BSIM 2013 – Workshop Nephrology

Glomerulonephritis

K.M. Wissing MD PhD

Department of Nephrology – UZ Brussel

Case number 1

83-year old man

Medical history

Arterial hypertension

Primary hyperparathyroidism with resection of an adenoma

several years ago

Surgical repair of inguinal hernia

Treatment:

Aprovel 150 mg/d, Aggrenox 200 mg/day and N-

acethylcysteine.

Infection of the upper respiratory tract in August 2011

with persistent cough and non-purulent sputum. No fever.

Persisting in spite of cessation of smoking over the

month. Loss of weight of 2 kg from 64 to 62.

Case history

Pneumology consultation: 29/09/2011:

only slight obstruction on LFT.

25/10/11: Hospitalisation in

pneumology for intermittent fever,

palpitations, anorexia, asthenia, weight

loss)

Physical examination relatively normal except

for wasting (BMI 19),

Extensive workup (CT thorax, MR abdomen,

PET scan thorax, TEE, colonoscopy, temporal

artery biopsy)

Laboratory analysis

Biology 10/2011:

Normal renal function (Urea 45, creatinine 1.0)

Normocytic anemia (Hb 10.8)

Inflammatory syndrome (CRP 150 mg/L)

Hypoalbuminemia and low cholesterol

No proteinuria

Microscopic hematuria (97/µL)

Case 1 autoimmune tests baseline

Case presentation

Important bilateral centrilobular emphysema

on CT.

Some small lymph nodes of moderate

metabolic activity at the mediastinal and

axillary level

Atrial Flutter with anticoagulation.

Villous adenoma of the colon with endoscopic

resection

Conclusion: Inflammatory syndrome, fever

and alteration of the general condition

probably due to ANCA vasculitis.

Treatment: usual treatment + Trazodone +

Fraxiparine

Case presentation

18/11/2011 Consultation of internal

medicine:

Sudden development of diplopia. Rest of

clinical condition in status quo

Ureum 42 mg/dl Creat 1.38 mg/dl Alb

2.7 g/dl CRP 122.4 mg/dl Hb 8.9 g/dl

Persistent microscopic hematuria.

Proteinuria 0.48 g/L (0.4 g/g creat)

Diagnosis of nervus abducens (VI)

paresis on the left side.

How to proceed

Additional work-up ?

Biopsy ?

Which organ to biopsy ?

Treatment ?

Which treatment regimen to chose ?

Kidney biopsy

Kidney biopsy 18/11/2013: 9 glomeruli (2 with complete sclerosis).

Numerous red blood cells in the tubular cells. Interstitial inflammation and

signs of tubulitis. 1 glomerulus with necrosis (presence of fibrin) with

extracapillary proliferation of podocytes. Immunofluorescence negative.

Treatment of ANCA vasculitis

KDIGO Guidelines June 2012 (kdigo.org)

NORAM Study

•Exlusion criteria:

• Organ or life-threatening manifestations: hemoptysis with

lung infiltrates, cerebral infarction, progressive

neuropathy…

• Creat >150 µmol/L, Proteinuria >1g/day

•Treatment regimen:

• MTX (N=51): 15 mg/w increasing to 20-25 mg/w. Stop by

month 12

• CYC (N=49): oral 2 mg/kg (max 150 mg); 1.5 mg/kg after

remission. Stop month 12

• Both groups: Pred: 1 mg/kg taper to 5 mg/d Stop month 12

De Groot et al. Arthritis Rheumatism 2005

NORAM

•Two deaths in both groups

•More leucopenia in CYC group more liver dysfunction in MTX group

•No difference in incidence of infections De Groot et al. Arthritis Rheumatism 2005

Survival free of relapse

69.5%

46.5%

Induction of remission

Treatment of ANCA vasculitis

Ledertrexate 2.5mg: 1 x 6 tablets /week.

Medrol 32mg: 1 x 2 tablets/day.

Folavit 0.8 mg/day

Pantoprazole eg 20mg: 1 x 1 /day

Steovit forte 1000mg/800ie: 1 x 1 /day.

Nobiten 5mg: 1 x 1 tablet/day.

Fraxodi 11.400ie axa pe/0.6ml s.c.: 1 x

/day.

Pentamidine 300mg 1x/month

D Cure 1/week

Evolution of ANCA and anti-PR3 antibodies

19/11/13 Ledertrexate 15 mg Medrol 64 mg

07/12/13 Medrol 32 mg/day

15/02/13 Medrol 24 mg/day

09/05/12 Medrol 12 mg /day

23/08/12 Medrol 6 mg/day

28/11/12 Medrol 4 mg/day

3/7/13 Stop Medrol

March 2013 Ledertrexate 7.5 mg/week

4/12/13 Ledertrexate 5 mg/ week

Follow up

5/12/2011 (3 weeks after start of treatment): Slight pain

at the right testis (at palpation and mobilization) with hard

mass of about 5 cm diameter. Strong suspicion for a

tumor at ultrasound examination.

