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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.
Patients diagnosed or being investigated for glomerulonephritis.
Medical and nursing staff managing children with renal disease.
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.
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.
|Classification of Henoch-Schonlein Purpura Glomerulonephritis
(recommended by International Study of Kidney Disease in Childhood)
Pure mesangial proliferation without crescents
Mesangial proliferative glomerulonephritis with less than 50% crescents
Mesangial Proliferative glomerulonephritis with 50-75% crescents
Mesangial proliferative glomerulonephritis with more than 75% crescents
|VI.||Membranoproliferative (mesangiocapillary) glomerulonephritis|
Discuss with Paediatric Nephrologist
|Classification of HSP||Management|
|Grades I, IIa & IIb||
Grades I, IIIa & IIIb
|Grades IVa, IVb, Va, Vb & VI||
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.
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.
Diffuse subepithelial and a few mesangial and focal subendothelial deposits on IF and EM.
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.
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.
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.
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:
30mg/m2 on alternate days
20mg/m2 on alternate days
15mg/m2 on alternate days
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.
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 .
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).
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]
In patients presenting with such features consideration should be given to
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:
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.
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.
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.
Please refer also to Guideline on Nephrotic Syndrome
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 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.
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.
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
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.
Hypocomplementaemia is present in SLE and MPGN but normal in other underlying conditions.
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.
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:
Anti-GBM antibody induced Crescentic GN
Alternate day oral prednisolone 2mg/Kg beginning day 5 with a slow tail over six months.
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.
Last reviewed: 01 October 2016
Next review: 14 October 2018
Author(s): David Hughes
Approved By: Clinical Effectiveness
Reviewer Name(s): Paeds CE & Risk