Pathological, Clinical Characteristics and Prognostic Analysis of Amyloid Nephropathy

Abstract

Background: The number of patients diagnosed with renal amyloidosis is increasing year by year, and the pathological grade and prognostic factors are not clear. This study attempts to investigate the pathological features of renal amyloidosis and the prognostic factors in patients with amyloidosis.

Method：To evaluate the pathological sections of 184 patients with renal amyloidosis in the Department of Pathology, Shandong University, and to retrospectively analyze the clinical data of 175 patients with amyloidosis in our center and to follow up them.

Results: There was a positive correlation between different pathological grades and creatinine levels (rs = 0.275, P = 0.38), the higher the pathological grade, the higher the incidence of renal insufficiency (χ2 = 8.44, P = 0.015); the more severe the tubulointerstitial damage, the higher the incidence of renal insufficiency (χ2 = 14.15, P = 0.007); different degrees of tubulointerstitial damage and glomerulosclerosis affected the urinary protein quantification, and the difference was statistically significant (P < 0.05). The treatment effect of older is worse (P=0.030，OR=1.040，95%CI=1.004，1.078) and the effect of selecting an effective treatment is better (P = 0.002, OR = 0.618, 95% CI = 0.456, 0.839). Hypotension, cardiac involvement, decreased serum albumin, and increased TnT were independent risk factors for survival; while receiving effective treatment modalities was an independent protective factor.

Conclusion: The pathological grade of renal amyloidosis is associated with the incidence of renal insufficiency, in which the degree of tubulointerstitial chronic lesions significantly affects renal function. 

Background

Amyloidosis is a systemic disease, mostly caused by extracellular deposition of amyloid from β-structured fibrin, which can be deposited in multiple organs such as kidney, heart, and skin causing damage(1), and can be secondary to a variety of diseases, such as plasma cell disease, chronic inflammatory diseases, and gene mutations, with an incidence of about 10 people/million per year in the population. There are different proteins in different types of amyloidosis. At present, 36 human proteins have been associated with amyloidosis, including immunoglobulin light chain (AL), serum amyloid A (AA), transthyretin (ATFR), etc.(2), and the mechanism is relatively complex. AL and AA are currently the two most common forms, the former being more common in developed countries, and as a plasma cell disease, monoclonal proteins can be detected in urine or serum in more than 95% of patients(3); the latter is common in developing countries and is secondary to active or recurrent inflammatory diseases(4). The clinical manifestations are complex and diverse due to different organs involved, such as heart failure, massive proteinuria, edema, skin ecchymotic papules, hepatosplenomegaly, and tongue hypertrophy, which are not specific, have a high rate of clinical misdiagnosis, and have a poor prognosis. Among them, renal involvement can be 74%(5). Compared with Western countries, the proportion of renal involvement in Chinese patients(6).

Studies have shown that its clinical manifestations may be related to the location and mode of amyloid deposition, glomerular deposition is mainly manifested as severe nephrotic syndrome with volume overload, while patients with tubulointerstitial or vascular deposition usually show lower proteinuria and progressive renal damage(7). Amyloid is deposited in glomeruli, renal interstitium, renal vessels, and tubules in different ways. Pathologists such as Watanabe and Saniter(8), Dikman(9), and Shiiki(10) continuously defined and updated the deposition pattern of amyloid, and Verine et al defined the distribution of glomerular amyloid deposits as six categories: nodular, diffuse intimal, capillary or mixed, mainly extramembranous or perimembranous, and pulmonary(11). However, a clear relationship between the degree of amyloid deposition and the severity of the clinical presentation remains unconfirmed, renal amyloid biopsy reports are not standardized, and amyloidosis progresses rapidly without a specific treatment regimen and has a poor prognosis. Based on the above reasons, Sait et al proposed a histopathological classification, scoring, and grading system for renal amyloidosis to provide ideas for pathological grading as well as prognosis(12).

In addition to the extent of amyloid deposition and other pathological changes, recent guidelines have shown that urinary protein quantification, serum creatinine levels and glomerular filtration rate(13), free light chains(14), cardiac involvement(15) and other markers (e.g. cTNT(16), BNP(17), albumin(18), etc.) all affect the prognosis of amyloidosis. To further investigate the relationship between pathological changes and clinical characteristics and prognosis of amyloidosis nephropathy, risk factors that may affect prognosis, and different clinical and prognostic characteristics of renal amyloidosis and amyloidosis in other organs, we evaluated the pathological sections of amyloidosis nephropathy and also retrospectively analyzed the clinical data of amyloidosis in our center.

