dr.mohessen

1. By
Dr Mohsen El Kossi
Consultant Renal Physician, Doncaster and Bassetlaw Teaching
Hospitals

3. Case 1
 A 55 year old male patient presented for evaluation of
recently diagnosed renal failure
 Immunoelectrophoresis : monoclonal band of λ type
 Free light chain revealed Ⱪ chain of 35 mg/l, λ 95
mg/l, K/λ ratio of 0.35 (normal range 0.5-2.5)
 Urine immunofixation study is pending.

4.  H&E Cast nephropathy,
fractured casts, atrophic
tubules
 Korbet and Schwartz JASN 2006

5. Myeloma Cast
A- Cast stained with λ Ig
light chain
B- Cast stained –ve for K Ig
light chain

6. Case 1
1) Is there a scenario in which a bone marrow biopsy result
might avoid the need for a renal biopsy?
2) Is there a scenario in which a kidney biopsy first might
avoid the need for a bone marrow biopsy?
3) If the bone marrow biopsy is normal, will you still
proceed with a renal biopsy?
4) If the kidney biopsy, done first, shows something other
than a MGRS, do you still need a bone marrow biopsy?

7. Case 1
 AKI in the context of MM:
 Can you differentiate between cast nephropathy versus
LCDD/AL Amyloidosis?
 Dialysis (PEX/HDF) modality has any impact in cases of
cast nephropathy?
 MGRS vs MGUS
 MGRS kidney involvement without overt MM (no bone
lesions/anaemia/hypercalcaemia) or lymphoma
 Monclone but no evidence of renal involvement

8. SPEF vs IFE
SPEF
 M spike
 Can detect monoclone as
low as 500mg/L
IFE
 More sensitive
 Detect as low as 150
mg/L
 Labour-intensive
 Usually used if SPEF +ve
 Used for monitoring
more than one clone

9. Case 2
 A 47-year-old woman presented with LL oedema and
active urinary sediment with urine PCT of 300
mg/mmol. Serum albumin was low at 22g/L. She had
no previous medical problems. A renal biopsy was
performed, and a diagnosis of focal segmental
glomerulosclerosis was made. Oral prednisolone was
initiated at a dose of 40 mg/day (0.8 mg/kg/day), and
was tapered to 10 mg daily for 2 years. However, her
urine protein increased to above 5.0 g/day.

10. Case 2
 Therefore, a second renal biopsy was performed. Light
microscopy showed mesangial hypercellularity with
mesangial matrix expansion. Immunofluorescence
revealed global glomerular capillary wall staining for
IgG, IgA, C1q, and C3. IgM and C4 staining results
were all negative. Electron microscopy showed
microtubular depositions in the epithelial layer.

11. Case 2

12. Irregular thickening of
the GBM with subepithelial
electron-dense deposits size of
microtubules 35-40 um

13. Case 2
Immunotactoid GN

14. Case 2
Immunotactoid Fibrillary GN
-B-cell malignancies/monoclonal
proteins , HCV infection
-"tactoid" deposits are positive for
a monoclonal ~60% of the time.
-1/3 hypocomplementemic
-Microtubules 35-40 um
-Treatment of the underlying B
Cell disorder e.g Rituximab
 Chronic HCV, malignancy,
autoimmune disease, DM
 DNA-J heat-shock protein
family member B9 (DNAJB9)
 Randomly oriented
nonbranching fibrillar
deposits with a mean
diameter of 20 nm (15-25)

15. Case 3
 65 years old male, heavily oedematous, SBP 80mmHg,
nephrotic range proteinuria (7g/24H), S Cr 350 umol/l,
S Albumin 1.8 g/L, Urine electrophoresis LLC and BNP
500 pg/ml.
 Kidney Bx:
 LM: eosinophilic infiltrate
 IF : λ LC deposits
 EM: Non branching, randomly scattered, 10-12 fibrils

16. Case 3 (Kidney Bx)

17. Management
 Other Ix:
 -Bone marrow
 -Free light chain
 -Control of B monoclone cells (Melphalan based
therapy/Bortizomib based therapy) followed by BSCT
 -Criteria:
 - Systolic BP>90 mmHg
 -EF>40%
 -NYHA functional class I and II
 -Uncontrolled coronary artery disease or arrhythmia
 -Troponin T < 0.06 and BNP < 5000

18. Screening Algorithm For
Monoclonal Protein

19. Screening Pathways for
Paraproteinaemia

20. Spectrum of Renal Disorders with
Paraproteinaemia

21. 

