GLOMERULOPATHY clinical categories

1
GLOMERULOPATHYclinical categories

• Acute nephritic syndrome
  haematuria, red blood cell casts,
  proteinuria, oliguria, hypertension, edema,
  circulatory congestion
• Rapidly progressive nephritic syndrome
  relentlessly progressive glomerulonephritis
  resulting in ESRF within weeks
• Recurrent gross haematuria

2
GLOMERULOPATHYclinical categories

• Asymptomatic glomerulopathy
  proteinuria, haematuria, or both without
  clinical symptoms
• Chronic nephritic (glomerular) syndrome
  glomerular disease that progress in chronic renal
  failure
• Nephrotic syndrome

3
GLOMERULOPATHYstructural characteristics

• Acute damage (diffuse or segmental)
  - proliferation of epithelial, endothelial and
  mesangial cells
  - exudation of
  polymorphonuclear leukocytes in the
  glomerulus
  - necrosis of glomerular capillaries

4
GLOMERULOPATHYstructural characteristics

• Chronic damage
  - proliferation of cellular elements
  (epithelium, endothelium,
  mesangium) - membranous involvement with
  thickening of glomerular basement membrane
  (GBM)
  - sclerosis of the
  glomerulus - tubular
  atrophy, nephrosclerosis,
  interstitial scarring (in ESRF)

5
GLOMERULOPATHYpathogenesis

• Immunologic reactions
• Vascular diseases
• Abnormalities in coagulation
• Metabolic defects
• Hereditary factors
• Unknown factors

6
GLOMERULOPATHYimmunologic mechanism

• Circulating immune complex mediated disease
• Antitissue antibody mediated disease
• Cell- mediated disease
• Disease associated with activation of
  alternative complement pathway

7
Physiology of protein excretion

• Protein filtration through the glomerulus is
  dependent on the protein size, shape and
  electrical charge

8
Physiology of protein excretion

• Protein charge
• At physiological pH, most proteins are negatively
  charged
• Since the basement membranes are also negatively
  charged, most proteins are retained

9
Physiology of protein excretion

• Protein size
• Proteins greater than 40kDa are almost completely
  retained
• Thus, only small proteins, e.g. retinol-binding
  protein, ß2 microglobulin, passes into the
  ultrafiltrate

10
Physiology of protein excretion

• However, most of the filtered proteins are
  reabsorbed by the proximal tubules.
• Consequently, very little plasma protein appears
  in the urine
• Normally lt 150mg/24hours

11
Physiological proteinuria

• In some non-pathological situations, a higher
  than normal urine protein level is found
• A concentrated spot urine
• Exercise
• Orthostatic proteinuria
• Contamination e.g. from vagina

12
Classification

• Tubular proteinuria
• Tubular dysfunction
• Overflow proteinuria
• Glomerular proteinuria
• Selective proteinuria
• Non-selective proteinuria
• microalbuminuria

13
Tubular proteinuria

• This occurs when glomerular function is intact,
  but protein is lost to the urine either because
  of
• Tubular dysfunction
• Overflow

14
Tubular proteinuria

• Tubular dysfunction
• The tubules are damaged and cannot function
  properly
• Therefore, the small MW proteins that are
  normally filtered are not reabsorbed by the
  tubules
• The small MW proteins include retinol-binding
  protein, ß2 microglobulin, lysozyme, light
  chains, haemoglobin, myoglobin

15
Tubular proteinuria

• Tubular dysfunction
• Pyelonephritis
• Acute tubular necrosis
• Papillary necrosis e.g. analgesic nephropathy
• Heavy metal poisoning
• SLE
• Fanconis syndrome

16
Tubular proteinuria

• Overflow proteinuria
• Occurs when the concentration of one of the small
  MW proteins is so high that the filtered load
  exceeds the tubular reabsorptive capacity
• Thus, the excess filtered load appears in the
  urine

17
Tubular proteinuria

• Overflow proteinuria
• Bence Jones proteinuria
• Myoglobinuria
• Haemoglobinuria

18
Glomerular proteinuria

• When there is glomerular dysfunction, proteins gt
  40kDa can escape into the urine
• The most common form of proteinuria

