1. health and fitness
2. disease

Guidelines on the Management of Glomerulonephritis
Renal Unit
Royal Hospital for Sick Children
Yorkhill Division
Please note: the following guideline has not been assessed according to the AGREE
(Appraisal of Guidelines for Research and Evaluation) criteria. This will take place at the
next guideline review.
Glomerulonephritis
Authors: Renal Clinicians Group
Revision date: Sept 2010
Version: 1.2
Authorised by: Dr Jim Beattie
Q-Pulse ref: YOR-REN-017
Page 1 of 16
Issue Date: Sept 2008
Contents
1. Introduction
2. Acute Glomerulonephritis
2.1 Introduction
2.2 Investigations
2.3 Management
3. Henoch-Schonlein Purpura
3.1 Classification
3.2 Renal Involvement
3.3 Investigation
3.4 Management
3.5 Indications for Renal Biopsy
4. SLE Glomerulonephritis
4.1 Introduction
4.2 WHO Classification of Lupus Nephritis
4.3 Clinical Management
4.4 Drug Therapy
5. Mebranoproliferative Glomerulonephritis
5.1 Introduction
5.2 Management
5.3 Patients with Severe MPGN
6. Primary IGA Neuropathy
6.2 Management
7. Focal Glomerulosclerosis
7.1 Introduction
7.2 Management
8. Rapidly Progressive Glomerulonephritis
8.1 Introduction
8.2 Clinical Features
8.3 Management
9. Future Guideline Development
Glomerulonephritis
Authors: Renal Clinicians Group
Revision date: Sept 2010
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1. Introduction
The following guideline has been developed and is regularly reviewed by clinicians
within the Renal Unit at Yorkhill. These guidelines are based on current evidence
and best practice relating to the Management of Glomerulonephritis.
This
document is intended for use by clinicians and nursing staff. For further discussion
of this guideline, please contact a consultant within the Renal Unit.
2. Acute Glomerulonephritis (AGN)
2.1 Introduction to AGN
Acute Glomerulonephritis (AGN) is a syndrome consisting of frank haematuria,
proteinuria, with accompanying oliguria, volume overload and usually, a mild
increase in plasma creatinine.
The underlying renal histology is typically an acute proliferative glomerulonephritis
and the main aetiological factor is prior streptococcal infection however, rapidly
progressive or crescentic GN may present in a similar manner. IGA nephropathy or
Henoch Schonlein purpura may also begin abruptly and consequently must be
included in the differential diagnosis of acute nephritic syndrome.
2.2 Investigation of AGN
Blood
Urine
Imaging
•
•
•
•
•
•
•
•
•
•
•
•
•
FBC
U&E’s
LFT’s
Immunoglobulins
ASO titre (anti-DNAse B)
Compliment Screen
ANF
ANCA
Anti-GBM antibody titre (rarely indicated
Varicella and Hep B
Urine Protein Creatinine Ratio (PCR)
Urine Culture
Renal Ultrasound
2.3 Management of AGN
The management of AGN is largely supportive and should include fluid and salt
restriction, and management of the associated hypertension with diuretic therapy,
Hydralazine or a calcium channel blocker. Resolution of the oliguria usually occurs
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within a week and this is associated with blood pressure normalisation and a fall in
plasma creatinine. Frank haematuria may remain for 2-3 weeks but in the longer
term, proteinuria is usually gone by 3-6 months and microscopic haematuria by 1-2
years.
3. Henoch-Schonlein Purpura
3.1 Classification of HSP
Classification of Henoch-Schonlein Purpura Glomerulonephritis
(recommended by International Study of Kidney Disease in Childhood)
I.
II.
Minimal Changes
Pure mesangial proliferation without crescents
(a) Focal
(b) Diffuse
III.
Mesangial proliferative glomerulonephritis with less than 50% crescents
(a) Focal
(b) Diffuse
IV.
Mesangial Proliferative glomerulonephritis with 50-75% crescents
(a) Focal
(b) Diffuse
V.
Mesangial proliferative glomerulonephritis with more than 75% crescents
(a) Focal
(b) Diffuse
VI.
Membranoproliferative (mesangiocapillary) glomerulonephritis
3.2 Renal Involvement in HSP
• Haematuria – May be microscopic or more commonly macroscopic.
