Tarek M. El TantawyNephrology Consultant

DM, MSc Nephrology - ASUHQM

Case PresentationNephrotic Syndrome “MN”

04/11/2023 1

Personal History:

• Male patient aged 48 years old, court officer, born in Gharbiah governorate, married and had 3 offspring.

• No other special habits of medical importance.

04/11/2023 2

Complaint

• Shortness of breathe with increasing face and lower limb swelling.

After patient's consent

04/11/2023 3

History of Present Illness:

• The condition started one month ago with face puffiness and lower limb oedema of gradual onset & progressive course.

• There was no history of recent upper or lower respiratory tract infection.

• No other symptoms suggestive for other systems affection.

04/11/2023 4

Past History:

• Nephrotic syndrome 5 years ago “membranous nephropathy".

• Hypertension 5 years ago (irregular treatment).

• Hernia repair 2009.• Traumatic fractures left lower limb

31/3/2011.• Bilhariziasis and treatment (childhood).• No past history of DM, renal stones,

smoking, drugs of medical importance.

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2008

oUrine analysis :• WBCs: (3– 5)/ HPF (0-

5).• RBC : (2 – 5)/ HPF(0-5).• ALB : (+++).• Specific gravity: 1020.• pH: 5.0 (Acidic).• Few hyaline and

granular casts.

oProtein in 24 hours urine:

• 8.69 gm/ 24 h. • 1230 ml/24 h.04/11/2023 6

2008

Hb 14.4

Hct 44.3

MCV 83.1

WBCs

5300

PLt 258000

HCV ab -ve

HBsAg -ve

HIV -ve

Anti-B ab IHA

-ve

S. Creatinine 0.93mg/dl

S. Cholesterol

475 mg/dl

S. Triglycerides

385 mg/dl

HDL 41 mg/dl

S. Albumin 2.3 g/dl

ALT 24 U/L

FBS 86 mg/dl

Prothrombin time

12.8 sec

Control time 12.8 sec

Prothrombin activity

97%

I.N.R 1.0

Cockcroft -Gault GFR

98.5 ml/min

Negative at serum dilution 1/40

ANA-ANF(HEP-2) BY IF

04/11/2023 7

5.45 ng/ml (Ref Range:

10.9)

Alpha Fetoprotein

2008

RENAL BIOPSY(1/3/2008):• Clinical diagnosis: Nephrotic syndrome, hypertension.• Gross appearance: 2 cores of needle biopsy tissue.• Microscopic examination: Biopsy shows 11 glomeruli/ section. Glomeruli: They show mild diffuse thickening of basement

membranes. Silver stain shows some vacuolization of the basement membranes. The mesangium shows mild focal proliferation in few glomeruli.

Tubules: Diffuse tubular injury (thinning of the lining epithelium).

Interstitium: Mild focal fibrosis. Blood vessels: They are unremarkable. DIAGNOSIS: Early membranous nephropathy.

04/11/2023 8

2008

He had received (3-2008/ 10-2009) :• Prednisolone (30 mg/day) for 6 months, then

gradual withdrawal.• Cyclosporine (200 mg/day)for 6 months, then

gradual tapering guided by CSA level. • Treatment duration: 19 months. with complete remission.

No relapses, until he comes today with the presenting features (01-2013) in relapse.

04/11/2023 9

General Examination “ 01-2013”:

• Patient was conscious, alert & well oriented to time, persons and places.

• Body mass index: 30.4 kg/m².• Puffy face and eyelids.• BP :150/110 mmHg.• Pulse: 80/ minute. regular & equal on

both sides.• Temperature :37.0 C.• No clubbing.• No skin rash.

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Local Examination

• Chest: Diminished intensity of air sounds on both sides more on the right side.

• Heart : Normal S1 & S2, no audible murmurs, nor pericardial rub.

• Abdomen: Ascites, no organomegaly, scar of previous operation.

• LL: Bilateral soft pitting oedema, scar of previous operation.

After patient's consent

04/11/2023 11

Investigations:

oUrine analysis :• WBCs: (4– 6)/ HPF (0-5).• RBC : (1 – 5)/ HPF(0-5).• ALB : (++).• Specific gravity: 1020.• pH: 5.0 (Acidic).

oProtein/ Creatinine ratio :• 7874.0 mg Protein/ gm Creatinine.