19
Glomerular proteinuria

• Causes
• Glomerulonephritis
• Diabetes mellitus
• Multiple myeloma
• Amyloidosis
• SLE
• Pre-eclampsia
• Penicillamine, gold

20
Definitions

• Proteinuria
• Urine protein excretion gt 150mg/day
• Microalbuminuria
• Urine albumin gt 30mg/day but not detectable by
  urine dipstick
• Nephrotic syndrome
• Urine protein excretion gt 3.5g/day (with
  hypoalbuminaemia, oedema and hyperlipidaemia)

21
Nephrotic Syndrome (NS)

• Is not a disease but a group of signs and
  symptoms seen in patients with heavy proteinuria
• presents with oedema
• proteinuria usually gt 3.5g / 24hrs (gt0.05g / kg /
  24hrs in children)
• serum albumin lt 30g/l
• other features hyperlipidaemia, and
  hypercoaguable state

22
NS pathophysiology

• proteinuria due to an increase in glomerular
  permeability
• hypoalbuminuria occurs when liver synthesis
  cannot keep up with urine losses
• oedema mechanism is complex and still in dispute
  primary salt and water retention associated with
  reduced renal function as well as reduced plasma
  oncotic pressure are primary factors (overfill
  and underfill)
• hyperlipidaemia increased liver synthesis
• hypercoagulation increased fibrinogen and loss
  of antithrombin III

23
Clinical Features in NS - Thrombosis

• Serious risk of thrombosis
• Increased fibrinogen concentration
• Antithrombin III concentration reduced
• NS patients resistant to heparin
• Platelets hyperaggregable
• Increased blood viscosity

24
NS - laboratory Features

• Hct may be elevated
• Hyponatremia is common
• Plasma creatinine is elevated in 33 of patients

25
NS laboratory- Plasma Protein

• Albumin
• Hypoalbuminemia due to loss via the kidney
• Urinary excretion
• Proximal tubular cells catabolism
• Immunoglobulins
• IgG levels reduced
• IgM levels elevated
• IgM-IgG-Switching

26
NS laboratory- Hyperlipidemia

• Increased synthesis of cholesterol, triglycerides
  and lipoproteins
• Decreased catabolism of lipoproteins
• Decreased activity of lipoprotein lipase
• Decreased LDL receptor activity
• Increased urinary loss of HDL
• Lp(a) levels are elevated

27
Primary glomerular diseases commonly causing the
nephrotic syndrome

• minimal change disease
• focal and segmental glomerulosclerosis
• membranous glomerulonephritis
• proliferative glomerulonephritis (various
  histology and less common cause)
• membranoproliferative (mesangiocapillary)
• focal proliferative
• diffuse proliferative
• mesangial proliferative

28
Other causes of the nephrotic syndrome 1

• Systemic diseases
• diabetes mellitus
• amyloidosis
• SLE and other connective tissue diseases
• HIV/AIDS
• nephrotoxins
• nsaids
• mercury poisoning
• penicillamine
• gold salts

29
Other causes of the nephrotic syndrome 2

• Allergies
• bee sting
• pollens
• poison ivy
• Circulatory effects
• congestive cardiac failure
• constrictive pericarditis
• renal vein thrombosis (cause or result?)
• Neoplastic
• leukaemia
• solid tumours

30
NS epidemiology
31
NS treatment- Diet

• Low protein
• Decreases albuminuria
• Malnutrition
• Salt restriction (Nalt 60 mmol/24 hrs)
• During edema
• Calorie control
• Steroids

32
NS treatment

• water restriction
• diuretics (if not volume depleted)
• reduced protein diet (controversial)
• treat infections
• prophylaxis for thrombosis
• specific therapy
• corticosteroids
• immunosuppression

33
NS treatment- Albumin

• Controversial
• Indication- Hypovolemia
• Abdominal pain
• Hypotension
• Oliguria
• Renal insufficiency

34
NS complications

• Mortality
• 1940s- 40 1 year mortality
• Now 1-2
• Main cause of death
• Infection
• Thrombosis