Method

1. Patients 184 patients with renal amyloidosis who underwent pathological analysis of renal biopsy in the Department of Pathology, Shandong University School of Medicine, 17 prefectural tertiary hospitals and 15 secondary hospitals in Shandong Province from March 2000 to March 2020 were selected. And 175 patients were confirmed to have amyloidosis by pathological biopsy in Shandong Provincial Hospital were selected as the study subjects.

2. Inclusion and exclusion criteria Inclusion criteria: (1) diagnosed with renal or other organ amyloidosis by pathological biopsy; (2) patients with case data in our hospital or other hospitals; Exclusion criteria: (1) patients with severe cardiovascular and cerebrovascular diseases, malignant tumors, end-stage renal disease, etc.; (2) do not cooperate with the follow-up.

3. Study methods (1) 184 cases of renal amyloidosis pathological sections and reports were repeatedly read and evaluated, the histopathological classification, scoring and grading of renal amyloidosis were performed, and the correlation between pathological changes and clinical characteristics of amyloidosis nephropathy was analyzed; (2) The clinical and pathological data of patients in our center were collected to determine the prognosis of patients (cure, remission, no improvement, death), and factors that may affect the prognosis. (3) follow-up was performed from definite diagnosis to patient death or the most recent clinical follow-up, with the endpoint of patient death.

Results

Discussion

As the number of confirmed cases of renal amyloidosis gradually increases, the disease is no longer rare and unfamiliar. Renal amyloidosis is mainly due to deposition of amyloid in the kidney, non-specifically manifested as edema, proteinuria and renal impairment. In our study, the number of amyloid patients diagnosed after 2014 was significantly higher than before, especially in patients with renal amyloidosis, with up to 89.13% of patients diagnosed in the past 5 years. The reasons are mainly related to the improvement of test methods and the continuous improvement of the understanding of the disease. After 2014, most hospitals in China carried out free light chain detection, combined with immunofixation electrophoresis and bone marrow aspiration results, for multi-level differential diagnosis, significantly improving the diagnosis rate. At the same time, the addition of light chain κ and λ staining items in immunofluorescence staining of pathological biopsy is also conducive to improve the diagnosis rate.

Sammer et al. collected 22,330 cases of renal biopsy in the United States, of which 474 cases were diagnosed as amyloidosis nephropathy, accounting for 2.1%(19); in relevant Spanish studies, renal amyloidosis accounted for 3.7% of renal biopsy(20), while the incidence in Italy was 2.5%(21). Compared with foreign countries, relevant studies in China reported that amyloidosis nephropathy accounted for 0.89% ~ 1.27% of renal biopsy cases in the same period(22); in this study, renal amyloidosis patients accounted for 1.30% of renal biopsy cases in the same period in Shandong Province, which was lower than the incidence in foreign countries and consistent with domestic studies. Some patients did not undergo renal biopsy due to personal reasons, some patients visited other departments with extrarenal manifestations and didn’t confirm by renal biopsy because of the insufficient communication between nephrology department and non-nephrology room doctors. What’s more, amyloidosis nephropathy was rare before 2010, only few case reports in China. There were lack of large-sample studies about amyloidosis and deep recognition of this disease, resulting in a high rate of clinical misdiagnosis.

With renal involvement in our study, amyloid was mainly deposited in the glomeruli, mostly in the interstitial small vessel wall, and only a small part was deposited in the renal tubules and renal interstitium; there were varying degrees of tubular atrophy and interstitial fibrosis, with inflammatory cell infiltration, which was consistent with most studies. Six patients showed a weak positive Congo red staining, possibly due to less amyloid deposition in the early stages of the disease, or inadequate staining due to inappropriate section thickness. Eight cases which showed minimal glomerular lesions were finally diagnosed with early amyloidosis nephropathy combined with the results of special staining. Hetzel and Sayed also showed that patients with amyloidosis nephropathy may present with minimal glomerular lesions in the early stage(23, 24), and the final diagnosis of amyloidosis is confirmed after electron microscopy, multiple stains, or repeated renal biopsy. The possible reasons include: patient has both of these diseases; the morphological variations of amyloid that are indistinguishable from minor glomerular lesions on light microscopy; or amyloid deposition is too small to detect in early stages. Therefore, the initial diagnosis of amyloidosis nephropathy needs to be combined with light microscopy, special staining, electron microscopy and clinical manifestations. Moreover, the time interval between the diagnosis of minimal glomerulopathy and renal amyloidosis was up to 241 days(24). Therefore, in clinical practice, for patients with pathological results of minimal glomerulopathy, accompanied by plasmacytosis, ineffective hormone therapy, or other organ involvement, and abnormal relevant clinical indicators (light chain, immunofixation electrophoresis, etc.), it is necessary to attach great importance to whether it is amyloidosis disease and timely make a correct diagnosis.

