Secondary Glomerulonephritis

1
Secondary Glomerulonephritis

• Serban Dragoi MD, PhD
• Georgetown University
• School of Medicine

2
Primary vs. Secondary

• IgA nephropathy
• Pauci-immune necrotizing and crescentic GN
• Anti-GBM glomerulonephritis
• Membranous glomerulopathy
• Type I MPGN

• Henoch-Schonlein purpura
• Pauci-immune small vessel vasculitis
• Goodpasture syndrome
• SLE
• Cryoglobulinemic vasculitis

3
Antibody-mediated GN

• 3 types
• Linear glomerular IgG staining (IF) with positive
  anti-GBM serology
• Paucity of glomerular Ig staining (IF) with
  positive ANCA serology
• Glomerular immune complex localization shown as
  granular staining (IF) with positive serology
  (a-DNA, hypocomplementemia, a-HCV, a-HBV, C3Nf,
  cryos, ASO, increased IgA)

4
Linear glomerular IgG staining (IF) with positive
anti-GBM serology

• With lung hemorrhage (Goodpasture syndrome)
• Without lung hemorrhage (a-GBM glomerulonephritis)

5
Paucity of glomerular Ig staining (IF) with
positive ANCA serology

• No systemic vasculitis (ANCA glomerulonephritis)
• Systemic vasculitis but no asthma no granuloma
  (microscopic polyangiitis)
• Systemic vasculitis granulomas but no asthma
  (Wegener granulomatosis)
• Systemic vasculitis eosinophilia asthma
  granulomas (Churg-Strauss syndrome)

6
Glomerular immune complex localization shown as
granular staining (IF) with positive serology

• IgA but no vasculitis (IgA nephropathy)
• IgA systemic vasculitis (H-S purpura)
• SLE (LN)
• Acute Strep/Staph infection (Acute
  post-infectious GN)
• Mesangiocapillary changes (Type I MPGN)
• GBM dense deposits (Type II MPGN)
• Sub-epithelial deposits (Membranous GN)
• 20 nm fibrils (Fibrillary GN)
• Other features (Other GNs)

7
(No Transcript)
8
SLE

• Activation and clonal expansion of CD4 T cells ?
  release of cytokines ? activation of autoreactive
  B cells, proliferation differentiation ? excess
  of antibodies against nuclear antigens ANA, DNA,
  Sm, RNA, Ro, La others.
• Immune complex deposition, complement activation
  ? complement-mediated damage
• Nuclear antigens can bind to glomerular sites
  (especially subepithelial) ? in situ immune
  complex formation
• HTN, APL antibodies can potentiate glomerular and
  vascular lesions

9
(No Transcript)
10
Modified WHO Classification of LN

• I normal glomeruli
• II pure mesangial alterations
• A normal LM, mesangial deposits on IF/EM
• B mesangial hypercellularity and deposits on
  IF/EM
• III focal segmental glomerulonephritis
• A w/ active necrotizing lesions
• B w/ active sclerosing lesions
• C w/ sclerosing lesions
• IV diffuse glomerulonephritis (severe
  mesangial, endocapillary or mesangiocapillary
  proliferation and/or extensive subendothelial
  deposits)
• A w/o segmental lesions
• B w/ active necrotizing lesions
• C w/ active and sclerosing lesions
• D w/ sclerosing lesions
• V diffuse membranous glomerulonephritis
• A pure membranous GN
• B associated with II-a or II-b lesions
• VI advanced sclerosing GN

11
Course and Prognosis of LN

• 129 pts with WHO class III (40) or class IV
  (60) LN between 1975-1997
• 18 M, 72 F mean age 29 yrs 43 white 17 AA
  40 Hisp
• 30 pts reached endpoint (doubling of
  Screatinine)
• R. Graham Barr, Stephen Seliger, Gerald B. Appel,
  Ricardo Zuniga, Vivette DAgati, Jane Salmon and
  Jai Radhakrishnan. Prognosis in proliferative
  lupus nephritis the role of socio-economic
  status and race/ethnicity

