Hereditary amyloidosis with renal damage as a clinical problem: a case report

Introduction

Amyloidosis is a group of diseases characterized by the pathological deposition of protein fibrils in various tissues and organs. Classification systems based on the precursor protein are of primary importance. The most common variants of amyloidosis are the following: AL (associated with the deposition of immunoglobulin light chains), AA (associated with the acute-phase SAA protein), and ATTR (amyloidosis associated with transthyretin) [1, 2]. However, along with them, there are ultra-rare genetically determined forms, one of which is lysozyme amyloidosis.

Lysozyme is a protein synthesized primarily by macrophage cells and liver cells that has antibacterial properties [3]. In lysozyme amyloidosis, this protein undergoes structural changes, which lead to the formation of amyloid fibrils and their deposition in tissues. Clinically, the disease can manifest itself in a variety of symptoms, from asymptomatic progression to severe damage to the kidneys, liver, gastrointestinal tract, and lymphoid system [4]. Given the rarity of this condition, diagnosis often presents a significant challenge for specialists because the clinical picture can imitate more common variants of renal pathology, such as chronic tubulointerstitial nephritis, chronic glomerulonephritis, or systemic amyloidosis.

The expanded use of specialized research methods – immunofluorescence and immunohistochemistry— allows not only the identification of amyloid deposits but also the determination of their primary protein composition (precursor protein). This is important because correct identification of the amyloid type determines the tactics of further observation and treatment and allows for genetic counseling of the patient’s family members [5]. The available literature notes that the timely detection of lysozyme amyloidosis can have a significant impact on the prognosis of the disease, despite the absence of specific therapy aimed directly at the amyloid process [2, 4].

This article presents an analysis of a clinical case in which repeated morphological consultation played a decisive role in establishing the final diagnosis. Particular attention was paid to the chronology of events, starting from the initial complaints and examinations in April 2024 to the repeated assessment of microscopic preparations in November 2024, which confirmed genetically determined lysozyme amyloidosis. This approach emphasizes the importance of dynamic observation and interdisciplinary interaction between nephrologists, hematologists, and pathologists (nephropathologists) for the early detection and correct interpretation of rare pathological processes.

Case description

Patient A., 28 years old, living in the Yaroslavl region, has been under the supervision of a nephrologist since 2017 for urinary syndrome and chronic anemia. Since 2022, hepatosplenomegaly of unknown genesis and mesenteric lymphadenopathy have been noted, which required consultation with a hematologist and rheumatologist to exclude myeloproliferative and autoimmune diseases. The anamnesis also includes chronic colitis, gastritis, and mild iron deficiency anemia. Additional examination excluded Krabbe, Pompe, Niemann-Pick, Gaucher and Fabry diseases. Myeloproliferative diseases were excluded (bone marrow trephine biopsy - no pathology). An extensive immunoserological study was conducted; autoimmune liver diseases and systemic autoimmune diseases were excluded. From 18.06.2024 to 25.06.2024, she underwent inpatient treatment for a comprehensive examination due to detected proteinuria and suspected chronic tubulointerstitial nephritis with stage 2 chronic kidney disease (glomerular filtration rate (GFR) = 61 ml/min). Upon admission, the main complaints were increased blood pressure (in one episode up to 198/140 mm Hg), headaches, and weakness. 

Laboratory tests revealed the following changes (data from 11/27/2024, relevant for the examination period):

• Proteinuria: 0.64 g/day.
• Creatinine: 91–109 μmol/l.
• Total serum protein: 63–71 g/l.
• Biochemical parameters (ALT, AST, urea, glucose) –– within normal limits.
• C-reactive protein (CRP): 0.1 mg/l.
• Complete blood count: hemoglobin 109 g/l, leukocytes 10.6 ×10⁹/l, ESR 2 mm/h.

During the instrumental examination, ultrasound examination of the abdominal organs revealed an enlarged liver and spleen and heterogeneity of the renal parenchyma with increased echogenicity, which confirmed the presence of a chronic inflammatory process. Additional ECG and echocardiographic examination did not reveal significant cardiac pathologies, except for moderately expressed changes in the myocardium.

To clarify the diagnosis, a nephrobiopsy of the left kidney was performed under ultrasound control on June 19, 2024. During the procedure, two samples of parenchymal tissue from the lower segment of the left kidney were obtained. The initial histological examination (June 25, 2024) revealed a morphological picture of hydronephrosis with protein casts in the lumen of the tubules and focal glomerulosclerosis. However, no amyloid deposits were detected. The clinical diagnosis was: Chronic tubulointerstitial nephritis. Stage 2 chronic kidney disease (GFR = 61 ml/min). Proteinuria. Hepatosplenomegaly of unknown genesis. Mesenteric lymphadenopathy. Chronic colitis. Chronic gastritis. Chronic anemia.