In this study, the light microscopic results of one patient who underwent renal biopsy at an outside hospital showed membranoproliferative glomerulonephritis, but electron microscopy revealed patchy irregular filamentous fibrous material deposited in the renal tissue, suggesting renal amyloidosis. The other case showed glomerular mesangial ganglion hyperplasia lesions, poor therapeutic effect after several months of hormone combined with immunosuppressive agents, and lower extremity venous thrombosis, and pathological sections were consulted in the pathology department of our hospital, and Congo red staining was performed again to show positivity, confirming the diagnosis of renal amyloidosis. Therefore, not only minimal glomerular lesions, but also other pathological types can present the same situation. So electron microscopy, Congo red counterstaining, and secondary renal biopsy are all important ways to reduce the misdiagnosis rate.

Amyloid nephropathy is easily confused with other renal diseases like as fibroid glomerulonephritis(25), immune vibrissae glomerulopathy(26), collagen type III glomerular disease(27), and light chain deposition disease(28), all of which present with proteinuria and edema, and there is fibroid or granular material deposition under electron microscopy, which has been poorly recognized by doctors in the early years, leading to easy misdiagnosis in clinical practice. These diseases can be differentiated by Congo red staining and electron microscopy. Recent studies have shown the presence of DNAJB9 protein in the glomeruli of patients with fibroid glomerulonephritis but not in patients with several other diseases, and immunohistochemical detection of glomerular DNAJB9 has 98% sensitivity and > 99% specificity(29, 30).In our study, one patient was not the age of high incidence of amyloidosis because of his young age, and there were pathological reports of fibroid glomerulonephritis with Congo red positivity(31), and to rule out the disease, DNAJB9 immunohistochemical detection was performed with negative results, combined with electron microscopic results to finally diagnose amyloidosis nephropathy. Therefore, the diagnosis rate can be improved by Congo red counterstaining, special immunofluorescence staining, and high magnification observation under electron microscope.

Sait et al classified and scored 305 cases of renal amyloidosis, 90% of which were AA type amyloidosis, and found that pathological grade was correlated with glomerular histopathological classification, and the severity of glomerular amyloid deposition was positively correlated with interstitial fibrosis and inflammation(12). Sasatomi’s study showed that serum creatinine level and pathological grade at renal biopsy were associated with accelerated progression of the disease, of which the most important prognostic factors were glomerular, tubulointerstitial and vascular lesions due to amyloid deposition(32). Yao Ying et al summarized the pathological changes of 199 patients with AL renal amyloidosis by semi-integral quantitative method and found that the degree of glomerular amyloidosis was positively correlated with the amount of urinary protein, and the incidence of renal insufficiency was higher in patients with GA and severe renal interstitial damage(22). This study found that different pathological grades were positively correlated with creatinine levels, and the higher the pathological grade, the higher the incidence of renal insufficiency; the more severe the tubulointerstitial damage, the incidence of renal insufficiency, and the relatively higher the urinary protein quantification; at the same time, the degree of glomerulosclerosis would also affect the urinary protein quantification. However, there were no significant correlations between the degree of amyloidosis in different renal tissues and proteinuria quantification or the incidence of renal insufficiency. There was also no correlation between pathological grade and mortality in patients with different amyloid nephropathy. Since the number of patients with complete renal pathology, clinical and follow-up data in our center is small, and the sample size is smaller in patients with severe pathological lesions, the relationship between the degree of amyloid deposition in different renal tissues and clinical indicators still needs to be further verified by large-sample study; the actual prognosis and clinical applicability of RAPS and renal amyloidosis patients need to be further validated.

AL amyloidosis is the most common type of amyloidosis nephropathy, accounting for 81.0–92.7%(19)]. In this study, the specific classification was not performed, but it is worth noting that the addition of light chain κ and λ staining in the immunofluorescence staining program after 2014. In this study, 141 patients underwent light chain κ/λ staining, of which 51.06% were λ positive and 26.95% were κ positive. For one of κ or λ staining, it showed positive ( + + or + + +), while the other showed negative, then the pathological report considered AL amyloidosis; for both κ and λ, it was considered very likely to be AL; if both κ and λ were negative or weakly positive (+/- or +), further immunohistochemical staining was required to determine their classification. Therefore, according to the results of light chain κ/λ immunofluorescence staining, in the absence of immunohistochemistry and genetic testing, whether the clinical rough classification can be made in combination with the results of free light chain and immunofixation electrophoresis will provide our clinical and pathologists with great preliminary diagnosis and treatment direction.

