Membranous Nephropathy - Case report

ABSTRACT

Membranous glomerulonephritis is one of the primary causes of nephrotic syndrome and

chronic renal insufficiency in adults. There has been documented evidence of poorer prognosis
with factors such as male gender, advanced age, increased blood pressure and persistent loss
of proteins in the urine, but the overall prognosis of this condition is excellent. This article
presents the case of a 20-year-old female patient who was diagnosed with primary
membranous nephropathy. It is extremely unusual for this syndrome to manifest in females and
especially unusual in this particular age group. Normally, primary Membranous Nephropathy has
a subsidiary course with basic conservative management and immunosuppressives but our
case had a worsening course and no major response even with immunosuppressive treatment.
This case has been recorded due to its unusual presentation, unnatural course and outcomes
contrary to what is seen in routine clinical practice.

INTRODUCTION

The most likely cause of nephrotic syndrome in adults (40–60 years of age) is Membranous
Nephropathy (MN), which is also the main culprit for development of renal failure in people with
primary glomerulonephritis.[1,2] Usually accompanied by low-grade blood loss in urine and
relatively well-preserved kidney function, it usually manifests as typical nephrotic syndrome with
heavy proteinuria as the major investigative finding. On routine urine analysis, it is found that the
majority of these patients only have asymptomatic milder grade or nephrotic-range proteinuria
with only a few who develop severe impairment and lose about 15-20 g of protein per day. Most
cases are primary or have no known cause, and the phospholipase A2 receptor of type-M is a
target antigen in 70% of people.[3] Secondary MN can be due to the use of specific drugs such
as penicillin, gold or less frequently, ACE inhibitor like captopril or even nonsteroidal
antiinflammatory drugs. It can also be linked to infections like hepatitis B and C, neoplasms of
the breast, lung or gastrointestinal system, or sometimes both. MN can occasionally develop in
people with existing autoimmune diseases such as systemic lupus erythematosus (class five
lupus nephritis).[1,2] Normal levels of serum complements along with a lack of pathognomonic
findings (clinical or laboratory) are typical in patients with idiopathic MN. The glomeruli often
seen are normocellular under light microscopy with thickening of the glomerular basement
membrane (GBM). Additional "spike like" protrusions, which are made of material resembling
basement membrane, can be seen on the epithelial side of GBM when silver methenamine is
used. IgG and C3 deposits present as a "granular" pattern along the capillary wall under the
immunofluorescence microscopy and are found in subepithelial areas under the electron
microscopy. The management of MN is multifactorial and includes medical therapy (diuretics,
ACE inhibitors, lipid control drugs and immunosuppressants) in combination with control of
blood pressure, restriction of salt and proteins in the diet and even use of prophylactic
anticoagulants in some cases.[4]
CASE PRESENTATION

Clinical Course
A 20-year-old female presented to OPD with complaints of notable swelling in both lower
extremities and face. Her history revealed that facial swelling began 1 month ago. There is also
an associated history of weight gain since a month and she had been complaining of frothy
urine since the past 2 weeks. The patient did not have any history of visible blood in the urine or
a complaint of reduced urine output. There had been no previous history of a similar
presentation, no personal or family history of thyroid disorders, and no associated co-morbidities
such as systemic hypertension or diabetes mellitus. In addition, the patient did not report any
recent sore throat or fever. On examination the patient showed facial puffiness along with
bilateral pedal oedema and the remaining systemic examination was otherwise non-remarkable.

Patient findings most likely pointed towards a diagnosis of Nephrotic Syndrome and was
subjected to subsequent investigations. Laboratory results showed elevated 24-hour urinary
protein and an increased urine protein-creatine ratio. Blood reports were also sent for lipid
(dyslipidemia commonly associated with nephrotic syndrome) and thyroid (to rule out a
hypothyroid cause of facial puffiness) profiles, which came out to be relatively abnormal. The
complement levels were, however, found to be within the normal range. Diuretics and statins
were started to treat the nephrotic presentation as well as the lipid abnormality, and the patient
was discharged with an advice to follow-up after 2 weeks. The patient appeared to be euthyroid
with slightly increased serum TSH levels but no signs or symptoms of any underlying thyroid
condition and hence was managed accordingly, independent of the nephrotic presentation. At
the follow-up visit after 2 weeks, patient findings had hardly subsided, and therefore further
investigations were ordered to understand the underlying aetiology of nephrotic syndrome.
Blood investigations on the second visit showed improvements in lipid profiles but worsening of
proteinuria and renal function. A core needle renal biopsy was ordered during the second visit
and the light microscopy findings showed the presence of spikes on the glomerular basement
membrane and an absence of fibrosis, which pointed towards Membranous
Glomerulonephropathy among nephrotic syndromes. The absence of any inflammatory infiltrate
in the interstitium was helpful in ruling out a nephritic syndrome etiology. Immunofluorescence
studies showed the presence of IgG and C3 on the capillary loops with subepithelial deposition
of immune complexes. The patient was then started on rituximab, which is an
immunosuppressant, and eventually the patient's condition improved.

