Clinical and pathological features of renal amyloidosis: An analysis of 32 patients in a single Chinese centre

Aim:   To summarize the clinical and pathological features of renal amyloidosis in order to achieve early diagnosis.
Methods:   The clinical and pathological data of 32 patients with renal amyloidosis, diagnosed by renal biopsy in one renal centre, were retrospectively analyzed. Immunohistochemistry of amyloid A protein and immunoglobulin light chains was further performed on the renal specimens for further classification.
Results:   Twenty-four out of the 32 patients (75%) were not considered to have renal amyloidosis by local physicians; 91.7% (22/24) of them had at least one of the following signs: bodyweight loss, organ enlargement and decreased blood pressure. Twenty-nine out of the 32 patients (90.6%) were over 40 years, 30 patients (93.8%) had nephrotic syndrome, and 21 patients (65.6%) were found to have monoclonal light chain in serum or urine by immunofixation. Six patients (18.8%) were negative by Congo red stain and were diagnosed as having early renal amyloidosis by electron microscopy. Twenty-eight patients were diagnosed as having AL amyloidosis, two were suspected of having AL amyloidosis, one had AA amyloidosis and the status of the remaining patient was undetermined.
Conclusion:   Renal amyloidosis is frequently neglected by local physicians in China. Middle-aged nephrotic patients with weight loss, organ enlargement and monoclonal light chains in serum or urine should be highly suspected of the disease. Renal biopsies, especially electron microscopy, play a crucial role in the early diagnosis of renal amyloidosis.     

Diagnosis and treatment of AL amyloidosis

AL (amyloid light-chain) amyloidosis is a plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure. Virtually all patients with AL amyloidosis have a monoclonal protein in the serum or urine or a monoclonal population of plasma cells in the bone marrow. The most common target organ is the kidney and renal amyloidosis manifests as proteinuria or nephrotic syndrome in 3/4 of the patients. The median survival is one to two years. It is important to recognize that the amyloidosis is a dynamic process, and chemotherapy induced reduction of the activity of the plasma cell clone reduces the supply of the amyloid precursor protein and can result in a major regression of the deposits. Amyloid-related nephrotic syndrome and renal failure are potentially reversible. Conventional-dose melphalan as standard treatment can prolong the median duration of survival about 10 months, but the clinical response rates with improvement of impaired organ function are low with a slow response. Upfront high-dose chemotherapy with autologous peripheral blood stem cell transplantation is much more effective and can result in a major improvement of the patient's clinical condition, but the treatment-related toxicity can be relevant due to impaired organ function. The initial use of a conventional-dose chemotherapy consisting of vincristine, doxorubicin and dexamethasone (VAD) to achieve a remission and subsequent high-dose chemotherapy is the concept of a German trial. The improvement of the condition of the patient by this approach may increase the tolerability of high-dose chemotherapy and reduce transplantation-related problems.     

A case of primary immunoglobulin light chain amyloidosis with a delayed appearance of Bence Jones protein in urine

We report here a case of a 58-year-old man who had nephrotic syndrome and immunoglobulin light chain (AL) amyloidosis. This patient underwent a renal biopsy to confirm the diagnosis. Treatment with permanganate before Congo red staining showed systemic secondary amyloidosis (AA) fibrils, which were sensitive to permanganate oxidation. Although this patient was initially diagnosed as having AA amyloidosis, he did not have any chronic inflammatory disease and/or malignancy. The level of amyloid A protein (7.9 microg/mL) in sera was within the normal range (0-8.0 microg/mL). Therefore, we performed an immunostaining of the precursor protein (amino terminus of constant region: kappa and lambda light chains, and AA protein) using duodenal biopsy specimens for a precise diagnosis. Immunostaining was positive for the amino terminus of constant region of the lambda light chain, and negative for the amino terminus of constant region of the kappa light chain and AA protein. No plasma cell proliferation in the bone marrow was observed. We finally diagnosed this patient as having primary AL amyloidosis. It appears that a pathological diagnosis must be performed by immunostaining the precursor proteins with the permanganate digestion technique in tissue of patients with amyloidosis. There were no abnormalities in serum and urine immunoelectrophoresis at the time of renal biopsy in this patient. During the follow-up period, after discharge, Bence Jones protein appeared in the urine, but not in the serum. It is necessary to observe patients with primary AL amyloidosis carefully to determine if they their condition will progress to multiple myeloma.     

