Polyglandular endocrine failure in a patient with amyloidosis secondary to familial Mediterranean fever

Familial Mediterranean fever (FMF) is 1 of the major causes of secondary amyloidosis. Renal involvement is the main clinical complication and it mostly presents with nephrotic syndrome and chronic renal failure. Although deposition of amyloid has been reported in several endocrine glands such as the adrenal, thyroid, and testes, clinically significant functional impairment is uncommon. Herein, we describe a patient in whom the diagnosis of FMF was based on molecular screening and who presented with recurrent hypoglycemic attacks and extensive amyloid deposition affecting various organ function including adrenal, thyroid, parathyroid, testes, intestinal system, and the heart. © 2001 by the National Kidney Foundation, Inc.     

From renal amyloid deposits to the identification of the culprit genes

Hereditary amyloidoses with renal involvement are classified in two groups. The first group is a growing family of autoinflammatory disorders characterized by recurrent fever attacks. Amyloidosis is caused by the deposition of amyloid A (AA) protein, which is a degradation product of a normal serum acute-phase protein: serum amyloid A (SAA). The prototype is familial Mediterranean fever (FMF). TNF Receptor Associated Periodic Syndrome (TRAPS) is a recently recognized periodic fever syndrome, differing from FMF in several characteristics: autosomal-dominant transmission, longer duration of attacks, and lack of response to colchicine prophylaxis. The second group comprises a variety of disorders, each characterized by the deposition of a specific mutant protein. The prototype is transthyretin amyloidosis (TTR). Identification of the form of amyloidosis has clinical implications. Therefore, in a patient with a history of recurrent fever attacks and AA amyloidosis, a diagnosis of FMF or TRAPS dictates appropriate genetic counseling and management. In patients with renal amyloidosis without a history of fever, identification of the mutant protein is therapeutically crucial; therefore, when the cell type that produces the precursor is (exclusively or mainly) the hepatocyte, a liver transplantation is to be considered.     

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.     

Renal transplantation in amyloid nephropathy

Renal transplantation was performed in 2 patients with end-stage renal disease due to AA-type amyloidosis. One patient with amyloidosis of rheumatoid arthritis (RA) origin died twelve months after renal transplantation in cardiogenic shock. AA-amyloid deposits were demonstrated in the graft even though there were excellent function and no proteinuria. The second patient with amyloid nephropathy due to familial Mediterranean fever (FMF) showed no impairment of graft function 24 months after transplantation. These 2 cases are compared to an additional 31 cases of renal transplantation for amyloid nephropathy described in the literature. Proteinuria was reported in 32.3% and amyloid was detected in the functioning graft in 41.4%. The function was excellent even when small amyloid deposits were present in the graft. Renal transplantation is indicated in cases of amyloid nephropathy of the AA-type, provided life threatening amyloid involvement of other organs is not present.     

High frequency of amyloid lymphadenopathy in uremic patients

Amyloid lymphadenopathy has only been reported in case report form, or in small groups of patient groups within large series. We believe that amyloid lymphadenopathy is common in uremic patients, and thus designed this study to determine the frequency of this condition in hemodialysis patients, and to assess its types and patterns. We reevaluated 46 uremic patients' lymph node biopsies for amyloid deposits. We also immunohistochemically identified the protein origin of these deposits using Amyloid A, kappa, lambda, beta2 microglobulin, and transthyretin antibodies. Histopathologically, we observed for vascular involvement, follicular deposition, and diffuse deposition. We detected amyloid deposits in 10 of the 46 (22%) patients' lymph nodes. The patterns of deposition were vascular involvement alone in six specimens, vascular involvement plus follicular deposition in three, and vascular involvement plus diffuse deposition in one specimen. Amyloid AA type protein was present in seven nodes, beta2 microglobulin-related amyloid in two nodes, and immunoglobulin-derived protein (AL) in one node. We assessed these 10 patients for causes of end-stage renal disease (ESRD) and other conditions that might relate to amyloidosis. The cause of ESRD in the seven patients with AA amyloid were renal amyloidosis secondary to Familial Mediterranean Fever in four, glomerulonephritis in one patient who had bronchiectasis and Castleman's disease, unknown in one patient who had bronchial asthma, and pyelonephritis in one patient who had no characteristics that could be linked with AA type amyloidosis. The causes of ESRD in the two individuals with beta2 microglobulin-related amyloidosis who had been on long-term hemodialysis were pyelonephritis and glomerulonephritis. The cause of ESRD in the patient with AL type protein was glomerulonephritis, and this patient had no systemic disease. We conclude that amyloid lymphadenopathy is, indeed, common in uremic patients. Amyloid type AA is the most prevalent form of amyloid protein in uremic patients, but amyloid type does not always correspond with underlying cause of renal failure, or with the presence of systemic disease.     

