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glomerulonephritis (GN)

introduction

  • inflammation of the renal glomeruli with virtually all forms being mediated by an immune process (except for Alport's syndrome and TGBM disease)
  • spectrum ranges from:
    • asymptomatic cases
    • isolated microhaematuria without proteinuria - which is usually benign but may become progressive
    • chronically progressive renal impairment associated with haematuria and proteinuria
    • acute nephritic syndrome

DDx of acute GN - like presentations

  • anaphylactoid purpura with nephritis
  • chronic GN with an acute exacerbation
  • idiopathic hematuria
  • familial nephritis

thin glomerular basement membrane (TGBM) nephropathy

  • usually autosomal dominant but may be sporadic
  • aka benign familial hematuria
  • it appears to be due to a missense mutation in the COL4A4 gene that codes for the alpha-4 chain of type IV collagen, resulting in a glycine to glutamic acid substitution producing defective collagen that interferes with the normal meshwork architecture of the GBM, in a similar manner to Alport's syndrome leading many to postulate that it is a heterozygous form of autosomal recessive Alport's syndrome but it could represent a different type of mutation
  • one of the most common causes of glomerular microhaematuria - may account for almost 30% of the cases of glomerular hematuria 1)
  • frequency of TGBM nephropathy may be as high as 5% to 9% of the general population, according to studies on kidneys used for renal transplantation 2)
  • most cases are benign but some may develop ESRF - particularly those who have proteinuria and hypertension
  • most cases are asymptomatic but some develop loin pain
  • unlike Alport's syndrome, there are no ocular associations of thin basement membrane disease

Alport's syndrome

  • rare heterogeneous collagen disorder syndrome affecting 1 in 5000 people
  • accounts for 1-2% of all patients who start renal replacement therapy
  • 85% are familial X-linked semi-dominant syndrome
    • primary abnormality appears to be due to mutations in the COL4A5 gene (OMIM #305010) on the X chromosome (Xq22 region) that codes for the alpha-5 chain of type IV collagen
    • females are generally less affected than males, microhematuria being the only sign present throughout life, although approximately 30% can progress to end-stage renal disease
    • affected males develop renal failure and usually have a high-tone sensorineural deafness by the age of 20 and:
      • glomerular haematuria and often thinning of glomerula basement membrane
      • high-tone sensorineural hearing loss in the 2000 to 8000 Hz range
      • ocular defects:
        • ant. lenticonus (in 25%), and retinal flecks in the macula and mid periphery (in ~85%) - these may be specific for Alport's
        • retinopathy similar to that of fundus albipunctatus
        • lens opacities are common
        • corneal erosions from mild trauma such as riding a bike without goggles
        • rarely, posterior polymorphous corneal dystrophy which is highly suggestive the patient has Alport's
        • other ocular abnormalities occur sporadically
      • may progress to ESRF
      • truncating mutations, comprising nonsense mutations, frame-shifts, and larger structural rearrangements, were found to cause a juvenile form of the disease with a mean age at ESRD of 21.6 years, compared to 33.1 years in patients with a non-truncating mutation. No significant differences in the presence of hearing defects or ocular manifestations between patients with the different types of mutations 3)
    • a subtype of X-linked Alport syndrome (XLAS) in which diffuse leiomyomatosis is an associated feature reflects deletion mutations involving the adjacent COL4A5 and COL4A6 genes
  • 10-14% are due to the rare autosomal recessive form (ARAS)
    • due to homozygous mutations in either alpha-3 (COL4A3 gene region) and alpha-4 (COL4A4 gene region) chains of type IV collagen
    • boys and girls will develop kidney failure and hearing loss by their teens or young adult years.
  • 1-5% are due to the rare “autosomal dominant form”
    • this form has only recently been identified in some families
    • this has been mapped to chromosome 2q in the region of COL4A3 and COL4A4
    • presumably heterozygous mutation and may be part of a spectrum along with TGBM disease
    • have a relatively mild phenotype, indicated by a slower rate of progression to ESRF than most patients with X-linked Alports
    • high clinical variability from complete asymptomatic state, to non-progressive isolated microhaematuria, to those developing ESRF in their 5th decade
    • usually well into middle age before kidney failure develops
    • the determinants of the phenotype remain largely unknown, so that it may be risky to predict renal prognosis in the individual with a single COL4A3/A4 mutation and an isolated microhematuria at the time of examination.4)
  • the ocular and other clinical features of autosomal recessive Alport syndrome are identical to those seen in X-linked disease, while retinopathy and cataracts are the only ocular abnormalities described in the rare autosomal dominant form of Alport syndrome.
  • there are no specific therapies for AS at present although gene therapy in the future may hold promise
  • hearing aids are usually very effective for patients with hearing loss caused by Alport Syndrome
  • see also: wikipedia

acute post-Streptococcal glomerulonephritis (APSGN)