12
Course and Prognosis of LN

• Multivariate analysis of predictors of
  progression showed
• Higher Screatinine
• Heavier proteinuria
• AA race
• Low socioeconomic status
• R. Graham Barr, Stephen Seliger, Gerald B.
  Appel, Ricardo Zuniga, Vivette DAgati, Jane
  Salmon and Jai Radhakrishnan. Prognosis in
  proliferative lupus nephritis the role of
  socio-economic status and race/ethnicity in NDT
  (2003) 18 2039-2046

13
Therapy of LN

• Controversial
• Class I II excellent renal prognosis
• Treat only extrarenal manifestations
• Class III
• Severity, of glomeruli involved, ?necrotizing
  lesion(s), ?crescent(s)
• Steroid-sensitive vs steroid-resistant

14
Therapy of LN

• Class IV
• Aggressive treatment to avoid irreversible renal
  damage (ESRD)

15
NIH Data

• Data from the NIH have shown that patients with
  lupus nephritis who are treated with
  glucocorticoids and a prolonged course of
  cytotoxic agents have better long-term renal
  function than those treated with glucocorticoids
  alone

16

• 107 patients with active lupus nephritis (median
  follow-up 7 yrs)
• With oral prednisone alone, the probability of
  renal failure began to increase substantially
  after 5 yrs of observation
• Renal function was better preserved in patients
  who received various cytotoxic-drug therapies,
  but the difference was statistically significant
  only for iv CyP plus low-dose prednisone as
  compared with high-dose prednisone alone (P
  0.027)
• The advantage of treatment with iv CyP over oral
  prednisone alone was particularly apparent in the
  high-risk subgroup of patients who had chronic
  histologic changes on renal biopsy at study entry
• Patients treated with iv CyP have not experienced
  hemorrhagic cystitis, cancer, or a
  disproportionate number of major infections
• As compared with high-dose oral prednisone alone,
  treatment of lupus glomerulonephritis with iv CyP
  reduces the risk of ESRD with few serious
  complications
• Austin HA III, Klippel JH, Balow JE, et al.
  Therapy of lupus nephritis controlled trial of
  prednisone and cytotoxic drugs. N Engl J Med
  1986314614-619

17
Plasmapheresis ?

• The prognosis of patients with SLE who have GN,
  especially class III IV is poor, despite
  treatment with immunosuppressive therapy
• Plasmapheresis therapy has been used, but there
  have been few controlled clinical observations of
  its efficacy

18

• RCT of 86 patients with severe lupus nephritis in
  14 medical centers
• Standard-therapy regimen of prednisone and CyP
  vs. standard therapy plus plasmapheresis (PEx)
• PEx 3x weekly for 4 weeks
• Drug therapy was standardized, with strict
  adherence to nine detailed medical-management
  protocols
• 46 patients received standard therapy and 40
  patients received standard therapy plus PEx (mean
  follow-up was 136 weeks)
• 6 patients in the standard-therapy group and 8
  patients in the PEx group died
• ESRD developed in 8 patients in the
  standard-therapy group vs. 10 in the PEx group
• 30 pts reached stopping points (14 in the
  standard-therapy group and 16 in the PEx group
• A similar number of patients in each group had a
  decrease in both the serum creatinine
  concentration and urinary protein excretion to
  approximately normal values
• Patients treated with PEx had a significantly
  more rapid reduction of serum concentrations of
  antibodies against double-stranded DNA and
  cryoglobulins
• CONCLUSIONS Treatment with PEx plus a standard
  regimen of prednisone and cyclophosphamide
  therapy DOES NOT improve the clinical outcome in
  patients with SLE and severe LN, as compared with
  the standard regimen alone
• Lewis EJ, Hunsicker LG, Lan S-P, Rohde RD,
  Lachin JM. A controlled trial of plasmapheresis
  therapy in severe lupus nephritis. N Engl J Med
  19923261373-1379

19
MMF ?

• The combination of cyclophosphamide and
  prednisolone is effective for the treatment of
  severe lupus nephritis but has serious adverse
  effects. Whether mycophenolate mofetil (MMF) can
  be substituted for cyclophosphamide is not known.
  