High Frequency of Amyloid Lymphadenopathy in Uremic Patients

Amyloid lymphadenopathy has only been reported in case report form, or in small groups of patient groups within large series. We believe that amyloid lymphadenopathy is common in uremic patients, and thus designed this study to determine the frequency of this condition in hemodialysis patients, and to assess its types and patterns. We reevaluated 46 uremic patients' lymph node biopsies for amyloid deposits. We also immunohistochemically identified the protein origin of these deposits using Amyloid A, kappa, lambda, β₂ microglobulin, and transthyretin antibodies. Histopathologically, we observed for vascular involvement, follicular deposition, and diffuse deposition. We detected amyloid deposits in 10 of the 46 (22%) patients' lymph nodes. The patterns of deposition were vascular involvement alone in six specimens, vascular involvement plus follicular deposition in three, and vascular involvement plus diffuse deposition in one specimen. Amyloid AA type protein was present in seven nodes, β₂ microglobulin-related amyloid in two nodes, and immunoglobulin-derived protein (AL) in one node. We assessed these 10 patients for causes of end-stage renal disease (ESRD) and other conditions that might relate to amyloidosis. The cause of ESRD in the seven patients with AA amyloid were renal amyloidosis secondary to Familial Mediterranean Fever in four, glomerulonephritis in one patient who had bronchiectasis and Castleman's disease, unknown in one patient who had bronchial asthma, and pyelonephritis in one patient who had no characteristics that could be linked with AA type amyloidosis. The causes of ESRD in the two individuals with β₂ microglobulin-related amyloidosis who had been on long-term hemodialysis were pyelonephritis and glomerulonephritis. The cause of ESRD in the patient with AL type protein was glomerulonephritis, and this patient had no systemic disease. We conclude that amyloid lymphadenopathy is, indeed, common in uremic patients. Amyloid type AA is the most prevalent form of amyloid protein in uremic patients, but amyloid type does not always correspond with underlying cause of renal failure, or with the presence of systemic disease.     

Long-Term Outcome of Renal Transplantation in Patients With Familial Mediterranean Fever Amyloidosis: A Single-Center Experience

IntroductionFamilial Mediterranean fever (FMF) is an autosomal-recessive disorder, affecting multiple organs. The AA type of amyloidosis is most common and serious complication cause nephropathy and end-stage renal disease (ESRD). Renal transplantation (RTX) remains treatment of choice for ESRD. We aimed to investigate long-term results of RTX in patients with FMF amyloidosis.Patients and MethodsWe compared the outcomes of 18 patients (12 men and 6 women) with FMF amyloidosis among 601 (2.9%) transplants with 200 control patients. Demographic data and gene analysis were evaluated.ResultsIn our study the 1-year graft and patient survivals were 94.44% and 100%, respectively. At 5 years after RTX, they were 94.73% and 88.88%, respectively, in the FMF group without difference from controls. Mean creatinine level at 1 and 5 years were 1.43 ± 0.54 and 1.73 ± 0.89, respectively. The results of MEFV mutation analyses were: M694V/M694V homozygote in 1 patient, M694V/EQ148 in 3, M694V/V726A in 2, 680M-I/E148Q in 3, M694V/M680I in 5, R202Q/M680I in 2, and M694V/R202Q in 2. Recurrence was noticed in 1 patient with M694V/M680I. One patient died because of graft loss and cardiac complications with M694V/M680I gene analysis. Colchicine was reduced in 4 patients owing to side effects.ConclusionLong-term outcomes of transplantation in patients with amyloidosis secondary to FMF is similar to that in the general transplant population and maintenance colchicine, even after decreasing its dose, effectively prevents recurrence of amyloidosis in the allograft.     

Renal transplantation in systemic amyloidosis

Renal transplantation was performed in a 24-yr-old woman with type AA systemic amyloidosis. Renal biopsy at 11 yr post-transplantation showed no amyloid recurrence, but the presence of mesangial proliferative glomerulonephritis and focal segmental glomerular sclerosis. Renal function was satisfactory with the exception of mild proteinuria. Symptoms related to systemic amyloidosis including goiter and cardiac deposition, improved post-transplantation. Renal transplantation is the recommended therapy for type AA systemic amyloidosis.     

Renal involvement in systemic amyloidosis: an Italian collaborative study on survival and renal outcome.