Correlation analysis of risk factors in our study showed that blood pressure, serum albumin, eGFR, cTnT and BNP, cardiac and multiple organ involvement, and treatment methods all affected mortality. And hypotension, cardiac involvement, decreased albumin, and increased TnT were independent risk factors for survival, while receiving effective treatment was an independent protective factor for survival. For renal amyloidosis, domestic studies have shown that massive proteinuria and creatinine level at the time of diagnosis will affect the prognosis of patients(15, 32). Mayo Group study indicated that creatinine level did not affect the survival time of patients, but the decrease of urinary protein quantification greater than 95% within 1 year may prolong the survival time of patients(33). However, in this study, it was found that decreased serum albumin was an independent risk factor for patient survival, which was related to massive proteinuria and renal impairment. So, it is crucial for doctor to pay close attention to the level of albumin, proteinuria, creatinine and eGFR.

The key to the treatment of this disease lies in stopping or reducing the production of amyloid sources and promoting clearance. At present, the removal of free light chains and small molecules mainly uses high cut-off dialysis, but inhibition of amyloid production is determined by its typing. Localized amyloidosis had a good effect of surgical treatment and a good prognosis in our study. The Mayo team followed up 413 patients with localized amyloidosis and showed that 61% of patients chose first-line surgery, with a 10-year survival rate as high as 78% and no systemic progression(34). Patients with multiple organ involvement are usually complicated to treat and have a significantly higher mortality rate than single organ involvement. Chemotherapy is the main treatment for AL amyloidosis. Studies have shown that the optimal regimen is high-dose melphalan combined with autologous stem cell transplantation (ASCT), which can achieve hematological remission in about 40% of cases and control the treatment-related mortality at 10%(35). However, this surgery requires strict requirements for patients and professional centers. In our center, only 6 patients underwent ASCT, with a mortality rate of 16.67%. The mortality rate is higher than other studies possibly because of small sample. Patients not eligible for ASCT receive standard-dose chemotherapy based on alkylating agents, steroids, proteasome inhibitors, and immunomodulatory drugs(3). The most commonly regimen is bortezomib combined with dexamethasone, and studies have shown that 65% of patients on this regimen can achieve complete or partial remission, with a 5-year survival rate of 80% in intermediate-risk patients(36). 18 patients chose this regimen in our study, with the 1-year survival rate was 70.6% which was lower than that in foreign studies. Recent studies have shown that monoclonal antibodies can not only provide treatment against malignant plasma cells, but also target and remove amyloid from organs, with the advantages of high selectivity and low toxicity, becoming one of the expected clinical treatments in the future(37, 38).AA amyloidosis is mainly associated with long-term inflammatory conditions(39, 40), and treatment is based on the control of inflammation, clinically mainly using factors, antibiotics, colchicine and other treatments(41, 42). For patients with poor efficacy or severe organ failure, organ transplantation was performed. Patients with hereditary amyloidosis are treated by liver transplantation or gene knockout. Although treatment modalities continue to be updated, organ failure is irreversible for patients with advanced disease. Therefore, early diagnosis, classification and treatment are particularly important, and clinicians should continuously improve their understanding and attention to the disease.

This study is a retrospective analysis. The time span of admission for the included patients is large, the pathological and clinical data and data of some patients are missing, the conditions for medical examination in the early years are limited, and only a small part of clinical indicators can be determined. The majority of patients diagnosed in our unit are not clearly classified, so the number of patients with AL, AA or other types of amyloidosis cannot be determined, with the pathological, clinical characteristics and prognosis analysis among different types cannot be performed. During the follow-up, some patients are lost to follow-up due to the change of contact information. For these reasons, the survival time of some clinical indicators cannot be obtained, which has impact on the later analysis and prediction, with some limitations. However, with the continuous refinement of diagnosis and treatment techniques, as well as the increase of clinician communication and cooperation in various departments, early and correct diagnosis and effective treatment will effectively improve the prognosis of amyloidosis patients.

Conclusion

The pathological grade of renal amyloidosis is associated with the incidence of renal insufficiency, in which the degree of tubulointerstitial chronic lesions significantly affects renal function. The relationship between the degree of starch deposition in different renal tissues and the levels of proteinuria and renal function still needs to be explored in large sample studies. At the same time, clinicians should pay more attention to the relevant risk factors to improve the early diagnosis rate and improve the prognosis of patients.

Declarations

Acknowledgements

We thank all patients, practice nurses, and investigators for their contributions to this study.

Funding

This work was supported by National Natural Science Foundation of China [grant number 81770723].

Availability of data and materials

The data sets in this study are available from the corresponding author on reasonable request.

Authors’ contribution

Study concept and design, drafting of manuscript: ZX. Acquisition of data, or analysis of data: ZX. Revision of manuscript for important intellectual content: YC, WR. All authors have read and approve of the final version of the manuscript.

Competing interests

The authors report no conflict of interest.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of the Provincial Hospital of Shandong University. Written informed consent was obtained from all patients participating in the study.

Consent for publication

Not applicable.

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