35
Corticosteroids Initiation in NS

• High dose steroids
• 2 mg/kg/day (max 80 mg)
• 60 mg/m2 (max 80 mg)
• 3 accepted protocols
• 80 respond within 2 weeks

36
Steroid Toxicity

• Cushingoid habitus
• Obesity
• Striae
• Hirsutism
• Acne
• Growth failure
• Avascular necrosis
• Osteoporosis

37
Steroid Toxicity

• Peptic ulceration
• Pancreatitis
• Posterior lens opacities
• Myopathy
• Increased ICP
• Susceptibility to infection

38
Options for Alternative Therapy in NS

• Alkylating Agents
• Nitrogen mustard
• Cyclophosphamide
• Chlorambucil
• Levamisole
• Cyclosporine

39
Indications for Alternative Therapy in NS

• Relapse on Prednisone Dosage gt0.5 mg/kg/alt day
  plus
• Severe steroid side effects
• High risk of toxicity- diabetes
• Unusually severe relapses
• Relapses on Prednisone Dosage gt1.0 mg/kg/alt day

40
Acute Nephritic Syndrome

• Syndrome characterised in typical cases by
• haematuria
• oliguria
• oedema
• hypertension
• reduced GFR
• proteinuria
• fluid overload

41
Clinical Features of the Acute Nephritic Syndrome

• haematuria is usually macroscopic with pink or
  brown urine (like coca cola)
• oliguria may be overlooked or absent in milder
  cases
• oedema is usually mild and is often just
  peri-orbital- weight gain may be detected
• hypertension common and associated with raised
  urea and creatinine
• proteinuria is variable but usually less than in
  the nephrotic syndrome

42
Etiology of the Nephritic Syndrome

• Most common cause is acute post infectious
  glomerulonephritis
• group A beta haemolytic streptococci of certain
  serotypes important in NZ
• IgA disease and Henoch-Schonlein purpura,
  crescentic glomerulonephritis and SLE can also
  present in this way

43
Complications of the Nephritic Syndrome

• Hypertensive encephalopathy (seizures, coma)
• Heart Failure (pulmonary oedema)
• Uraemia requiring dialysis

44
Acute poststreptococcal GN

• Archetype of acute nephritic syndrome
• Proliferative character
• Only certain varietes of beta-hemolytic
  streptococci (nephritogenic strains) induce
  abnormalities in kidneys
• Production of nonspecific evidence of
  streptococcal exposure (elevated antistreptolisin
  titers)
• Antibody production and immune complexes

45
Acute poststreptococcal GN

• Kidneys are enlarged, edematosus, pale
• Electron-dense deposits on the epithelial side of
  GBM
• Reduced GFR
• Elevation of urea and creatinine is
  characteristic
• Urine reduced in volume, concentrated, reddish
  brown contains as much as 2 to 4 mg/day of
  protein

46
Acute poststreptococcal GN

• More common in males than females and most
  frequent between the ages of 3 and 7 years
• Classically, 10 days after sore throat
• Acute nephritic syndrome
• Gross hematuria and fever
• Worse prognosis in adults

47
Definition of glomerulonephritis

• Glomerulonephritides are supposedly
  immunologically mediated glomerular diseases,
• often, but not always,
• inflammatory in nature

48
Glomerular inflammation

• Exsudation of neutrophils and/or macrophages
• 2. Proliferation of mesangial and/or
  endothelial cells

49
Ultrastructural changes in non-proliferative vs.
proliferative glomerulonephritides
50
Mechanisms of glomerular damage
51
Simplified classification of primary
glomerulonephritides

• 1. Nonproliferative
• - minimal change disease
• - focal segmental glomerulosclerosis
• - membranous nephropathy
• 2. Proliferative
• - IgA nephropathy
• - membranoproliferative GN

52
Ultrastructural changes in glomerular capillaries
in different glomerular diseases
53
Podocytes and slit diaphragms
54
Major causes of podocyte effacement