22. FSGS

23. Case 1
 80 year old gentleman with nephrotic range
proteinuria (urine PCR 480 mg/mmol)
 Serum Albumin 1.9 g/L
 Normotensive, immunology –ve
 Anti PLAR-2 -ve
 Serum urea 17 mmol/l
 Serum Cr 160 umol/l
 Serum Cholesterol 7.8 mmol/l
 US KUB normal kidneys

24. Case 1
Do you need any more information from the biopsy?

25. Case 1
 Treated with ACEI, Statins, and Diuretics
 No response
 Steroids 12 weeks excellent response
 Compression fracture of dorsal vertebra?
 Rapid withdrawal of setroids and added
bisphosphonates!

26. Case 1
 Nephrotic syndrome relapse within few weeks
 Any concern with bisphosphonates?
 Pamidronate, zoledronate, etidronate, ibandronate,
and alendronate
 Denosumab
 Reduced dose, slow infusion rate, avoid zoledronate
likely more nephrotoxic

27. Case 1
Steroid Alternatives
 CNI
 Cyclophosphamide
 Rituximab
 MMF
 Nephrotoxicity
 Relapse on withdrawal
 Some differential response
to CyA versus Tac
 Cytotoxic
 May be effective but no
evidence base
 Screen for ongoing
infection e.g TB
 Better to avoid if steroid
resistant
 Relapse rate is high

28. Case 2
- A 30 years old female presented with nephrotic
syndrome and biopsy revealed tip variant FSGS
- Mum has had ESRD due to unknown aetiology when
she was 23 years old
- Maternal aunt had ESRD and FSGS
- Cousin has kidney transplantation from a deceased
donor

29. Tip Lesion

30. Case 2
 High dose steroid was given for 6 month but no response
 MMF and Cya tried without any effect
 Would Tacrolimus is expected to be of any help?
 Would Rituximab a valuable alternative
 Would cyclophosphamide differ
 Is transplantation an option and if so live versus deceased

31. Case 3
 A 61 years old female presented with a mass right arm,
excised and histology lymphoma
 Did not F/U for further treatment, 6 month later
developed severe nephrotic syndrome and AKI
 Immunology: Rh factor, DsDNA, C3, Cryoglobulins,
serum electrophoresis all unremarkable, HIV and
hepatitis serology negative
 C4 low

32. Histopathology

33. Histopathology

34. Collapsing FSGS
Infection
HIV, CMV, parvovirus B1, pulmonary
TB, leishmaniasis
Autoimmune
Adult Still's disease, lupus-like
syndrome, mixed CT disorder,
cerebral arteritis
Malignancy
Multiple myeloma, acute monoblastic
leukemia, hemophagocytic syndrome
Genetic
Action myoclonus-renal failure
syndrome, mitochondrial cytopathy,
familial, sickle cell disease, MYH9 and
APOL1 gene polymorphisms
Drug exposure
Interferon-alpha, beta, or gamma;
anabolic steroids, pamidronate
Post transplanation
De novo, recurrent, arteriopathy, acute
vascular rejection, thrombotic
microangiopathy

35. Case 4
 18 years old male diagnosed with primary FSGS, did
not respond to treatment (steroids/Cyclophosamide)
and required HD a year later after diagnosis.
 6 Month on dialysis received a live related kidney from
his mum, lost the kidney 9 month later because of
recurrence and failed to respond to treatment
including PEX.

36. Case 4
 Remained on HD for 6 years and received deceased
donor transplant, few month later he developed
recurrence of FSGS on biopsy with extensive foot
process effacement.
 Surprisingly he had a spontaneous remission after 4
month of recurrence.
 15 years he developed another recurrence with acute
onset nephrotic syndrome, serum Cr of 160 umol/l,
serum albumin 2.5 g/L, urine protein 6g/24H

37. Case 4
 A kidney biopsy had 12
glomeruli ,3 of which are
globally sclerotic and 3 show
segmental sclerosis. The
remaining glomeruli range
from normal to mildly
enlarged. IF shows Mesangial
and capillary wall deposits
which stain 1 + for IgM, trace
for C3 and trace for C1q.The
rest of the panel is negative
including C4d in the
peritubular capillaries. EM is
significant for severe foot
process effacement.

38. Case 4
Suggestions
 What in favour of primary versus secondary FSGS
 (acute onset/diffuse foot process effacement, previous
recurrence versus late onset)
 CD80/serum anti-Angiotensin II Receptor antibodies
 Steroids/PEX/ACEI
 Rituximab/ Immunoadsorption (Cytosorb), lipoprotein
apheresis, Abatacept (when B7-1 is positive in glomeruli)
and Natural ACTH. No evidence of any!!!!!

