L. Lobato

End-stage renal disease in familial amyloidosis ATTR Val30Met: a definitive indication to combined liver-kidney transplantation

AUTOSOMAL dominant amyloidoses characterized so far are most commonly associated with transthyretin (TTR), a plasma protein synthesized by the liver. The single gene for TTR is located on human chromosome 18; more than 70 TTR mutations have been documented. The most common type of hereditary amyloidosis is familial amyloid polyneuropathy type I (FAP, Portuguese type), a neuropathic form associated with a substitution of methionine for valine at position 30 of the TTR gene, TTR Val30Met. The largest number of patients and families with this mutation has been identified in Portugal, but now it has been recognized worldwide. FAP in Portugal usually begins in the third or fourth decade of life with death occuring about 11 years later. The clinical disease usually starts as a sensory neuropathy in the lower extremities, but autonomic and gastrointestinal features may occur early. Motor neuropathy usually manifests itself later with cardiac conduction disturbances frequently leading to the need for artificial pacing. Vitreous deposits of amyloid have been reported, most particularly in Swedish families. Cachexia has been described as a significant factor in mortality. Orthotopic liver transplantation (OLT) is widely recommended for patients affected by FAP; it is recognized as the only specific treatment for this disease. Virtually all TTR is produced by the liver, and, therefore, OLT halts the supply of variant amyloidogenic TTR (ATTR). Amyloid proteins have different organ specificity, leading to variations in clinical features. Classically, nephropathic and nonneuropathic autosomal dominant amyloidoses are associated with apolipoprotein A-I and A-II, fibrinogen A -chain, and lysozyme. Renal amyloidosis also has been described in FAP. In Portugal, approximately one third of FAP patients have clinical renal features with varying degrees of proteinuria and renal failure. The progression to end-stage renal disease (ESRD) occurs in 10% of Portuguese patients, more than 10 years after the onset of symptoms (Lobato et al, unpublished data). Although dialysis may prolong life, it does not prevent the progression of systemic amyloid involvement; death occurred, on average, at 22 months after renal replacement therapy. The cause was infection in one half of the patients (Lobato et al, unpublished data). The first successful renal transplantation in a patient with renal amyloidosis was reported in 1968, but until now this treatment has been associated with poor graft and patient survival. Most published series concerning renal transplantation in amyloidosis deal with familial Mediterranean fever or other forms of reactive amyloidosis (AA type). The results of kidney transplantation in ATTR have not been described. In patients with FAP undergoing dialysis, the potential advantages of simultaneous liver-kidney transplantation instead of isolated kidney transplantation are to avoid the progression of systemic manifestations and the recurrence of renal amyloidosis. The obstacles to renal transplantation

Characterization of End-Stage Renal Disease After Liver Transplantation in Transthyretin Amyloidosis (ATTR V30M)

Transthyretin (TTR) amyloidosis, an autosomal-dominant disease, is characterized by peripheral and autonomic neuropathy--familial amyloidotic polyneuropathy (FAP). End-stage renal disease (ESRD) occurs at 10 years after the onset of neuropathy. Orthotopic liver transplantation (OLT) is the usual treatment of choice. We evaluated FAP patients, ATTR V30M, before and after OLT who started dialysis within 3 months after surgery. The 11 patients had an age at the onset of neuropathy of 31.9 ± 6.3 years with a mean evolution of disease to OLT of 4.54 ± 2.5 years. The glomerular filtration rate was <60 mL/min in 2 patients, 2 displayed nephrotic range proteinuria, and 3 had microalbuminuria. Elective pacemaker implantation was necessary in 8 subjects. Post-OLT 3 patients developed proteinuria, 2 of whom showed increasing nephrotic syndrome. Dysautonomia worsened leading to bladder catheterization in 6. In patients with previous normal renal function and proteinuria <3 g/d, the evolution of neuropathy to the first dialysis was 14.6 ± 4.2 years versus 7.5 ± 1.1 among the other subjects. Overall, dialysis was implemented at 7.4 ± 4.9 years after surgery. There was no liver graft dysfunction. The heart evaluation post-OLT showed the following: 3 patients with de novo dysrhythmias requiring pacemaker implantation and 3 with N-terminal pro-natriuretic peptide levels >10,000 pg/mL. Death occurred in 4 subjects at an average of 26 months after initiation of dialysis. Concerning ESRD, there was no clear benefit of transplantation in the early stages. Patients with normal renal function and lower levels of proteinuria showed slower progression to ESRD, irrespective of their duration of neuropathy.