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.     

Longterm complete remission of AL-amyloid-related nephrotic syndrome

We describe a 59-year-old man with nephrotic syndrome that was diagnosed as suspected minimal change nephrotic syndrome by the routine examination of renal tissues at first biopsy, because renal histology showed segmental mild mesangial expansion with argyrophilic staining and partial foot process fusion without any deposition. Prednisolone therapy induced complete remission of nephrotic syndrome. Relapse occurred after 4 years of complete remission, and the second renal biopsy revealed amyloid light-chain (AL)-amyloidosis. Re-examination of the first biopsy tissues by Congo red staining confirmed a small amount of amyloid deposition in the mesangial areas although the mesangial areas showed argyrophilic staining, which is atypical for amyloid deposition. This case raises a caution that even when renal histology is not suggestive of amyloidosis and prednisolone therapy is very effective, when a renal histology diagnosis is not confirmed, the clinician should suspect amyloidosis and should, at least, undertake Congo red staining to definitively rule out amyloidosis.     

Successful treatment of nephrotic syndrome due to systemic AL amyloidosis after autologous stem cell transplantation: renal response is an important therapeutic end point

Primary systemic (AL) amyloidosis involves vital organs from the early phase of illness, resulting in poor prognosis. Today, high-dose melphalan followed by autologous peripheral blood stem cell transplantation is an effective treatment for systemic AL amyloidosis. We report a patient with nephrotic syndrome due to systemic AL amyloidosis, who was successfully treated with autologous peripheral blood stem cell transplantation. At follow-up 36 months from ASCT, the patient showed a significant improvement in the signs of peripheral neuropathy and reduction in proteinuria without further organ involvement. Due to poor prognosis with conventional therapy, autologous stem cell transplantation should be considered for treatment in patients with systemic AL amyloidosis, and favorable outcome is ensured with achievement of renal response after ASCT.     

Perimembranous-type renal amyloidosis: a peculiar form of AL amyloidosis

Six cases of perimembranous-type renal amyloidosis were reported. This type of renal amyloidosis was characterized by amyloid deposition predominantly involving the epithelial aspect of the glomerular capillary wall. Florid spicular arrangement was another representative feature. This type of amyloid deposition was found in 8% of autopsy cases of systemic amyloidosis. All cases were categorized as AL amyloidosis and developed the nephrotic syndrome irrespective of the amount of amyloid within the glomeruli. The results obtained suggest that perimembranous-type renal amyloidosis is a peculiar form of AL amyloidosis both in morphology and clinical manifestations. autopsy cases of systemic amyloidosis. All cases were categorized as AL amyloidosis and developed the nephrotic syndrome irrespective of the amount of amyloid within the glomeruli. The results obtained suggest that perimembranous-type renal amyloidosis is a peculiar form of AL amyloidosis both in morphology and clinical manifestations. autopsy cases of systemic amyloidosis. All cases were categorized as AL amyloidosis and developed the nephrotic syndrome irrespective of the amount of amyloid within the glomeruli. The results obtained suggest that perimembranous-type renal amyloidosis is a peculiar form of AL amyloidosis both in morphology and clinical manifestations.     

