     

Liver transplantation for argininosuccinic aciduria: clinical, biochemical, and metabolic outcome.

We report successful liver transplantation in a young adult with argininosuccinic aciduria but without cirrhosis. Plasma amino acid profile normalized and brain magnetic resonance spectroscopy indicated improved metabolism after transplantation. The general well-being of the patient and his quality of life improved. We suggest that orthotopic liver transplantation should be considered for patients with argininosuccinic aciduria even in the absence of cirrhosis, with the aim of correcting (at least in part) central nervous system metabolism, thereby preventing further neurological deterioration.     

Long-term outcome of renal transplantation in patients with familial Mediterranean fever amyloidosis: a single-center experience

Although recurrence of amyloid A deposition in the allograft can be seen in patients with secondary amyloidosis due to familial Mediterranean fever (FMF), renal transplantation remains to be a choice of treatment for end-stage renal disease. The aim of this study was to determine short- and long-term results of renal transplantation in patients with FMF amyloidosis. We compared the outcomes of 17 patients with FMF amyloidosis among 431 (3.9%) transplants with 209 control patients. We observed 93% and 94% graft and patient survivals at 1 year, and 89% and 90% at 5 years. Also, the mean serum creatinine levels at 1 and 5 years posttransplant were similar. Recurrence of amyloidosis was documented in two allograft recipients presenting with nephrotic range proteinuria (12%), one of whom lost the allograft due to recurrence. Eleven patients had FMF gene analysis. The results of MEFV mutation analyses were: M694V/M694V homozygote in six patients, M694V/EQ148 in one patient, M694V/V726A in one patient, 680M-I/E148Q in one patient. FMF gene analysis was negative in two patients. Recurrence was noticed in one patient with M694V/M694V, while the other did not have an FMF gene analysis. Colchicine was reduced in nine patients due to side effects. In conclusion, the long-term outcomes of transplantation in patients with amyloidosis secondary to FMF is similar to that in the general transplant population and maintenance colchicine, even at low dose, appears to effectively prevent recurrence of amyloidosis in the allograft.     

Clinical outcome of preemptive kidney transplantation in patients with diabetes mellitus

End-stage renal disease (ESRD) caused by diabetic nephropathy is increasing throughout the world. The survival of diabetic patients treated by transplantation has improved nowadays. Although recent studies have demonstrated preemptive kidney transplantation to be associated with better graft survival in CKD patients, the effect of pre-transplantation dialysis on graft outcomes among diabetic ESRD patients is unclear. This analysis summarized our experience with preemptive kidney transplantation in diabetic ESRD patients by retrospectively comparing 70 such patients transplanted between 1995 and 2009. These 70 patients were divided into two groups: 30 patients underwent preemptive and the other 40 transplantation after maintenance hemodialysis or peritoneal dialysis. We compared graft survivals, acute rejection episodes, postoperative complications, and delayed graft function rates. The 10-year patient survival of 100% in the preemptive group was similar to that of the nonpreemptive group (85%, P = .11). But the 10 year graft survival was higher among the preemptive than the nonpreemptive group (100% vs 75%, P = .02). Pre-transplantation modality did not affect graft survival. Therefore, preemptive kidney transplantation should be applied to eligible patients with diabetic ESRD.     

Successful simultaneous liver‐kidney transplantation for renal failure associated with hereditary complement C3 deficiency

Hereditary complement C3 deficiency is associated with recurrent bacterial infections and proliferative glomerulonephritis. We describe a case of an adult with complete deficiency of complement C3 due to homozygous mutations in C3 gene: c.1811delT (Val604Glyfs*2), recurrent bacterial infections, crescentic glomerulonephritis, and end‐stage renal failure. Following isolated kidney transplantation he would remain C3 deficient with a similar, or increased, risk of infections and glomerulonephritis. As C3 is predominantly synthesized in the liver, with a small proportion of C3 monocyte derived and kidney derived, he proceeded to simultaneous liver‐kidney transplantation. The procedure has been successful with restoration of his circulating C3 levels, normal liver and kidney function at 26 months of follow‐up. Simultaneous liver‐kidney transplant is a viable option to be considered in this rare setting.     

Pretreatment multiparametric MRI is independently associated with biochemical outcome in men treated with radiation therapy for prostate cancer

Purpose

The purpose of this study was to investigate the utility of pre-treatment multiparametric magnetic resonance imaging (mpMRI) in a modern cohort of intermediate and high-risk prostate cancer patients treated with primary radiotherapy.

Positive serum cryoglobulin is associated with worse outcome after liver transplantation for chronic hepatitis C

BACKGROUND: Recurrent hepatitis C virus (HCV) infection in patients after liver transplantation is an important clinical problem. Because serum cryoglobulins (CG) are known to be associated with an increased incidence of cirrhosis in nontransplant patients, the authors tested the hypothesis that CG would also predict aggressive recurrent HCV in patients after liver transplantation. METHODS: Using a longitudinal database, the outcomes of 105 allografts transplanted into 97 HCV-positive patients from 1991 through 2002 were analyzed on the basis of CG status using a retrospective cohort design. Fifty-nine CG-negative and 38 CG-positive patients were identified. Histologic outcomes and graft survival were analyzed using Kaplan-Meier estimates and Cox univariate and multivariate analyses. Both overall survival and HCV-specific survival (non-HVC-related deaths and graft losses censored) were analyzed. RESULTS: By Kaplan-Meier estimates, CG-positive patients showed earlier graft failure with decreased time to severe histologic activity and fibrosis as compared with CG-negative patients (P<0.05 for all outcomes). By univariate analysis, CG-positive patients had significantly higher risk ratios for shortened HCV-specific graft survival, severe activity-free survival, and severe fibrosis-free survival as compared with CG-negative patients (P<0.05 for all outcomes). In the multivariate model, CG was an independent predictor for severe activity-free, severe fibrosis-free, and HCV-specific graft survival (P<0.05 for all outcomes). CONCLUSIONS: CG-positivity is associated with severe recurrent HCV disease in liver transplant recipients.