Glomerulonephritis

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Glomerulonephritis

• Cherelle Fitzclarence
• August 2009

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Plan

• General over view
• Bit of revision re anatomy

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Glomerulonephritis

• Nephros kidney
• -itis inflammation of
• Glomus small round ball or knot
• Pathos suffering or disease
• -osis diseased condition
• Glomerulonephritis inflammation of the
  glomeruli
• Glomerulopathy disease of the glomeruli

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• Light micrograph of a normal glomerulus. There
  are only 1 or 2 cells per capillary tuft, the
  capillary lumens are open, the thickness of the
  glomerular capillary wall (long arrow) is similar
  to that of the tubular basement membranes (short
  arrow), and the mesangial cells and mesangial
  matrix are located in the central or stalk
  regions of the tuft (arrows). Courtesy of Helmut
  G Rennke.

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• Light micrograph in membranoproliferative
  glomerulonephritis showing a lobular appearance
  of the glomerular tuft with focal areas of
  increased glomerular cellularity (large arrows),
  mesangial expansion (), narrowing of the
  capillary lumens, and diffuse thickening of the
  glomerular capillary walls (small arrows).
  Courtesy of Helmut Rennke, MD.

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• Electron micrograph of a normal glomerular
  capillary loop showing the fenestrated
  endothelial cell (Endo), the glomerular basement
  membrane (GBM), and the epithelial cells with its
  interdigitating foot processes (arrow). The GBM
  is thin and no electron dense deposits are
  present. Two normal platelets are seen in the
  capillary lumen. Courtesy of Helmut Rennke, MD.

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• Electron micrograph in dense deposit disease
  (DDD) showing dense, ribbon-like appearance of
  subendothelial and intramembranous material
  (arrow) and narrowing of the capillary lumen due
  to proliferation of cells (double arrow).
  Courtesy of Helmut Rennke, MD.

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Glomerular disease

• Primary confined to the kidney
• Secondary due to a systemic disease

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Glomerular injury

• Impairment of selective filtering properties of
  the kidney leading to a decreased GFR
• Molecules normally not filtered such as
  constituents of the blood, pass into the urine
  and are excreted

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Anatomy of Kidney

• Note the positions of
• Glomerulus
• Loop of Henle
• PCT, DCT, CT
• Cortex, Medulla, Pelvis.

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Ultrastructure Glom. capillary
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Filtration Membrane Electron Micro.
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Possible Clinical Manifestations

• Proteinuria asymptomatic
• Haematuria asymptomatic
• Hypertension
• Nephrotic syndrome
• Nephritic syndrome
• Acute renal failure
• Rapidly progressive renal failure
• End stage renal failure

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Glomerulonephritis

• Presence of glomerular disease as opposed to
  tubulointersititial or vascular disease is
  suspected from history
• Haematuria (especially dysmorphic red cells)
• Red cell casts
• Lipiduria (glomerular permeability must be
  increased to allow the filtration of large
  lipoproteins)
• Proteinuria (may be in nephrotic range of gt3.5
  g/24hours)

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• Phase contrast microscopy showing dysmorphic red
  cells in a patient with glomerular bleeding.
  Acanthocytes can be recognized as ring forms with
  vesicle-shaped protrusions (arrows). Courtesy of
  Hans Köhler, MD.

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Diagnosis

• Look for clues
• History
• Haematuria
• Proteinuria
• Azotemia
• azote nitrogen
• A without
• Zoe life
• The gas does not support life
• (French chemists Gayton de Morveau
  (1737-1816) and Antoine Lavoisier (1743-1794) )

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McCarthy ET, November 2008
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Diagnosis

• Can be difficult to distinguish between
  Glomerular disease and tubulo-interstitial
  disease
• Tubular disease does not directly increase
  protein excretion but nephron loss due to the
  disease can have the same end result

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Clinical patterns

• Patients age and characteristics of the urine
  sediment can allow narrowing of the differential
  diagnosis options prior to biopsy
• URINE IS THE LIQUID BIOPSY OF THE KIDNEY
  Walter Piering MD Prof Med Wisconsin

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Urinary patterns

• 3 different patterns
• Focal nephritic
• Diffuse nephritic
• Nephrotic

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Urinary patterns

• Focal nephritic
• Associated with inflammatory to less than half of
  the glomeruli on light microscopy
• Red cells often dysmorphic
• Occasional red cell casts
• Mild proteinuria (lt1.5g/day)

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Urinary Patterns

• Diffuse nephritic
• Damage to all or almost all of the glomeruli
• Similar to focal disease but may also have heavy
  proteinuria (even nephrotic range), oedema,
  hypertension and/or renal insufficiency
• - full house urinary sediment red cells,
  white cells, red cell casts, white cell casts,
  hyaline casts