Renal involvement in juvenile chronic arthritis: clinical and pathologic features

Over an 18-year period, renal involvement was diagnosed in 13 patients, who represent 1% of the total juvenile chronic arthritis population referred to us. All had severe arthritis. This study illustrates the importance of renal biopsy and indicates that renal involvement in juvenile chronic arthritis is a heterogeneous group of diseases, with a variety of causes. In eight patients with nephrotic syndrome, renal biopsy revealed amyloidosis. One rapidly died of diffuse amyloidosis and infection. The other seven received chlorambucil. Disappearance of proteinuria was noted in three of them. Four patients have persistent proteinuria but normal serum creatinine. It is suggested that, despite the long-term oncogenic risk of the drug, chlorambucil may be beneficial in patients with amyloid deposits. In one patient, the nephrotic syndrome was attributed to systemic lupus erythematosus, and in another, the chance association of an arthritis and nephrotic syndrome with minimal glomerular changes was considered. Although drug responsibility is difficult to determine in these patients receiving several medications in association, the renal involvement presented by the remaining three patients was probably related to drug(s). Moreover, it is possible that the effect of the association of medications is deleterious to the kidney. Drug-induced nephropathy is usually reversible when drugs are stopped. Unfortunately, because of persistent joint pain, these patients will continue to require pain-relieving drugs over prolonged periods.     

误诊为过敏性紫癜性肾炎的AL型肾脏淀粉样变性病一例报道及文献复习

目的：通过报道1例以皮肤紫癜和肾损害为主要临床表现的免疫球蛋白轻链κ亚型淀粉样变性病（immunoglobulin light-chain kappa subtypes amyloidosis）的病例,并结合文献系统复习淀粉样变的分型、病理、临床表现、诊断与鉴别诊断及治疗原则,以期提高对该病的认识和重视,避免误漏诊,早期获得正确合理的治疗。方法患者1例,多处反复皮肤紫癜及肾病综合征（nephrotic syn-drome,NS）、镜下血尿、水肿等肾脏受累为主的临床表现,曾为多家医院诊断为“过敏性紫癜性肾炎”。入我院经肾穿刺病理活检。病理诊断：AL-κ亚型肾淀粉样变性病。根据以上临床资料,总结复习相关文献。结果患者经对症及口服激素治疗,病情稳定。结论肾淀粉样变性病是中老年继发性肾病综合征常见的病因之一,并非罕见,应予高度重视。凡具有大量蛋白尿或 NS 的中老年患者,特别是伴皮肤紫癜、低血压、肝大、舌肥大、心脏受累等应进一步行血、尿免疫固定电泳检查,对可疑患者应尽早进行肾活检,争取早期明确诊断、以期早期合理治疗,提高生存质量和生存时间。     

Immunoglobulin heavy chain can be amyloidogenic: morphologic characterization including immunoelectron microscopy

It is not well recognized that monoclonal immunoglobulin heavy chains or their fragments can be amyloidogenic. Amyloidosis due to heavy chains, referred to as AH amyloidosis, is rare with only three cases previously reported. An additional case of AH amyloidosis is reported. To the best of our knowledge, this is the first case of IgM heavy chain amyloidosis. A 59-year-old man presented with nephrotic syndrome. Immunoelectrophoresis detected a monoclonal IgM lambda in his serum and free lambda light chains in his urine. A renal biopsy showed amyloidosis, in which the amyloid deposits stained only for mu heavy chain by immunofluorescent and immunoelectron microscopic studies. This case suggests that monoclonal immunoglobulin heavy chains can be amyloidogenic. Furthermore, this type of amyloidosis shares the same morphologic features with other types of amyloidosis and can involve the kidney to produce nephrotic syndrome.     