• Proteinuria – May be absent or up to nephritic range associated with
hypoalbuminaemia.
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• Hypertension – May be severe and may occur in the absence of urinary
abnormalities.
• Abnormal renal function – May be absent or severe reflecting acute
renal failure.
3.3 Investigation of patients with HSP
• U & E’s, Creatinine, Protein & Albumin -Initially and if abnormalities in
urinalysis develop
• Urinalysis - Weekly until 3 months after disappearance of systemic
symptoms
• EMU Protein/Creatinine ratio
In the presence of abnormal
Microscopy
urinalysis
• Blood Pressure
3.4 Management of HSP
Refer Urgently:
Nephritic
• Hypertension
• Haematuria
• Proteinuria
• Abnormal renal function
Discuss with
•
•
•
Nephrotic
• Proteinuria > 200mg/mmol
of Creatinine
• Hypoalbuminaemia
• Oedema
Paediatric Nephrologist
Proteinuria (>100mg/mmol creatinine) ± haematuria
Hypertension
Abnormal renal function
Observe
Haematuria
• Microscopic
• Macroscopic
• ± Minimal proteinuria
3.5 Indications for renal biopsy
• Abnormal renal function
• Persistent Proteinuria (>100mg/mmol creatinine) ± haematuria
• Hypertension
Management:
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Classification of HSP
Grades I, IIa & IIb
Management
• No treatment
• ± ACE inhibitor if persistent proteinuria
Grades I, IIIa & IIIb
• Pulsed Methylprednisolone 600mg/m2 for 3 days
• Oral Prednisolone 2mg/kg/day (max 60mg) for 1 month
& then taper
• Consider Cyclophosphamide 2.5mg/kg/day for 8 weeks
• ±ACE inhibitor if persistent proteinuria
Grades IVa, IVb, Va, Vb & VI
•
•
•
•
Steroids as above
Cyclophosphamide 2.5mg/kg/day for 8 weeks
Consider Plasmapheresis
± ACE inhibitor if persistent proteinuria
4. SLE Glomerulonephritis
4.1 Introduction
Renal manifestations are present in nearly two thirds of children with SLE and may
present with a combination of symptomatic hypertension, nephrotic syndrome or
gross haematuria. A wide range of extra renal manifestations is commonly
present and in some children the extra renal manifestations predominate. Often
the choice of therapy is influenced by potential renal or extra renal complications
of the regimens under consideration.
4.2 WHO Classification of Lupus Nephritis
There is a wide variation in the histological appearances in lupus nephritis. The
World Health Organisation (WHO) system which incorporates IF and ultrastructural
studies is the most frequently used:
1. Normal glomeruli
a) Negative IF and EM
b) Deposits on IF or EM
2. Mesangial alterations
a) Mesangial hypercellularity (mild)
b) Mesangial hypercellularity (moderate)
Both categories have diffuse mesangial deposits on IF and EM
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3. Focal Proliferative Glomerulonephritis
Diffuse mesangial and focal subendothelial and subepithelial deposits on IF and
EM
4. Diffuse proliferative
Mesangial, subendothelial and subepithelial deposits on IF and EM.
5. Membranous
Diffuse subepithelial and a few mesangial and focal subendothelial deposits on
IF and EM.
4.3 Clinical Management of SLE
Glomerulonephritis may be present in any child with SLE and although the
experienced clinician often predicts the results of the renal biopsy with accuracy,
silent “nephritis” has been well documented. Renal biopsy is useful when major
changes in therapy are initiated even when significant disease has been
recognised previously.
4.4 Drug Therapy
Renal involvement in children with SLE is often well controlled with corticosteroids
alone. Focal segmental glomerulonephritis and mild nephrotic syndrome often can
be controlled with corticosteroids, diuretic and anti hypertensive agents if
necessary.
Most children without DPGN are satisfactorily controlled with
Prednisolone at a dosage of 1mg/kg preferably given by alternate days.
For
the
child
or
adolescent
2
with
severe
lupus
nephritis,
intravenous
Methylprednisolone (60mg/m ) may provide dramatic anti-inflammatory effect but
is not satisfactory for long term control.
For the child with cortico-steroid unresponsive lupus nephritis, intermittent
intravenous Cyclophosphamide has been associated with dramatically improved
outcome.