BACKGROUND: Few data are available from large population-based studies on survival and renal outcome of patients with renal involvement and different types of systemic amyloidosis. METHODS: Two hundred and ninety of over 373 patients affected from systemic amyloidosis with renal involvement diagnosed in Italy between January 1995 and December 2000 were followed from diagnosis to death or until the last available clinical control. Eighty-three patients were excluded from analysis either because the amyloid type remained undetermined or they were lost at follow-up. Clinical and laboratory information was collected according to the different types of amyloidosis using a specific form which included renal function with 24 h proteinuria at diagnosis and at the end of follow-up, the type and the date of onset of dialysis and the kind of treatment they underwent. RESULTS: The median time of follow-up was 24 months in primary (AL) amyloidosis (range: 1-88 months), 16 months in AL with associated multiple myeloma (MM + AL: range 1-76 months), 30 months in reactive (AA) amyloidosis (range: 1-99 months) and 52 months in patients with familial forms (AF: range 14-82 months). Patients with AL showed a significantly shorter survival than AA. Despite no significant differences of renal outcome or survival on dialysis being observed between the two groups, a lower renal survival with a higher number of patients who progressed to end-stage renal disease (ESRD) was observed in patients with AA. Overall survival was markedly improved in patients with AL who underwent a specific therapy (conventional chemotherapy or autologous stem cell transplantation (ASCT)) even in the absence of a positive kidney response. Multivariate analysis showed cardiac involvement and specific therapy to significantly influence survival in AL whereas age, serum creatinine (sCr) and heart involvement significantly affected survival in AA. In both groups, sCr and heart involvement were the most relevant predictors for renal outcome, together with urinary protein excretion, in patients with AA. CONCLUSIONS: Our results show a worse survival in AL due to the higher prevalence of heart involvement in this group and emphasize that a specific therapy significantly prolongs survival and slows the progression of renal disease in patients with AL. We suggest that a late nephrological referral is likely the cause of the higher sCr found at presentation in patients with AA and probably accounts for the lower renal survival observed in the short term in these patients. At the time being, renal transplantation and ASCT are still rare therapeutic options for renal patients affected from systemic amyloidosis.     

Long-term experience with renal transplantation in systemic amyloidosis: a case report

Renal transplantation was performed on a 39-year old woman with secondary amyloidosis due to rheumatoid arthritis. She remains alive and renal function has been maintained satistfactorily with the exception of proteinuria ten years after transplantation. Recent renal biopsy showed no amyloid recurrence, but the presence of chronic rejection reaction and mild cyclosporin arteriolopathy. Symptoms related to systemic amyloidosis and rheumatoid arthritis improved after transplantation. Renal transplantation is the recommended therapy for the type AA systemic amyloidosis. This is the second report of long-term experience with renal transplantation in systemic amyloidosis in Japan.     

Familial Mediterranean fever and mesangial proliferative glomerulonephritis: report of a case and review of the literature

In familial Mediterranean fever (FMF), a genetically inherited disease characterized by fever and serositis, renal involvement is mainly AA amyloidosis. We report a patient with FMF who developed mesangial proliferative glomerulonephritis; presumably in response to colchicine treatment, the activity of the disease decreased and renal function tests and urinary findings normalized. This report emphasizes the concurrent existence of mesangial proliferative glomerulonephritis with FMF in the absence of renal amyloidosis. Due to increased inflammatory response observed in FMF, immunologic glomerular injury, a common cause of glomerulonephritis, may occur more frequently in patients with FMF.     

Clinical and biochemical outcome of hepatorenal transplantation for hereditary systemic amyloidosis associated with apolipoprotein AI Gly26Arg

BACKGROUND: Treatment of systemic amyloidosis comprises measures to support failing organ function coupled with attempts to reduce the supply of the respective amyloid fibril precursor protein. Orthotopic hepatic transplantation is effective in familial amyloid polyneuropathy associated with variant transthyretin, because this protein is produced almost exclusively in the liver. Hepatic transplantation has not been performed in hereditary apolipoprotein AI (apoAI) amyloidosis, and the liver's contribution to plasma apoAI levels has not been determined in vivo. METHODS: A 57-year-old Irish man with hereditary systemic amyloidosis associated with apoAI Gly26Arg, which had led to end-stage renal failure and progressive liver dysfunction, underwent hepatorenal transplantation. His outcome was followed clinically and his amyloid deposits were monitored with serum amyloid P component scintigraphy. The proportion of variant apoAI in the plasma was estimated by quantitative isoelectric focusing before and after liver transplantation. RESULTS: Plasma levels of variant apoAI decreased by 50% after liver transplantation, and the patient was asymptomatic 2 years after surgery. Subclinical amyloid deposits that were present in his spleen and heart preoperatively have regressed and stabilized respectively. CONCLUSIONS: Orthotopic liver transplantation substantially reduces the supply of the amyloid fibril precursor protein in hereditary apoAI amyloidosis, and the excellent outcome in this patient probably reflects the balance between deposition and turnover of amyloid having been altered in favor of the latter. These findings support the use of liver transplantation in patients with hereditary apoAI amyloidosis who develop hepatic dysfunction.     

