Membranous glomerulonephritis (membranous nephropathy)

Membranous glomerulonephritis (membranous nephropathy) is characterized by a diffuse thickening of the walls of the glomerular capillaries associated with diffuse subepithelial deposition of immune complexes, splitting and doubling of the GBM. There is no cell proliferation or it is minimal. The antigen responsible for the formation of immune complexes in primary membranous nephropathy is not known.

[1], [2]

Epidemiology

The frequency of membranous nephropathy among all morphological types of nephritis is, according to various authors, 3-15%. According to P. Zucchelli and S. Pasquali (1998), among 4060 biopsies performed for 25 years, membranous nephropathy was found in 319 cases (7.8%).

Membranous glomerulonephritis (membranous nephropathy) develops at any age, more often in adults (especially at the age of 30-50 years) than in children. Men are more likely than women, and it is harder. In adults, membranous nephropathy is the most common cause of nephrotic syndrome (20-40% of cases), in children with nephrotic syndrome, less than 1% of cases occur.

In most patients, the main symptoms of membranous glomerulonephritis (membranous nephropathy) are a nephrotic syndrome, less often proteinuria without a nephrotic syndrome. In 25-40% of patients, microhematuria is possible. Macrogematuria and hypertension at the onset of the disease are rare, in the future hypertension develops in 20-50% of patients. The serum complement content is almost always normal, rarely reduced (for example, in cases etiologically associated with viral hepatitis B or with systemic lupus erythematosus).

In this type of jade, often (in 30-35% of patients) it is possible to establish a connection with the known antigens - HBV, tumor, drug.

In connection with this, in clinical practice, patients with membranous nephropathy should be especially carefully examined for the possible detection of primarily a tumor (especially the lungs, kidneys), infection with hepatitis viruses, etc.

Another feature is the frequent association with various systemic and other diseases:  systemic lupus erythematosus, autoimmune thyroiditis, Sjogren's syndrome, diabetes mellitus, psoriasis, etc.

In patients with membranous nephropathy with nephrotic syndrome, thrombotic complications develop more often than in other morphological variants of glomerulonephritis.

RC Atkins and R. Bellomo (1993), based on their observations and literature data, give the following figures for the frequency of thrombosis in patients with membranous nephropathy: renal vein thrombosis in 29%, pulmonary embolism in 17% and deep thrombosis of the extremities in 17%.

[3], [4], [5]

Causes of the membranous glomerulonephritis (membranous nephropathy)

Infections	Tumors	Medicinal products
Hepatitis B, C Malaria Tuberculosis Schistosomiasis Filariasis Syphilis Echinococcosis	Cancer of the kidney, lungs, intestines Lymphomas Chronic lymphatic leukemia	D-Penicillamine Preparations of gold Captopril NSAIDs

The course of membranous glomerulonephritis (membranous nephropathy) is relatively favorable (especially in women), spontaneous remissions are possible. Renal insufficiency develops only in 50% of patients. S. Hogan et al. (1995), based on a meta-analysis of numerous published reports, the following frequency of re-development of terminal renal failure results: 14% in 5 years, 35% in 10 years and 41% in 15 years. Factors that adversely affect the prognosis are: male sex; age over 50; marked nephrotic syndrome; proteinuria more than 10 g / day; arterial hypertension; early increase in serum creatinine (in the first 3-5 years); pronounced tubulointerstitial changes; no remissions (spontaneous or after treatment).

Membranous nephropathy recurs in the transplant in approximately 10% of patients, and can also develop in a de novo kidney transplant.

[6], [7], [8], [9], [10], [11]

Treatment of the membranous glomerulonephritis (membranous nephropathy)

Treatment of membranous glomerulonephritis (membranous nephropathy) will be different in patients without and with nephrotic syndrome.

Patients without a nephrotic syndrome with normal renal function do not need immunosuppressive therapy, since the risk of developing renal insufficiency in them is minimal and there is no danger of complications associated with nephrotic syndrome. These patients should be under regular supervision to promptly detect elevated levels of blood pressure, proteinuria, and creatinine.

Proteinuria more than 1.5-2.0 g / day shows ACE inhibitors that reduce proteinuria and slow down the profession of the disease, and with increased cholesterol - lipid-lowering drugs.

In patients with nephrotic syndrome and preserved renal function, therapeutic approaches are different.

It is common for these patients to have adequate symptomatic therapy: diuretics, ACE inhibitors - to reduce proteinuria and slow down the profession, if necessary - other antihypertensive, lipid-lowering drugs, anticoagulants to prevent thrombotic complications (the latter effect is ambiguous).

The need for immunosuppressants is the most controversial issue in the treatment of membranous glomerulonephritis (membranous nephropathy).