Investigations

Blood reports

During first visit

Parameter Patient Units Normal Value
Values
BLOOD PARAMETERS
C3 Level 190 mg/dl mg/dl 90-180
 C4 Level 40 mg/dl mg/dl 10-40
RENAL FUNCTION TESTS

24 hr Urine Protein 2216 mg/24 hour < 140

mg/24hour
S. Urea 11.9 mg/dl mg/dl 15-45
S. Creatinine 0.59 mg/dl mg/dl 0.80-1.30
Sodium 138 mmol/l mmol/l 136-145
Potassium 4.7 mmol/l mmol/l 3.5-5.1
Chloride 106 mmol/l mmol/l 98-107
Bicarbonate 25 mmol/l mmol/l 21-30
BLOOD HAEMATOLOGY
Prothrombin Time (PT) 11 seconds 10-15
aPTT 25.5 seconds 21-38
COMPLETE BLOOD COUNT
Total WBC Count 7100 Cells/cumm 4000-11000
Neutrophils 54 % 40-70
Lymphocytes 33 % 20-40
Eosinophils 10 % 0-8
Monocytes 2 % 1-10
Basophils 0 % 0-1
Haemoglobin 9.8 g/dl 11-15 ( AdultFemale)
PCV 34.5 % 35-48
Total RBC Count 5.2 Million/cumm 3.8-5.8
MCV 67 Fl 80-100
MCH 19 Pg 27-31
MCHC 28 % 31-35
Platelet Count 1.9 Lakhs/cumm 1.5-4.5
ESR 1hr 82 mm 0-22/hr
LIPID PROFILE
Total Cholesterol 304.5 mg/dL <170
HDL Cholesterol 45.3 mg/dL 40-60
Triglycerides 317.5 mg/dL <150
LDL Cholesterol 195.7 mg/dL <129
THYROID PROFILE
S. TSH 7.15 meu IU/mL 0.35-5
Total T4 6.37 mcg/dL 4.6-12
Total T3 127.5 mg/dL 80-200

During second visit

 Parameter Patient Units Normal Value
Values
BLOOD PARAMETERS
C3 Level 155 mg/dl mg/dl 90-180
C4 Level 30 mg/dl mg/dl 10-40
RENAL FUNCTION TESTS

24 hr Urine Protein 5719 mg/24 hour < 140

mg/24hour
S. Urea 15.9 mg/dl mg/dl 15-45
S. Creatinine 0.8 mg/dl mg/dl 0.80-1.30
Sodium 142 mmol/l mmol/l 136-145
Potassium 4.5 mmol/l mmol/l 3.5-5.1
Chloride 106 mmol/l mmol/l 98-107
Bicarbonate 26 mmol/l mmol/l 21-30
BLOOD HAEMATOLOGY
Prothrombin Time (PT) 13.4 seconds 10-15
aPTT 31.6 seconds 21-38
COMPLETE BLOOD COUNT
Total WBC Count 7100 Cells/cumm 4000-11000
Neutrophils 58 % 40-70
Lymphocytes 34 % 20-40
Eosinophils 6 % 0-8
Monocytes 2 % 1-10
Basophils 0 % 0-1
Haemoglobin 8.9 g/dl 11-15 ( AdultFemale)
PCV 29 % 35-48
Total RBC Count 4.3 Million/cumm 3.8-5.8
MCV 67 Fl 80-100
MCH 21 Pg 27-31
MCHC 31 % 31-35
Platelet Count 3.1 Lakhs/cumm 1.5-4.5
ESR 1hr 32 mm 0-22/hr
LIPID PROFILE
Total Cholesterol 260 mg/dL <170
LDL cholesterol 180 mg/dL <129
HDL cholesterol 44 mg/dL 40-60
Triglycerides 302 mg/dL <150

Antibody Test was also done for Anti-Nuclear antibody (ANA) which turned out to be negative.
Biopsy results

A piece of tissue measuring 0.4×0.6cm preserved in formalin was sent for light microscopy,
which showed seventeen glomeruli and none were globally sclerotic. Cellularity was normal with
a patent capillary lumen. There was spike formation in the glomerular basement membrane, but
no segmental sclerosis, endocapillary hypercellularity, or crescent formation was observed.
There were no signs of interstitial fibrosis or tubular atrophy, and there were no inflammatory
cells in the interstitial space.

A piece of tissue measuring 0.3×0.6cm in Michel's Medium was sent for immunofluorescence.
Eight glomeruli were considered for evaluation, and sections were stained for antibodies such
as IgG, IgM, IgA, complement C3 and C1q, and even the light chains kappa and lambda. The
result was positive for IgG (+3) and C3 (+2) and showed granular positivity on the capillary
loops. The rest of the antisera were negative.

