membranous nephropathy

NEPHROLOGY MORNING SESSION

BY: DR. K. M. NAHID UL HAQUE

DEM STUDENT

Membranous Nephropathy


Membranous nephropathy (MN) is among the most common causes of the nephrotic syndrome in nondiabetic adults accounting for up to one-third of biopsy diagnoses. (Uptodate19.2)


Membranous GN may be Idiopathic or Secondary.

IMN is more common in adults approximately 75 % of cases /uptodate 19.2

Secondary MN is more common in children (75%) than adults (25%) /KDIGO

MN is typically a disease of adults (fewer than 3% of cases are found in children) and primary cause of Nephrotic syndrome in adults. /KDIGO

Why Called Membranous ???

Primary pathology involved in thickening of glomerular basement membrane due to sub epithelial deposits.

Clinical Features

The commonest presentation of IMN is nephrotic syndrome with preserved kidney function.

The disease course may be punctuated with spontaneous remissions and relapses.

KDIGO

About 80% of adults with IMN have nephrotic syndrome at presentation.

About 50% of patients with persistent high-grade proteinuria eventually progress to ESRD.

About 20 % adults presets with subnephrotic proteinuria.

KDIGO

Clinical Features

Clinical FeaturesBecause the underlying pathology is due to the

gradual accumulation of subepithelial deposits and resultant podocyte damage, the features of the nephrotic syndrome, especially weight gain and lower extremity edema, develop at a slower pace than that observed in patients with minimal change disease or primary FSGS; thus, the precise onset of disease is less likely to be noticed by the patient or clinician.

Uptodate 19.2

Clinical FeaturesApproximately 70 percent of patients have

normal blood pressure and glomerular filtration rate (GFR) at presentation.

Acute renal failure (ARF) is uncommon, and may be due to hypovolemia due to aggressive diuresis, acute interstitial nephritis due to diuretics or other offending drugs or rarely from acute renal vein thrombosis leading to renal infarction.

Clinical Features

Natural HistorySpontaneous complete remission of proteinuria

occurs in 5 to 30 percent at five years.

Spontaneous partial remission (≤2 g of proteinuria per day) occurs in 25 to 40 percent at five years.

The occurrence of ESRD in untreated patients is approximately 14 percent at five years, 35 percent at 10 years, and 41 percent at 15 years.

Uptodate 19.2

Differential DiagnosisMinimal change disease.

Membranoproliferative glomerulonephritis.

Focal segmental glomerulosclorosis.Medscap

PathologyDiagnostic features include capillary wall

thickening but normal cellularity.

Thickening of the capillary walls is due to gradual accumulation of subepithelial deposits (IgG and C3) and resultant podocyte damage.

In some cases the injury is focal and segmental.

KDIGO

Diagnosis - MNThe diagnosis of MN is made on kidney biopsy. On light microscopy: Features include capillary

wall thickening, normal cellularity.

On immunofluorescence: IgG and C3 deposition along the capillary walls. In IMN, deposition of the IgG4 subclass of IgG is dominant, whereas other IgG subclasses dominate in secondary forms of MN

On electron microscopy: Subepithelial deposits.

Membranous Vs Normal Glomeruli

Fluresence Microscopy

Electron Microscopy

Idiopathic Vs Secondary

The diagnosis of IMN is made by exclusion of secondary causes using- History Physical exam Apppropriate laboratory tests (e.g., serology,

imaging) and By careful examination of the kidney biopsy by light,

immunofluorescence, and electron microscope.

Why Idiopathic Vs Secondary diagnosis is necessary?

Distinguishing secondary MN from IMN is very important, since the therapy in the former must be directed at the underlying cause.

Some of the treatments for IMN ( e.g. immunosuppressive agents) are potentially toxic both to the patient and for the kidney.

Perform appropriate investigations to exclude secondary causes in all cases of biopsy-proven MN.

Phospholipage A2 Autoantibodies

A recent study has shown that about 70–80% of IMN patients exhibit circulating antibodies of IgG4 subtype against the M-type phospholipase A2 receptor.

Such autoantibodies appear to be absent or very uncommon in patients with secondary MN.

Studies are needed to validate the utility of antibody against M-type phospholipase A2 receptor in terms of its accuracy in separating primary from secondary MN.

Phospholipage A2 Autoantibodies

If the absence of autoantibodies to phos-pholipase A2 receptor in secondary MN is validated and a sensitive and specific assay for autoantibodies becomes available, it could become a valuable marker to positively identify (‘‘rule in’’) IMN.

The IgG4 subclass dominates in the deposits of IMN, while IgG1, IgG2, and/or IgG3 dominate in secondary forms of MN.

Secondary causesAutoimmuneInfection MalignancyDrugs

Autoimmune

SLE

Rheumatoid arthritis

Mixed connective tissue

disease

Dermatomyositis

Systemic sclerosis

Myasthenia gravis

Bullous pemphigoid

Autoimmune thyroid disease

Sjogren’s syndrome

Crohn’s disease

Graft-versus-host disease

Ankylosing spondylitis

Infections Hepatitis B

Hepatitis C

Human

immunodeficiency

Malaria

Schistosomiasis

Filariasis

Syphilis

Enterococcal

endocarditis

Hydatid disease

Leprosy

Malignancies Carcinomas

Lung

Esophageal

Colon

Leukemia

Breast

Stomach

Mesothelioma

Melanoma

Ovary

Prostate

Oropharynx

Drugs/ Toxins: Penicillamine

Lithium

Probencid

Murcury

NSAID

Captopril

Clopidogrel

COX-2 inhibitor

Formaldehyde

Hydrocarbon

Common Causes Systemic lupus (in younger women)

Chronic hepatitis B infection(especially in East Asia)

Drugs (such as NSAID, penicillamine, gold and

mercury).

