Case Approach in Glomerular Disease

Bancha Satirapoj, MD

Division of Nephrology

Department of Medicine

Phramongkutklao Hospital and College of Medicine



Asymptomatic Crtaivistainorms nooncheckup

Raff A nephropathy
Ig

Isolated proteinuria 150 mg to 3 g/day thinbasementmembrane

Hematuria > 2 red blood cells (RBC)/high-power field in spun urine (RBC

usually dysmorphic)

Nephritic syndrome

Nephrotic syndrome

• Proteinuria 3 ใน 5 • An abrupt onset of glomerular hematuria

• Adult >3.5 g/day (RBC cast or dysmorphic RBCs) sp.grEnoEo

• Child > 40 mg/h per m2 • Proteinuria <3 g/day

มีแต่ไม่เยอะ

• Edema • AzotemiaMosierprogressiveAcuterenalfailurein

• • Edema

Hypoalbuminemia <3.5 g/dl

• Hypercholesterolemia • Oliguria

• Lipiduria • Recent onset hypertension

Rapidly progressive glomerulonephritis Kosta win

znogto.no Chronic
a glomerulonephritis
crescent

• Glomerular disease characterized by glomerulisclerosis 750• Slowing developing renal insufficiency

extensive crescents (usually >50%) • Proteinuria > 3 g/day and hematuria

A rapid loss of renal function (usually a 50% • Hypertension

decline in GFR within 3 months) Wks to • Shrunken smooth kidneys

months

Satirapoj B. Common Problems in Internal Medicine. Bangkok 2010. p. 498-513.

Glomerular Disease

❖ Primary Glomerular Disease

❖ Idiopathic

❖ Secondary Glomerular Disease

❖ Systemic disease involving multiple organs

Secondary glomerular disease

Systemic Diseases

Infections

- Diabetes mellitus - HIV infection

- SLE/vasculitis - Hepatitis B and C

- Amyloidosis - Malaria

- Carcinoma - Syphilis

- Lymphoma and myeloma

- Preeclampsia

Drugs Inherited Disorders

- Gold - Alport syndrome

- Antibiotics - Congenital NS

- NSAIDs - Nail-patella syndrome

- Penicillamine

- Heroin

Primary glomerular disease

เรียกชื่อตาม patho

❖ Minimal change nephrotic syndrome (MCD)

❖ Focal segmental glomerulosclerosis (FSGS)

❖ Membranous nephropathy (MN)

❖ IgM nephropathy

❖ IgA nephropathy

❖ Membranoproliferative glomerulonephritis (MPGN)

Picture glomerulus

Minimal change disease (MCD) Focal segment glomerulosclerosis (FSGS) Membranous nephropathy (MN)

Nephrotic เด่น cell ไม่เพิ่มแค่

Gbm หนา

endothelium หนา
Mesangial proliferative GN Membranoproliferative GN (MPGN)

(IgA or IgM nephropathy)

Mesangial cell increased Endocapillary proliferation nephritis



Manifestation of glomerular diseases

In AN
nephrito nephrotic DDI
Ig
MPGN

LN

Disease Nephrotic features Nephritic features

Minimal change glomerulopathy ++++ -

Membranous glomerulopathy ++++ +

Focal segmental glomerulosclerosis +++ ++

Fibrillary glomerulonephritis +++ ++

Mesangioproliferative glomerulopathy (IgAN, LN) ++ ++

Membranoproliferative glomerulonephritis (MPGN) ++ +++

Proliferative glomerulonephritis (IgAN, LN) ++ +++

Acute diffuse proliferative glomerulonephritis (PSGN) + ++++

Crescentic glomerulonephritis + ++++

Drop เกิน 50% in 1 months

Adapted from Brenner & Rector’s the kidney 10th edition, 2016

Nephrotic syndrome

Diseases Associations Serologic Tests

Minimal change disease Allery, atopy, NSAIDs, Hodgkin disease -

African American,
Focal segmental glomerulosclerosis HIV antibody

HIV infection, heroin, pamidronate, obesity

CollapsingFsos

Drugs; gold, penicillamine, NSAIDs Anti-PLA-R2 antibody Positive

Infection; hepatitis B, C; malaria in

Hepatitis B surface antigen, anti-

Membranous nephropathy Lupus nephritis Class v primary

HCV antibody negative

Malignancy; breast, lung gastrointestinal ANA, Anti-DNA antibodyเปน

tract

primary

Diabetic nephropathy Other diabetic microangiopathy -

หรือ

Myeloma Plasma free light chainseconda

ry ก็ได้

Amyloidosis Rheumatoid arthritis, bronchiectasis, Crohn Serum protein electrophoresis,

disease, Familial Mediterranean fever urine immunoelectrophoresis

Aa rheumato disease

Adapted from Johnson RJ, Feehally, J and Floege R . Comprehensive clinical nephrology. 2015, 189.

Nephritis syndrome

Diseases

Associations Serologic Tests

MPGN type I Primary เจอนิยามเจอ C4 nephritic factor Low C3 and C4

MPGN type II พวก secondary C3 nephritic factor Low C3 and normal C4

Post-streptococcal glomerulonephritis Pharyngitis, impetigo ASO titer, streptozyme antibody

Post-infectious disease

-Endocarditis Cardiac murmur Blood cultures, low C3

-Shunt พวกนี้เป็น secondary mpgnTreated hydrocephalus Blood cultures, low C3

Upper respiratory or gastrointestinal

IgA nephropathy Synpharyngitis mucosal -

infection
infection with hematuria

Other multi-systemic features of ANA, anti-ds DNA antibody, low C3 and

Lupus nephritis
lupus C4

Anti-hepatitis C virus antibody,

Cryoglobulinemic glomerulonephritis False positive

Hepatitis C rheumatoid factor, cryoglobulinemia,

low C3 and C4

Adapted from Johnson RJ, Feehally, J and Floege R . Comprehensive clinical nephrology. 2015, 189.


History/physical examination

❖ Family history of CKD, hearing loss

❖ Perimacular white dot-and-fleck retinopathy, ant lenticonus:

❖ Alport syndrome

❖ History of diabetes

Dot-and-fleck retinopathy

Anterior lenticonus

❖ DR/diabetic neuropathy

❖ Diabetic nephropathy

Diabetic retinopathy


History/physical examination

❖ Photosensitivity, arthritis, alopecia, oral ulcer, malar rash, Roth spot, discoid lesion:

❖ Lupus nephritis

❖ Palpable purpura, vasculitis; Malar rash Cytoid body

With glomerulonephritis

❖ Systemic vasculitis/ SLE

❖ Cryoglobulinemia

❖ Sub acute endocarditis

Palpable purpura


History/physical examination

❖ Hepatosplenomegaly, periorbital purpura, macroglossia, carpal tunnel syndrome

❖
Amyloidosis

Periorbital purpura Macroglossia

Kidney biopsy rations'E

❖ Secondary glomerular diseases

❖ High risk for progressive disease (rising SCr, HT, proteinuria)