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Urinary Patterns

• Nephrotic
• Heavy proteinuria
• Lipiduria refractile fat bodies that look like
  a maltese cross under polarised light
• Few cells
• Few casts but those present are hyaline and
  granular

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Non specific nature of histologic patterns

• Membranous GN usually Immune complex disease
  (infective endocarditis, SLE, Hepatitis C)
• Membranous nephropathy drugs (gold,
  penicillamine), SLE, Hepatitis B, malignancy
• Focal glomerulosclerosis can be primary ( minimal
  change), or secondary (intraglomerular
  hypertension, or healing previous glomerular
  injury)

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Pattern diagnosisFocal GN

• lt15 years mild post infectious GN, IgA
  nephropathy, thin basement membrane disease,
  hereditary nephritis, Henoch Schonlein Purpura,
  mesangial proliferative GN
• 15-40 years IgA nephropathy, thin basement
  membrane disease, lupus hereditary nephritis,
  mesangial proliferative GN
• gt40 years IgA nephropathy

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Pattern DiagnosisDiffuse GN

• Post infectious GN, lupus GN, membranoproliferativ
  e GN, mixed cryoglobulinaemia
• Often associated with decreased complement
• Classic findings
• PSGN (anti strep antibodies)
• Lupus nephritis (ANA)
• Anti-GBM disease (anti GBM Abs)
• Mixed cryoglobulinaemia (circulating
  cryoglobulins)
• Wegener's granulomatosis (anti neutrophil
  cytoplasmic abs)

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Pattern DiagnosisDiffuse GN

• lt15 years Post infectious GN,
  membranoproliferative GN
• 15-40 years Post infectious GN, rapidly
  progressive GN, fibrillary GN, membranoproliferati
  ve GN
• gt40years rapidly progressive GN, vasculitis,
  fibrillary glomerulonephritis

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Pattern DiagnosisNephrotic syndrome

• lt15 years minimal change disease, focal
  glomerulosclerosis, mesangial proliferative GN
• 15-40 years focal glomerulosclerosis, minimal
  change disease, membranous nephropathy including
  lupus, diabetic nephropathy, preeclampsia, post
  infectious GN
• gt40 years focal glomerulosclerosis, membranous
  nephropathy, diabetic nephropathy, minimal change
  disease, IgA nephropathy, primary amyloidosis or
  related disorder light chain deposition disease
  (up to 20 of pts over 60), benign
  nephrosclerosis, post infectious GN

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General Workup ? Glomerular disease

• History
• Family history kidney disease and hearing trouble
  (Alports syndrome)
• Medications that can damage the kidney (NSAIDs,
  ACEI, penicillamine, gold, mercury in some skin
  lightening creams)
• Recent throat infection - ? Strep- PSGN or viral
  Wegener's granulomatosis, IgA
• Cancer solid tumours, Hodgkins (minimal
  change) or non Hodgkins (MPGN)

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General Workup ? Glomerular disease

• Physical Examination
• Inspection appearance, colour, pitting oedema,
  xanthelasma, alopecia, facial rash, purpura,
  clubbing, livedo reticularis
• Palpation pulse, hepatomegaly, palpable
  kidneys, splenomegaly, palapable bladder
• Percussion hepatomegaly, splenomegaly
• Auscultation renal artery bruits, other bruits,
  cardiac lesions, hypertension,

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General Workup ? Glomerular disease

• Laboratory work
• UECB
• LFT
• BSL
• FBC
• Urine microscopy and culture
• ACR
• Serum and urine protein electrophoresis
• Renal ultrasound

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General Workup ? Glomerular disease

• Laboratory work
• Specific serology
• For a nephrotic type picture
• HIV, HCV, HBV, ANA, serum cryoglobulins, anti DNA
  ab, complements
• For a nephritic type picture
• Blood cultures, ASOT, AntiDNAse B, ANA, Anti DNA
  ab, anti GBM ab, anti neutrophil cytoplasmic ab,
  complements

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Case 1

• 16 year old male
• Presents with headache, malaise, anorexia swollen
  legs. Not peeing much. Thinks he might have put
  on some weight, belt is bit tight
• History nasty cold with a really sore throat
  2-3 weeks ago otherwise has been well. Took a
  while to get better from the URTI

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Case 1

• Examination
• Inspection bit pale, puffy face, oedematous
  legs
• Palpation oedema pitting to mid thigh, nil else
  to find
• Percussion nil to find
• Auscultation systolic flow murmur, nil else

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Case 1

• U/A large blood, 4 protein, large leucocytes
• Microscopy gt100 red cells, gt100 white cells,
  red and white cell casts

