Conventional Therapy

Primary Glomerulonephritis

General information

Objective :

This study protocol was introduced in order to find consensus regarding the therapy of different glomerular diseases. The recording of relevant clinical findings, laboratory data and biopsy reports is done by a computerized data system in the local centers. Data are finally transferred to a central data bank which is presently located in Tübingen. Biometric analysis is performed in coordination with the Institute of Medical Biometry of the University of Tübingen.

Conventional therapy protocols are assigned to a patient by random numbers in the case of several available treatment modalities for one and the same form of glomerulonephritis. The treatment effect is compared by a randomized, controlled, open trial. The randomization is done on-site at each centre by a computer program (random number generator).

Inclusion criteria:

The inclusion criteria for the treatment following the underneath mentioned therapy protocol are:

For all glomerular diseases except IgA-Nephropathy:

1. Proteinuria over 3.5 g/die, measured three times in series

2. Creatinine-concentration in sera < 2,0 mg/dl (exception: rapid-progressive glomerulonephritis)

IgA-Nephropathy:

Histologically proven diagnosis independently of serum creatinine or proteinuria.

If inclusion criteria are not given and the patient is suffering from biopsy proven glomerulonephritis patients data and follow-up are nevertheless registered in the central data bank. Analysis on this subgroup of patients will be performed separately.

Study endpoint :

The study endpoint is determined five years after inclusion. An intermittent analysis of the data will be done after six months.

Follow-up :

Follow-up examinations of the patient have to be carried out at least every 4 weeks, in case of intensified therapy at least every 2 weeks.

Adjuvant therapy:

As supporting therapy a protein diet with 0.6 g protein/kgBW/day plus protein amount in the 24 hours-urine (until a maximum 1 g protein/kgBW/day) is recommended. A professional dietary advise has to be given to each patient.

Information and consent :

According to the Declaration of Helsinki written consent has to be obtained from every patient who takes part in the glomerulonephritis therapy trial. The patient has to be informed about the treatment modality, the expected benefits and the possible risks of the study. Furthermore the patients should be informed about their right to disagree in participation at any time. If the study patient is in a depended position toward the doctor or if the consent could be given under constraint the consent should be done by an independent doctor. If the patient is considered before law as not to be competent (e.g. minority, mentally ill) the consent must be given by the parents, the legal guardian or by the legal representative.

Minimal Change Glomerulonephritis

(MCGN, minimal proliferative intercapillary glomerulonephritis with nephrotic syndrome (MPI + NS), glomerular minimal changes, lipoid nephrosis, minimal change nephrotic syndrome)

Prednisolone: 1 mg/kgBW/d for 6 weeks or until 14 days after positive respond to therapy (24 h Proteinuria < 1 g). Thereafter step by step reduction (weekly reduction of 50% to 20 mg/d, then every third day reduction of 5 mg).

In the case of non-response or relapse this therapy is repeated in the same way.

In the case of frequent relapse, rebiopsy is advised.

In the case of treatment-failure to Prednisolone or for frequent relapsers, randomization will be performed.

Group A:

Combination therapy with Prednisolone 1 mg/kgBW/d and chlorambucil 0.15 mg/kgBW/d for two weeks, thereafter 0.3 mg/kgBW/d for four weeks in total.

The maximal dose for chlorambucil is 11 mg/kgBW and will be achieved after six weeks.

Group B:

Monotherapy with cyclosporin A 5 mg/kgBW/d; increase dose according to whole blood level within 14 days (to achieve blood levels of 80 -120 ng/dl).

Duration of therapy: 6 months.

Focal -segmental Glomerulonephritis (FSGS)

(Focal-Segmental Glomerulosclerosis)

There will be a randomization into two groups.

Group A:

Prednisolone 1.5 mg/kgBW/d po (Dose reduction see group B) plus ASS 500 mg/d

If remission cannot be achieved, cyclosporin A will be given as monotherapy. Start with 3 mg/kgBW/d, increase dose until therapeutical whole blood levels are reached (80 - 120 ng/dl) within two weeks.