❖ Non response with corticosteroids (steroid resistance, steroid

dependent, frequency relapse nephrotic syndrome)

❖ Longterm immunosuppressive agents (cyclophosphamide,

cyclosporine)

Risk factors of Progressive Disease

❖ Male

❖ Advanced age (>50 years)

❖ Persistent heavy proteinuria (>3.5 g/d)

❖ Hypertension

❖ Impaired GFR

Grade and Quality of evidence

KDIGO. Kidney International Supplements (2012) 2, 143–153



An Analysis of 1,135 Cases of Kidney Biopsy: Thailand Glomerular

Research Network (TGRN)

Pathology n (%)

Primary glomerular diseases 507 (46.7)

1. IgA nephropathy 158 (31.2)

2. Focal segmental glomerulosclerosis 104 (20.5)

3. Membranous nephropathy 85 (16.8)

4. Minimal change disease 63 (12.4)

5. IgM nephropathy 52 (10.3)

6. Membranoproliferative GN 18 (3.6)

3smth.tnpersistentproteinuria pred

An Analysis of 1,135 Cases of Kidney Biopsy: Thailand Glomerular

Research Network (TGRN)

Pathology n (%)

Primary glomerular diseases 507 (46.7)

1. IgA nephropathy 158 (31.2)

2. Focal segmental glomerulosclerosis 104 (20.5)

3. Membranous nephropathy 85 (16.8)

4. Minimal change disease 63 (12.4)

5. IgM nephropathy 52 (10.3)

6. Membranoproliferative GN 18 (3.6)

IgAritornooios crescenticIgA

57IgAsown lmaoinann RBCWga ischemia

IgA nephropathy

IgA nephropathy: Pathology

❖ Immunohistology is the clue of diagnosis

❖ Mesangial cell proliferation with IgA deposit predominate

ติดได้หลายตัวแต่ iga เด่นสุด แต่ติดเท่ากันเป็น

lupus

Magistroni R, et al. Kidney International (2015) 88, 974–989

Aberrant IgA1 antibody

Abnormal iga

พอสร้างผิดปกติ เพราะว่าร่างกายคิดว่าเป็นสิ่ง

แปลกปลอมไป form immune complex

Kidney Int 2012:81:833



Abnormality in mucosal immune system or

Abnormal systemic response to mucosal antigens

Decreased clearance of IgA1 immune Increased production of IgA1 in bone

complexes Abnormal glycosylation of iga marrow

Circulation : 

AberrantIgA
asuna

IgA1 immune complexes

IgA1 on FcRγ associated

Liver ASGP-Receptor Glomerulus: transmembrane Fc∞RI

Liver Aberrant IgA 1 /immune complex

ASGP-Receptor Activated

Liver ASGP-Receptor
deposits on Mesangial Transferrin receptor (TfR) Monocytes

-Cytokines

-Chemokines

-Complement activation

Chemotaxis

Mesangial IgA nephropathy

and

Fibrosis Inflammation

Renal interstitial inflammation

Satirapoj B. IgA nephrology: a clinical prespective. Royal Thai Army Medical Journal. 2009; 62(2):77-86.


Multi-hit pathogenesis model of IgA nephropathy

Magistroni R, et al. Kidney International (2015) 88, 974–989



IgA nephropathy and associated disorders

IgA vasculitis Hsp Neoplasia: Mycosis fungoides, CA lung

HIV infection Cyclic neutropenia

Toxoplasmosis Immunothrombocytopenia

Seronegative spondyloarthropathy Gluten-sensitive enteropathy

Celiac disease Scleritis

Dermatitis herpetiformis Sicca syndrome

Crohn’s disease Mastitis

Alcoholic cirrhosis mostcommon20 Pulmonary hemosiderosis

Ankylosing spondylitis Berger’s disease

Reiter’s syndrome Leprosy

Adapted from Brenner & Rector’s the kidney 10th edition, 2016


IgA nephropathy Spectrum disease กว้าง

Lupus nephritis

Clinical presentation

Asymptomatic Acute nephritic/ Rapidly progressive Chronic

hematuria/proteinuria
Nephrotic syndrome Glomerulonephritis Glomerulonephritis

Renal pathology

Mesangial proliferative

Sclerosing

Normal glomeruli
Membranoproliferative or Necrotizing

Crescentic

glomerulonephritis

Clinical presentations relation to age

Skin vasculitis

Adapted from Johnson RJ, Feehally, J and Floege R . Comprehensive clinical nephrology. 2015.


IgA (Henoch-Schönlein) vasculitis

❖Anaphylactoid purpura

Male > Female, predominant in Children

❖Severity in Adult > children

❖ 1. Palpable purpura

❖ 2. Arthritis

❖ 3. Abdominal pain due to mesenteric angina

❖ 4. Renal involvement vary 20-100%

IgA nephropathy: Clinical feature

❖ Wide spectrum of clinical presentations

lotvomucosal
Houston

❖ Recurrent macroscopic hematuria provoke by mucosal infection

(synpharyngitis) (40-50%)

❖ Microscopic hematuria with or without proteinuria (30-40%)

❖ Nephrotic syndrome (5%)

❖ RPGN (<10%)

Treatment of IgA Nephropathy

❖ Long-term ACE-I or ARB treatment: proteinuria >1 g/d, with up-titration

of the drug depending on blood pressure (1B)

❖ ACE-I or ARB be titrated upwards to achieve proteinuria <1 g/d (2C)

AnACEI OoCtrlbitof
Bp น้อยกว่า 130/80 mmHg

fishoilonFarnum2b

❖ Fish oil: Persistent proteinuria >1 g/d, despite 3–6 months of optimized

supportive care (including ACE-I or ARBs and BP control) (2D)

ให้ได้ไม่ผิด

KDIGO. Kidney International Supplements (2012) 2, 143–153



Meta-analysis


Subgroup analysis for the effect of corticosteroid on

composite renal endpoint

❖ High-dose and short-term steroid therapy (prednisone>30 mg/d or high-dose

IVMP with duration <1 year) produced significant renal protection

❖ Low-dose and long-term steroid therapy did not benefit. lowdoseYivo

❖ Steroid therapy was associated with a 55% higher risk for adverse events

Lv J, et al. J Am Soc Nephrol: 2012: 23: 1108–1116.



Corticosteroids in IgA nephropathy

❖ Persistent proteinuria >1 g/d, despite 3–6 months of optimized supportive care,

and GFR >50 ml/min per 1.73m2

❖ A 6-month course of corticosteroid therapy (2C)

❖ Pozzi C et al.

❖ IV 1 g methylprednisolone for 3 days each at months 1, 3, and 5, followed by

oral steroid 0.5 mg/kg prednisone on alternate days for 6 months

❖ Manno C et al.; Lv J et al.