Malignancy- esp. over the age of 65 years.

Prognosis1/3 Rule:Third of the case will go spontaneous

remission.Third of the case will continue heavy

proteinuria but normal kidney function.Third of the cases will develops ESRD.

Ref:Pocket Tutor Renal Medicine/By Oliveria

PrognosisComplete remission of nephrotic syndrome

predicts excellent long-term kidney function & patient survival.

A partial remission also significantly reduces the risk of progression to ESRD.

The primary aims of treatment, therefore, are to induce a lasting reduction in proteinuria.

KDIGO

Definitions of complete and partial remission

Complete Remission: Urinary protein excretion <0.3 g/d confirmed by two values at least 1 week apart, accompanied by a normal serum albumin concentration, and a normal SCr.

Partial Remission: Urinary protein excretion <3.5 and a 50% or greater reduction from peak values; confirmed by two values at least 1 week apart, accompanied by an improvement or normalization of the serum albumin concentrationand stable SCr.

KDIGO

All currently used treatment modalities have significant toxicity; therefore, selecting patients at high risk of progression is important so that exposure to treatment-related adverse events is minimized.

Treatment

Treatment

Non immunosuppressive therapy

Immunosuppressive therapy

Uptodate 19.2

Non Immunosuppressive Therapy

1. Angiotensin inhibition

2. Control of blood pressure

3. Lipid lowering agents

4. Anticoagulation

Uptodate 19.2


1. Angiotensin inhibition: The evidence for a renal protective effect with an ACE inhibitor

or an ARB is relatively weak among patients with MN. Possible benefits with use of an ACE inhibitor or ARB were

noted in a study from the Spanish Group for the Study of Glomerular Disease (GLOSEN), which retrospectively examined the outcomes of 328 patients with MN and nephrotic range proteinuria (>3.5 g/day).

Although none were treated with immunosuppressive medication, 67 percent of patients received either an ACE inhibitor or ARB and 32 percent developed complete or partial remission.

Uptodate 19.2

Angiotensin Inhibition cont… However, because this was not a randomized controlled

trial, it is not possible to draw definitive conclusions about the benefit of ACE inhibitors or ARBs on the frequency of spontaneous remission.

Furthermore there was a significant rise in the serum creatinine among patients who did not remit in this study, suggesting that there is a significant hazard associated with withholding immunosuppressive therapy in all patients while waiting for spontaneous remission.

Uptodate 19.2


2. Goal blood pressure: The goal blood pressure in patients with any form of

proteinuric chronic kidney disease is less than 130/80 mmHg, or perhaps lower.

Uptodate 19.2


3. Lipid-lowering : Hyperlipidemia, with often dramatic elevations in the

serum cholesterol concentration, is commonly present in patients with membranous nephropathy.

The mainstay of therapy for such hypercholesterolemia is statins.

Uptodate 19.2


4. Anticoagulation: Patients with MN, are at increased risk for thrombotic

events, such as deep vein and renal vein thrombosis or pulmonary embolism.

All patients who have a thromboembolic event should be treated initially with low molecular weight or unfractionated heparin, followed by oral anticoagulation (eg, warfarin).

Uptodate 19.2 Patients with IMN with marked reduction in serum albumin

(o2.5 g/dl) and additional risks for thrombosis, be considered for prophylactic anticoagulant therapy, using oral warfarin.

KDIGO

Immunosuppressive Therapy

Selection of adult patients with IMN to be considered for treatment with immunosuppressive agents when at least one of the following conditions is met:

Urinary protein excretion persistently exceeds 4 g/d & remains at over 50% of the baseline value & does not show progressive decline, during antihypertensive and antiproteinuric therapy during an observation period of at least 6 months.

The presence of severe, disabling, or life-threatening symptoms related to the nephrotic syndrome.

SCr has risen by 30% or more within 6 to 12 months from the time of diagnosis but the eGFR is not less than 25–30 ml/min per 1.73 m2 & this change is not explained by superimposed complications.

KDIGO

Immunosuppressive Therapy cont..

Do not use immunosuppressive therapy in patients with a S. Cr persistently 3.5 mg/dl (430µlmol/l) eGFR <30 ml/min per 1.73 m2

Reduction of kidney size on ultrasound (e.g. <8 cm in length) Those with concomitant severe or potentially life-threatening infections.

KDIGO


Corticosteroid mono-therapy is not recommended for initial therapy of IMN.

KDIGO

Ponticelli Regimen

Month 1: i.v. methylprednisolone (1 g) daily for three doses, then oral methyprednisolone (0.5 mg/kg/d) for 27 days.

Month 2: oral cyclophosphamide (2.0 mg/kg/d) for 30 days

Month 3: Repeat Month 1Month 4: Repeat Month 2Month 5: Repeat Month 1Month 6: Repeat Month 2

Latest KDIGO recommendation

Other Agents

Oral chlorambucil CyclosporineTacrolimusRutiximabACTH – on trial.

Risk Benefits

Opportunistic infection Reactivation of viral hepatitis Alopecia Gonadal damage Hemorrhagic cystitis

(cyclophosphamide only) Neoplasia Transitional cell carcinoma

of the bladder, ureter or pelvis

Toxic hepatitis

Prevention of CKD and ESRD Avoidance of complications

of nephrotic syndrome (thrombosis, accelerated atherogenesis)

Prolongation of life; improved quality of life

KDIGO


Relapsing patients

KDIGO suggest that relapses of nephrotic syndrome in IMN be treated by reinstitution of the same therapy that resulted in the initial remission.

Resistant cases

Patient who fail to response to cyclical cyclophosphamide/corticosteroid therapy a trail of Rutiximab/other agent can be given.

Uptodate 19.2

Thank you all

membranous nephropathy

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