肾淀粉样变的诊断与病理分型分析

Objective To clarify the clinicopathological features of renal amyloidosis in order to achieve early diagnosis and treatment. Methods Clinicopathological data of 26 biopsy-proven renal amyloidosis cases in Department of Nephrology, Zhongshan Hospital, Fudan University between 2006 and 2010 were analyzed retrospectively. Immunohistochemistry and immunofluorescence of amyloid A protein, immunoglobulin light chains such as ?资、?姿 were performed on renal specimens for further classification. Results Age of 26 patients ranged from 40 to 77 years old, average (58.54±10.07) years. Twenty-two out of 26 patients (84.62%) were treated in local hospital before admitted to our department, and 21 patients (95.45%) were misdiagnosed as chronic primary glomerulonephritis. The prominent clinical manifestations of renal amyloidosis were nephrotic syndrome (17 cases, 65.38%), decreased blood pressure (16 cases, 61.53%), organ enlargement (8 cases, 30.77%) and bodyweight loss (6 cases, 23.08%). Fourteen out of 25 patients (56.00%) were found to have monoclonal light chains in serum by immunofixation electrophoresis. Three patients with mild pathological changes who had no confirmable Congo red stain were confirmed by electron microscopy. Twenty-three (88.46%) patients were diagnosed as AL amyloidosis, one (3.85%) as AA amyloidosis, one was strongly suspected of hereditary amyloidosis, and one was undetermined. Conclusions Renal amyloidosis is frequently misdiagnosed. Middle-aged and old nephrotic patients with decreased blood presure, organ enlargement and bodyweight loss may be the most helpful clues of the disease. Most patients have monoclonal light chains in serum or urine. Renal biopsy, especially electronic microscopy plays a crucial role in the early diagnosis of renal amyloidosis. Immunohistochemistry is important for patients with renal amyloidosis in pathological classification and treatment.     

Diagnosis and treatment of multiple myeloma and AL amyloidosis with focus on improvement of renal lesion

Multiple myeloma (MM) and AL amyloidosis are caused by the expansion of monoclonal plasma cells and secretion of dysproteinemia (Bence Jones protein and free light chain) and some patients require the hemodialysis. Myeloma kidney is mainly caused by the cast nephropathy of the distal tubuli, whereas, AL amyloid-protein is mainly deposited in glomeruli with massive fibrillar involvement. Therefore, almost MM patients presents a symptom of renal insufficiency, whereas, almost patients of AL amyloidosis present a nephrotic syndrome with severe hypoalbuminemia. These two diseases have some similar characteristics such as up-regulation of cyclin D1 gene by 11:14 chromosomal translocation. High-dose chemotherapy supported with autologous peripheral blood stem cells is effective for these two diseases. However, they are still difficult to be cured and require long-term disease control. In recent years, introduction of novel agents has changed their treatment strategies from the palliation therapy to the clinical cure.     

Late onset renal failure and nephrotic syndrome after autologous stem cell transplant for Al amyloidosis

We present a patient with AL amyloidosis who had an autologous stem cell transplant (ASCT) over 9 years ago. She has since then developed slowly progressive renal insufficiency and the nephrotic syndrome. Hematologic evaluation has failed to identify recurrent disease and a renal biopsy demonstrated extensive amyloid deposition and substantial glomerulosclerosis. We suggest that the patient has chronic glomerulosclerosis as a consequence of renal damage associated with her disease process and her treatment.     

Resolution of nephrotic syndrome and lack of progression of heroin-associated renal amyloidosis

The case of a patient with nephrotic syndrome and renal insufficiency due to renal amyloidosis secondary to chronic subcutaneous heroin abuse who discontinued her drug habit is reported. During the 6 years following the initial renal biopsy, the patient's nephrotic syndrome remitted: urinary protein decreased from 6.8 g/d to 170 mg/d, serum albumin increased from 2.5 g/dL to 3.9 g/dL, and she was no longer edematous. Serum creatinine remained stable at 1.8 mg/dL and creatinine clearance was also unchanged at 34 mL/min. Repeat renal biopsy showed AA amyloidosis involving the glomeruli, with minimal interstitial inflammation. This appears to be the first case of clinical improvement in heroin-associated renal amyloidosis after cessation of drug injections. As in other cases of AA amyloidosis that have improved, the clinical picture does not correlate with the findings on renal biopsy.     