However others believe that Prednisolone with the addition of
Azathioprine to be a satisfactory alternative. Intravenous Cyclophosphamide is
2
given by monthly intravenous infusion of 500-1000 mg/m and in comparison with
daily oral therapy the immunosuppressive effects of this regime appears to be
greater and the toxicity (especially bladder toxicity) appears to be less.
Nonetheless, nausea, vomiting and alopecia, myelosuppression, pulmonary
fibrosis, haemorraghic cystitis and secondary oncogenesis are potential
complications.
Glomerulonephritis
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The optimal duration of intravenous Cyclophosphamide therapy for a child with
severe lupus nephritis has not been conclusively established. Once six months of
therapy (7 doses) has been completed continued administration at three month
intervals could be considered or alternatively oral Azathioprine maybe substituted.
5. Mebranoproliferative Glomerulonephritis (MPGN)
5.1 Introduction to MPGN
MPGN is uncommon but primarily affects children and young adults with the mean
age of onset ranging between 8 and 30 years. It has been classified as idiopathic
or secondary with idiopathic MPGN further subdivided into types 1-3 based on
biopsy morphological patterns. The diagnosis of MPGN requires the exclusion of
all secondary causes such as hepatitis B or C, HIV, other infections or collagen
vascular disease.
5.2 Management of MPGN
Patients with plasma albumin > 25g/l with or without hypertension should receive
no specific therapy although if hypertension is present and ACE inhibitor should be
used. Three monthly monitoring by urinary PCR, plasma creatinine and albumin is
advisable. In patients with plasma albumin < 25g/l who have a normal or
2
elevated plasma creatinine should receive Prednisolone 40mg/m on alternate
days for 6-12 months along with Aspirin (1mg/kg three times per week) and
Dipyridamole 1.5mg/kg three times a day.
These patients should be evaluated on a three monthly basis as above and if at six
months there has been an increase in the plasma creatinine of > 30%, decrease in
the plasma albumin or increasing proteinuria this should be regarded as a
treatment failure and steroids should be withdrawn at this point.
If there is improvement or clinical/biochemical stability a suggested regimen after
the first six months is as follows:
2
6-12 months
30mg/m on alternate days
12-24 months
20mg/m on alternate days
36-48 months
15mg/m on alternate days
48-60 months
10mg/m on alternate days
2
2
2
At the end of each six month period the child should be assessed for treatment
failure as defined above and if present steroids should be withdrawn.
Glomerulonephritis
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5.3 Patients with severe MPGN; Membranoproliferative glomerulonephritis
(MCGN; Mesangialcapillary glomerulonephritis)
This document is in addition to the above guidelines and pertains to the more
severely affected patients. It is a consideration of current UK guidelines which are
loosely based upon one paper, the only available level 1 evidence; however, even
this study was inadequately powered [1].
Current guidelines, described above, and summarised in box, suggest therapy if
patients are nephrotic (serum albumin <25 g/L) and/or demonstrate a reduction
in renal function (serum creatinine out with normal range).
Current Guidelines
Suggested therapy is 6 months prednisolone @40mg/m2 alternate
days; if patients improve prednisolone should be weaned over a
period of up to 3½ years.
The symptomatic treatment of proteinuria and/or hypertension with
ACE-I and/or ARB therapy is recommended although there is little
direct proof of efficacy in this paediatric patient group.
In addition the use of aspirin and dipyridamole should be considered
in adolescent patients.
In light of a recent internal review of current practice and other available,
although less robust, evidence (retrospective, uncontrolled, case series,
descriptive or comparative studies), the following comments are made with
respect to the treatment of the more severely affected patients.
Features likely to be indicative of poor outcome [2-4]
1. Nephrotic syndrome
2. Subnormal eGFR
3. Hypertension
4. Macroscopic haematuria
5. Chronic damage (and interstitial damage) on biopsy
6. Crescents
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In patients presenting with such features consideration should be given to
1. Initiation of therapy with pulsed methyl prednisolone [5-7]
2. High dose oral steroid (1-2 mg/kg or 30-60 mg/m2) daily for 1 month and
then alternate day therapy for a prolonged period, with weaning of dose
over several years (perhaps greater than 5 years [5;8;9])
3. When steroid dosage weaned regular assessment for ‘relapse’ is
recommended and, if occurs, treatment with a higher dose of steroid is
suggested.