❖ 6-month regimen of oral prednisone starting with 0.8–1 mg/kg/d for 2 months

and then reduced by 0.2 mg/kg/d per month for the next 4 months

KDIGO. Kidney International Supplements (2012) 2, 143–153



Variants of IgA nephropathy

❖MCD with mesangial IgA deposits

❖ Treatment as for MCD in nephrotic patients showing pathological

findings of MCD with mesangial IgA deposits on kidney biopsy (2B)

❖Crescentic IgA Nephropathy

❖ Steroids and cyclophosphamide, analogous to the treatment of

ANCA vasculitis (2D)

KDIGO. Kidney International Supplements (2012) 2, 143–153



Immunosuppressive agents

❖ No treating with corticosteroids combined with cyclophosphamide or

azathioprine in IgAN patients except crescentic IgAN (2D)

❖ No using immunosuppressive therapy in patients with GFR <30 ml/min

per 1.73m2 except crescentic IgAN (2C)

❖ No using MMF in IgAN (2C)

KDIGO. Kidney International Supplements (2012) 2, 143–153



VALIGA-Consortium: Corticosteroids in IgAN

Tesar V, et al. J Am Soc Nephrol: 2015: 26: 2248–2258.



Response to CS and RASB compared with RASB alone in propensity-matched

individuals. (A) Entire propensity-matched cohort. (B) Stratified by initial eGFR.

Steroids reduced proteinuria and the rate of renal function decline and increased renal survival

extended to those with an eGFR<50 ml/min per 1.73 m2

Tesar V, et al. J Am Soc Nephrol: 2015: 26: 2248–2258.



ยังงัยก็ prefer steroid

Stop IgAN study

N Engl J Med 2015;373:2225-36.



Stop IgAN study

Comprehensive supportive care : RAS blocker, keep BP< 125/75 mmHg

High risk patients Persistent proteinuria

> 0.75 g/day, but < 3.5 g/day

Supportive care group Immunosuppression group

eGFR> 60 ml/min/1.73m2 eGFR 30-59 ml/min/1.73m2

Glucocorticoid monotherapy Cyclophosphamide 1.5 mg/kg/d for

IVMP 1 g/d x3 day of months 1,3, and 3 months,

5) followed by azathioprine 1.5 mg/kg/

prednisolone 0.5 mg/kg AD on the d during months 4 through 36,

other days plus oral prednisolone

N Engl J Med 2015;373:2225-36.



After 3 years, 4 patients (5%) in the supportive-care group, as compared with 14 (17%) in the

immunosuppression group, had a full clinical remission (P=0.01).

Addition of immunosuppressive therapy to intensive supportive care in patients with high-risk

IgA nephropathy did not significantly improve the outcome

Full clinical remission (UPCR <0.2)

Stable renal function (decrease in the eGFR of <5 ml/min/1.73m2 from baseline eGFR at the end of the 3-year trial phase)

N Engl J Med 2015;373:2225-36.



Secondary End Points on the Basis of the Analysis of Available Cases at

the End of the Trial Phase

ยากดภูมิอื่นแค่ลด hematuria เฉยๆ

N Engl J Med 2015;373:2225-36.



Patients with AKI associated with macroscopic hematuria

AKI and macroscopic hematuria

Renal biopsy

Causes other than IgAN: IgAN

(Crescentic GN, vasculitis, LN, postinfectious GN) (Dominant with IgA in glomeruli by immunohistology)

ATN and intratubular Crescentic IgAN

erythrocytic casts

Steroids and

Supportive treatment cyclophosphamide as in

as in crescentic ANCA vasculitis

other types of ATN.

Repeated episodes of AKI accompanying macroscopic hematuria:

Consider a kidney biopsy when no improvement of kidney function is observed after at

least 5 days from the onset of kidney function worsening

KDIGO. Kidney International Supplements (2012) 2, 143–153



IgA nephropathy: Poor prognosis

❖ Older age ❖ Diffuse proliferative lesion with

❖ Increase BMI crescents

❖ Severity of proteinuria ❖ Glomerulosclerosis

Tubular atrophy, interstitial fibrosis

❖

❖ Persistent microscopic hematuria

❖ Hypertension ❖ Vascular wall thickening

❖ Renal impairment ❖ Capillary loop IgA deposit

Goto M, et al. Nephrol Dial Transplant 2009;24:3068-74.

Cattran DC, et al. Kidney Int 2009;76:534-45.



An Analysis of 1,135 Cases of Kidney Biopsy: Thailand Glomerular

Research Network (TGRN)

Pathology n (%)

Primary glomerular diseases 507 (46.7)

1. IgA nephropathy 158 (31.2)

2. Focal segmental glomerulosclerosis 104 (20.5)

3. Membranous nephropathy 85 (16.8)

4. Minimal change disease 63 (12.4)

5. IgM nephropathy 52 (10.3)

6. Membranoproliferative GN 18 (3.6)

An Analysis of 1,135 Cases of Kidney Biopsy: Thailand Glomerular

Research Network (TGRN)

Pathology n (%)

Primary glomerular diseases 507 (46.7)

1. IgA nephropathy 158 (31.2)

2. Focal segmental glomerulosclerosis 104 (20.5)

3. Membranous nephropathy 85 (16.8)

4. Minimal change disease 63 (12.4)

5. IgM nephropathy 52 (10.3)

6. Membranoproliferative GN 18 (3.6)

Membranoproliferative GN

MPGN: Pathology

Endocapillary proliferation with GBM thickening/double contour

Granular deposition of IgG and C3 in the mesangium and capillary wall

Electron microscope: MPGN

ไม่ใช้แล้ว

MPGN Type 1 MPGN Type 2 MPGN Type 3

Immune

deposits in the mesangium Continuous, dense ribbon-like Complex disruption of the GBM with

and subendothelial space deposits along the GBM large lucent areas

Newer classification based on

immunopathology

IgG and/or C3 component

MPGN pattern

(Double contour and mesangial expansion)

C3 and Ig C3 staining No staining

staining

Dense deposit disease

GN with isolated C3

C3 nephritic factor (C3 NeF)

and Circulating IgG resulting

in persistent C3 breakdown

Very rare disease

❖ Infection (sub acute IE) Thrombotic

❖ Monoclonal gammopathy microangiopathy

❖ Autoimmune disease (SLE)

Immune complex: classical pathway, low C3/C4 or alternative pathway: low C3

MPGN: Clinical manifestration

Focal glomerulonephritis (dysmorphic RBC, occasionally red cell

casts, and proteinuria)

❖ Hypertension: 50-80%

❖ Nephritic syndrome/RPGN: 25%

❖ Non nephrotic range proteinuria: 25%

❖ Nephrotic syndrome: 50%

❖ Spontaneous improvement < 10%

KDIGO. Kidney International Supplements (2012) 2, 143–153



MPGN: treatment

❖ Optimal therapy of idiopathic MPGN remains uncertain

❖ Nephrotic syndrome and progressive decline of kidney

function

❖ Oral cyclophosphamide or MMF plus low-dose alternate day

or daily corticosteroids with initial therapy <6 mo (2D)

Evaluate patients with the histological (light-microscopic) pattern of MPGN for

underlying diseases before considering a specific treatment regimen

(Not Graded)