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Case 1

• Differential Dx at this point?
• Post infectious GN
• Pathogenesis is an immune reaction to certain
  pathogens, in this instance probably group A, ß
  haemolytic strep (endostreptosin and pyrogenic
  exotoxin B)
• Throat cultures are usually negative by the time
  pt presents with GN but ASOT, antiDNAse B should
  be high along with low complements

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Case 1

• Management
• Should get better over 2-3 weeks
• Many cases do not present as asymptomatic
• Supportive fluid restriction, sodium
  restriction, diuretics to help control
  hypertension
• Modest protein restriction if the patient has
  azotemia
• If pt not improving in a couple of weeks then
  consider biopsy
• Biopsy will show, immune complex deposition in
  the capillary walls (immunofluorescence),
  irregular subepithelial deposits along the
  capillary loops (EM)
• Steroids are not generally indicated but are used
  in patients who have renal failure or if the
  biopsy reveals crescents (proliferation of
  extraglomerular cells within Bowmans capsule)
  which makes for a more guarded prognosis
• Consult Nephrologist

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Case 1

• Children usually do well
• Adults less like to have full recovery
• Acute GN follows other infections
• Bacterial sepsis, acute or subacute bacterial
  endocarditis, visceral abscess, infected
  ventriculoperitoneal shunt, osteomyelitis
• Treatment is aimed at eradicating the primary
  disease

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IgA Nephropathy Buergers Disease

• Most common cause of GN in Asia but uncommon in
  Sth America or Africa
• 15-40 of all biopsy proven GN
• Male gt Females
• 2nd-3rd decade
• Most commonly asymptomatic with serendipitous
  finding of haematuria and mild proteinuria
• Another classic presentation is macroscopic
  haematuria in conjunction with a viral infection
• Renal function is usually normal but occasionally
  a patient will present with acute renal failure
  due to acute tubular necrosis secondary to the
  gross haematuria
• Biopsy mild to moderate mesangial cell
  proliferation, IgA deposits in the mesangium on
  immunofluorescence, often with C3 deposition also

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IgA Nephropathy Buergers Disease

• Slowly progressive
• By 20 years, 50 have end stage kidney disease
• Worse prognosis if gt1g/day proteinuria,
  hypertension, increased creatinine of glomerular
  fibrosis at biopsy, on presentation

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IgA Nephropathy Buergers Disease

• Management
• Aggressive control of blood pressure and
  proteinuria with ACEIs or AR2Bs
• Corticosteroids /- azathiprine varied schools
  of thought
• However if rapidly progressive GN with crescent
  deposition treatment should be aggressive with
  high dose steroids and cyclophosphamide
• Consult the Nephrologist

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Rapidly Progressive GN (PRGN)

• Medical emergency
• full house nephritic urinary sediment
• Immediate hospitalisation and biopsy
• Crescentic GN proliferation of cells outside
  the glomerulus, but within Bowmans space
• If IgG present in linear stain along the basement
  membrane consistent with anti glomerular
  basement membrane antibiodies (AGBM abs) which
  is a marker of Goodpastures syndrome
• Presence of a linear pattern or complement in a
  granular pattern on the capillary wall suggests
  an immune complex associated disease such as
  lupus, IgA nephropathy of PSGN
• Absence of immune deposition suggests a
  vasculitic process such as Wegeners
  granulomatosis or microscopic polyangiitis

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RPGN eg Goodpastures

• Autoimmune
• Commonly 2nd-3rd decade and second peak in 60
  age group
• Some present with renal involvement
  (Goodpastures disease)
• Some present with pulmonary haemorrhage and
  nephritis (Goodpastures syndrome)
• Rarely some present with only pulmonary
  involvement

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Goodpastures
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RPGN eg Goodpastures

• Classic haemoptysis after upper respiratory
  infection and have nephritic urinary sediment
• History of smoking or hydrocarbon exposure is
  common
• CXR pulmonary haemorrhage
• Lab- iron deficiency anaemia and renal
  dysfunction, circulating anti-GBM antibodies
• Kidney biopsy crescentic GN with linear staining
  IgG and C3 along the glomerular basement membrane

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RPGN eg Goodpastures

• Treatment
• High dose IV steroids (methyl pred 500mg daily
  for 3 days) followed by oral prednisolone and
  cyclophosphamide
• Plasma exchange every other day until anti-GBM Ab
  titire is negative
• Px guarded (if present with oliguria and elevated
  creatinine, or severe scarring unlikely to
  recover renal function)