Late Onset Renal Failure and Nephrotic Syndrome after Autologous Stem Cell Transplant for AL Amyloidosis

We present a patient with AL amyloidosis who had an autologous stem cell transplant (ASCT) over 9 years ago. She has since then developed slowly progressive renal insufficiency and the nephrotic syndrome. Hematologic evaluation has failed to identify recurrent disease and a renal biopsy demonstrated extensive amyloid deposition and substantial glomerulosclerosis. We suggest that the patient has chronic glomerulosclerosis as a consequence of renal damage associated with her disease process and her treatment.     

Remission of the nephrotic syndrome in a patient with renal amyloidosis due to rheumatoid arthritis treated with prednisolone and methotrexate

A 46-year-old woman developed nephrotic syndrome secondary to rheumatoid arthritis (RA). A renal biopsy showed deposition of amyloid fibrils in the subendothelial space of the glomerular capillary walls. After treatment with prednisolone (PSL, 40 mg/day), the levels of C- reactive protein (CRP) and serum amyloid A decreased to within normal limits for 2 weeks. However, the nephrotic syndrome persisted for 6 months after the therapy. To maintain the suppression of disease activity and to reduce PSL, methotrexate (5 mg/week) was added. The nephrotic syndrome resolved gradually, and the level of serum albumin returned to normal. Although renal prognosis of patients with nephrotic syndrome due to amyloidosis caused by RA has been considered poor, adequate and long-term treatment of RA with antiinflammatory drugs, including PSL and methotrexate, is useful for patients with secondary amyloidosis complicated by RA. (Am J Kidney Dis 1998 Nov;32(5):E7)     

Renal amyloidosis in a child with sickle cell anemia

The kidney is frequently affected in patients with sickle cell syndrome, i.e., homozygous and heterozygous patients, with a consequently large spectrum of renal abnormalities that may range from minimal functional changes to chronic renal failure. Here, we present a 13-year-old boy with sickle cell anemia (SCA) (HbSS) who was referred to our unit with nephrotic syndrome. Renal biopsy revealed AA type amyloidosis on the basis of light microscopic findings, indicating Congo red staining and immunohistochemistry. He had neither a family history of familial Mediterranean fever (FMF) nor any complaint of recurrent abdominal pain, arthritis, and fever, but frequent painful vaso-occlusive crises. The patient was found to have no MEFV gene (Mediterranean feVer) mutations either. Painful episodic attacks might provoke recurrent acute inflammation, leading to repeated stimulation of acute phase responses and cause secondary amyloidosis. To our knowledge, this boy is the first case of SCA complicated by renal amyloidosis observed in childhood.     

De novo AL Amyloidosis in the Kidney Allograft

We report four cases of de novo amyloidosis occurring after 16, 18, 28 and 31 years following kidney transplantation. These patients presented with proteinuria and progressive allograft dysfunction. Kidney biopsy showed AL amyloidosis in all compartments of the allograft kidney. Serum immunofixation studies revealed monoclonal lambda light chains in all four cases. Bone marrow examination showed 10% plasma cells in one case, 5–10% in two cases and less than 5% in one case. Two patients died unexpectedly within 3 months and 1 year of the diagnosis of allograft AL amyloidosis. Of the remaining two, one underwent autologous stem cell transplant that resulted in complete hematologic remission. However, the patient relapsed within 2 years and also developed progressive kidney allograft failure. The patient received a second autologous stem cell transplant with complete hematologic response, followed by a second kidney transplant, which showed no evidence of amyloid at 1‐year posttransplant. The remaining case was treated with prednisone and bortezomib, which has stabilized kidney function in the short term. In conclusion, this study shows that AL amyloidosis is an uncommon but important cause of late onset proteinuria in the kidney allograft that results in kidney allograft failure.     

Distribution of pathologic findings in individuals with nephrotic proteinuria according to serum albumin.