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Investigations:

Hb 15.1

Hct 46.9

MCV 89

WBCs

6300

PLt 188000

HCV ab -ve

HBsAg -ve

HIV -ve

S. Creatinine

1.16 mg/dl

S. Cholesterol

376 mg/dl

S. Triglycerides

290 mg/dl

FBS 100 mg/dl

S. Albumin 2.8 g/dl

ALT 16 U/L

Prothrombin time

12.9 sec

Control time 12.9 sec

Prothrombin activity

96%

I.N.R 1.0

Cockcroft -Gault GFR

92.5 ml/min

04/11/2023 13

Abdominal and Pelvic Ultrasound:

• Kidneys: Average sized both kidneys (Rt= 12 x 4.5 cm) (Lt = 12 x 5.0 cm), with normal cortical thickness and parenchymal echogenicity.

- No stones or back pressure changes in both kidneys.

- No cysts or masses, clear perinephric spaces.

• Urinary bladder: Free with no stones or masses.

• Liver: Average size with normal echopattern.

• Moderate ascites.• Right and left pleural effusion.• Spleen: normal size and

echogenicity with no focal lesions.04/11/2023 14

Is kidney biopsy indicated?

o Perform a repeat kidney biopsy only if the patients has rapidly deteriorating kidney function ( doubling of serum creatinine over 1-2 months of observation), in the absence of massive proteinuria ( > 15gm/day).

Not graded o Since the decline in GFR in IMN is

often very gradual, any acceleration of the rate of decline indicates the possibility of a superimposed disease (such as crescentic glomerulonephritis or acute interstitial nephritis, which is often drug-related) that might dictate a change in treatment approach.

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Treatment for relapses of nephrotic syndrome in adults with IMN:• Low salt diet.• ACE inhibitor.• Diuretics.• Statin (20 mg/day).• Combination steroid and cyclosporine therapy.

7.7.1: We suggest that relapses of nephrotic

syndrome in IMN be treated by reinstitution of the same therapy that resulted in the initial remission. (2D)

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After patient's consent

Definition of MN:

o Membranous nephropathy is a glomerular disease in which immune deposits of IgG and complement components develop exclusively beneath podocytes on the subepithelial surface of the glomerular capillary wall.

o Deposit formation is associated with marked increase in glomerular permeability to protein, which is manifested clinically as nephrotic syndrome.

o It may be idiopathic “ No systemic disease factor” 2/3 or secondary to underlying disease 1/3 .

o MN is typically a disease of adults (fewer than 3% of cases are found in children).

o It the most common cause of idiopathic NS in adults (30%).

o 2ry MN is more common in children (75%) than adults (25%).

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Diagnosis of MN:

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o Diagnosticfeatures include capillary wall thickening, normal cellularity LM , IgG and C3 along capillary walls on IF, and subepithelial deposits on EM.

o The diagnosis of MN is made on kidney biopsy.

Causes of secondary MN:

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D.D between 1ry and 2ry forms of MN:

o Both 1ry MN and 2ry MN have similar clinical presentations; Therefore before treatment we have to rule out 2ry causes first. Since the therapy in 2ry MN must be directed at the underlying cause.

o Circulating Abs against PLA2r ( M-type phospholipase A2 receptor ) or staining with anti-PLA2r in the glomeruli speak for 1ry MN while they are lacking in 2ry MN.

o IgG4 is more frequent and intense in the IMN while IgG1, IgG2and IgG3 are more frequent in the 2ry MN.

o In some cases of 2ry MN small mesangial or subendothelial deposits can be seen.

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Idiopathic “1ry” MN:

Age: All ages (but rare in children), Peak incidence during 4th and 5th decade.

Gender: Male / Female 3/1. Nephrotic syndrome: 70-90%. ME hematuria: in 30-

40%. Natural course: i. Spontaneous remission 20-30% .ii. Persistent proteinuria 20-40% .iii. ESRD/Death 30-50% Risk factors for ESRD:i. Older Age and Male Sex. ii. Superimposed FSGS. iii. Tubulointerstitial lesions. iv. Elevated serum creatinine and Persistent severe

proteinuria.v. Persistently elevated urinary C5b-9, and excretion of

increased quantities of high-molecular-weight proteins (ß2- microglobulin and IgG) in urine.