• Slit diaphragm and its lipid raft
• nephrin, podocin
• Podocyte cytoskeleton
• ?-actinin
• Adhesion of podocyte to GBM
• ? -dystroglycan, ?1-integrins
• 4. Loss of podocyte electronegative charge
• podocalyxin

55
Non-proliferative glomerulopathies

• Damage to the glomerular capillary wall resulting
  in
• 1. nephrotic selective proteinuria
• - minimal change disease
• 2. nephrotic non-selective proteinuria with
  microscopic hematuria
• - focal segmental glomerulosclerosis
• - idiopathic membranous nephropathy

56
Primary glomerulonephritides as a cause of
nephrotic syndrome Korbet et al., Am. J. Kidney
Dis., 1996, 27 647 - 651
57
Role of renal biopsy in glomerular disease

• 1. Diagnosis of glomerulopathy
• 2. Assessment of activity intention to treat
• 3. Assesment of chronicity outcome of the
  disease

58
Indications for Biopsy

• Pretreatment
• Recommended
• Onset age lt 6 months
• Macroscopic hematuria
• Microscopic hematuria and HTN
• Low C3
• Renal failure
• Discretionary
• Onset between 6-12 months or gt 12 years
• Persistent HTN of hematuria

59
Indications for Biopsy

• Post treatment
• Steroid resistance
• Frequent relapsers

60
Minimal change disease
61
Minimal change disease
62
Pathogenesis of minimal change disease

• circulating permeability factor
• (hemopexin?)
• decreased synthesis of glomerular polyanions
  (heparan sulfate) by podocytes
• impaired adhesion of podocytes to GBM
• (? -dystroglycan, ?1-integrins?)
• 4. expression of TGF?1 detectable almost only
  in steroid resistant MCD and FSGS

63
Minimal change disease

• full-blown nephrotic syndrome with selective
  proteinuria
• hematuria, hypertension and reduced renal
  function uncommon
• absence of glomerular abnormalities on LM and IF
• fusion of epithelial cells foot processes on
  electron microscopy

64
Minimal change disease-prevalence among
nephrotic patients

• Children - 85 95
• Young adults - 50
• Adults gt 40 years - 20 25

65
Classification of patients with minimal change
disease based on response to corticosteroids

• Steroid responsive (sensitive)
• develop complete remission of proteinuria
• within 8 12 weeks of treatment
• (in adults remission should develop within 16
  weeks)
• 2. Steroid dependent
• develop relapse during tapering of steroids or
  within 2 weeks after cessation of therapy
• 3. Steroid resistant
• fail to respond to steroid treatment at all

66
Definitions

• Steroid Dependence- Two consecutive relapses
  occurring during corticosteroid treatment or
  within 14 days of its cessation
• Steroid Resistance- Failure to achieve response
  in spite of 4 weeks of prednisone 60 mg/m2day

67
Clinical course of MCD in children

• Remission - 90
• a. no relapses - 20
• b. infrequent relapses - 40
• c. frequent relapses and
• steroid dependent - 30
• 2. Resistance to steroids - 10
• a. response to alternative treatment - 8
• b. refractory to any kind of treatment - 2
• In adults, initial response rate is lower,
  relapses and steroid dependence are less frequent

68
Therapy of MCD in children current
recommendations

• Initially course of prednisone 60 mg/m2 for 4-6
  weeks with 40 mg/m2 every alternate day for
  another 4-6 weeks
• Relapses treated in a similar way, but tapering
  of prednisone starts when urine becomes protein
  free
• Frequent relapsers and steroid dependent patients
  treated either by cyclophosphamide
• 2 mg/kg/day for 8 weeks or by cyclosporine
• 5 mg/kg/day for 6-12 months
• 4. Treatment of steroid resistant patients is
  usually unsatisfactory

69
Therapy of MCD modifications in adults

• Initially course of prednisone 1mg/kg for 8-16
  weeks or for one week after remission is
  achieved, then several weeks (one month) 1 mg/kg
  on alternate days, thereafter corticosteroids are
  slowly tapered during several months
• Relapses treated in a similar way
• Frequent relapsers and steroid dependent patients
  treated either by CPH 2 mg/kg/day for 8 weeks or
  by CyA 5 mg/kg/day for 6-12 months
• 4. Treatment of steroid resistant patients is
  usually unsatisfactory