20

• 42 patients with diffuse proliferative lupus
  nephritis
• 21 pts in Group I Prednisolone and MMF given
  for 12 months
• vs.
• 21 pts in Group II Prednisolone and CyP given
  for 6 months, followed by prednisolone and
  azathioprine for 6 months
• 81 of the 21 patients in Group I had a complete
  remission, and 14 had a partial remission vs.
  76 and 14, respectively, of the 21 patients in
  Group II
• The improvements in the degree of proteinuria and
  the Salbumin and Screatinine concentrations were
  similar in the two groups
• One patient in each group discontinued treatment
  because of side effects.
• Infections were noted in 19 of the patients in
  Group I and in 33 of those in Group II (P0.29)
• Other adverse effects occurred only in group 2
  they included amenorrhea (23), hair loss (19),
  leukopenia (10), and death (10)
• Relapse rates were 15 and 11, respectively
• Conclusions For the treatment of diffuse
  proliferative lupus nephritis, the combination of
  MMF and prednisolone is as effective as a regimen
  of CyP and prednisolone followed by azathioprine
  and prednisolone
• Chan TM, Li FK, Tang CSO, et al. Efficacy of
  mycophenolate mofetil in patients with diffuse
  proliferative lupus nephritis. N Engl J Med
  20003431156-1162

21
More data for MMF
22

• 59 pts w/ LN (12 III, 46 IV, 1 V-b) all received
  induction therapy w/ iv CyP steroids (up to 7
  mos) followed by maintenance therapy (1-3 yrs)
• Group I quarterly iv CyP ? 4 died, 3 ESRD
• Group II azathioprine (1-3 mg/kg/d) ? 1 ESRD
• Group III MMF (500-3000 mg/d) ? 1 died, 1 ESRD
• Chronicity index was 1.9 points lower in the CyP
  group than in the MMF group (P0.009)
• For patients with proliferative lupus nephritis,
  short-term therapy with iv CyP followed by
  maintenance therapy with MMF or azathioprine
  appears to be more efficacious and safer than
  long-term therapy with iv CyP.
• Gabriel Contreras, M.D., M.P.H., Victoriano
  Pardo, M.D., Baudouin Leclercq, M.D., Oliver
  Lenz, M.D., Elaine Tozman, M.D., Patricia ONan,
  R.N., and David Roth, M.D. Sequential Therapies
  for Proliferative Lupus Nephritis, N Engl J Med
  2004350971-80.

23
Antiphospholipid Antibody Syndrome

• Associated with
• Glomerular disease
• Large-vessel renal involvement
• Secondary hypercoagulable state
• Dialysis patients
• Kidney transplant patients

24
Anti-Phospholipid Antibodies

• 4 types
• Antibodies causing a false-positive VDRL
• Lupus anticoagulants
• Anticardiolipin antibodies
• Antibodies to beta-2 glycoprotein-1

25
Antiphospholipid Antibody Syndrome

• 30-50 of pts with APL antibodies have the
  primary APL syndrome (no identified autoimmune
  disease)
• Lupus anticoagulant
• Antiphospholipid antibodies
• Cardiolipin
• Phosphatidylserine
• Other phospholipids
• Renal involvement in up to 25 of pts with
  primary APL syndrome
• thrombosis of blood vessels arterial, glomerular
  capillaries, venous
• Interstitial fibrosis and cortical atrophy
  (ischemia)
• HUS-TTP

26
Antiphospholipid Antibody Syndrome

• ESRD on HD 10-30 prevalence of APL antibodies
• CKD and ESRD on PD much lower prevalence of APL
  antibodies
• 20-60 SLE patients with APL antibodies who
  received renal transplants had
• Venous thromboses (i.e. DVT)
• PE
• Persistent thrombocytopenia

27
Antiphospholipid Antibody Syndrome

• 28 of 178 non-SLE transplant recipients had APL
  antibodies that were assoc w/ 3-4 fold increased
  risk of arterial and venous thromboses
• HCV-positive renal transplant recipients with
  anticardiolipin antibodies appear to have a
  higher risk of TMA in the allograft

28
Therapy

• Remains to be defined
• Higher IgG APL antibody titers blamed for
  increased incidence of thrombotic events
• Aspirin for APL antibodies w/o thrombotic events
• High-dose anticoagulation for APL syndrome
  (primary or sec to SLE)
• Uncertain role of immunosuppression
• In pregnancy with APL syndrome
• Heparin and low-dose aspirin successful in
  several studies
• Prednisone no success
• In case of bleeding // thromboses despite
  adequate anticoagulation // pregnacy, some
  success reported with
• Plasmapheresis corticosteroids
• Other immunosuppressives
• IVIG, Plaquenil (anecdotal)