A number of researchers believe that the MH has a very favorable prognosis, so patients should not be exposed to dangerous therapy, except in those cases when renal dysfunction, pronounced proteinuria (> 10 g / day) or severe manifestations of the NOS that worsen the patient's condition develop.

Advocates of immunosuppressive therapy favor early treatment, as some patients may develop renal failure and severe complications of the nephrotic syndrome (especially thromboses and other cardiovascular disasters). Late initiation of therapy, when renal failure and tubulointerstitial changes occur, is less effective; In addition, in patients with renal insufficiency, the risk of complications of immunosuppressive therapy is higher. We consider active therapy shown to all patients with MN with nephrotic syndrome.

Data from recent large studies indicate that 10-year renal survival of untreated MH patients with nephrotic syndrome is 60-65%. Spontaneous (complete or partial) remissions of the nephrotic syndrome develop in 38% of untreated patients, but in most cases they appear only after 2 years of nephrotic syndrome and are extremely unstable.

The main factors predicting the renal prognosis are determined to a certain extent: elderly men, patients with high and persistent proteinuria (> 1 g / day), the initial decrease in kidney function, focal glomerulosclerosis and severe tubulointerstitial changes are the most at risk of developing profound renal failure. At the same time, it is impossible to predict with certainty which of the patients will develop spontaneous remission.

The results of various treatments for membranous glomerulonephritis (membranous nephropathy)

With respect to the methods of active (immunosuppressive) therapy, cytostatics (alkylating drugs) or a combination of glucocorticoids and cytostatics are preferred.

The best results were obtained in a 10-year-old Italian multicentre study: a 6-month treatment with a monthly alternation of methyl-prednisolone and chlorbutin (S. Ponticelli scheme), compared with symptomatic treatment, doubled the frequency of remission of the nephrotic syndrome (62% and 33%, respectively) and reduced the incidence of chronic renal failure (in 10 years 8% and 40%).

With the exception of two uncontrolled studies in a small number of patients, there is no evidence to confirm the efficacy of azathioprine.

A possible alternative to the combination of prednisolone and chlorbutin is the treatment of membranous glomerulonephritis (membranous nephropathy) with only corticosteroids or cyclosporine.

Corticosteroids  as a monotherapy are used less often. In 5-10% of patients, remission can develop in a short time, but for the majority to achieve it, corticosteroids should be used in high doses for a long time.

Offer the use of prednisolone every other day (200 mg every 48 hours) for 6-12 months.

Intravenous pulses of methylprednisolone (1 g for 3 days - in the 1 st, 3 rd and 5 th month) on the background of taking prednisolone every other day (0.5 mg / kg every 48 h) is another well-tolerated regimen, although less effective than the combination of prednisolone with chlorobutin.

Cyclosporine in uncontrolled clinical trials in 20% of cases caused complete remission of the nephrotic syndrome and another 25% - partial, but after the abolition of cyclosporine in most patients quickly developed relapses. In some patients, remission can be sustained for a long time at relatively low doses [3.0-3.5 mgDkgsut]], and with a slow withdrawal of the drug the risk of exacerbation is significantly reduced.

Treatment of membranous glomerulonephritis (membranous nephropathy) in elderly patients

Renal prognosis in people older than 65 years is usually worse than in younger patients. However, in the observations of P. Passerini (1993) and S. Rollino (1995), the results of 6-month therapy with MP and chlorbutin in individuals older and younger than 65 years did not differ significantly. At the same time, side effects in the elderly were more often and heavier, so with immunosuppressive therapy, the doses of drugs should be less in the elderly than in the young.

Approaches to the treatment of patients with renal insufficiency are the same as those with patients with normal renal function. However, due to the high sensitivity of these patients to the side effect of immunosuppressants, treatment should be started only with real chances of success.

Pulsing with methylprednisolone followed by oral administration of prednisolone at a moderate dose in some patients with renal insufficiency contributes to a transient decrease in the level of creatinine. More encouraging results were obtained with long-term (1-2 years) administration of cyclophosphamide or a 6-month treatment with methylprednisolone and chlorobutin, but in order to reduce toxicity, the dose of MP should be reduced to 0.5 g intravenously, and chlorbutin 0.1 mg / kghs.

With contraindications to active immunosuppressive therapy or if it is ineffective, treatment with ACE inhibitors, hypolipidemic drugs, dipyridamole is indicated; possibly, heparin.

Indications for treatment of patients with membranous nephropathy with slowly progressing renal failure

Index	Treat	Do not treat
Creatinine	<4.5 mg%	> 4.5 mg%
Kidney ultrasound:
The size	Subnormal	Reduced
Increased echogenicity	Moderate	Expressive
Kidney biopsy:
Mesangial sclerosis	Moderate	Expressed
Interstitial fibrosis	Moderate	Expressed
Immune deposits	Fresh	None