6/3/2012: Hospitalization for pneumonia of the left lower

lobe with good evolution under IV Amoxicilline

Clavulanate therapy

Normalization of microscopic hematuria and proteinuria

from 02/2012.

Normalization of CRP from March 2012 (after resolution of

pneumonia).

21/3/2012: No more pain but persistent mass. Surgical

removal to exclude tumor. Pathology ischemic necrosis

with granuloma. Blood vessels with images of vasculitis

and fibrinoid necrosis.

Necrotizing vasculitis of the testis

Necrotizing vasculitis with granuloma formation compatible

with granulomatous microscopic polyangitis of the testis

Case number 2

27 year-old women:

2006 microscopic hematuria. Sometimes

macroscopic hematuria during infectious episodes.

Biopsy in another hospital with mesangiocapillary

glomerulonephritis and isolated deposits of C3.

IgA negative (original and control staining)

Proteinuria of about 4 grams with normal renal

function. Treatment with ace inhibitors and

reduction of proteinuria to about 1 gram/day.

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Case number 2

No more follow up between 2009 and

2011

12/2011: Diagnosis of renal

insufficiency during surgery for

endometriosis

04/2012: Blood analysis by the general

practitioner shows creatinine of 1.55

mg/dl and proteinuria of 5.4 g/24 h.

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Laboratory results

30/05/12 10/04/12 06/05/11 27/07/09 31/03/08

Urea mg/dl 54 57 52 49

Creatinine mg/dl 1.65 1.55 0.97 1.2 0.91

eGFR ml/min

.

38

Hemoglobin g/dl 11.3 15.6 12.8 11.0 12

Protein g/dl 6,7 6,1

Albumin g/dl 3.8 4.5

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31/03/2008

C3: 0.71 g/l (N: 0.79-1.52); C4: 0.2 (N: 0.16-0.38)

30/05/2012 (UZ Brussel)

IgA: 355 mg/dl; complement C3c: 84 mg/dl (N: 72-143 mg/dl);

complement C4: 27 mg/dl; hemolytic complement CH50: 422 U/ml

ANA: neg; ANCA: neg; HBV neg, HCV neg

Laboratory analysis

30/05/12 10/04/12 27/07/09 19/09/08

Volume ml/24 u sample 1900 1000 sample Proteïnurie g/l

g/g creat

g/24 uur

5,44

8,1

2,86

7,3

5,4

0,34

0,5

0,6

0,99

1,13

MAU mg/g creat

WBC/µl /µl 6 11

RBC/µl /µl 143 640

Aerobe

kweek

kiemen/ml Neg Neg

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Evaluation of alternate complement

pathway

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Differential diagnosis

C3 glomerulopathy

Inherited or acquired defect in control of

activation of alternate complement pathway

No effect of immunosuppressive treatment

Recurrence on an eventual renal transplant

IgA nephropathy

Error in first biopsy

Potential for immunosuppressive therapy

Better prognosis in case of renal

transplantation

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Additional workup

Repeat kidney biopsy

Kidney biopsy: mesangial expansion and

increased mesangial cellularity. 3/10

glomeruli with sclerosis. Moderate

tubular atrophy and significant tubular

atrophy with thickened basal

membranes. Fibrosis score 3/6

IF 3+ positive for IGA and 3+ for C3

Conclusion: IgA nephropathy.

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IgA nephropathy

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IgA Etiology and Pathogenesis

Unknown: racial disparities – familial

aggregation suggest important genetic

background

Complex disease with gene-environment and

immunological interactions.

Hypothesis

Environmental stimulus triggers IgA secretion

Production of polymeric Gal-deficient IgA1 that form

immune complexes

Mesangial binding of macromolecular complexes

triggering local inflammation

Glomerulonephritis

IgA nephropathy

Normal

IgA nephropathy (Gd-IgA1)

GalNac: N-acethyl-galactosamine

Gal: galactose

NeuAc: sialyc acid

Beerman I et al. Nat Clin Pract Nephrol 2007; 3:325

Sporadic IgA nephropathy

78% of patients with

sporadic IgAN had

increased Gd-IgA1

25% of relatives (28% 1st

degree, 17% 2d degree)

with increased Gd-IgA1

Genetic model

compatible with major

dominant gene.

