Understanding And Thinking Of Membranous Nephropathy Complicated With Other Kidney Diseases

On June 30, Professor Sun Shiren, Director of the Nephrology Department of Xijing Hospital of Air Force Military Medical University, gave an introduction on "Recognition and Thinking of Membranous Nephropathy Combined with Other Kidney Diseases" at the 2023 Academic Annual Meeting of Nephrology Branch of Zhejiang Medical Association.

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At the beginning of the lecture, Professor Sun Shiren said that there are many patients with membranous nephropathy (MN) in China, with different causes, including primary MN, secondary MN, and MN combined with other kidney diseases. Among them, the clinical features of MN combined with other renal diseases are as follows:

(1) The pathogenesis is still unclear.

(2) The clinical manifestations of each disease are different from a single disease.

(3) Various performances.

(4) Lack of consensus treatment options.

(5) The prognosis is different.

Professor Sun Shiren introduced MN with other kidney diseases through specific cases and now focuses on the characteristics, examination, treatment, and prognosis of MN with other kidney diseases.

MN with IgA nephropathy (MN-IgAN)

1. Clinical features

Compared with MN, the onset age of MN-IgAN is younger, and the protein level, renal function, and incidence of nephrotic syndrome are similar. Compared with IgA nephropathy, MN-IgAN had a higher proportion of proteinuria and an estimated glomerular filtration rate at the onset.

2. Check

The level of Gd-IgA1 was not significantly different between MN-IgAN and IgA nephropathy patients, and the detection rate of serum anti-phospholipase A2 receptor (PLA2R) antibody was lower in the MN-IgAN group than in the MN group.

3. Pathological features

MN-IgAN is a combination of the pathological manifestations of the two glomerular diseases, but it is more inclined to MN. Compared with MN-IgAN alone, the pathological changes are milder, endothelial damage, and segmental sclerosis lesions are milder, and the percentage of crescents is lower. The specific manifestations are as follows: (1) Optical microscope: glomerular mesangial cells and matrix are slightly hyperplastic, the basement membrane is thickened, and spikes can be seen. There is the deposition of hemoglobin in the subepithelial and mesangial areas and a few glomeruli with crescent formation. (2) Immunofluorescence: Granular deposition of IgG along the capillary wall, and massive deposition of IgA in the mesangium. The immunoglobulin subtypes were mainly IgG4 and PLA2R were positive. (3) Electron microscope: Electron-dense deposits in the subepithelial and mesangial areas.

4. Treatment

(1) MN-IgAN uses more renin-angiotensin-aldosterone system inhibitors than MN.

(2) MN-IgA uses more immunosuppressants than IgA nephropathy.

5. Prognosis

MN-IgAN may be an independent glomerular disease, which cannot be divided into subtypes of IgA nephropathy or MN. The pathogenetic mechanism is unknown, but the positive rate of serum PLA2R in patients with MN-IgAN is low, and its mechanism is speculated to be different in idiopathic MN (iMN). The prognosis is unclear.

MN with diabetic nephropathy (MN-DN)

1. Clinical features

Patients with MN-DN were older, had a longer duration of diabetes, and had more severe diabetic retinopathy.

2. Check

Compared with MN, the glomerular filtration rate of MN-DN is lower, and the pathological damage is more severe. The specific manifestations are (1) glomerulus sclerosis: MN-DN > MN-2DM > MN. (2) Interstitial fibrosis/tubular atrophy: MN-DN > MN-2 diabetes mellitus > MN. (3) Lesions of afferent arterioles: MN-DN>MN-2DM>MN.

3. Diagnosis and treatment dilemma

Proteinuria and abnormal renal function are common in diabetic patients, and MN can exist alone or combined with diabetic nephropathy. It is difficult to distinguish between the two clinically, and renal biopsy is the "gold standard" for diagnosis.

A study involving 101 diabetic patients found that 51% had diabetic nephropathy, 20% had non-diabetic nephropathy, 29% had diabetic nephropathy combined with non-diabetic nephropathy, and up to 49% of diabetic patients had non-diabetic nephropathy. Improving the biopsy rate of diabetic patients can reduce the rate of clinical misdiagnosis and missed diagnosis. Clinical clues and biopsy indications suggesting non-diabetic nephropathy are as follows: (1) No diabetic retinopathy. (2) The glomerular filtration rate is very low or rapidly decreased. (3) A sharp increase in urinary protein or nephrotic syndrome. (4) Urinary sediment activity manifested as hematuria. (5) Refractory hypertension. (6) Symptoms or signs of other systemic diseases. (7) 2 to 3 months after starting treatment with an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker, the glomerular filtration rate does not decrease by more than 30%.

MN with crescentic glomerulonephritis

●MN with anti-GBM glomerulonephritis (MN-anti-GBM glomerulonephritis)

1. Clinical features

Occurs in young men aged 20 to 40. Compared with patients with anti-glomerular basement membrane (GBM) nephritis, the serum creatinine level, the proportion of patients with oliguria and anuria, and the incidence of gross hematuria were lower.

2. Characteristics of autoantibodies

(1) The autoantibodies of MN-anti-GBM glomerulonephritis are mainly anti-α3(IV)NC1, which have limited recognition of other α-chains and a narrower antibody spectrum.

(2) The antibody level against α3(IV)NC1 EB conformational epitope was lower, and the EB conformational epitope was associated with more severe kidney damage.

3. Occurrence mechanism

The mechanism of MN-anti-GBM glomerulonephritis is as follows: (1) Anti-GBM antibody damages glomerular podocytes, releases podocyte antigens, and triggers MN. (2) MN causes GBM damage, thereby releasing the a3 chain, resulting in the production of anti-GBM antibodies.