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Treatment of IMN:

A) Conservative Therapy (non-immunosuppressive) :

o About 30–35% of patients with IMN eventually undergo spontaneous remission of nephrotic syndrome; so it is reasonable to delay specific therapy for at least 6 months utilizing supportive therapy, unless the patient has unexplained rapid deterioration in kidney function or there are complications related to uncontrolled nephrotic syndrome.

o Diet ; Low salt diet. Restrict dietary protein intake (0.8g/kg ideal body weight per day, high quality protein).

o RASS blockade; ACEI/ARB with prompt control of BP ( Target BP <130/80 mm Hg).

o Control dyslipidemia with statins.

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Prophylactic anticoagulants in IMN:

o It might be considered when the serum albumin is <2.5 g/dl with one or more of the following:

a - Proteinuria > 10 g/d. b- BMI > 35 kg/m2. c- Prior history of thromboembolism. d- Family history of thromboembolism with documented genetic predisposition. e- NYHA class III or IV congestive heart failure. f- Recent abdominal or orthopedic surgery. g- Prolonged immobilization.

7.9.1: We suggest that patients with IMN and nephrotic syndrome, with marked reduction in serum albumin(<2.5 g/dl ) and additional risks for thrombosis, be considered for prophylactic anticoagulant therapy, using oral warfarin. (2C)04/11/2023 23

Treatment of IMN:

B) Immunosuppressive drugs indicated when :i. Urinary protein excretion persistently > 4 gm/d that

remains over 50% of the baseline value and does not show progressive decline with conservative therapy during an observation period of at least 6 months. (1B).

ii. The presence of severe, disabling, or life threatening symptoms related to the nephrotic syndrome. (1C).

iii. S.Cr has risen by 30% or more within 6 to 12 months from the time of diagnosis but the eGFR is not <30 ml/min per 1.73m2 and this change is not explained by superimposed complications. (2C).

NB: Do not use IS therapy in patients when:iv. S.Cr persistently >3.5 mg/dl (or an eGFR <30 ml/min per

1.73m2) .v. Reduction of kidney size on ultrasound (e.g <8 cm in

length) .vi. Concomitant severe or potentially life threatening

infections. (Not Graded).

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I- Steroid monotherapy, AZA in IMN:

o RCTs have shown that monotherapy with oral corticosteroid is not superior to conservative therapy and showed no improvement during drug exposure, or over a 3-year follow-up in either proteinuria or kidney function.

7.5.1: We recommend that corticosteroid

monotherapy not be used for initial therapy of IMN. (1B)

o Azathioprine does not favorably influence the course of IMN, either alone or with corticosteroids.04/11/2023 25

II- Cyclical steroids/alkylating agents in IMN:

o Orally administered alkylating agents (cyclophosphamide or chlorambucil) in conjunction with steroids, are effective in inducing remission and preventing ESRD.

o The toxicity profile suggests that cyclophosphamide might be preferred to chlorambucil.

o Treated patients may continue to enter complete or partial remission for as long as 12–18 months following completion of the regimen.

o So it is reasonable to wait this period of time before deciding whether the initial treatment has been unsuccessful, providing that serum albumin levels or kidney function are not deteriorating.

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II- Cyclical steroids/alkylating agents in IMN:

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II- Cyclical steroids/alkylating agents in IMN:

7.3.1: We recommend that initial therapy consist of a 6-month course of alternating monthly cycles of oral and i.v. corticosteroids, and oral alkylating agents. (1B)

7.3.2: We suggest using cyclophosphamide rather than chlorambucil for initial therapy. (2B)

7.3.5: Adjust the dose of cyclophosphamide or chlorambucil according to the age of the patient and eGFR. (Not Graded)

7.3.6: We suggest that continuous daily (noncyclical) use of oral alkylating agents may also be effective, but can be associated with greater risk of toxicity, particularly when administered for > 6 months. (2C)

04/11/2023 28

Benefits and Risks of the cyclical steroids/alkylating agent regimen in IMN

BENEFITSo Prevention of CKD

and ESRD. o Avoidance of

complications of nephrotic syndrome (thrombosis, accelerated atherogenesis).

o Prolongation of life; improved quality of life.

RISKSo Enhanced risk of opportunistic

infection. Reactivation of viral hepatitis.

o Alopecia.o Gonadal damage

(aspermatogenesis, ovulation failure).

o Hemorrhagic cystitis (cy. only).

o Neoplasia (myelodysplastic syndrome, acute myelogenous leukemia.

o Transitional cell carcinoma of the bladder, ureter or pelvis.

o Toxic hepatitis.