  • results from an antecedent infection of the skin (develops 3-6 weeks after episode of pyoderma) or throat (develops 1-2 weeks after episode of pharyngitis) caused by nephritogenic strains of group A beta-hemolytic streptococci
  • risk of APSGN following infection with these nephritogenic strains is 5% if throat infection (this is more common in temperate zones) and 25% if skin infection (this is more common in tropics and sub-tropics)
  • most frequent in children 2-12 years old, peak at 5-6 years old but may affect any age persons
  • 50% may be sublinical
  • nearly all children recover fully
  • elderly have high mortality rate of 20-25%
  • children develop:
    • proteinuria which may take months to resolve and may recur over the next 2 years
    • haematuria which usually settles within 1-3 weeks
    • gross oedema which usually resolves within 5-10 days
    • hypertension which usually settles within 2-3 weeks but may take 6 weeks resolve
    • 5% may develop hypertensive encephalopathy
    • dilutional anaemia is common early
  • Mx in ED:
    • antibiotics to eradicate Strept.
    • have a low threshold for admitting patients with suspected acute glomerulonephritis
    • admit if present with oliguria, renal failure, nephrotic syndrome, massive proteinuria, significant hypertension, or pulmonary symptoms
  • DDx includes:
    • IgA nephritis
    • membranoproliferative GN
    • lupus nephritis (but gross haematuria is unusual)
    • GN of chronic infection
    • vasculitis
    • predominantly non-glomerular diseases such as HUS, TTP, atheroembolic renal disease, acute hypersensitivity interstitial nephritis
    • irradiation of Wilm's tumour

rapidly progressive crescentic GN (RPGN)

  • usually associated with a rapid decline in renal function (eg. 50% in GFR over 3 months)
  • idiopathic primary type (>10% of all primary GN) is classified into 5 types
    • type I is associated with IgG anti–glomerular basement membrane [GBM] disease and mainly affects young adults
    • type II is immune complex mediated
    • type III is pauci-immune and associated with ANCA
    • type IV are combinations of I and III
    • type V accounts for 5-10% and is ANCA-negative renal vasculitis
    • type II and III mainly occur in middle age
  • 40% are secondary to multisystem disease such as Goodpasture syndrome, Wegener granulomatosis, systemic lupus erythematosus
  • over half present with nephritic syndrome and rapidly deteriorating GFR
  • ~70% will either die or require dialysis
  • DDx includes HUS, TTP

diffuse proliferative glomerulonephritis (DPGN)

membranoproliferative glomerulonephritis (MPGN)

minimal change disease (MCD)

  • the most common single form of nephrotic syndrome in children accounting for 85-95% of cases
  • 80% are younger than 6 years old at presentation with peak incidence in 2 year olds
  • in adults, the mean age of onset is 40 years
  • corticosteroids are the treatment of choice, leading to complete remission of proteinuria in most cases.
  • ~90% of children respond within 2 weeks to prednisone at a dose of 60 mg/msq/d. Rx is continued for another 6 weeks, at lower doses of prednisone, after the remission of proteinuria.

IgA nephropathy

  • aka Berger disease
  • the most common cause of glomerulonephritis in the world, being found in 40% of renal biopsies performed for GN in Asia, 20% in Europe and 10% in USA
  • highly variable ranging from asymptomatic haematuria to rapidly progressive glomerulonephritis
  • usually sporadic with onset often preceded by resp. tract infection (has been linked to H. parainfluenzae in some cases), but familial forms have been reported
  • many have sporadic, transient frank haematuria within the 1st 72 hours of onset of pharyngitis, but may be associated with other infections, strenuous physical exercise and trauma.
  • usually benign course but 20% may develop ESRD over 20 years, and 1-2% of all patients with IgA nephropathy develop ESRD each year.
  • 80% are diagnosed at age range 16-35years but can affect all ages

Goodpasture syndrome

  • a rare form of glomerulonephritis with pulmonary hemorrhage due to an anti-GBM disease of complex pathogeneses
  • note that cases where there is no pulmonary involvement are usually just called anti-GBM disease (10-40% may be ANCA positive)
  • 1-2% of all cases of crescentic rapidly progressive glomerulonephritis are secondary to this disorder
  • 1st described in 1919 by Goodpasture who documented 3 cases in the influenza epidemic
  • an initial insult to the pulmonary vasculature is required for exposure of the alveolar capillaries to the anti-GBM antibodies.
  • predisposing factors for such exposure include the following:
    • association with HLA-DR2
    • exposure to organic solvents or hydrocarbons
    • smoking
    • infection (eg, influenza A2)
    • cocaine inhalation
    • exposure to metal dusts
1)
Perry GJ, George CR, Field MJ, et al: Thin-membrane nephropathy – a common cause of glomerular haematuria. Med J Aust 1989; 151:638-642
2)
Dische FE, Anderson VE, Keane SJ: Incidence of thin basement nephropathy: morphometric investigation of a population sample. J Clin Pathol 1990; 45:457-460
gn.txt · Last modified: 2013/10/28 18:49 (external edit)