KDIGO. Kidney International Supplements (2012) 2, 143–153



Secondary Causes of MPGN

Associated with infection Associated with Rheumatologic disease

Hepatitis B and C Systemic lupus erythematosus

Visceral abscesses Scleroderma

Infective endocarditis

Mixed essential cryoglobulinemia with or

Shunt nephritis without hepatitis C infection

Quartan malaria Sarcoidosis

Schistosoma nephropathy Anti–smooth muscle syndrome

Mycoplasma infection Sjögren’s syndrome

Associated with Malignancy Associated with an Inherited Disorder

Carcinoma α1-Antitrypsin de ciency

Lymphoma Complement de ciency (C2 or C3), with or

without partial lipodystrophy

Leukemia

Adapted from Brenner & Rector’s the kidney 10th edition, 2016


Pathogenesis of systemic lupus erythematosus (SLE)

Harrison’s Principle of Internal Medicine 19th edition



SLE: Pathogenesis

Apoptosis Lymphoid compartment Loss of tolerance of

IgM

defect apoptosis self

TCR
Apoptosis cells B cell T cell

MHC I

B cell and T cell co-operation

Defect clearance of Hyperactivation of self

apoptosis cells IgG

reactive B cells

Complement deficiency C1 Immune complex

C2b C4b

C3 Kidney Immune complex deposit

C3a
Clear cell ไม่ได้

C3b ไป detect cell ตัวเอง

Clearance hypothesis Neutrophil Tolerance hypothesis

Macrophage

Organ Involvement in the Course of SLE

❖ Systemic (fatigue, malaise, fever) 95% ❖ Kidney 30-50%

❖ Musculoskeletal 95% ❖ Gastrointestinal 40%

❖ Cutaneous 80% ❖ Thrombosis 15%

❖ Hematologic 85% ❖ Ocular 15%

Neurological 60% Vasculitis 5%

❖ ❖

❖ Cardiopulmonary 60%

Adapted from Harrison’s Principle of Internal Medicine 19th edition



2012 American College of Rheumatology criteria for lupus nephritis

❖ Spot urine protein/creatinine ratio >0.5

“Active urinary sediment” (5 RBCs/HPF, 5 WBCs/HPF in the absence of

infection, or cellular casts limited to RBC or WBC casts)

Systemic Lupus International Collaborating Clinics Classification

Criteria for SLE

> 4 criterion OR Biopsy-proven lupus nephritis and ANA or anti-dsDNA Ab

At least one Clinical criteria At least one Immunologic criteria

ANA level

• Acute cutaneous lupus •

• Anti-dsDNA antibody

• Chronic cutaneous lupus

• Anti-Sm antibody

• Oral ulcers • Antiphospholipid antibody

• Non-scarring alopecia • Low complement

• Direct Coombs’ test in the absence of

• Synovitis

hemolytic anemia

• Serositis

• Renal

Sensitivity 94% and specificity 92%, 4 item

• Neurologic

Petri M, et al. ARTHRITIS & RHEUMATISM, 2012, 2677–268



CLINICAL MANIFESTRATION RELATED RENAL PATHOLOGICAL

CLASSIFICATION

Urine
Nephrotic 5-year

Class sediment Proteinuria Renal insuff

syndrome renal survival

active

I 0 0 0 0 100%

II <25% 25-50% 0 <15% >90%

III 50% 67% 25-33% 10-25% 70-80%

IV 75% >95% 50% >50% 60-80%

V 30% >95% 90% 10% 80-90%

ไม่มีอะไรเลย 1-2

Active urine sediment มี proteinurua ht 3-4

Proteinuria 5


Renal Pathology Classification

RelateTv

7 HUSTTP DIC

TMA
f 20 LN

PathovooTMA othersclotNegashw

Lupus nephritis biopsy ISN/RPS Classification

No endocapillary Endocapillary hypercellularity

hypercellularity

Mesangial Mesangial Subepithelial Involving Involving >50%

deposits only Hypercellularity deposits <50% glom Glom

class I class II class V Class III*

Segmental distribution Global distribution

Class IV S* Class IV G*

*Give the proportion of glomeruli with active and chronic lesions, necrosis, and crecents

ISN/RPS 2003 classification

Class % involved glomeruli Pathology of each Activity and chronicity

glomerulus

I Minimal mesangial LN (normal LM and immune-complex deposit in IF)

II Mesangial proliferation

III – focal < 50% of total glom S=segment A=active

G=global C=chronic

IV - diffuse > 50% of total glom S=segment A=active T

G=global C=chronic t

IFTA 4

V I 20MW Membranous vonachronic

VI Diffuse glomerulosclerosis AI Iv CIT

Minimum 10 glomeruli , Diagnosis of LN dominant IgG, C3 and C1q deposits are absolutely required.

Weening J. J., et al.  Journal of the American Society of Nephrology. 2004; 241–250.



Initial therapy of SLE

ดู life threatening or non life treatening ก่อน

Non-life or organ threatening Life or organ threatening

High dose steroids, usually with addition of

Quality of life: Quality of life: second agent

Acceptable Not-acceptable

Mycofenolate mofetil (or Cyclophosphamide (Low/high dose)

myfortic acid) Do not exceed 6 months of Rx

After D/C cyclophosphamide;

Conservative Conservative Maintain with MMF or azathioprine

management

treatment plus low

Non-response Response

dose steroids

Consider belimumab Belimumab, rituximab

Taper dose of all agents especially

Calcineurin inhibitors or

steroids
Experimental therapies

Harrison’s Principle of Internal Medicine 19th edition



Treatment of lupus nephritis

Class I
❖

❖ Treated as dictated by the extrarenal clinical manifestations of lupus (2D)

Class II

❖ Proteinuria <1 g/d as dictated by the extrarenal clinical manifestations of

lupus (2D)

❖ Proteinuria >3 g/d be treated with corticosteroids or CNIs as described for

MCD (2D)

KDIGO. Kidney International Supplements (2012) 2, 143–153



Treatment of Proliferative Lupus Nephritis (Class III-IV)

❖ Induction phase

❖ Renal remission at presentation and during follow up

❖ Maintenance phase

❖ Prevent relapse and minimizing the side effects of

treatment

Regimens for initial therapy in class III/class IV LN

รุนแรงเลือกอันนี้

Regimen A. NIH B. Euro-Lupus C. Oral cyclophosphamide D. MMF

Oral cyclophosphamide

i.v. cyclophosphamide i.v. cyclophosphamide

1.0–1.5 mg/kg/d

Cyclophosphamide 0.5–1 g/m2; monthly 500 mg; every 2 weeks

(maximum dose 150 mg/ owToo

for 6 months for 3 months
d) for 2–4 months nJoinfertile

i enterprise

MMF up to 3 g/d for

MMF
6 months

Benefit shown by RCT

Yes Yes Yes Yes

in proliferative LN

Benefit shown by

RCT in severe Yes Untested Untested Untested

proliferative LN

Effective in whites,

Effective in whites, Effective in whites. blacks, Chinese; easy to Effective in whites,