Signs
a.
b.
c.
of relapse
hypocomplementaemia
haematuria (return of/worsening)
worsening proteinuria
4. Other Therapies
a. Aspirin and dipyridamole
Antiplatelet therapy may be of benefit in adults patients, it could be
considered for adolescents [10]
b. ACE-I/ARBs
Prescription of these therapies is currently recommended in the
guideline. Although there is no direct proof of long term efficacy in
this paediatric patient group; there are however strong theoretic
reasons for prescription.
c. MMF/tacrolimus
The use of these immunosuppressant agents should be reserved for
the most difficult and severe cases. We have anecdotal evidence of
good efficacy; there is little literature. [11;12]
Reference List
1. Tarshish P, Bernstein J, Tobin JN, Edelmann CM, Jr. (1992) Treatment of
mesangiocapillary glomerulonephritis with alternate-day prednisone--a report
of the International Study of Kidney Disease in Children. Pediatr Nephrol 6
(2) : 123-130
2. Garcia-de la PS, Orozco-Loza IL, Zaltzman-Girshevich S, de Leon BB (2008)
Prognostic factors in children with membranoproliferative glomerulonephritis
type I. Pediatr Nephrol
Glomerulonephritis
Authors: Renal Clinicians Group
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3. Vikse BE, Bostad L, Aasarod K, Lysebo DE, Iversen BM (2002) Prognostic
factors in mesangioproliferative glomerulonephritis. Nephrol Dial Transplant
17 (9) : 1603-1613
4. Cansick JC, Lennon R, Cummins CL, Howie AJ, McGraw ME, Saleem MA,
Tizard EJ, Hulton SA, Milford DV, Taylor CM (2004) Prognosis, treatment and
outcome of childhood mesangiocapillary (membranoproliferative)
glomerulonephritis. Nephrol Dial Transplant 19 (11) : 2769-2777
5. Yanagihara T, Hayakawa M, Yoshida J, Tsuchiya M, Morita T, Murakami M,
Fukunaga Y (2005) Long-term follow-up of diffuse membranoproliferative
glomerulonephritis type I. Pediatr Nephrol 20 (5) : 585-590
6. Bergstein JM, Andreoli SP (1995) Response of type I membranoproliferative
glomerulonephritis to pulse methylprednisolone and alternate-day prednisone
therapy. Pediatr Nephrol 9 (3) : 268-271
7. Bahat E, Akkaya BK, Akman S, Karpuzoglu G, Guven AG (2007) Comparison
of pulse and oral steroid in childhood membranoproliferative
glomerulonephritis. J Nephrol 20 (2) : 234-245
8. McEnery PT (1990) Membranoproliferative glomerulonephritis: the Cincinnati
experience--cumulative renal survival from 1957 to 1989. J Pediatr 116 (5) :
S109-S114
9. Iitaka K, Ishidate T, Hojo M, Kuwao S, Kasai N, Sakai T (1995) Idiopathic
membranoproliferative glomerulonephritis in Japanese children. Pediatr
Nephrol 9 (3) : 272-277
10. Levin A (1999) Management of membranoproliferative glomerulonephritis:
evidence-based recommendations. Kidney Int Suppl 70 : S41-S46
11. Sahin GM, Sahin S, Kantarci G, Ergin H (2007) Mycophenolate mofetil
treatment for therapy-resistant glomerulopathies. Nephrology (Carlton ) 12
(3) : 285-288
12. Butani L, Afshinnik A, Johnson J, Javaheri D, Peck S, German JB, Perez RV
(2003) Amelioration of tacrolimus-induced nephrotoxicity in rats using juniper
oil. Transplantation 76 (2) : 306-311
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6. Primary IGA Nephropathy
6.1 Introduction of Primary IgAN
Primary IgAN occurs at all ages but is most common during the second or third
decades of life and affects males more often than females.
The clinical
presentation of IgAN varies but five different clinical syndromes can generally be
identified at onset:
1.
2.
3.
4.
5.