Combined liver-kidney transplantation in familial amyloidotic polyneuropathy TTR V30M: nephrological assessment.

We analyze our results of combined liver– kidney transplantation (LKT) in familial amyloidotic polyneuropathy (FAP), ATTR V30M. Six patients were submitted to LKT. The time on dialysis before transplantation was 14.25+ 7.9 months. The age at LKT was 45.8+ 4.6 years, with 8 years of evolution of neuropathy. All kidney grafts had immediate function and no rejection episodes; one patient developed liver graft rejection with death 2 months later due to septic shock. The urinary tract infections were the leading cause of morbidity. The mean follow-up was 84 months. One patient had an ischemic stroke, and other was submitted to partial colectomy. At the end of follow-up: average serum creatinine was 1.2 mg/dl, proteinuria was absent and liver function was normal; two patients had Nterminal pro-BNP levels higher than 1000 pg/ml. In summary, LKT was a valid therapy and avoided clinical recurrence of nephropathy. Introduction: Nephrological indications for combined liver–kidney transplantation (LKT) have increased in recent years. The MELD classification for liver allocation extended this practice to multiple centers [1]. The aim of liver transplantation in hereditary amyloidosis [2] is different from that of chronic liver diseases and we can expect that the proposal and benefit of LKT may differ. Usually, patients with familial amyloidotic polyneuropathy (FAP) due to ATTR V30M have a progression of neuropathy higher than 10 years at end-stage renal disease (ESRD) [3], which is substantially longer than what is recommended for liver transplant alone. The survival of FAP patients in renal replacement therapy is poor, less than 2 years, because infections, decubitus ulcers, and malnutrition complicate the course of the disease. In FAP the potential advantage of LKT instead of isolated kidney is the avoidance of the progression of systemic manifestations and the recurrence of amyloidosis in the renal graft. Moreover, liver transplantation alone, with a glomerular filtration rate (GFR) 530 ml/min, does not reverse or improve renal function, quite the contrary. Nephrotoxic drugs, intraoperative hemodynamic instability, and urinary tract infections can lead to the decline in GFR. We would be tempted to think that we should extend the indication of LKT to earlier stages of renal failure. However, this may create an unfair situation over patients in the kidney list without prior clarification of the advantage of LKT. The aim of this study was to analyze whether the results of LKT in FAP patients were associated with long-term benefit. Methods: Data from all patients with FAP, ATTR V30M, submitted to LKT from the same donor at Hospital de Santo António (Porto, Portugal) were reviewed. The criteria to perform a LKT in our unit were as follows: (1) ability to walk without aid or no more than one crutch, (2) absence of permanent bladder catheter, (3) absence of neurogenic or decubitus nonhealing ulcers, (4) absence of dialysis-related syncope or persisting vomiting due to autonomic neuropathy, and (5) general conditions suitable for LKT. All patients required hemodialysis except in one case, where a pre-emptive renal graft was the option when the glomerular filtration rate was estimated in 21 ml/min. Amyloid deposits were demonstrated in all, including in the explanted liver. A pacemaker was implanted prior to surgery. Selection of donors was based on ABO compatibility, organ size, and quality of donor. HLA matching was disregarded. Before transplantation cross-matches were negative. The kidney was inserted after the liver according to standard technique. In one patient suprapubic cystostomy was performed simultaneous with kidney transplantation. The immunosuppressive induction therapy included antithymocyte globulin, cyclosporine, prednisone, and azathioprine or mycophenolic acid. Longterm protocol contains low dose of cyclosporine and mycophenolic acid; corticoids were suspended one or two years after transplantation. The follow-up was done by the same nephrologists responsible for monitoring dialysis patients with FAP. Results and discussion: Six patients (3 males, 3 females) were submitted to LKT between January 190

Erythropoietin production by distal nephron in normal and familial amyloidotic adult human kidneys.