Comments blacks, Hispanics, Untested in blacks, administer and lower cost blacks, Hispanics,

Chinese Hispanics, Chinese than i.v. Chinese; high cost

cyclophosphamide

KDIGO. Kidney International Supplements (2012) 2, 143–153



IV Pulse Cyclophosphamide: NIH regimen

Induction IVCY Maintenance IVCY q 3 mo x 6

q 1 mo x 6

❖ Initial IVCY 0.5-1.0 g/m2 (0.5 g/m2 if GFR 1/3 normal)

❖ Adjust subsequent IVCY to maximum dose of 1 g/m2 unless WBC nadir at 10-14
days after ICVY falls below 1,500/mm3
❖ Prednisolone 0.5-1 mg/kg/day for 4-8 weeks, which is subsequently tapered to
low dose maintenance therapy
Boumpas DT, Austin HA, et al. Lancet 1992: 340.
KDIGO guideline: Class III-IV: initial therapy

❖ Corticosteroids (1A), combined with

❖ Cyclophosphamide (1B)

❖ OR

❖ Corticosteroids (1A), combined with MMF (1B)

KDIGO. Kidney International Supplements (2012) 2, 143–153

ACR Guidelines for induction Rx in LN class III-IV
MMF 2-3 gm a day for 6 mo (preferred to CYC
CYC in AA and Hispanics)
PLUS PLUS
GC IV pulse x 3 days then prednisone 0.5-1.0 GC IV pulse x 3 days then prednisone 0.5-1.0
MKD tapered after a few weeks to lowest MKD tapered after a few weeks to lowest
effective dose (1 MKD if crescents seen) effective dose (1 MKD if crescents seen)

High dose CYC Low dose CYC

500-1000 mg/m2 BSA IV q 1 500 mg IV q 2 wks x 6 followed by
mo x 6 maintenance with oral MMF or AZA
(regimen for white with European
background))
Adaped form ACR Guidelines for Lupus Nephritis . Arthritis Care & Research; 2012, 797–808
KDIGO guideline: Class III-IV: maintenance therapy

❖ AZA (1.5–2.5 mg/kg/d) or MMF (1–2 g/d in divided doses),

and low-dose prednisolone (<10 mg/d) (1B)

❖ Maintenance therapy be continued for at least 1 year before

consideration is given to tapering the immunosuppressio (2D)

KDIGO. Kidney International Supplements (2012) 2, 143–153

Beyond Disease Activity: Hydroxychloroquine
❖ Reduced damage accrual (renal, skin)
❖ Decrease in flares

❖ Improved survival
❖ Improved lipid profiles (TC, LDL)
❖ Less neonatal lupus
❖ Less the risk of clotting events in SLE
LUMINA (Multiethnic longitudinal cohort, n=635)
Guillermo J Arthritis Care Res 2010
Alarcon GS Ann Rheum Dis 2007

 General treatment of LN

❖ All patients with any class LN

❖ Hydroxychloroquine (maximum daily dose of 6–6.5 mg/kg
ideal body weight) (2C) or Level C

KDIGO. Kidney International Supplements (2012) 2, 143–153

ACR Guidelines for Lupus Nephritis . Arthritis Care & Research; 2012, 797–808
 Further investigation and Monitoring
❖ Clinical monitoring: ❖ Immunologic monitoring:

❖ Systemic symptoms and signs ❖ Complements: CH50, C3, C4

❖ BUN, serum creatinine ❖ Anti-ds DNA antibody titer
❖ CBC ❖ Kidney biopsy
❖ Urinalysis
❖ Spot or 24 hr urine protein
❖ Serum albumin, cholesterol
❖ Infections: CXR, stool
examination
caseE oTainenmo
YayoiInu2 I 2.3de
 An Analysis of 1,135 Cases of Kidney Biopsy: Thailand Glomerular
Research Network (TGRN)

Pathology n (%)
Primary glomerular diseases 507 (46.7)
1. IgA nephropathy 158 (31.2)
2. Focal segmental glomerulosclerosis 104 (20.5)
3. Membranous nephropathy 85 (16.8)
4. Minimal change disease 63 (12.4)
5. IgM nephropathy 52 (10.3)
6. Membranoproliferative GN 18 (3.6)
 Minimal-change disease in adults
Tosteroid
Responserate

MCD 801
FSGS 501
MN
 MCD: Pathology
❖ Normal light microscopy and IF
❖ Effacement of GEC foot processes by electron microscopy
 MCD: Pathogenesis

❖ Systemic T cell dysfunction results in the production of a glomerular

permeability factor
❖ Associated with HD or allergy

❖ Diminishes the heparin sulfate negative-charge barrier (anionic)

properties of the GBM
Podocytopathies
Koyama A, et al. Kidney Int 1991;40:453-60.
 MCD: clinical feature

❖ Nil (Nothing-In-Light microscopy) disease

❖ Children > adult (Male > female)
❖ 70% of children <10 years
❖ 10-15% of adults
❖ Bimodal with peak incidences in young children and older adults
Gesualdo L, et al. Kidney Int 2004: 66: 890.
Tune BM, et al. J Am Soc Nephrol 1997: 8: 824
Cameron JS. Am J Kidney Dis 1987; 10:157
 MCD: clinical feature

BUTnokgin a wk
❖ Relatively abrupt onset of proteinuria ❖ Adult MCD 1/3
ของ
case
❖ Heavy proteinuria ❖ HT (40%)
❖ Hypoalbuminemia (<1.5-2.0 g/dL) ❖ Microscopic hematuria (29%)
❖ Hyperlipidemia ❖ Reversible AKI (18%),
ischemic ATN
❖ Rare signs of glomerulonephritis (HT,
hematuria, rising Cr)

Waldman M, et al. Clin J Am Soc Nephrol 2007: 2: 445-53.

 MCD with AKI
❖ Acute tubular injury: sloughed epithelial cells, and loss of proximal tubular
brush borders ATN Feira v highUna

❖ Risk factors
❖ Older age
❖ Hypertension
❖ Severe nephrotic syndrome
❖ Underlying arteriosclerosis of the kidney
❖ NSAIDS Functional renal insufficiency
Jennette JC, et al. Am J Kidney Dis 1990; 16: 432–437.
 Common associations with MCD
Infection Allergies
Virus Food, dust
Parasitic Bee stings
Pharmaceutical agents Pollen
Nonsteroidal anti-inflammatory drugs Poison ivey and poison oak
Gold, lithium, interferon Dermatitis herpetiformis
Ampicillin, rifampin Disease and other associations
Trimethadione, tiopronin SLE
Tumors Following allogeneic stem cell
Hodgkin’s lymphoma transplantation for leukaemia
Lymphoma, leukemia Following hematopoietic cell
Solid tumors transplantation
Adapted from Brenner & Rector’s the kidney 10th edition, 2016
 Minimal change disease
❖ Complete remission: 75 %
❖ Prednisolone 1 mg /kg/day or 2 mg/kg/AD