Duration of therapy: 6 months

Group B:

(Grupe-Schema: Grupe et al., N. Engl.J. Med. 295, 746 - 749, 1976)

Prednisolone 1.5 mg/kgBW/d po for at least two weeks. If there is a positive response decrease dose gradually.

If no treatment response can be obtained within 6 weeks (continued Proteinuria), add (as combination therapy): Chlorambucil 0.1 to 0.4 mg/kgBW/d according to blood counts (absolute lymphocyte count < 1000/l).

Duration of therapy: 6 to maximum 12 weeks.

In this combination therapy the steroids should be given alternatively every second day in the morning.

If no remission is achieved (continued Proteinuria > 1 g/24 h) cyclosporin A should be given as monotherapy: start with 3 mg/kgBW/d, increase dose until therapeutical blood levels of 80 to 120 ng/dl in whole blood.

Duration of therapy: 6 months

FSGN (group B/CyA) Code 9

Membranous glomerulonephritis

(MGN, peri-membranous glomerulonephritis)

There will be a randomization into three groups.

Group A:

The treatment follows the De Santo-Scheme (De Santo et.al., Am.J. Nephrol. 7, 74 - 76, 1987) with a combination therapy of Prednisolone and Cyclosporin A.

Prednisolone: beginning with 1,0 mg/kgBW/d over one week; stepwise reduction to 0,3 mg/kgBW/d until the end of the first month, ongoing dose reduction to 0,15 mg/kgBW/d until the end of the second month, the then achieved dose will be carried on as continuous medication.

Cyclosporin A: slow begin with 3 mg/kgBW/d, dose adaption until a therapeutical concentration of 80 to 120 ng/dl (whole blood) within two weeks.

Duration of therapy: 6 months.

MGN (group A/De Santo) Code 10

During the treatment period a salt depleted diet has to be ordered; if necessary there should be given additionally diuretics and antihypertensive drugs.

When Proteinuria rises again therapy according to the Ponticelli-scheme (below). Between the two therapies a pause of one month must be kept.

MGN (group A/Ponticelli) Code 19

If a second relapse occurs the therapy will be stopped.

Group B:

Ponticelli-scheme: N.Engl. J. Med. 310; 946 - 950; 1984

Cycle A, 1. month:

Methylprednisolone: 1 g iv for three days (20 to 30 minutes).

Prednisolon: 0,5 mg/kgBW/d po day 4 to 30, dose of Prednisolone should be given in the morning between 7 and 9 o' clock, no slow reduction on day 30) .

Cyclus B, 2. month:

Chlorambucil: 0,2 mg/kgBW/d po day 1 to 30.

If the leucocyte count falls under 5000/l reduction of the dose. Cycle A and B should be repeated each twice, thereafter dose reduction of the Prednisolone.

Duration of therapy: ca. 6 months.

During this time a salt depleted diet has to be given, if necessary diuretics and antihypertensive drugs have to be prescribed.

MGN (group B/Ponticelli) Code 17

In case of relapse: Monotherapy with Cyclosporin A (6 months); slow begin with 3 mg/kgBW/d, dose adaption until a therapeutical concentration of 80 to 120 ng/dl (whole blood) within two weeks.

MGN Code 20

Group C:

Control group: only symptomatic therapy of the hypertension.

MGN (group C) Code 21

Membranoproliferative glomerulonephritis type I and II (MPGN)

There will be a randomization into two groups.

Group A:

Control group: symptomatic therapy of the hypertension.

MPGN (group A) Code 22

Group B:

The therapy follows the Donadio-scheme (Donadio et.al., N.Engl.J. Med. 410, 1426, 1984)

Dipyridamole: 75 mg/d p.o. as continuous medication

ASS: 500 mg/d po as continuous medication

MPGN (group B) Code 11

Mesangioproliferative Glomerulonephritis (MESGN)

There will be a randomization into three groups.

