Glomerulonephritis, management

exp date isn't null, but text field is

Objectives

The following guideline has been developed and is regularly reviewed by clinicianswithin 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. 

Scope

Patients diagnosed or being investigated for glomerulonephritis.

Audience

Medical and nursing staff managing children with renal disease.

Acute Glomerulonephritis (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.    

 

Investigation of AGN

Blood
  • FBC
  • U&Es
  • LFTs
  • Immunoglobulins
  • ASO titre (anti-DNAse B)
  • Compliment screen
  • ANF
  • ANCA
  • Anti-GBM antibody titre (rarely indicated)
  • Varicella and Hep B
Urine
  • Urine Protein Creatinine Ratio (PCR)
  • Urine Culture
Imaging
  • Renal Ultrasound

 

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 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.    

Henoch-Schonlein Purpura

Classification of HSP

Classification of Henoch-Schonlein Purpura Glomerulonephritis
(recommended by International Study of Kidney Disease in Childhood)
 
 I. Minimal Changes  
 II.

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  

 

Renal involvement in HSP

  • Haematuria – May be microscopic or more commonly macroscopic. 
  • Proteinuria – May be absent or up to nephritic range associated with hypoalbuminaemia. 
  • 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.  

 

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 urinalysis  
  • Microscopy            
  • Blood Pressure  

 

Management of HSP

Refer Urgently:  

Nephritic

  • Hypertension 
  • Haematuria 
  • Proteinuria 
  • Abnormal renal function  

Nephrotic  

  • Proteinuria > 200mg/mmol of Creatinine 
  • Hypoalbuminaemia 
  • Oedema  

Discuss with Paediatric Nephrologist

  • Proteinuria   (>100mg/mmol creatinine) ± haematuria 
  • Hypertension 
  • Abnormal renal function  

Observe

Haematuria

  • Microscopic
  • Macroscopic
  • ± Minimal proteinuria  

 

Indications for renal biopsy

  • Abnormal renal function 
  • Persistent Proteinuria   (>100mg/mmol creatinine) ± haematuria 
  • Hypertension  

Management:

Classification of HSP   Management  
Grades I, IIa & IIb  
  • 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  

 

SLE Glomerulonephritis

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.  

 

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  

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.

 

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.    

 

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 with severe lupus nephritis, intravenous Methylprednisolone (60mg/m2) 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 given by monthly intravenous infusion of 500-1000 mg/m2 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.    

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.   

Mebranoproliferative Glomerulonephritis (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.      

 

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 elevated plasma creatinine should receive Prednisolone 40mg/m2 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:  

6-12 months 

30mg/m2 on alternate days  

12-24 months 

20mg/m2 on alternate days

36-48 months 

15mg/m2 on alternate days

48-60 months 

10mg/m2 on alternate days 

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.  

 

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
  1. Hypertension
  2. Macroscopic haematuria
  1. Chronic damage (and interstitial damage) on biopsy
  2. Crescents  

In patients presenting with such features consideration should be given to  

  1. Initiation of therapy with pulsed methyl prednisolone [5-7]
  1. 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])
  1. When steroid dosage weaned regular assessment for ‘relapse’ is recommended and, if occurs, treatment with a higher dose of steroid is suggested. 
    Signs of relapse
    1. hypocomplementaemia
    2. haematuria (return of/worsening)
    3. worsening proteinuria 

  2. Other therapies
    1. Aspirin and dipyridamole
      Antiplatelet therapy may be of benefit in adults patients, it could be considered for adolescents [10]

    2. 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.

    3. 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
Primary IGA Nephropathy

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.    Recurrent macroscopic haematuria 
  2.    Asymptomatic microscopic haematuria and proteinuria 
  3.    Acute nephritic syndrome 
  4.    Nephrotic syndrome 
  5.    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.    

 

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 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.
Focal Glomerulosclerosis (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.

 

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 weeks of 60mg/m2 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 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.  

Rapidly Progressive Glomerlulonephritis (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  
  • IgA nephropathy  
  • Membranous GN 
   

Systemic Diseases  

 
  • PSAGN 
  • Shunt nephritis  
  • Infective endocarditis  
  • SLE
  • HSP
  • PAN  
  • Wegener’s granulomatosis  
  • Cryglobulinaemia 

The diseases underlying crescentic GN may be classified by three immunoflourescent staining patterns on biopsy:  

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.

 

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.  

 

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  

The following regime should be considered in patients who are ANCA positive and negative:

  1. Methylprednisolone 600mg/m2 /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 

  1. IV Pulse Methylprednisolone 600mg/m2 /day for three days, followed by oral prednisolone as above 

  2. Daily plasma exchange, 4 litre/1.73 m2 (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.

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.

References
  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 
  1. 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

  2. Vikse BE, Bostad L, Aasarod K, Lysebo DE, Iversen BM (2002) Prognostic factors in mesangioproliferative glomerulonephritis. Nephrol Dial Transplant 17 (9) : 1603-1613 

  3. 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

  4. 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 

  5. 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 

  6. 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 

  7. McEnery PT (1990) Membranoproliferative glomerulonephritis: the Cincinnati experience--cumulative renal survival from 1957 to 1989. J Pediatr 116 (5) : S109-S114 

  8. 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 

  9. Levin A (1999) Management of membranoproliferative glomerulonephritis: evidence-based recommendations. Kidney Int Suppl 70 : S41-S46 

  10. Sahin GM, Sahin S, Kantarci G, Ergin H (2007) Mycophenolate mofetil treatment for therapy-resistant glomerulopathies. Nephrology (Carlton ) 12(2): 285-288 

  11. 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  

 

Editorial Information

Last reviewed: 01 October 2016

Next review: 14 October 2018

Author(s): David Hughes

Approved By: Clinical Effectiveness

Reviewer Name(s): Paeds CE & Risk