❖ Duration 100- Children

Percent in complete
80-
Adults
remission
❖ > 8 wk (remission 60%) 60-
40- hiduratamuno'sinn
❖ 16-20 wk (remission 76-81%) 20-
0-
0 2 4 8 16
Weeks from beginning of corticosteroid therapy
Nolasco F, et al. Kidney Int, 1986. 29: 1215-23.
 Treatment of initial episode of adult MCD

❖ Prednisolone 1 mg/kg/day (maximum 80 mg) OD or 2 mg/kg

(maximum 120 mg) AD (2C)
❖ High dose corticosteroids for a minimum period of 4 weeks, and for
a maximum period of 16 weeks if complete remission is not achieved
(2C)
❖ Corticosteroids be tapered slowly (5-10 mg/wk) over a total period of
up to 6 months after achieving remission (2D)

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Treatment of initial episode of adult MCD

❖ Relative contraindications or intolerance to high-dose corticosteroids

❖ Uncontrolled diabetes, psychiatric conditions, severe osteoporosis
❖ Oral cyclophosphamide or cyclosporine (2D)

❖ Using the same initial dose and duration of corticosteroids for infrequent
relapses Ensino (2D)

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Frequently relapsing and steroid-dependent MCD

❖ Oral cyclophosphamide 2–2.5 mg/kg/day for 8 wks (2C)

❖ Oral cyclosporine 3–5mg/kg/day or tacrolimus 0.05–0.1 mg/kg/d in divided

doses for 1–2 yrs (2C)

❖ MMF 500–1000 mg twice daily for 1–2 yrs in pts who are intolerant of
corticosteroids, cyclophosphamide, and CNIs (2D)

KDIGO. Kidney International Supplements (2012) 2, 143–153

 MCD: prognosis

❖ Highly remission & relapse rate

❖ 50-75 % relapse within 6-12 mo
❖ 25 % frequent relapses
Resistance คิดถึง fsgs
❖ 25 % steroid dependence ไว้ก่อน

❖ Good prognosis: 5% turn to ESRD in 25 yr

7 to 12 % of adults with steroids resistance

Nakayama, M, et al. Am J Kidney Dis, 2002. 39: 503-12.
 Complication of MCD
❖ Risk of mortality due to infection (peritonitis) Sbp เจอบ่อยสุด

❖ Less commonly thromboembolism

❖ 5% develop ESRD in 9.4 yr
❖ Related to treatment
❖ Side effects of steroids
❖ Side effects of cyclophosphamie: infertility, malignancy
❖ Side effects of cyclosporine: hypertension, impair renal function
 Steroid-resistant MCD

❖ Re-evaluate other causes of nephrotic syndrome

❖ Corticosteroid-resistant MCD suggests FSGS

❖ Steroid resistance may be due to undetected FSGS

 An Analysis of 1,135 Cases of Kidney Biopsy: Thailand Glomerular
Research Network (TGRN)

Pathology Nephrotic n (%)

syndrome อายุน้อย
Primary glomerular diseases ไม่ค่อย response 507 (46.7)
steroid
1. IgA nephropathy 158 (31.2)
2. Focal segmental glomerulosclerosis 104 (20.5)
3. Membranous nephropathy 85 (16.8)
4. Minimal change disease 63 (12.4)
5. IgM nephropathy 52 (10.3)
6. Membranoproliferative GN 18 (3.6)

อ้วน fsgs
 An Analysis of 1,135 Cases of Kidney Biopsy: Thailand Glomerular
Research Network (TGRN)

Pathology n (%)
Primary glomerular diseases 507 (46.7)
1. IgA nephropathy 158 (31.2)
2. Focal segmental glomerulosclerosis 104 (20.5)
3. Membranous nephropathy 85 (16.8)
4. Minimal change disease 63 (12.4)
5. IgM nephropathy 52 (10.3)
6. Membranoproliferative GN 18 (3.6)
Focal segmental glomerulosclerosis
 Primary FSGS
Hilar variant Tip variant Collapsing variant
 Primary FSGS
Classic FSGS Cellular variant FSGS

FSGS NOS (not otherwise specified) 

 

Most common
 Primary FSGS
Hilar variant Tip variant MCD Collapsing variant

2nd FSGS: obesity Good respond to steroid Poor prognosis

 Primary FSGS
Yaimaimmuneprocess
❖ Normal IF
❖ IgM, C1q and C3 at sclerosis area

❖ EM: foot processes effacement

 FSGS: Pathogenesis

❖ Alterations in T cell function and glomerular permeability

factor
❖ Recurrent FSGS after KT
❖ Plasmapheresis & anti-IgG columns: absent of proteinuria
❖ Elevated circulating soluble urokinase receptors (suPAR)
levels: 55-84%

Wei C, Trachtman H, Li J, et al. J Am Soc Nephrol 2012; 23:2051.

Gene mutation causally linked to FSGS
Nephrin: Chromosome 19q13
Congenital nephrotic syndrome of Finnish type

Focal Segmental Sclerosis; N Engl J Med 2011;365:2398-411

 Secondary FSGS
HIV disease IV drug abuse heroin

Other drugs (pamidronate, interferon, Genetic abnormalities (pdocin, alpha

anabolic steroids) actinin-4, TRPC6)
Glomerulomegaly Reduce nephron numbers
- Unilateral renal genesis
- Morbid obesity
- Oligomeganephrnia
- Sickle cell disease
- Reflux interstitial nephritis
- Cyanotic congenital heart disease
- After focal cortical necrosis
- Hypoxic pulmonary disease
- After nephrectomy
Adapted from Brenner & Rector’s the kidney 10th edition, 2016
 Secondary FSGS
HIV disease IV drug abuse
Other drugs (pamidronate, interferon, Genetic abnormalities (pdocin, alpha
anabolic steroids) actinin-4, TRPC6)
Glomerulomegaly Reduce nephron numbers
- Unilateral renal genesis
- Morbid obesity
- Oligomeganephrnia
- Sickle cell disease
- Reflux interstitial nephritis
- Cyanotic congenital heart disease
- After focal cortical necrosis
- Hypoxic pulmonary disease
- After nephrectomy
Adapted from Brenner & Rector’s the kidney 10th edition, 2016
 FSGS: Clinical feature
❖ Acute or insidious onset of proteinuria
❖ Degree of proteinuria varies from non-nephrotic (1-2 g/day) to massive
proteinuria (> 10 g/day)
❖ Nephrotic syndrome 60-75 %
❖ Associated findings
❖ Hypertension 45-65%
❖ Microscropic hematuria 30-50%
❖ Renal insufficiency 25-50%
 Clinical Features of FSGS
Histologic subtype Clinical features

NOS Nephrotic syndrome or sub-nephrotic proteinuria

Perihilar More likely to present with subnephrotic proteinuria and normal

serum albumin levels

Cellular Nephrotic syndrome

Tip Abrupt onset of the nephrotic syndrome

Best prognosis, with response to glucocorticoids
Collapse Aggressive variant of primary FSGS with black racial predominance
and severe nephrotic syndrome
Worst prognosis, with poor response to glucocorticoids
N Engl J Med 2011; 365:2398-411.
 Perihilar variant FSGS: Massive obesity
❖ Renal hypertrophy and increase GFR and RBF
❖ Excessive glomerulomegaly with vascular dilatation and mesangial expansion in five
grossly obese individuals

Cohen AH. Am J Pathol 1975; 81:117–130.