BACKGROUND: Previous studies of the nephrotic syndrome have not carefully examined the relationship between serum albumin and the distribution of pathologic diagnoses found at the time of biopsy. The spectrum of pathologic findings in individuals with nephrotic proteinuria and a normal serum albumin has not been determined. Knowledge regarding the spectrum of findings in nephrotic proteinuria according to serum albumin levels may help nephrologists in the clinical decision making of when to perform a renal biopsy and in determining proper management of these patients. METHODS: Pathologic reports of native kidney biopsies performed for idiopathic proteinuria >3 g/24 h were reviewed. Clinical characteristics and biopsy findings were compared for individuals with serum albumin <30 g/L (Group I), 30 to <35 g/L (Group II) and >/=35 g/L (Group III). RESULTS: There were 57 patients in Group I, 20 in Group II and 35 in Group III. The proportion of individuals with focal and segmental glomerulosclerosis (FSGS) increased according to group: 26% in Group I, 45% in Group II and 74% in Group III. Of 35 patients in Group III, 34 had FSGS or advanced nephrosclerosis from another cause. Seven of 17 Group III patients with follow-up required dialysis after a mean interval of 6 years. Few of these patients received immunosuppressive therapy. CONCLUSIONS: As serum albumin increases in the nephrotic syndrome, the proportion of patients with FSGS increases. Patients with nephrotic proteinuria and a serum albumin >35 g/L suffer from FSGS, nephrosclerosis and have poor renal survival. When evaluating nephrotic patients, nephrologists should use this knowledge about the spectrum of disease in the clinical decision making of when to perform a biopsy and in providing the patient more precise information regarding risks, benefits and alternatives of the kidney biopsy procedure.     

Kidney and liver involvement in monoclonal light chain disorders

Monoclonal light chains (LCs) are responsible for a wide spectrum of renal and hepatic diseases, that above all include amyloid light-chain (AL) amyloidosis and light chain deposition disease (LCDD). Amyloid deposits stain for Congo red on light microscopy and have fibrillar aspect on electron microscopy, whereas deposits in LCDD are positive using monotypic LCs on immunofluorescence and have a granular aspect on electron microscopy. Sometimes fibrillar and granular deposits are observed in the same organ or in different organs of the same patient. Kidney and liver involvement is a frequent finding, both in primary amyloidosis (AL amyloidosis) or in LCDD. Renal manifestations include proteinuria, nephrotic syndrome, and progressive renal failure. End-stage renal disease requiring dialysis is observed in about 20% of patients with AL amyloidosis and in 70% of patients with LCDD. The mean survival time is about 12 to 18 months in AL amyloidosis and 34 months in LCDD. The most important prognostic factor is severe cardiac involvement, which reduces the mean survival to only 6 months. Hepatic manifestations include hepatomegaly, portal hypertension, ascites, intrahepatic cholostatic jaundice, and hepatic insufficiency. The mean survival of patients with liver damage is 14 months, but it is reduced to 5 months in patients with cholostatic jaundice. Contemporary kidney and liver involvement is usually observed on histologic examination, less frequently as clinical manifestation. No specific treatment exists for AL amyloidosis and LCDD, and the prognosis remains severe. The aim of treatment is to suppress proliferation of the abnormal clone of plasma cells and remove tissue deposits. The regimens, including melphalan-prednisone (MP) or vincristine-doxorubicin-dexamethasone (VAD), are used both in AL amyloidosis or in LCDD with some effectiveness. New approaches, especially the use of 4'-iodo-4'deoxydoxorubicin, could achieve better results. Dialysis seems to not worsen the outcome in both diseases because survival of patients on dialysis is not different from that of patients not reaching uremia. Also, kidney and liver transplantation is effective, though amyloidosis or LCDD may occur in transplanted organs. The most interesting therapeutic approach is autologous-blood stem-cell transplantation, which may produce a complete remission of the plasma-cell dyscrasia and a substantial improvement of clinical manifestations related to LC deposits.