39. Causes of FSGS
De Vriese et al JASN 2018

40. KDIGO Recommendations
 FSGS Types
 1- Primary: caused by as yet unknown permeability factors
 Soluble urokinase plasminogen activator receptor
 Cardiotrophin-like cytokine-1
 Diffuse podocyte effacement and acute onset nephrotic syndrome
 2- Secondary:
 Adaptive: reduced nephron mass
 Infection
 Drugs
 3-Genetic

41. KDIGO Recommendations (2)
 General:
 Adoptive is treatment to lower intraglomerular pressure
(BP control preferably ACEI/ARB)
 Statins
 Genetic:
 Immunosuppression of no use
 Replace the missing factor when applicable ((e.g., coenzyme
Q-10, vitamin B12)
 Primary:
 Immunosuppression:
 Steroids high dose for minimum 16 weeks
 CNI: second line
 MMF: third line

43. Case 1
 27 years old male presented with active urinary
sediment, urine PCR was nephrotic range (854
mg/mmol) serum albumin 2.6 g/L, immunology low
C3 and normal C4, ANA, ANCA, and AGBM–ve.
Kidney Bx as shown.

44. Normal Glomerulus

46. IgG Deposits
Newly Formed Basement Membrane
Red
C3 Deposits

47. Case 2
 78 female admitted with generalized oedema
 11 month earlier serum Cr normal 60 umol/l and urine
was negative for any blood or protein
 8 month earlier prescribed NSAIDs for artharalgia
 6 Weeks earlier serum Cr 101 umol/l and urine PCR
was 0.65 mg/mmol with microscopic haematuria
 NSAIDs stopped and Cr improved to 68 umol/l but
active urinary sediment has not changed
 6 Weeks later admitted with proteinuria of 10 g/24
hour and serum albumin of 26 g/L
 Immunology was negative and BP was high at 150/95
mmHg

48. Bx Findings

50. Case 3
 26 y old male presented with nephrotic range
proteinuria (5g/24H), active urinary sediment, raised
serum creatinine 1.79 umol/l
 Normal haemodynamics
 U/S normal
 Immunology low C3, normal electrophoresis, ANA,
ANCA, HCV and HbsAg –ve
 Bx

51. MPGN with characteristic lobulation on H&E MPGN with characteristic lobulation on H&E
C3 deposition predominance on IF Subendothelial E dense deposition on EM

52. Treatment & Follow Up
 High sMAC (SC5b-9) level of 1965 ng/ml (normal <
245)
 C3 level low and a persistently positive C3 nephritic
factor
 Proteinuria 1 g/24 hour

54. Case 4
 61 years old female presented with non specific
symptoms, LL oedema, AKI with Cr 170 umol/l, urine
PCR is raised to 210 mg/mmol
 O/E haemodynamically was stable
 U/S normal kidneys
 Immunology normal (C3, C4, ANCA, ANA, Hepatitis
serology –ve, anti GBM -ve)

55. Case 4
C3 GBM Deposition
Cellular Crescents
Intramembranous Deposits
Cellular Crescents

56. Outcome of C3 GP with Different
Immunosuppressives
Avasare et al 2018

57. KDIGO Recommendation
 Cause
 Biomarkers
 Abnormal complement
activation, deposition and/or
degradation
 Nephritic factor or single
gene pathogenetic link is
lacking in most cases
 Soluble complement
components unclear to
guide treatment or
prognosis
 Low C3 and +nephritic
factor not uncommon but
not a must
 Growing evidence for MGR
screening

58. KDIGO Recommendation
 Treatment
 Genetic complement
abnormality
 No evidence of genetic
cause
 Post infectious
 MGRS
 Treatment is largely non
specific (inflammation and
proliferation)
 Eculizimab
 MMF + steroids
 Treat infection
 Treatment is directed to
the monoclone

59. Differential Diagnosis
MPGN
MPGN
Type 1 DDD Type III
Subendothelial Intramembranous Subendothelial
& subepithelial
C3G
Negative
Light microscopy
EM
IF C3-positive
Positive PositiveIF immunoglobulin
Light microscopy MPGN
Immunoglobulin
positive
Immunoglobulin
Negative
IF
Classical pathway Alternative pathway:
C3 glomerulopathies
Complement
activation
Infectious Immune
complex
C3 glomerulo
- nephritis
Dense deposit
disease
Neoplastic Other