Recurrent macroscopic haematuria
Asymptomatic microscopic haematuria and proteinuria
Acute nephritic syndrome
Nephrotic syndrome
Nephritic nephrotic syndrome
Several studies of IgAN in children have demonstrated that the degree of
proteinuria correlates with the morphological severity of the glomerular lesion.
The commonest presentation of primary IgAN in children is recurrent macroscopic
haematuria occurring in association with URTI and less often with other mucosal
infections such as diarrhoea and sinusitis. The interval between precipitating URTI
and the appearance of haematuria ranges from 1-2 days compared to 1-2 weeks
in APSAGN.
Patients with a nephritic and/or nephrotic onset tend to have the most significant
glomerular damage. Serum IgA levels are increased in 30-50% of adult patients
but only in 16-18 % of children with primary IgAN.
Serum compliment
concentrations are usually normal.
Diffuse mesangial IgA deposits may be observed in other disorders such as HSP,
SLE and chronic liver disease.
6.2 Management of Primary IgAN
The most appropriate treatment for patients with Primary IgAN remains
controversial. Although prophylactic antibiotics and tonsillectomy may reduce the
frequency of episodes of macroscopic haematuria the long term benefit remains
questionable.
Glucocorticoids may benefit the few patients presenting with
nephrotic syndrome and minimal mesangial lesions but long term glucocorticoid
and immunosuppressant treatments generally does not confer any benefit. A
double blind controlled trial of Fish oil in adults with IgAN and proteinuria resulted
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in a slower decline in renal function in the treatment group although proteinuria
was unaffected. Although the use of ACE was not evaluated in this trial, the
combination should have additional benefit.
1. Patients with mild proteinuria (PCR 20-100mg/mmol), observation and
regular assessment alone is necessary.
2. Patients with urinary PCR 100-200 mg/mmol and diminished GFR should be
offered treatment with fish oil and an ACE inhibitor.
3. Glucocorticoid therapy should be considered in patients who have nephrotic
range proteinuria and a normal GFR, but if the GFR is diminished a combination
of fish oil and ACE inhibitor is appropriate.
7. Focal Glomerulosclerosis (FSGS)
7.1 Introduction to FSGS
FSGS is a diagnosis based on the presence of focal and glomerular segmental
scarring on biopsy and usually presents with a steroid resistant nephrotic
syndrome but may also present with asymptomatic proteinuria and/or haematuria.
7.2 Management of FSGS
Please refer also to Guideline on Nephrotic Syndrome.
• Corticosteroids
If the child presents with nephrotic syndrome steroid resistance, typical of
FSGS is defined by the persistence of proteinuria following at least four
2
weeks of 60mg/m of oral Prednisolone. Methylprednisolone pulse therapy
has been advocated in these patients (Mendosa Protocol). This consists of
Methylprednisolone 30mg/kg intravenously administered every other day
for two weeks, weekly for 8 weeks, every other week for 8 weeks, monthly
for nine months and then every other month for six months in association
with oral Prednisolone and if necessary Cyclophosphamide or Chlorambucil.
Data on this schedule is predominantly based on comparison with historical
controls and the efficacy is not generally acknowledged.
• Cyclophosphamide and Chlorambucil
Cylcophosphamide has been used more often than Chlorambucil in FSGS
but the data on efficacy is conflicting. Full or partial remission is higher in
patients with partial steroid resistance, those with late steroid resistance,
those in whom initial renal biopsy showed MCN compared with those
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showing initial resistance to corticosteroids or FSGS on biopsy. Regimens
used are Cyclophosphamide 2.5mg/kg/day for 90 days or Chlorambucil 0.15
– 0.2 mg/kg/day given for 8-12 weeks.
• Cyclosporin
Cyclosporin has been given to patients with FSGS in a few small
uncontrolled trials in doses of approximately 5mg/kg/day and found to be
affective in reducing urinary protein excretion and perhaps delaying the
progression to ESRF. The above dose is usually given in association with
low dose alternate day steroids but many patients who respond to
Cyclosporin tend to relapse when the dosage is tapered or the drug is
stopped.
• Clinical Course
A number of patients with FSGS have a “malignant” clinical course with
rapid deterioration in renal function and are completely unresponsive to all
the above therapies. In these patients, regular salt poor albumin infusion
with diuretics is helpful. ACE inhibitors are useful to reduce the amount of
proteinuria and the rate of reduction in GFR. In addition in adult patients
with FSGS lipid lower agents have been shown to influence the reduction in
GFR.