29
Mixed Connective Tissue Disease

• Overlap SLE/scleroderma/polymyositis
• Very high ANA titer (often speckled)
• ENA with anti-U1RNP antibodies
• Glomerular lesions resemble the spectrum found in
  SLE
• Glomerular disease is the most common kidney
  lesion in MCTD
• Up to 30 have mesangial deposits of IgG and C3
• Focal proliferative GN with mesangial and
  subendothelial deposits
• Glomerular fibrinoid necrosis and crescent
  formation are rare
• Vascular lesions (when present) resemble those
  found in scleroderma

30
Primary systemic sclerosis

• Anti-centromere antibodies (96) in pts with
  limited cutaneous scleroderma (including CREST
  syndrome) w/o renal disease
• sensitivity is only 43 for cutaneous scleroderma
• Presence of anti-centromere antibodies reduces
  the likelihood of developing renal complications

31
Primary systemic sclerosis

• Anti-Scl-70 antibodies 90 positive predictive
  value for systemic sclerosis
• Insensitive and not good for excluding systemic
  sclerosis
• Presence of anti-Scl-70 antibodies is a predictor
  of likelihood of renal involvement or patient
  survival

32
Wegener Granulomatosis

• Systemic vasculitis
• Necrotizing glomerular lesions
• The classic histopathologic finding is focal
  segmental necrotizing and crescentic GN
• Large number of crescents are more often found in
  c-ANCA positive pts

33
Wegener Granulomatosis Therapy

• The heterogeneity of vasculitis and differing
  approaches to classification have hindered the
  accumulation of evidence to direct therapy
• Most clinical trials have had sample sizes too
  small to allow conclusions to be made and
  treatment protocols have developed along
  empirical and, more recently, consensus lines
• Vasculitis occurring in the context of Wegener's
  granulomatosis, microscopic polyangiitis,
  ChurgStrauss angiitis and polyarteritis nodosa
  appears to respond in a similar way to therapy
  and it is probable that disease severity should
  determine the protocol rather than diagnostic
  subgroup

34
Wegener Granulomatosis Therapy

• When threatened vital organ damage is present,
  early effective treatment will improve long-term
  outcome, as has been demonstrated for renal
  vasculitis, where renal function at remission
  determines long-term renal survival. In this
  regard, early diagnosis, before organ damage is
  sustained, is more important than therapeutic
  protocol
• The importance of balancing treatment efficacy
  with toxicity recurs in the existing literature
  and has inspired the use of protocols of graded
  intensity for progressively severe vasculitis.
  The CYCAZAREM protocols also appear to favor
  efficacy over toxicity, because the remission
  rate was very high yet treatment toxicity
  contributed to deaths in six and caused serious
  adverse effects in over one quarter
• In addition to the need for less toxic therapies
  overall, there is a more urgent requirement for
  the elderly to be regarded as a separate subgroup
  and appropriate protocols designed to offer a
  more favorable balance with less toxicity

35
Wegener Granulomatosis Therapy

• The advent of newer immunosuppressives and
  biological agents targeting specific immune
  components offers exciting possibilities for the
  vasculitis specialist
• Unfortunately, experience with these drugs in
  vasculitis is usually delayed until they are
  licensed for a particular indication, typically
  transplantation or rheumatoid arthritis. If
  proven effective and safe, the expense of these
  agents will also require the design of
  costbenefit strategies in vasculitis before they
  can be routinely recommended

36
(No Transcript)
37
(No Transcript)
38
(No Transcript)
39
Microscopic polyangiitis

• Systemic vasculitis
• Necrotizing glomerular lesions
• The classic histopathologic finding is focal
  segmental necrotizing and crescentic GN
• Large number of crescents are more often found in
  c-ANCA positive pts