70
Mild FSGS
71
Moderate FSGS
72
Tip lesion in early FSGS
73
Collapsing FSGS
74
Etiology of FSGS

• Primary FSGS
• a. glomerular tip lesion
• b. collapsing glomerulopathy
• 2. Secondary FSGS
• a. healing focal lesions (FSGN)
• b. hyperfiltration in residual nephrons
• - agenesis of one kidney
• - vesicoureteral reflux
• - morbid obesity
• c. damage to epithelial cells
• - HIV nephropathy
• - heroin nephropathy

75
Classification of FSGS

• Genetic FSGS
• a. podocin
• b. ?-actinin
• 2. Immunologic
• mechanisms not yet identified
• 3. Viral FSGS
• a. HIV
• b. hepatitis C
• 4. Toxic FSGS
• a. heroin
• b. pamidronate

76
Pathogenesis of primary FSGS

• Late onset congenital FSGS
• deficiency of podocyte proteins
• (podocin, ?-actinin, CD2AP, et al.)
• Circulating permeability factors
• a. imunoglobulin, or Ig-like molecule
• b. protein of MW about 30-50 kDa
• c. factor inhibiting inducible NO
  synthase in mesangial cells (hemopexin)
• 3. Deficient inhibitors of permeability factors
  lost in urine
• apolipoproteins of HDL complex
• (e.g. apo J, apo E2 and apo E4)

77
Permeability factors in MCD and FSGSGlassock, J
Am Soc Nephrol, 2003, 14 541 - 543

1. Permeability factors in MCD and FSGS may be
   different
2. Among PF described in MCD (e.g. heparanase, VEGF)
   hemopexin is best characterized (Cheung et al.,
   Kidney Int, 2000, 57 1512 1520)
3. In FSGS 30-50 kD weakly anionic, heat labile,
   protease-sensitive factor inhibiting NO
   production in mesangial cells was identified with
   the Palb assay (Sharma et al., Kidney Int, 2000,
   58 1073 - 1079).
4. This PF is increased also in pts with genetic
   mutation of podocin (Carraro et al., JASN, 2002,
   13 1946 - 1952).

78
Serial estimates of permeability factors in
FSGSCattran et al., J Am Soc Nephrol, 2003, 14
448 - 453

1. Serum permeability activity assessed in 27 pts
   with FSGS treated either by cyclosporine or
   placebo before and after 26 weeks of treatment
   (Cattran et al., Kidney Int., 1999, 56 2220
   2226)
2. Proteinuria decreased in cyclosporine treated
   patients from 7.2 to 3.1 g/day and did not change
   in pts on placebo (from 9.5 to 7.4 g/day)
3. Serum permeability activity changed neither in
   cyclosporine (from 0.31 to 0.46), nor in placebo
   (from 0.41 to 0.36) treated pts
4. Antiproteinuric effect of cyclosporine seemed to
   be independent on changes of Palb

79
Focal segmental glomerulosclerosis

• Asymptomatic proteinuria or full blown nephrotic
  syndrome
• Hypertension, microscopic hematuria and decreased
  renal function common
• Slowly progressive disease
• 50 10-year renal survival
• 4. Sclerosis of segments of glomerular tuft

80
Cumulative renal survival in FSGS Korbet, NDT,
1999, 14 (Suppl. 3) 68 - 73
81
Cumulative renal survival in FSGS Korbet, NDT,
1999, 14 (Suppl. 3) 68 - 73
82
Treatment of primary FSGS current
recommendations

• Response to corticosteroids may increase from
  only 10-30 up to 60 with longer treatment with
  higher dose (60 mg/m2 at least 3 months, patients
  should be considered steroid resistant after 6
  months)
• Cyclosporine may reduce proteinuria and lower the
  risk of progression to ESRD even in steroid
  resistant patients, treatment should be long (at
  least 6 months), relapses after cyclosporine
  withdrawal common
• Cytotoxics remain only second-line therapy, the
  evidence for their effect in steroid resistant
  patients is not conclusive