A case of living-donor renal transplantation for chronic renal failure caused by secondary amyloidosis

In Japan, amyloidosis is a rare cause of renal failure and of renal transplantation. We treated a patient who underwent a renal transplantation because of chronic renal failure caused by secondary amyloidosis with a good result. The patient was a 50-year-old woman who was diagnosed with secondary amyloidosis and an amyloid kidney. She underwent living donor renal transplantation after about 7 years of hemodialysis. During the 3-year posttransplantation period, she maintained good allograft function with a serum creatinine level about 1.2 mg/dL. Because of amyloidosis is a systemic disease, amyloid kidney patients often experience fatal complications, so the indications for renal transplantation in amyloid patients are still controversial. But if the patient's general condition is good, renal transplantation can be an effective therapy for patients with kidney failure caused by amyloidosis.     

Kidney transplantation for end‐stage renal disease secondary to familial Mediterranean fever

Although kidney transplantation (KT) is widely used for treating renal amyloidosis secondary to familial Mediterranean fever (FMF), data concerning transplant outcome are limited and inconsistent. The aim of this study was to determine the long‐term outcome of KT in patients with amyloidosis secondary to FMF. Kidney transplantation outcome in 24 patients with FMF was compared to that in 72 controls matched for age, gender of recipient, and type of the donor that underwent KT due to end‐stage renal disease (ESRD) not caused by FMF. Mean follow‐up time was 80.3 ± 55.1 months in the FMF group, vs. 86.5 ± 47.6 months in the control group. Death‐censored graft survival at five and 10 yr in the FMF group was 95.8% and 78.4%, respectively, and was comparable to that in the control group. In the FMF group, five‐ and 10‐yr patient survival (87.5 and 65.6%) was shorter than in the control group, but the difference was not statistically significant. The findings show that long‐term outcome of KT in the patients with amyloidosis secondary to FMF was comparable to that in patients with ESRD not caused by FMF. Recurrence of amyloidosis in the allograft, gastrointestinal intolerance, and fatal infections remain as major complications during the post‐transplant period.     

Prognosis of renal amyloidosis: a clinicopathological study using cluster analysis

Progression of renal amyloidosis is associated with severe proteinuria or nephrotic syndrome, and various mechanisms have been postulated to explain these complications. We studied the acceleration of proteinuria and reduced renal function by cluster analysis using clinical parameters, renal histological findings, type of renal amyloidosis and follow-up data. We divided 97 cases into three groups of renal amyloidosis. Accelerated progression correlated with serum creatinine (s-Cr) levels at renal biopsy and histological grade of renal damage by amyloid deposition (p < 0.0001). The most influential prognostic factors (s-Cr level > or =2.0 mg/dl) were tubulointerstitial and vascular damage induced by amyloid deposition at biopsy (odds ratio 96.9 and 69.2, respectively). In addition, we found amyloidosis type amyloid associated (AA) correlated with more amyloid-mediated vascular and tubulointerstitial damage than amyloidosis type amyloid light chain (AL) (p < 0.001, p < 0.01, respectively). Proteinuria and nephrotic syndrome were more severe in cases of amyloidosis AL than in amyloidosis AA (p = 0.076). In conclusion, less tubulointerstitial and vascular damage was caused by amyloid deposition; this was slowly progressive. Amyloid AA was detected in tubulointerstitial tissue and vessels more frequently than amyloid AL. Heavy proteinuria and/or nephrosis were not indicators of rapid progression.     

Secondary amyloidosis: a severe complication of ankylosing spondylitis. Two case-reports

STUDY OBJECTIVE: To report two cases of amyloidosis secondary to ankylosing spondylitis. PATIENTS AND RESULTS: Of the 47 ankylosing spondylitis patients who have received follow-up at our department over the last few years, two have developed AA amyloidosis. Both have extremely severe, long-standing joint disease, with virtually complete spinal ankylosis and destructive peripheral arthritis of the hips and wrists; one also has tarsal joint destruction. Renal dysfunction was the first manifestation of amyloidosis in both cases. One patient required chronic hemodialysis and developed peritonitis due to colonic perforation, probably at a site of amyloid deposition. CONCLUSIONS: Secondary amyloidosis is a rare complication of ankylosing spondylitis that can cause severe renal and gastrointestinal complications. No treatment capable of clearing established amyloid deposits is available to date.     