04/11/2023 29

Contraindications to the use of the cyclicalsteroids/alkylating agent regimen in IMN

I. Untreated infection ( e.g HIV, hepatitis B and C, tuberculosis, fungal infection).

II. Neoplasia ( e.g lung, skin [except squamous cell], breast, colon).

III. Urinary retention.IV. Inability to comply with monitoring.V. Pre-existing leukopenia (<4000

leukocytes/mm3).VI. SCr >3.5 mg/dl .

04/11/2023 30

Complete versus partial remission

COMPLETE REMISSIONo Urinary protein

excretion < 0.3 g/d , confirmed

by two values at least 1 week apart.

o Accompanied by a normal serum albumin concentration, and a normal SCr.

PARTIAL REMISSION

o Urinary protein excretion < 3.5 g/d and a 50% or greater reduction from peak values; confirmed by two values at least 1 week apart.

o Accompanied by an improvement or normalization of the serum albumin concentration and stable SCr.

04/11/2023 31

II- Cyclical steroids/ alkylating agents in IMN:

04/11/2023 32

II- Cyclical steroids/alkylating

agents in IMN:

04/11/2023 33

III- CNI-based regimens for IMN

CYCLOSPORINEo 3.5–5.0 mg/kg/d given

orally in two equally divided doses 12 hours apart, with prednisone 0.15 mg/kg/d, for 6 months.

o CSA levels usually regarded as nontoxic are C0 125–175 ng/ml or C2 400–600 ng/ml .

TACROLIMUS

o 0.05–0.075 mg/kg/d given orally in two divided doses 12 hours apart, without prednisone, for 6–12 months.

04/11/2023 34

o We suggest starting at the low range of the dosage and gradually increasing to avoid acute nephrotoxicity.

III- CNI-based regimens for IMN

7.4.1: We recommend that cyclosporine or tacrolimus be used for a period of at least 6 months in patients who meet the criteria for initial therapy, but who choose not to receive the cyclical corticosteroid/alkylating-agent regimen or who have contraindications to this regimen. (1C)

7.4.2: We suggest that CNIs be discontinued in patients who do not achieve complete or partial remission after 6 m. of treatment. (2C)

7.4.3: We suggest that the dosage of CNI be reduced at intervals of 4–8 weeks to a level of about 50% of the starting dosage, provided that remission is maintained and no treatment limiting CNI-related nephrotoxicity occurs, and continued for at least 12 months. (2C)

7.4.4: We suggest that CNI blood levels be monitored regularly during the initial treatment period, and whenever there is an unexplained rise in S.Cr (>20%) during therapy. (Not Graded)

04/11/2023 35

III- CNI-based regimens for IMN

04/11/2023 36

IV-ACTH in IMN:

04/11/2023 37

IV-ACTH in IMN:

04/11/2023 38

V- MMF in IMN:

04/11/2023 39

7.5.2: We suggest that monotherapy with MMF not be used for initial therapy of IMN. (2C)

V- MMF in IMN:

04/11/2023 40

VI- Rituximab in IMN:

04/11/2023 41

VI- Rituximab in IMN:

04/11/2023 42

Treatment for relapses of nephrotic syndrome in adults with IMN:

7.7.1: We suggest that relapses of nephrotic syndrome in IMN be treated by reinstitution of the same therapy that resulted in the initial remission. (2D)

7.7.2: We suggest that, if a 6-month cyclical corticosteroid/ alkylating-agent regimen was used for initial therapy, the regimen be repeated only once for treatment of a relapse. (2B)

04/11/2023 43

CONCLUSIONS: IMN is an autoimmune disease triggered by autoAbs

directed against variants of podocyte enzymes. Patients with persistent nephrotic proteinuria, kidney

dysfunction, or tubulointerstitial lesions are at risk of ESRD.

Complete remission of nephrotic syndrome predicts excellent long-term kidney and patient survival. A partial remission also significantly reduces the risk of progression to ESRD.

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.

RCT with adequate size , long-term follow-up, and fair definition of endpoints are needed to identify the treatment with better therapeutic index in IMN.

Treatment with RAAS blockade, and a 50% decline of proteinuria from baseline during the first year of follow-up, were significant independent predictors for remission.

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04/11/2023 45

THANK YOU