83
Membranous nephropathy
84
Membranous nephropathy
85
Membranous nephropathy
86
Membranous nephropathy

• Secondary
• - infections
• (hepatitis B, syphilis, malaria)
• - drugs
• (organic gold, penicillamine,
• NSAID)
• - neoplasms
• (carcinomas, e.g. Colon, lung, or stomach,
  and lymphomas)
• - systemic lupus erythematosus
• 2. Idiopathic

87
Idiopathic membranous nephropathy

• Membranous nephropathy represents 15-25 of
  adult nephrotic syndrome
• Nephrotic proteinuria is present in about 80 of
  patients, remaining patients have asymptomatic
  proteinuria
• Microscopic hematuria is common
• Hypertension and chronic renal failure are
  uncommon at presentation, but may develop during
  follow-up
• Histology subepithelial deposits along often
  thickened GBM

88
Natural course of idiopathic membranous
nephropathy

• Spontaneous remission may develop in about one
  third of patients
• Nephrotic syndrome persists in another third of
  patients
• Only 20-30 of patients progress to ESRD during
  20-30 years of follow up

89
Cyclosporine in membranous nephropathyGuasch et
al., Am. J. Kidney Dis., 1992, 20 472 - 481

• 14 previously untreated patients with MN were
  treated for 12 weeks with CyA and compared with
  similarly treated pts with MCD
• proteinuria decreased below 3.5 g/day in 10 out
  of 14 pts, fractional clearance of albumin
  decreased by 59, fractional clearance of IgG by
  73 (in MCD albuminuria decreased by 99)
• glomerular filtration rate did not change
  significantly
• antiproteinuric effect of CyA in MN is less
  pronounced than in MCD, but cannot be explained
  only by hemodynamic changes

90
Cyclosporine in steroid-resistant MNCattran et
al., Kidney Int., 2001, 59 1484 - 1490

• complete or partial remission developed after 26
  weeks in 75 of pts treated by CyA vs. in 22 of
  pts treated by placebo
• during 52 weeks relapse developed in 43 of pts
  treated by CyA and 40 of pts treated by placebo
• at the end of follow-up in remission was 39 of
  pts treated by CyA and 13 of pts treated by
  placebo

91
Treatment of idiopathic membranous nephropathy
current recommendations

• Corticosteroids should not be used a sole therapy
• Azathioprine is not effective in reversing or
  stabilizing progressive renal insufficiency
• Cytotoxics induce prolonged remission of
  nephrotic syndrome and improve renal survival,
  their use should be reserved for patients with
  progressive disease
• Cyclosporine seems to be effective in progressive
  renal insufficiency

92
Guidelines for the treatment of IMN Cattran,
Kidney Int., 2001, 59 1983 - 1994
93
Proliferative glomerulonephritides

• Microscopic hematuria and/or bouts of macroscopic
  hematuria
• - mesangial proliferation
• (IgA nephropathy)
• 2. Microscopic hematuria with proteinuria
• - mesangial proliferation with peripheral
  expansion of mesangium
• (membranoproliferative GN)

94
Ultrastructural changes in glomerular capillaries
in mesangio- and membranoproliferative GN
95
IgA nephropathy mesangioproliferative
glomerulonephritis
96
IgA nephropathy
97
Pathogenesis of IgA nephropathyGómez-Guerrero et
al., Kidney Int, 2002, 62 715 - 717

1. Aberrantly O-glycosylated IgA1 with exposed
   GalNAc may be recognized as antigens by IgG
2. Circulating immune complexes of IgA1 and IgG
   and/or IgA1 and soluble Fc?RI (CD89) were
   identified in pts with IgA nephropathy
3. Except from ASGP-R, CD89, Fc?/?R and TfR
   mesangial cells may express further, not yet
   described IgA receptors
4. Patients with IgA nephropathy have increased
   expression of megsin (serine protease inhibitor
   serpin). Overexpression of megsin leads to
   progressive mesangial matrix expansion