Management
Initial management included oral torsemide 5mg OD for 3 days and rosuvastatin 10mg OD for 1
week. During the follow-up visit, the patient showed mild improvement in lipid profile and
swelling but worsening of proteinuria and renal function tests (RFTs). The patient was then
prescribed Telmisartan 40mg OD and Rituximab once a week for a period of four weeks. The
patient was followed up with regular phone calls and during the third visit, after a period of four
weeks, the patient showed significant clinical improvement as well as improvement in lab
reports, with proteiuria and RFTs returning to the baseline.

DISCUSSION

Differential diagnosis of the symptoms presented by our patient includes glomerular disease,
heart failure, liver disease, and myxedema. Membranous nephropathy (MN) is found in up to
one-third of the biopsied cases of nephrotic syndrome, making it one of the most common
causes of nephrotic syndrome, especially in nondiabetic adults. Clinical presentation includes
peripheral edema, frothy urine, hypertension and even features suggesting thromboembolic
states in severe cases. Lab investigations may show hypoalbuminemia, dyslipidemia, massive
proteinuria (>3.5g/day) and acute kidney injury with elevated serum creatinine levels. Three
possible mechanisms have been suggested in the pathogenesis of MN. The first one is the
direct glomerular deposition of the immune complexes which are already formed in the blood
circulation. Second, the circulating antibodies react with an antigen intrinsic to the glomeruli,
which is not continuously distributed along the laminar membrane adjacent to the podocytes,
resulting in the formation of immune complexes directly in the glomeruli. Third possibility is that
there is a reaction of circulating antibodies with an antigen not intrinsic to the glomerulus but
deposited there due to some kind of affinity for the glomerular basement membrane. These
mechanisms disrupt the podocyte structure, hamper the integrity of the slit diaphragm, and
cause loss of the negatively charged membrane barrier, which ultimately results in massive
proteinuria.[5]
Renal biopsy and microscopic evaluation is the gold standard investigation for diagnosing the
cause of nephrotic syndrome. The characteristic lesion on light microscopy, which was seen in
our patient, is the diffusely thickened GBM throughout all the glomeruli without any significant
hypercellularity. A diffuse granular staining pattern of IgG and C3 is seen along the GBM on
immunofluorescence microscopy. Electron microscopy shows electron-dense deposits on the
subepithelial outer segment of the GBM, which is considered as the hallmark lesion. It also
shows the effacement of podocyte foot processes, and GBM expansion due to accumulation of
new matrix extracellularly in between these deposits (which appear as “spikes” on visualising
with special stains). Some studies indicate that, for the progression of the disease, degree of
atrophy in the tubules or degree of fibrosis in the interstitium, is more predictive than the stage
of glomerular disease. Some studies also suggest that an elevated titer of antibodies is
associated with a lower response to immunosuppressive therapy and a longer time to return to
normal.[7] Even though our patient didn't have any of these symptoms, the disease was getting
worse.

There is a need for effective and prompt therapy, with favourable outcomes, for patients
diagnosed with MN and a more personalised approach should be sought for the management of
these patients. Treatment for patients diagnosed with MN should be directed towards improving
the elevated blood pressure, reducing the generalised or pedal edema, and limiting the risks of
thromboembolism and adverse cardiovascular events. A complete remission of proteinuria has
shown to have a majorly improved long-term survival in patients with MN, preventing the
progression to renal failure. Good long-term results are also seen with partial remission, which
stops the kidney function from getting worse.[8] ACE inhibitors or angiotensin II receptor
blockers (ARB) are preferred antihypertensives over the other classes of blood pressure
lowering drugs due to their proven renoprotective effects and substantial potential to reduce
proteinuria. Patients with MN and nephrotic syndrome, especially those with albumin levels of
2.2 g/dl, are more likely to have thromboembolic events. This suggests the need for prophylactic
anticoagulation therapy.[4,9] Some patients like ours are not responsive to conservative
treatment, and hence alternative approaches are sometimes required to prevent worsening
outcomes. Alternating alkylating agents plus intravenous pulse or oral corticosteroids have
shown to be comparatively more effective in treating MN than the current regime. A 6-month
cycle could potentially aid in returning the patient to complete normal.[10] Some recent studies
have even demonstrated the effectiveness of Rituximab for the treatment of MN. It is a
monoclonal IgG1 antibody that has an effect on B-cell depletion by binding and inhibiting
CD20.[11] It is often used to treat lymphomas, ANCA-associated vasculitis, rheumatoid arthritis,
and other autoimmune diseases like membranous nephropathy, which was the case in our
report.

CONCLUSION

A young patient who presents with signs and symptoms of acute nephrotic syndrome should be
evaluated promptly. A biopsy should be taken earlier in the course of management to identify
the cause and initiate prompt therapy. Appropriate treatment should be aimed at reducing
proteinuria, which is the single most important factor determining renal functioning. The focus
should be gradually shifted towards newer and relatively safer treatment modalities like
immunomodulators and monoclonal antibodies.

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