Barisoni L et al. CJASN 2007;2:529-542
 Obesity related glomerulomegaly
❖ Clinical: lower incidence of nephrotic syndrome, normal serum
albumin and cholesterol เจอ proteinuria อย่างเดียว ไม่มี
อากา
❖ Natural history: more indolent progression
❖ Pathology:
❖ Glomerulomegaly
❖ Milder foot process effacement
❖ Less segmental sclerosis
Kambham N, et al. Kidney Int; 2001: 59: 1498–1509.
 Primary VS Secondary FSGS
Primary Secondary

Onset Acute onset of nephrotic Slowly increasing proteinuria and

syndrome renal insufficiency
Proteinuria Nephrotic range Sub-nephrotic range
Clinical NS + +/-
Normoalbuminuria
Pathology Diffuse foot process fusion Focal foot process effacement

Healed lesion - Obsolescent segment of

capillary tuft
(PAS staining less intensely )

Praga, M., et al., Am J Kidney Dis, 1999. 33(1): 52-8.

Weight loss in overweight patients with proteinuric nephropathies

-3

Proteinuria (g/day)
BMI (kg/m2)

- 2.5

- 2.0

- 1.5

- 1.0

Proteinuria decreased by 31.2% in the diet group

Morales E, et al. Am J Kidney Dis 2003 Feb;41(2):319-27.
Clinical interventions for obesity related glomerulomegaly

❖ Lifestyle modification
❖ Weight reduction
❖ BP-lowering medication (RAAS antagonists)
❖ Glucose-lowering medication (metformin, thiazolidinediones)
❖ Lipid-lowering medication

Prasad GV, et al. World J Nephrol. 2014: 6;3(4):210-9.

 Collapsing FSGS ไม่ค่อยเจอ

❖ Collapse and sclerosis of the entire glomerular tuft

❖ Marked hypertrophy and hyperplasia of podocytes
❖ Africa american
❖ HIV nephropathy nastnetaino
❖ Pamidonate
❖ Heroin
 Treatment of idiopathic FSGS

❖ Idiopathic FSGS associated with clinical features of the nephrotic syndrome (1C)

nforofoo
response
❖ Prednisone 1 MKD OD or 2 MKD (maximum 120 mg) AD: Remission 28-74% (2C)
❖ Minimum of 4 wks; continue high-dose corticosteroids up to a maximum of 16
wks (2D)
❖ Corticosteroids be tapered slowly over a period of 6 months after achieving
complete remission (2D)

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Intolerance to high-dose corticosteroids

❖ Cyclosporine (CNIs) be considered as first-line therapy for

patients with relative contraindications or intolerance to
high-dose corticosteroids
❖ Remission 50 – 60 % (steroid response)
❖ Remission 20 – 70 % (steroid non response) (2D)

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Treatment for steroid-resistant FSGS

❖ Cyclosporine at 3–5 mg/kg/d (initial target levels 125–175 ng/ml)

in divided doses be given for at least 4–6 months (2B)
❖ Continuing cyclosporine treatment for at least 12 months,
followed by a slow taper (2D)
❖ Combination of MMF and high-dose dexamethasone for not
tolerate with cyclosporine (2C)

KDIGO. Kidney International Supplements (2012) 2, 143–153

 FSGS: Prognosis
❖ Relatively poor outcome, with 50% reaching ESRD by 10 years
❖ Risk factors
❖ Massive proteinuria
❖ Increase serum creatinine
❖ Interstitial fibrosis and tubular atrophy
❖ Collapsing variant (ESRD within 15 months)
❖ Failure to CR/PR
Korbet, S.M. et al. Nephrol Dial Transplant, 1999. 14 S3: 68-73.
Grcevska L, et al. Am J Kidney Dis 1999;33:652-7.
 An Analysis of 1,135 Cases of Kidney Biopsy: Thailand Glomerular
Research Network (TGRN)
Nephrotic in elderly
Pathology n (%)
Primary glomerular diseases 507 (46.7)
1. IgA nephropathy 158 (31.2)
2. Focal segmental glomerulosclerosis 104 (20.5)
3. Membranous nephropathy 85 (16.8)
4. Minimal change disease 63 (12.4)
5. IgM nephropathy 52 (10.3)
6. Membranoproliferative GN 18 (3.6)
Idiopathic membranous nephropathy
 Membranous nephropathy
Light microscopy:
GBM thickening Spike appearance
 Staging of Membranous Nephropathy
Stage I has subepithelial dense
Stage IV has thickened basement deposits (arrow) without adjacent
membrane with irregular lucent basement membrane reaction.
zones

Stage II has projections of basement

Stage III has deposits surrounded membrane adjacent to deposits.
by basement membrane.
 Membranous nephropathy
Immunofluorescene Electron microscopy

Diffuse granular capillary wall Electron dense deposits across the

staining of IgG and C3 GBM in the subepithelial space
Membranous nephropathy: Pathogenesis
LNclassV PMN MNrelatemalignancy
Circulating Immune In situ Circulating Immune In situ Circulating Immune
complex complex complex
“Native Ag” “Planted Ag”

Glassock RJ. N Engl J Med 2009; 361:81-83.

 Phospholipase A2 receptor (PLA2R)
Agogvivog podocyte
AtIoanTv
❖ In situ deposit through binding of circulating anti-PLA2R autoantibodies
to the PLA2R antigen expressed on the surface of podocytes

Beck LH Jr, et al. N Engl J Med; 2009: 361: 11–21.

 Membranous associated disorders
Infection:
Hepatitis B and C, syphilis, malaria, schistosomiasis, leprosy
Cancer:
Breast, colon, lung, stomach, kidney, esophagus, ovary, prostate
Drugs:
Gold, mercury, penicillamine, NSAIDS, probenecid, captopil 87Rheumato
Autoimmune diseases:
SLE, RA, dermatitis herpetiformis, myasthenia gravis, Sjögren's syndrome
Systemic diseases:
Fanconi's syndrome, Crohn's disease, Sarcoidosis, Guillain-Barré syndrome

Satirapoj B. Common Problems in Internal Medicine. 2010. 487-97.