4. Prognosis

The prognosis of MN-anti-GBM glomerulonephritis may be related to the sequence of onset. The study found that the renal prognosis of 5 patients with MN first occurring in anti-GBM glomerulonephritis was poor, and all of them developed into an end-stage renal disease. 4/5 patients with anti-GBM glomerulonephritis first developed a good renal prognosis. In addition, studies have found that the prognosis of patients with MN-anti-GBM glomerulonephritis is not good. The above studies need more data support.

●MN with ANCA-associated vasculitis (MN-AAV)

clinical features

1. Clinical manifestations

Compared with ANCA-associated vasculitis (AAV), MN-AAV has more common renal damage, nephrotic syndrome, less fever and gross hematuria, and a higher BVAS score. Compared with iMN, the clinical manifestations are similar.

2. Check

Compared with pure AVV renal damage, C-reactive protein, serum creatinine at onset, and urine protein were higher. Compared with iMN, there was no significant difference in urine protein quantification, and the positive rate of serum PLA2R was lower.

3. Histological features

In the IgG subtype, the positive rate of IgG4 is lower, the positive rate of IgG2 and IgG3 is higher, the histological damage is more serious, and the prognosis is worse. Compared with pure AAV renal damage, the renal survival rate and overall survival rate of MN-AAV were lower.

MN with light chain deposition disease

1. Clinical features

MN combined with light chain deposition disease is not uncommon in clinical practice. The age of onset is between 30 and 60 years old. It is related to race, infection, and lymphoproliferative diseases. They all manifest as proteinuria and are often accompanied by mild renal impairment. About 73% manifested as nephrotic syndrome, which may be combined with lymphoproliferative diseases, autoimmune diseases, viral hepatitis B, and syphilis.

2. Check

PLA2R (-), IgG subtype single (+), focal hyperplasia, or crescent formation can be seen under a light microscope. Even if the serum MIg is negative, it is still recommended to exclude the potential of lymphoproliferative disease clinically. Attention should be paid to the role of renal tissue IgG subtypes and light chain staining in the diagnosis of MIg-related renal damage.

MN with IgG4-related disease

1. Clinical features

MN is the most common glomerular disease associated with IgG4-related disease (IgG4-RD), and MN secondary to IgG4-RD is named IgG4-related MN. The average age of onset is 58 years old (34-75 years old), and the ratio of male to female is 2:1. Most of the manifestations are nephrotic syndrome, mild renal impairment, and extrarenal involvement are common in the pancreas, salivary glands, eyes, lymph nodes, liver, lungs, skin, thyroid, and other parts.

2. Check

Creatinine mean 2.2 mg/dl, elevated serum IgG, elevated serum IgG4, elevated peripheral blood eosinophils, decreased C3 and C4, and negative for ANCA, viral hepatitis B, and hepatitis C virus.

Under the light microscope, diffuse plasma cell infiltration with a small number of eosinophils, interstitial sheet fibrosis, showing "mat pattern" changes. Immunofluorescence showed positive IgG and PLA2R.

A study of 28 patients with IgG4-related MN found: (1) 20/28 patients had tubulointerstitial nephritis. (2) Of the 15 cases with IgG subclass IF, 93% were positive for IgG4 and 78% were positive for IgG1. (3) 20 cases were monitored for PLA2R, 2 cases were positive for PLA2R staining, and 2 cases were positive for serum antibodies. (4) 10/25 cases had subendothelial or sub-mesangial electron-dense deposits at the same time. (5) There is a case report that initially manifested as PLA2R-negative MN, and later developed IgG4-related interstitial nephritis + MN.

Summary

In summary, MN and other types of renal diseases can coexist, with complex clinical manifestations, low histological PLA2R and IgG4 positive rates (except IgG4-RD), and different prognoses of different diseases. In the future, it is still necessary to further study its pathogenesis and find more effective treatment options.

How does Cistanche treat kidney disease? 

Cistanche is a traditional Chinese herbal medicine that has been used for centuries to treat various health conditions, including kidney disease. It is derived from the dried stems of Cistanche deserticola, a plant native to the deserts of China and Mongolia. The main active components of cistanche are phenylethanoid glycosides, echinacoside, and acteoside, which have been found to have beneficial effects on kidney health.

Kidney disease, also known as renal disease, refers to a condition in which the kidneys are not functioning properly. This can result in a buildup of waste products and toxins in the body, leading to various symptoms and complications. Cistanche may help treat kidney disease through several mechanisms.

Firstly, cistanche has been found to have diuretic properties, meaning it can increase urine production and help eliminate waste products from the body. This can help relieve the burden on the kidneys and prevent the buildup of toxins. By promoting diuresis, cistanche may also help reduce high blood pressure, a common complication of kidney disease.

Moreover, cistanche has been shown to have antioxidant effects. Oxidative stress, caused by an imbalance between the production of free radicals and the body's antioxidant defenses, plays a key role in the progression of kidney disease. Cistanche's antioxidant properties help neutralize free radicals and reduce oxidative stress, thereby protecting the kidneys from damage. The phenylethanoid glycosides found in cistanche have been particularly effective in scavenging free radicals and inhibiting lipid peroxidation.

Additionally, cistanche has been found to have anti-inflammatory effects. Inflammation is another key factor in the development and progression of kidney disease. Cistanche's anti-inflammatory properties help reduce the production of pro-inflammatory cytokines and inhibit the activation of inflammatory pathways, thus alleviating inflammation in the kidneys.