Group A:

Prednisolone: 1 mg/kgBW/d for 6 weeks po or until 14 days after a positive reaction (Proteinuria < 1 g/24 h, thereafter stepwise dose reduction, weekly for 50% until 20 mg/d, then every three days for another 5 mg).

Additional therapy with ACE-Inhibitors:

Enalapril: The dose has to be chosen until normotension is achieved; therefore should a dose until a maximum of 20 mg/d be given.

Duration of therapy: 6 weeks.

If normalization with this medication can not be achieved, enalapril should be given in combination with a diuretic (e.g. fursemide).

MESGN (group A) Code 12

Group B:

Prednisolone: 1 mg/kgBW/d for 6 weeks or until 14 days after positive reaction (Proteinuria < 1 g/24 h). Dose reduction as described above.

Therapy without ACE-Inhibitors. Even the possible hypertension should not be treated with ACE-Inhibitors.

Duration of therapy: 6 weeks.

In the case of relapse repeat protocol.

MESGN (group B) Code 13

Group C:

Control group: no steroids, no ACE-Inhibitors, symptomatic therapy of the hypertension.

MESGN (group C) Code 23

IgA-Nephritis (IgAN)

There will be a randomization into three groups.

Group A:

Indomethacin 100 mg 1 x 1 cpm?./d po

Acetyl-salicyl acid 1 X 100 mg/d po

Duration of therapy: 1 year

IgAN (group A) Code 25

Group B:

Prednisolone: 1 mg/kgBW/d for 6 weeks or until 14 days after positive response to therapy (Proteinuria < 1 g/24h). Thereafter stepwise dose reduction (weekly for 50% until 20 mg/d, thereafter every three days for 5 mg).

IgAN (group B) Code 26

Group C:

Control group: Symptomatic therapy

IgAN (group C) Code 27

Rapid Progressively Glomerulonephritis (RPGN)

RPGN-Type I , Anti-GBM-Disease, linear immunofluorescence

No randomization!

Threefold combination therapy with

1. Plasmapheresis: 40 to 50 ml/kgBW plasma should be exchanged against albumin and fresh frozen plasma (50 to 100 %) during two weeks at least. A minimum of 15 plasmapheresis are to be performed on the patient before effectiveness can be assessed..

2. Modified "pulse therapy" with Prednisolone: 1/2 g iv day 1 to 3: 100 mg po; over one week 80 mg po; over 1 week 40 mg po; then weekly reduction of 5 mg.

3. Cyclophosphamide: beginning with 2 mg/kgBW/d po; dose adaption so that the absolute lymphocyte count lays beneath 1000/l.

Duration of treatment: at least 6 months.

The Cyclophosphamide therapy plus low dosed Prednisolone therapy should be remained for at least 6 month after the end of the signs of activity.

RPGN Code 14

RPGN-Type II , Immune-Complex-Nephritis (granular immunofluorescence) and

RPGN-Type III (negative Immunofluorescence)

There will be a randomization into two groups:

Group A:

No plasmapheresis.

Pulse therapy with Prednisolone as by RPGN type I described beginning on day 1 and

Cyclophosphamide beginning with 2 mg/kgBW/d po Absolute lymphocyte count < 1000/l; dose adaption according to lymphocyte counts.

RPGN (group A) Code 15

Group B:

Modified Euler-Scheme:

Combination therapy with:

1. Plasmapheresis: 3 times, day 1,2,3

then

2. Prednisolone pulse therapy from day 1 to 3 (see RPGN type I) every time after plasmapheresis.

3. Cyclophosphamide-therapy after the third plasmapheresis 375 mg/m body surface iv once just after the last plasmapheresis.

Continuation with Cyclophosphamide 2 mg/kgBW/d po for at least 6 months. Absolute lymphocyte count < 1000/l, eventual dose adaption.

RPGN (group B) Code 24

If no response is noted after 8-weeks of therapy a rebiopsy should be carried out in all three forms of RPGN. If marked interstitial fibrosis is reported or most of the glomeruli are necrotic the therapy should be stopped and the patient should receive chronic dialysis treatment.