Patients with the malignant course have a significant risk of recurrence post renal
transplantation. In patients with recurrent disease post transplantation high dose
Cyclosporin with or without plasma exchange has been successful.
8. Rapidly Progressive Glomerlulonephritis (RPGN)
8.1 Introduction to RPGN
RPGN is a clinical definition, usually associated with a crescentic
glomerulonephritis on renal biopsy, characterised by severe proliferation that
results in circumferential layers of fibroblasts, macrophages and epithelial cells
within Bowman’s space described as crescents.
Crescentic GN occurs either as a primary disease phenomenon, in which it is
termed idiopathic, or secondary to a number of other disease processes.
Primary Renal Disease
• Idiopathic
• Anti GBM disease
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• IgA nephropathy
• Membranous GN
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Systemic Diseases
• PSAGN
• Shunt nephritis
• Infective endocarditis
• SLE
• HSP
• PAN
• Wegener’s granulomatosis
• Cryglobulinaemia
The diseases underlying crescentic GN may
immunoflourescent staining patterns on biopsy:
be
classified
by
three
Immune
complex:
PSAGN,
HSPGN,
SLE,
MPGN,
MGN
and
Mixed
Cryoglobulinaemia. These conditions have granular immune deposition on IF and
this is the commonest observed pattern.
Pauci-immune: Vasculitis e.g. PAN, Wegener’s and Idiopathic. These conditions
are typified by the absence of immune deposits on IF and ANCA positivity.
Anti-GBM antibody disease: This condition is typified by linear GBM staining and
the presence of circulating anti-GBM antibody and may be associated with antialveolar basement membrane antibody staining and pulmonary haemorrhage.
Complement levels
Hypocomplementaemia is present in SLE and MPGN but normal in other underlying
conditions.
8.2 Clinical Features of RPGN
Children with crescentic GN tend to be older and present with oliguria, a significant
and rapid elevation in plasma creatinine, hypoproteinaemia, nephrotic range
proteinuria in association with other signs of AGN.
8.3 Management of RPGN
Therapeutic abstention should be considered in the presence of diffusely sclerotic
glomeruli except if life threatening extra-renal disease is present.
Immune Complex Crescentic GN
Patients with Immune Complex Crescentic GN should be managed according to their
specific underlying condition, but it is likely that a regime including Pulse
Methylprednisolone, alkylating agents and plasma exchange (see below) will be
considered.
Pauci-immune Crescentic GN
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The following regime should be considered in patients who are ANCA positive and
negative
2
1. Methylprednisolone 600mg/m /day for three days
2. Oral Cyclophosphamide 2.5mg/kg/day for 6-8 weeks beginning day four
3. Alternate day oral Prednisolone 2mg/kg beginning day five with a slow tail
over six months.
4. Data in support of the efficacy of plasma exchange in pauci-immune
Crescentic GN is limited but should be considered in those who are dialysis
dependent on presentation, and those with pulmonary haemorrhage or no
response to the above therapy.
Anti-GBM antibody induced Crescentic GN
2
1. IV Pulse Methylprednisolone 600mg/m /day for three days, followed by oral
prednisolone as above
2
2. Daily plasma exchange, 4 litre/1.73 m (PPS), for 14 days or until anti-GBM
antibody is no longer detectable. Patients who are anuric and have >85%
crescents on biopsy are very unlikely to benefit from plasma exchange unless
they have pulmonary haemorrhage.
3. Oral cyclophosphamide 2.5mg/Kg/day for 6-8 weeks beginning day 4 with
weekly blood counts.
4. Alternate day oral prednisolone 2mg/Kg beginning day 5 with a slow tail over
six months
9. Future Guideline Development
• Future review of this guideline should make use of the AGREE document to
ensure that up-to-date evidence and best clinical practice has been used to
inform this guideline.
For further information regarding guideline
development please contact the Multi-Professional Clinical Practice
Committee.
Glomerulonephritis
Authors: Renal Clinicians Group
Revision date: Sept 2010
Version: 1.2
Authorised by: Dr Jim Beattie
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Issue Date: Sept 2008