Patients with low Gd-

IgA1 also have relatives

with low Gd-IgA1

Gharavi AG et al. J Am Soc Nephrol 19: 1008, 2008

Identification of B-cell clones producing

glycan-specific anti-Gd-IgA1 antibodies

Suzuki H et al. J Clin Invest 119:1668; 2009

• 54 of 60 patients with

binding above P95 of healthy

controls

• Correlation of rIgG levels

with clinical severity

• Sensitivity 88% en specificity

95% as predictive test in ROC

analysis

Treatment of IgA Nephropathy

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KDIGO Guidelines June 2012 (kdigo.org)

Immunosuppressive therapy in IgA

nephropathy

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KDIGO Guidelines June 2012 (kdigo.org)

Pozzi regimen

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Pozzi et al JASN 2004

Manno – Lv regimen

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Manno et al NDT 2009

Lv et al AJKD 2009

Role of combination therapy in the

treatment of IgA nephropathy

Renal transplant patients

Aggressive recurrence in exceptional although

most of these patients had aggressive disease

on their native kidneys

Possibility to reduce the dose of steroids in

order to improve the side effect profile

Antibody-mediated disease. Potential for IS

agents that reduce Ab production

Problem of inadequate studies

MMF monotherapy without effect

AZA added to Pozzi regimen : no benefit

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KIDIGO guidelines

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Combination therapy in patients with

aggressive IgA nephropathy

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Balantine JASN 2002

• Cyclophosphamide oral 1.5 mg/kg for 3M

then AZA 1.5 mg/kg thereafter

• Pred 40 mg/day with progressive taper

• Control group with supportive care

Combination therapy with AZA and

steroids in children

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Yoshigawa CJASN 2006

How to treat our patient ?

GFR <50ml/min

High sclerosis score on biopsy

No crescents on renal biopsy

Reluctant to experience severe steroid-

mediated side effects

Conservative care ?

High dose steroids for 6 months ?

(Cyc)-AZA in combination with lower dose of

steroids although not recommended in

guidelines ?

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Combination therapy with

Azathioprine and steroids

Discussed extensively with the patient

Physician and patient reluctant to use high dose long-term

steroids

Outside indications for CYC and risk for fertility in young

woman

Good results of proposed strategy in transplant recipients

Good personal experience by doctor

Not in accordance with current guidelines

Low risk of serious adverse effects

Medrol 32 mg (0.5 mg/kg) with rapid taper in

combination with Imuran 100 mg (1.5 mg/kg)

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Evolution under combination therapy

with AZA and low-dose steroids

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Immunosupp 8/11/13 28/06/13 25/03/13 23/01/13 7/12/2012 16/10/12 13/09/12 7/08/12 11/07/12

Aza dose 100 100 100 100 100 100 100 100 100

MPDS dose 4 4 6 6 8 16 16 16 32

Proteinuria/

Hematuria

Proteinuria g/l 0.5 negative 0.41 0.45 negative 0.65 3.4 4.9 4.9

Proteinuria

g/g

creat 0.4 0.6 0.65 6.4 7.8

WBC /µl 13 4 12 6 6 4 3 14 5

RBC /µl 22 13 20 21 83 48 425 542 331

Urine Culture negative negative Lactobacill

us species negative negative

Lactobacill

us species negative negative negative

Creatinin slightly improved over last year: 1.55 mg last FU

Case number 3

23 year-old women

No significant medical history

Hairdresser; non-smoker

No medical therapy except hormonal

contraception

June 2011 sudden development of a

nephrotic syndrome.

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Nephrotic syndrome

Diffuse edema of the lower extremities en

palpebral edema

Weight increase from 51 to 56 kg 2-3 days.

Laboratory analysis:

Albumin 2 g/dl, Total Cholesterol 456 mg/dl; LDL

cholesterol 283 mg/dl; Proteinuria 18 g/day (non-

selective proteinuria)

Normal kidney function and normal urinary

sediment

Normal ultrasound of the kidneys

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Differential Diagnosis

??

Minimal change disease

Focal Segmental glomerulosclerosis

Membranous glomerulonephritis

Amyloidosis

(Diabetic nephropathy, renal vein

thrombosis ….)

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Additional Workup

??

Kidney Biopsy

Baseline Bone Mineral Density

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Minimal change disease

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Treatment

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KDIGO Guidelines June 2012 (kdigo.org)

Treatment

Date Medrol dose Proteinuria

30/6/11 48 mg 18 g/day

Full remission in 2 weeks with weight loss

of 5 kg.

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Steroid taper

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Recurrence of MCD

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What to do next?

Iatrogenic Cushing – Multiple striae on

the back / Hirsutism

Additional examinations?

Repeat biopsy ?

Other ?

Therapy ?

Lumbar BMD (QCT)

Date T-Score BMD

05/07/11 +0.2 166 mg/ml

29/10/12 -1.5 119 mg/ml

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What to do next ?

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KDIGO Guidelines June 2012 (kdigo.org)

What to do next ?

25/12/12: Start Advagraf 3 mg/day with same

dose of steroids

07/02/13: Proteinuria Neg - Stop steroids

Complete remission with tacrolimus

monotherapy and trough levels between 2 and

4 ng/ml

Lumbar BMD (QCT)

Date T-Score BMD

05/07/11 +0.2 166 mg/ml

29/10/12 -1.5 119 mg/ml

28/10/13 -0.3 161 mg/ml

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