Due to the continued progression of proteinuria and the persistence of hepatosplenomegaly, a decision was made to re-consult the previously obtained morphological material in the morphological research laboratory of the N.I. Pirogov National Medical and Surgical Center of the Ministry of Health of the Russian Federation (11/27/2024). Upon review of the micropreparations performed using standard staining techniques (hematoxylin and eosin, PAS, Masson trichrome, Jones silver salt impregnation) and special methods (Congo red staining with polarized light assessment), the following was revealed:

• Of the 73 glomeruli analyzed, the vast majority showed giant enlargement, with the mesangial and subendothelial space of the glomeruli being totally or subtotally replaced by homogeneous amyloid material.
• Amyloid deposits demonstrated a bright apple-greenish fluorescence in polarized light, which is a characteristic morphological feature when stained with Congo red.
• The immunofluorescence examination did not reveal the specific expression of immunoglobulins or complement components.
• A key step was the immunohistochemical study using antibodies to lysozyme, transthyretin, amyloid A component and DNAJB9. The results showed diffusely pronounced expression of lysozyme (Lys+++), in the absence of expression of other markers.

Thus, the final diagnosis was established as lysozyme amyloidosis of the kidneys, a genetically determined disease in which amyloid deposits predominantly consist of lysozyme.

Discussion

Lysozyme amyloidosis is one of the ultra-rare types of amyloidosis, characterized by changes in the protein structure of lysozyme, which leads to its aggregation and deposition in tissues. Unlike the more common forms (AL, AA, ATTR), the diagnosis of this disease requires not only classical histological analysis but also the use of specialized staining and immunohistochemistry methods [1, 5].

In the case under consideration, the initial examination of the nephrobiopsy, conducted in April 2024, did not reveal amyloid deposits.

A repeat assessment of the micropreparations in November 2024, performed using an extended set of methods (including Congo red staining and immunohistochemical diagnostics), revealed massive amyloid deposits characteristic of lysozyme amyloidosis. A pronounced apple-green glow in polarized light is pathognomonic for amyloid structures, which in combination with a positive reaction to lysozyme (Lys+++) and a negative result in assessing other protein markers allows for a definitive diagnosis. Morphological diagnosis: ALys-amyloidosis of the kidneys (Lysozyme) with massive damage and subtotal replacement of the glomerular apparatus, with pronounced tubulo-interstitial deposition; without tubulo-interstitial fibrosis and arteriolosclerosis.

The differential diagnosis in this case included the exclusion of the more common forms of amyloidosis (AL, AA, ATTR) and fibrillary glomerulonephritis. The patient’s clinical phenotype — hepatosplenomegaly, presence of mesenteric lymphadenopathy, and chronic colitis — responds to the characteristics of lysozyme amyloidosis described in the literature [3]. In addition, the genetically determined nature of the disease suggests the need for genetic testing for the LYZ gene and examination of family members to identify hereditary predisposition. Final diagnosis: Systemic renal amyloidosis (ALys amyloidosis), morphologically verified (nephrobiopsy dated 06/19/2024) with damage to the kidneys, liver, and mesenteric lymph nodes. Chronic kidney disease stage 3 a A2. Arterial hypertension. Anemia. An important aspect is that this disease often progresses relatively slowly; however, kidney involvement can lead to the development of chronic renal failure. Early diagnosis is of great importance for optimizing therapy, diet correction, and organizing regular monitoring, which in the long term can slow down the progression of organ damage. An interdisciplinary approach, including consultations with a nephrologist, hematologist, therapist and geneticist, is a prerequisite for the comprehensive management of patients with rare forms of amyloidosis [2, 4].

The case presented in this article illustrates the difficulties of diagnosing ultra-rare lysozyme amyloidosis. The initial examination did not reveal the pathological changes characteristic of amyloidosis, which could have led to an incorrect diagnosis. Repeated examination using additional methods allowed us to correct the diagnosis and, thus, determine the tactics of further monitoring and treatment. The literature notes that such cases require increased vigilance on the part of specialists because early detection of amyloidosis can significantly affect the prognosis of the disease [1, 5, 6].

Conclusions

1. Clinical aspect. This case demonstrates that despite its rarity, lysozyme amyloidosis should be considered in the differential diagnosis of chronic tubulointerstitial nephritis and chronic kidney disease, especially in the presence of systemic changes (hepatosplenomegaly, lymphadenopathy, gastrointestinal disorders).
2. Diagnostic approach. Repeated morphological examination using special staining methods (Congo red staining, immunofluorescence, immunohistochemistry) is key to establishing a definitive diagnosis if initial studies prove uninformative.
3. Genetic aspect. Establishing the genetically determined nature of the disease requires genetic testing for the LYZ gene and examination of family members to identify the hereditary forms of amyloidosis.
4. Treatment and observation. Organization of interdisciplinary observation (nephrologist, therapist, hematologist, geneticist) and correction of therapy (dietary treatment, use of drug and non-drug methods of nephroprotection) help to slow down the progression of renal dysfunction and improve the patient’s quality of life.

Thus, the presented case emphasizes the importance of a comprehensive and dynamic approach to the diagnosis of rare forms of amyloidosis, the need for repeated morphological examination in case of clinical discordance, and the use of specialized laboratory methods to clarify the diagnosis.