40
Churg-Strauss Syndrome(aka. Allergic
Granulomatosis)

• Rare systemic vasculitis
• Only several hundred cases reported in the
  literature since the first case in 1951 (?
  underrecognized)
• Vasculitis, asthma, organ infiltration by
  eosinophils, and peripheral eosinophilia
• 50 have kidney involvement in autopsy series
• Clinical renal disease described in 25-90
• Variety of lesions found on K. Bxs from normal
  to severe GN, vasculitis and interstitial
  inflammation
• Necrotizing glomerular lesions are seen less
  often
• The classic histopathologic finding is focal
  segmental necrotizing GN, sometimes with small
  crescents
• In most cases the GN is mild, affects only
  several glomeruli and involves the tuft
  segmentally
• Least likely (among the pauci-imune GNs) to be
  c-ANCA positive to have large number of
  crescents

41
Temporal arteritis

• Renal manifestations rare
• Mild hematuria
• Mild proteinuria
• No renal failure

42
Takayasu Arteritis

• Obliterative arteritis of the main renal artery ?
  renovascular HTN
• Narrowing of the renal ostia due to abdominal
  aortitis ? renovascular HTN
• Mild hematuria
• Mild proteinuria
• No renal failure
• High BUN/serum creatinine ratio
• Mild mesangial proliferative GN (IgG, IgM, IgA,
  C3, C4)

43
Anti-Endothelial Cell Antibodies (AECA)

• Detected in the serum of pts with renal disease
  caused by GN and thrombotic angiopathies
• Assay rarely used as diagnostic tool due to
  technical difficulty
• AECA can be directed against large vessel
  endothelial cells (Takayasu arteritis, Kawasaki
  disease) and to microvascular endothelium in HIT,
  TTP, Behcet, multiple sclerosis

44
(No Transcript)
45
Henoch-Schonlein Purpura

• Discussed under Primary GN

46
Anti-GBM Disease and Goodpasture Syndrome

• Discussed under Primary GN

47
Sjogren Syndrome

• Tubulointerstitial involvement
• Distal RTA
• Impaired concentrating ability
• Hypercalciuria
• PT defects (less often)
• Bland UA
• Mild elevations of serum creatinine
• GN (rarely) hematuria, proteinuria, renal
  insufficiency, NS, renal vasculitis (renal
  insufficiency and severe HTN)

48
Sarcoidois

• Interstitial nephritis (typically granulomatos)
• Nephrolithiasis
• Tubular fxn abnormalities

49
Mixed Cryoglobulinemia

• Assoc with a variety of
• Infections
• Collagen-vascular diseases
• Lymphoproliferative diseases
• Cryo
• Type I single monoclonal Ig (Waldenstroms,
  myeloma)
• Type II (mixed) monoclonal Ig (IgM kappa in
  90) against polyclonal IgG (RF positive)
• Type III (mixed) both polyclonal IgG IgM
• Most types II III have HCV infection

50
(No Transcript)
51
(No Transcript)
52
(No Transcript)
53
(No Transcript)
54
(No Transcript)
55
(No Transcript)
56
(No Transcript)
57
Inherited Disorders

• Hereditary Nephritis (Alport disease)
• Thin GBM Disease
• Fabry Disease(Angiokeratoma Corporis Diffusum
  Universale)
• Nail-Patella Syndrome(Hereditary
  Osteo-onychodysplasia)

58
Inherited Mutations of Podocyte Proteins

• Congenital NS of the Finnish Type (CNF)
• Nephrin mutations
• AR Nephrotic Syndrome
• Podocin mutations

59
Inherited Mutations of Podocyte Proteins

• AD Nephrotic Syndrome (FSGS)
• Alpha-actinin-4 mutations
• Altered mechanical properties of the podocytes
  (impaired cytoskeletal fxn)
• Penetrancehigh
• Subnephrotic proteinuria and progressive renal
  insufficiency

60
Glomerular Manifestations of Liver Disease

• Depends on the liver disease
• Hepatitis B
• Hepatitis C
• Autoimmune Chronic Active Hepatitis
• Cirrhosis

61
Glomerular Manifestations of Liver Disease

• Cirrhosis
• Clinically manifest GN is rare
• IgA deposition noted in more than 50 of pts at
  both necropsy and bx (also found in some
  noncirrhotic kidney autopsy series)
• Kidney biopsy
• Mesangial Sclerosis (cirrhotic glomerular
  sclerosis)
• MPGN
• Henoch-Schonlein Purpura with RPGN (rarely)

62
Others

• Amyloidosis
• Primary
• Secondary
• Waldenstrom macroglobulinemia
• Sickle Cell Nephropathy

63
(No Transcript)