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Nephrotic Syndrome

• Can be due to systemic or local renal disease
• Diabetic nephropathy most common cause
• Other common causes include amyloidosis (often
  secondary to multiple myeloma), light chain
  deposition disease, minimal change disease, focal
  segmental glomerulosclerosis, membranous
  nephropathy, membranoproliferative
  glomerulonephritis, fibrillary glomerulonephritis

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Nephrotic Syndrome eg Minimal Change Disease

• Other name lipoid nephrosis or nil disease
• Most common cause of nephrotic syndrome in kids
  2-12 years but also in adults
• Onset often acute and precipitant my be beesting,
  viral infection, allergy or immunization
• Association with Hodgkins lymphoma and other T
  cell malignancies

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Nephrotic Syndrome eg Minimal Change Disease

• Clinical dramatic weight gain, pitting oedema,
  normal blood pressure. Urine proteinuria,
  hyaline casts, oval fat bodies. Usually no red
  cells. Normal renal function but sometimes
  failure secondary to severe hypoalbuminaemia or
  prerenal azotemia leading to volume contraction.
• Children dont need biopsy unless hypertensive or
  other complications
• If biopsy done, EM fusion of podocytes (foot
  processes of glomerular visceral epithelial cells)

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Nephrotic Syndrome eg Minimal Change Disease

• Treatment
• Oral corticosteroids prednisolone 2mg/kg/day
• Cyclophosphamide if relapsing diseas

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Nephrotic Syndrome eg FSGN

• Most common cause of nephrotic syndrome in young
  adults
• Classic nephrotic syndrome and a small amount of
  blood in the urine
• Can occur in minimal change disease which becomes
  resistant to prednisolone
• Can be secondary heroin use
• Can be secondary to HIV infection
• Associated with other diseases (morbid obesity,
  persistent reflux nephropathy, sickle cell
  disease , cyanotic congenital heart disease)

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Nephrotic Syndrome eg FSGN

• Diagnosis biopsy light microscopic pattern of
  segmental or total sclerosis of glomerular tufts
• Treatment prednisolone 1mg/kg/day often for 6-8
  months
• Complete remission only in 50
• ACEI
• Poor prognosticators tubulointerstitial
  disease, increased creatinine, marked proteinuria

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Nephrotic Syndrome eg Membranous Nephropathy

• Most common cause of nephrotic syndrome in 40-60
  yos
• Usually frank nephrotic syndrome, low grade
  microhaematuria, relatively preserved renal
  function
• Some people asymptomatic
• Others can lose 10-20g of protein a day and be
  quite sick
• Associated with certain medications eg
  penicillamine, gold, captopril, NSAIDs, certain
  viral infections eg Hep B and HCV and malignancies

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Nephrotic Syndrome eg Membranous Nephropathy

• Diagnosis is on kidney biopsy glomeruli appear
  normocellular with thickening of the GBM, immune
  deposits on outer side of GBM
• Mx rule out secondary causes
• Mx supportive ACEI/AR2B for proteinuria,
  statins for hypercholesterolaemia, prophylactic
  warfarin (if very low albumin markedly increased
  risk of venous thrombosis)
• Prednisolone may be used
• Some may not progress over 10 years, but marked
  proteinuria and increased creatinine 40
  progress to ESKD

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Nephrotic Syndrome eg Membranoproliferative
Glomerulonephritis

• Idiopathic if between 10-30 year
• Between 35-60 years usually secondary to
  Hepatitis C
• Clinical- hypertension, mild nephrotic syndrome,
  microhaematuria, relatively preserved renal
  function
• Pts with HCV may have circulating cryoglobulins
  including triad of weakness, arthralgias and
  palpable purpura
• In kids 2 forms
• MPGN 1 circulating immune complexes passively
  trapped in glomeruli
• MPGN 2 circulating IgG (nephritic factor) that
  activates complement via the alternative pathway

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Nephrotic Syndrome eg Membranoproliferative
Glomerulonephritis

• Diagnosis serum complement (depressed),
  hepatitis serologies, biopsy glomeruli are
  hypercellular, often lobular in appearance more
  detailed changes.
• Treatment manage hypertension, ACEI/AR2B, salt
  restriction, diuretics, treat HCV with interferon
• 50 progress to ESKD
• Tends to recur in a kidney transplant

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Nephrotic syndrome eg fibrillary
glomerulonephritis

• Recently recognised 40-60 years
• Similar to MPGN but serum complement normal and
  microscopy of biopsy demonstrates fibrilllar
  deposist in the mesangium.
• Prognosis guarded

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Conclusions

• Take a history
• Do a urine test
• If haematuria and proteinuria - ?GN
• Exclude secondary causes
• Biosy is the definitive way to diagnose but some
  hints from history and

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Acknowledgements

• Handbook of nephrology..Wilcox et al
• Up to date
• MD Consult

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