Clinicopathological and epidemiological analysis of amyloidosis in Turkish patients.

BACKGROUND: The aim of the present study was to assess the correlation of immunohistochemical subtyping with clinical diagnosis in order to achieve useful epidemiological data regarding amyloidosis in Turkish patients. METHOD: We carried out immunohistochemical studies on 128 biopsies from various sites of 111 patients with biopsy-proven amyloidosis and, based on the results, classified the patients. We assessed the correlation of immunohistochemical subtype with clinical diagnosis and gathered epidemiological data. RESULTS: The sites most biopsied were kidney and rectum, followed by the testicle, liver, small intestine and bladder. Amyloid deposits showed positive staining with a single antibody in 120 biopsies. Pure amyloid A (AA) positivity was seen in 113 biopsies; six biopsies were positive for amyloid lambda (AL) and one for beta2-microglobulin (beta2MG). The clinical diagnoses of 81 patients (98 biopsies all AA positive) were suggestive of familial Mediterranean fever (FMF). Also AA positive were eight patients with tuberculosis, seven patients with rheumatoid arthritis, four patients with bronchiectasis and one patient with Crohn's disease. The biopsies from seven patients clinically suspected to have plasma cell dyscrasias were AL positive. One patient undergoing haemodialysis was beta2MG positive. Two patients without definite diagnoses showed double or triple positivity, which could not be interpreted and classified immunohistochemically. CONCLUSIONS: This study demonstrates that the predominant association of AA amyloidosis is with FMF. It also suggests that the routine immunohistochemical study of patients with amyloidosis who are of certain ethnic backgrounds suffices for classifying the subtype of amyloid fibril protein and the related disease.     

Renal amyloidosis in children

Renal amyloidosis is a detrimental disease caused by the deposition of amyloid fibrils. A child with renal amyloidosis may present with proteinuria or nephrotic syndrome. Chronic renal failure may follow. Amyloid fibrils may deposit in other organs as well. The diagnosis is through the typical appearance on histopathology. Although chronic infections and chronic inflammatory diseases used to be the causes of secondary amyloidosis in children, the most frequent cause is now autoinflammatory diseases. Among this group of diseases, the most frequent one throughout the world is familial Mediterranean fever (FMF). FMF is typically characterized by attacks of clinical inflammation in the form of fever and serositis and high acute-phase reactants. Persisting inflammation in inadequately treated disease is associated with the development of secondary amyloidosis. The main treatment is colchicine. A number of other monogenic autoinflammatory diseases have also been identified. Among them cryopyrin-associated periodic syndrome (CAPS) is outstanding with its clinical features and the predilection to develop secondary amyloidosis in untreated cases. The treatment of secondary amyloidosis mainly depends on the treatment of the disease. However, a number of new treatments for amyloid per se are in the pipeline.     

Cholestasis and renal failure in a patient with secondary amyloidosis

Amyloid, was first described in the 19th century by Virchow, which means starch or cellulose. Extracellular deposition of this unique protein fibrils in tissues, often leading organ dysfunction is known as amyloidosis. In systemic amyloidosis, amyloid fibrils may deposit in different organs including kidneys, heart and liver. Although liver is effected frequently, clinical liver disease is rare. There are a few cases that secondary amyloidosis presented with hepatic involvement and cholestasis which seems to be limited to primary amyloidosis. Hepatic amyloidosis with cholestasis may be a predictor of involvement of other organs and thus of poor prognosis. We report a case of a 67 year old man with renal failure and prominent cholestasis due to AA amyloid deposition in the liver.     

Spontaneous regression of bilateral surrenal haematoma and subclinical hypoaldosteronism in a patient with renal amyloidosis secondary to Familial Mediterranean Fever

This report describes a patient with Familial Mediterranean Fever (FMF) associated with renal amyloidosis, bilaretal surrenal haematomas andhypoaldosteronism which was clinically asymptomatic. The deposition of AAamyloide was found on the renal and bone marrow biopsies. Bilateralsurrenal haematoma regressed after six month from the first events.Colchicine therapy controlled the attacks of the disease. This revised version was published online in August 2006 with corrections to the Cover Date.