Membranous nephropathy: Clinical feature

❖ Adult > 40 yr (30-50 yr) and men: women = 2-3:1

❖ > 80% have more than 3 g/d of proteinuria
❖ Almost always insidious onset ptNewmanyr tight
❖ Bland urine sediment
❖ Mild microhematuria (30-40%)
❖ Hypertension (15-55%)
Membranous nephropathy: Clinical feature

❖ Normal or slightly decreased renal function (impair renal function

< 10%)
❖ Hypoalbuminemia, elevated LDL and VLDL
❖ Thromboembolic manifestation (RVT, PE, DVT)
❖ Risk of malignancy increase with age simootway 65J inCA

❖ Spontaneous remission 30%, stable 30% and progression 30%

Treat เฉพาะคนที่ progress Hogan SL. Am J Kidney Dis 1995; 25:862.
Schieppati A. N Engl J Med 1993; 329:85.
Ponticelli C. Kidney Int 1995; 48:1600.
Predicting chronic renal insufficiency in idiopathic MN

❖ Pei and et al.; likelihood of progressing to CKD at 5-6 years

❖ 66 % in proteinuria > 8g/d for > 6 mo
❖ 55 % in proteinuria > 6g/d for > 9 mo
❖ 44 % in proteinuria > 4g/d for > 1 year

❖ Adequate assessment of proteinuria requires following

patients for at least 6 to 12 months
Pei Y, et al. Kidney Int. 1992;42(4): 960.
 Treatment of membranous nephropathy

❖ 35% spontaneous remission

Treat ในคนพวกนี้
❖ Patients with nephrotic syndrome with
❖ Persistent urinary protein >4 g/d and remains at over 50% of the baseline
value, during therapy at least 6 months (1B)
❖ Presence of severe, disabling, or life-threatening symptoms related to the
nephrotic syndrome (1C)
❖ Serum Cr has risen by 30% within 6 to 12 months (2C)

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Initial therapy of membranous nephropathy

❖ A 6-month course of alternating monthly cycles of oral and i.v. corticosteroids,

and oral alkylating agents (1B)
❖ Cyclophosphamide > chlorambucil for initial therapy (2B)
❖ At least 6 months before being considered a treatment failure (1C)
❖ Continuous daily use of oral alkylating agents for 4-6 months may also be
effective (2C)

KDIGO. Kidney International Supplements (2012) 2, 143–153

 ‘‘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 chlorambucil (0.15–0.2 mg/kg/d) or oral cyclophosphamide (2.0
mg/kg/d) for 30 days
❖ Month 3: Repeat Month 1
❖ Month 4: Repeat Month 2
❖ Month 5: Repeat Month 1
❖ Month 6: Repeat Month 2

If total leukocyte count falls to <3500/mm3, then hold chlorambucil or cyclophosphamide until recovery to >4000/mm3
 UK Membranous Trial
108 subjects with proteinuria 8.5 g/day and progressive decline in eGFR (>20%)
during 2 yrs, serum Cr < 3.4 mg/dL (High risk)
100-
Prednisolone+ chlorambucil
Patients without decline (%)

75- Cyclosporin
Support
50-

25-

0-
0 1 2 3
Time to 20% decline in GFR (years)

Time to 20% decline in GFR (years)

Howman A, et al. Lancet 2013; 381:744

 Alternative regimens

❖ Cyclosporine (3.5–5.0 MKD) or tacrolimus (0.05-0.075)

MKD) at least 6 months (1C)
❖ Discontinued CNI in patients who do not achieve remission
after 6 months (2C)

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Poor prognosis
❖ Male
❖ Advanced age (>50 years)
❖ Persistent heavy proteinuria (>3.5 g/d)
❖ Decreased serum albumin
❖ Hypertension
New Predictors Levels of circulating anti-PLA2R revealed a
❖ Hyperlipidemia strong correlation with clinical disease activity
❖ Impaired GFR
❖ Poor protein selectivity, or persistent excretion of β2 microglobulin or C5b-C9,C3d
❖ Advanced stage of MN Zuccheli P, Oxford Medical, 1998, 570-612
Coggins CH. Semin Nephrol 2: 264-273, 1982
Ponticelli C. Oxford Medical Publications, 1997
Management of Complications
 Hypertension

❖ Lifestyle modification
❖ Salt restriction, weight normalization, regular exercise, and
smoking cessation
❖ ACE-I and ARB to be first-choice therapy
❖ Recommendations <130/80mmHg

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Proteinuria

❖ Toxic to the tubulointerstitium

❖ ACE-I or ARB may reduce proteinuria by up to 40–50% in a dose
dependent manner
❖ Adequate dietary protein (0.8–1.0 g/kg daily) with a high
carbohydrate intake to maximize utilization of protein
Yaioiooiwwprot.mnUrineprot

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Hyperlipidemia

❖ Follow the guidelines at high risk for the development of

cardiovascular disease
❖ Statins are effective in correcting the lipid profile
TxNSF Yvoisoo

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Nephrotic edema
❖ Moderate dietary sodium restriction (1.5–2 g sodium per 24 hours)
❖ Diuretic-resistant nephrotic syndrome
❖ Intestinal-wall edema YaignFw

❖ Oral loop diuretics with once- or twice-daily administration are

usually preferred ไม่ให้ thiazide
❖ Ease of administration and longer therapeutic effect compared
to i.v. therapy In Ivformlad

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Severe nephrotic edema
ไล่ลงไป ถ้าไม่หาย

❖ IV diuretic, by bolus injection or infusion

❖ Combining a loop diuretic with a thiazide diuretic
❖ IV albumin infusions combined with diuretics, but
unproven benefit
❖ Mechanical ultrafiltration

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Hypercoagulability
❖ Anti-coagulant drugs considered if serum albumin <2.0–2.5 g/dl with one or
more of the following Mcd หายเร็วเลยไม่ค่อยให้
❖ Proteinuria >10 g/d
❖ BMI> 35 kg/m2
❖ Family history of thromboembolism
❖ CHF class III or IV
❖ Recent abdominal or orthopedic surgery
❖ Prolonged immobilization

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Risk of infection
❖ Nephrotic children with ascites
❖ Fluid should be examined microscopically for SBP
❖ Parenteral antibiotics should treat as pneumococcal infection
❖ If repeated infections occur, serum immunoglobulins should be
measured
❖ Serum IgG < 600 mg/dl, monthly administration of i.v. immunoglobulin
10–15 g to keep serum IgG >600 mg/dL

KDIGO. Kidney International Supplements (2012) 2, 143–153

 Risk of infection

❖ Pneumococcal vaccination and annual influenza vaccination

❖ Live vaccines (measles, mumps, rubella, varicella, rotavirus, yellow
fever) is contraindicated while on immunosuppressive or cytotoxic
agents
❖ Deferred until prednisone <20 mg/d and/or immunosuppressive
agents have been stopped for at least 1–3 months
เลียงแสงแดด 10-16

ข้อ bonus ถ่ายใหม่

KDIGO. Kidney International Supplements (2012) 2, 143–153
 Severe proteinuria ควร severe dr

Thank you for your attention

Orthostatic
hypotension

Intelligence Dialysis Center

Nephrology Unit
Myeloma
Phramongkutklao Hospital and College of Medicine cast มัก
aki ไม่ใช่
proteinuria