BACKGROUND/AIMnthe kidney is the major site of erythropoietin production. Many efforts have been made to identify renal erythropoietin-producing cells. Previous studies showed conflicting results, but the predominant localization reported was the peritubular interstitial and tubular epithelial cells. This study was conducted to identify the erythropoietin-producing cells in renal biopsies from 10 cadaveric donors and 45 patients with familial amyloidosis ATTR V30M, thirteen of them with anemia. Familial amyloidosis Type I (FAP-I) is a genetic disorder caused by a transthyretin (TTR) protein variant presenting a single amino acid substitution of methionine for valine at position 30 of the polypeptide chain (TTR V30M). Anemia in FAP-I is associated with inappropriately low serum erythropoietin levels.nnnMETHODSnerythropoietin expression was detected by in situ hybridization (ISH) and confirmed by laser capture microdissection followed by PCR. Renal segments were identified by immunohistochemistry.nnnRESULTSnerythropoietin was mainly expressed by epithelial distal tubular cells and collecting tubules and additionally, in a few biopsies, by glomerular cells. A similar expression pattern was observed in donors and FAP-I patients. No increased mRNA erythropoietin expression was found in anemic patients, all of them presenting only a slight expression in medulla and cortex.nnnCONCLUSIONSnthese results suggest the distal nephron as the major site of erythropoietin production, and support the notion that an inappropriate erythropoietin production is the cause of anemia in familial amyloidosis ATTR V30M.

End-stage renal disease in familial amyloidosis ATTR Val30Met

AUTOSOMAL dominant amyloidoses characterized so far are most commonly associated with transthyretin (TTR), a plasma protein synthesized by the liver. The single gene for TTR is located on human chromosome 18; more than 70 TTR mutations have been documented. The most common type of hereditary amyloidosis is familial amyloid polyneuropathy type I (FAP, Portuguese type), a neuropathic form associated with a substitution of methionine for valine at position 30 of the TTR gene, TTR Val30Met. The largest number of patients and families with this mutation has been identified in Portugal, but now it has been recognized worldwide. FAP in Portugal usually begins in the third or fourth decade of life with death occuring about 11 years later. The clinical disease usually starts as a sensory neuropathy in the lower extremities, but autonomic and gastrointestinal features may occur early. Motor neuropathy usually manifests itself later with cardiac conduction disturbances frequently leading to the need for artificial pacing. Vitreous deposits of amyloid have been reported, most particularly in Swedish families. Cachexia has been described as a significant factor in mortality. Orthotopic liver transplantation (OLT) is widely recommended for patients affected by FAP; it is recognized as the only specific treatment for this disease. Virtually all TTR is produced by the liver, and, therefore, OLT halts the supply of variant amyloidogenic TTR (ATTR). Amyloid proteins have different organ specificity, leading to variations in clinical features. Classically, nephropathic and nonneuropathic autosomal dominant amyloidoses are associated with apolipoprotein A-I and A-II, fibrinogen A -chain, and lysozyme. Renal amyloidosis also has been described in FAP. In Portugal, approximately one third of FAP patients have clinical renal features with varying degrees of proteinuria and renal failure. The progression to end-stage renal disease (ESRD) occurs in 10% of Portuguese patients, more than 10 years after the onset of symptoms (Lobato et al, unpublished data). Although dialysis may prolong life, it does not prevent the progression of systemic amyloid involvement; death occurred, on average, at 22 months after renal replacement therapy. The cause was infection in one half of the patients (Lobato et al, unpublished data). The first successful renal transplantation in a patient with renal amyloidosis was reported in 1968, but until now this treatment has been associated with poor graft and patient survival. Most published series concerning renal transplantation in amyloidosis deal with familial Mediterranean fever or other forms of reactive amyloidosis (AA type). The results of kidney transplantation in ATTR have not been described. In patients with FAP undergoing dialysis, the potential advantages of simultaneous liver-kidney transplantation instead of isolated kidney transplantation are to avoid the progression of systemic manifestations and the recurrence of renal amyloidosis. The obstacles to renal transplantation

Long-term follow-up of patients with hereditary fibrinogen A alpha-chain amyloidosis

: Fibrinogen A alpha-chain amyloidosis (AFib) is an autosomal dominant condition with variable penetrance, usually of late onset. Progression to stage V chronic kidney disease is a consiste...