98
IgA nephropathy

• Commonest glomerulonephritis in Europe (20-40 of
  primary glomerulonephritides)
• Typical clinical presentation asymptomatic
  microscopic hematuria or episodes of
  parainfectious macroscopic hematuria
• Natural history is not benign at least 20 of
  patients develop ESRD during 20 years

99
IgA nephropathy negative prognostic factors

• a. clinical
• hypertension
• proteinuria (gt 1 g/24 hrs)
• decreased renal function at presentation
• b. histologic
• glomerulosclerosis
• interstitial fibrosis
• vascular sclerosis

100
IgA nephropathy - treatment

• Strict control of hypertension with ACE
  inhibitors
• Fish oil in patients with slowly progressive
  course of renal insufficiency
• Corticosteroids in proteinuric patients with
  preserved renal function
• Cytotoxics in patients with progressive renal
  insufficiency

101
Corticosteroids in IgA nephropathy long-term
resultsPozzi et al., J Am Soc Nephrol, 2004, 15
157 - 163

1. Secondary analysis of a multicenter, randomized,
   controlled trial of 86 adult IgAN treated for 6
   months either with intravenous methylprednisolone
   followed by oral steroids of supportive therapy
2. Ten-year renal survival was significantly better
   in the steroid than in the control group (97 vs.
   53, p0.0003)
3. Proteinuria decreased in patients who did not
   double baseline serum creatinine and increased in
   progressive patients

102
Evidence-based recommendations for IST in IgAN
handle with cautionFloege, Nephrol Dial
Transplant, 2003, 18 241 - 245

1. In low risk pts with Pu lt 1.5 g/day and normal
   GFR, steroid therapy may reduce proteinuria, but
   its effect on long-term outcome is uncertain
2. In pts with Pu 1 3.5 g/day and preserved renal
   function 6 month steroid course is indicated
3. In pts with progressive renal failure as long as
   serum creatinine does not exceed 250 ?mol/l
   steroids plus cytotoxics are recommended

103
Membranoproliferative glomerulonephritis
104
Membranoproliferative glomerulonephritis

• Type I
• Secondary
• infection
• (visceral abscesses, endocardisis,
  infected ventriculoatrial shunts,
  malaria)
• - systemic diseases
• (type III-IV of lupus nephritis)
• - paraproteinemias
• ( LCDD, cryoglobulinemia)
• - thrombotic microangiopathies
• ( HUS/TTP, APS)
• b. Idiopathic
• Type II dense deposit disease

105
Membranoproliferative glomerulonephritis type I
106
Membranoproliferative glomerulonephritis type
II (dense deposit disease)
107
Idiopathic MPGN type I

1. relatively rare in developed countries
2. occurs in younger adults
3. presents with nephrotic syndrome and microscopic
   hematuria
4. slowly progressive disease 50 10-year renal
   survival
5. treatment of nephrotic adults is controversial
   (corticosteroids, or antiplatelet agents?)

108
MPGN type II (dense deposit disease)

• very rare disease
• nephritic factor with hypocomplementemia
• more expressed nephritic features and more
  aggressive course
• no effective therapy

109
Therapy of glomerular diseases

• Drugs and procedures with relatively well defined
  indications
• corticosteroids
• cytotoxics (CPH, chlorambucil)
• cyclosporine
• symptomatic treatment
• (ACEI, AIIA, and other antihypertensives,
• NSAIDS
• lipid lowering drugs)

110
Therapy of glomerular diseases

• 2. Drugs and procedures with limited experience
  and not well defined indications
• mycophenolate mofetil
• tacrolimus
• rapamycin
• intravenous immunoglobulins
• monoclonal antibodies (e.g. infliximab,
  rituximab)
• soluble cytokine receptors (e.g. etanercept)
• plasma exchange
• immunoadsorption

111
Conclusions

• Patients suffering from primary GN are endangered
  by
• a. complications of nephrotic syndrome
• b. progression to ESRF
• 2. Urinary findings are important, but renal
  biopsy remains essential for diagnosis, treatment
  and assesment of outcome
• primary GN are treatable diseases, patients
  should be treated according to available evidence
• further progress in treatment depends on better
  understanding of their pathogenesis