1. Nephrotic Syndrome Deputy Director Dept. of Nephrology
Farid Nakhoul M.D.
Deputy Director
Dept. of Nephrology
Rambam Medical Ctr.
Faculty of Medicine Haifa
Tel: Fax:

2. Structure of the Glomerulus(1)
One of the central function of the kidney is to excrete low molecular weight water-soluble plasma waste products into the urine. Whereas macromolecules the size of albumin and larger are retained. The filtration of plasma occurs in specialized filtration units called Glomeruli.

3. Structure of the Glomerulus(2)
The glomerular filtration barrier consists of the three layers of the capillary wall:
1. The innermost fenestrated vascular endothelium.
2. The GBM: the GBM is regarded as a primary size and charge-selective molecular sieve of the glomerulus . The GBM contains type IV collagen, laminin, nidogen, and proteoglycans as its main components.
3. Podocyte cell layer facing the urinary space.

7. Proteinuria
Is the halmark of glomerular disease !!

8. Clinical Evaluation of Glomerular disease
1. History
2. Physical Examination
3. Laboratory Studies
4. Imaging: Ultrasound
5. Renal Biopsy ( Open, Closed, Laparoscopic).

9. Proteinuria
Asymptomatic Non-nephrotic Proteinuria (<3.5 gr Protein/day).
- Glomerular
- Non-glomerular
Nephrotic Syndrome: Pathognomonic of glomerular disease

10. Non-Nephrotic Proteinuria
Defined as a urine protein excretion of less than 3.5 gr/d, and is absolutely characteristic of glomerular disease, but may occure in many non-glomerular parenchymal disease.

11. Clinical Classification
Isolated Hematuria
Proteinuria / Nephrotic Syndrome
Acute Nephritic Syndrome
Rapidly Progressive Glomerulonephritis
Chronic Glomerulonephritis

12. Clinical Features of Glomerular Diseases
Proteinuria
Hematuria
Edema
Hypertension
Renal Dysfunction

13. Evaluation of Proteinuria – General Practice

15. Quantifying protein excretion
Should perform quantitative measure in persistent proteinuria
24 hour urine collection
Readily quantified
Wide understanding
Cumbersome
Protein-to-creatinine ratio (PCR)
Simple
Validated

16. Nephrotic Syndrome Definition
Urinary protein level exceeding 3.5 gr per 1.73m2 of body-surface area/day.
Hypoalbuminemia.
Sodium retention (Edema-State).
Hyperlipoproteinemia.
Hypercoagulopathy

19. Prognosis Depends upon degree of proteinuria 20 year follow up:
Hypertension in 50%
Renal Insufficiency in 40%

20. Diagnostic Approach 24 urine collection
Serum electrolytes, BUN, creatinine, lipid profile, serum albumin
Serological work up - depends upon the clinical presentation - common serological tests done are ANA; Anti-ds DNA Complement levels (C3, C4) Hepatitis B and C serologies SPEP; UPEP, ANCA, anti GBM Abs
Renal Ultrasound
Renal Biopsy - Indications

21. Nephrotic Syndrome Primary Membranous Glomerulopathy
Focal Segmental Glomerulosclerosis
Minimal Change Disease
Membranoproliferative GN
Secondary Diabetic glomerulosclerosis Paraproteinemia /Amyloidosis
Lupus Nephritis

25. Nephrotic Syndrome Thromboembolic Complications
Major hazard of the nephrotic syndrome
RVT( membranous GN) in 20-30% of adult patients, 10% are symptomatic: flank pain, gross hematuria
Pulmonary emboli(Silent)
DVT(frequent)
Arterial thrombosis is less common
Prophylaxis : Albumin< 2 gr, Uprotein>10 gr/d. decreased level of antithrombin III, Increased fibrinogen, Hypovolemia

27. Nephrotic Syndrome Infections
Decreased levels of immunoglobulin IgG
Decreased the alternative complement factor B
Pneumococcal peritonitis
Recurrent Cellulitis

28. General Management Edema - salt restriction, diuretics
Hyperlipidemia - lipid lowering agents
ACE/ARB -
decrease Pgc and decrease proteinuria
Renal protective
Hypercoagulable - ASA
Specific treatment based on biopsy

31. Minimal Change Disease MCD
Introduction and Definition

32. Minimal Change Disease
Pathogenesis - unknown, most likely autoimmune
Treatment
85% respond to steroids
If resistant to steroid may require cyclophosphamide

33. Minimal Change Nephropathy (MCD)
Minimal change disease (MCD) :is defined by the absence of histologic glomerular abnormality, other than evidence of epithelial cell foot process fusion (EM).

34. Minimal Change Disease MCD
Pathology

36. Minimal Change Disease

37. Nephrotic Syndrome Minimal Change Disease
Is the major cause of the nephrotic syndrome in children(85-90%) and 10% in adults
Malignancies account for 10% of cases of idiopathic nephrotic syndrome in adults
LM: Normal glomeruli
EM: Fusion of the epithelial cell foot Processes ( KNB).

38. Minimal Change Disease MCD
Etiology and Pathogenesis

39. Minimal Change Disease
Idiopathic
Secondary: Malignancy
Drugs
Infections

41. Minimal Change Disease MCD
Clinical manifestations

42. Minimal Change Nephropathy MCD
Patients with Minimal change disease present with edema that develops over a short period of time, with fluid retention exceeding 3% of the body weight.
Up to two-thirds of presentation and relapses follow an infection, most commonly upper respiratory tract infection.

43. Minimal Change Nephropathy
Clinical Feature: Heavy proteinuria, low serum albumin, edema formation and elevated serum cholesterol.
Normal urinary sediment
Normal C3, C4
Negative ANA and Cryoglobulins
MCD patients are at risk of venous thromboembolism.
Hypovolemia and ARF, especially patients with diuretic therapy.

44. Minimal Change Disease
Natural History

45. Minimal Change Disease
There is a tendency for patients with MCD to run a relapsing-remitting course and this is more frequent in children.
Long-term remission can be expected in 75% of initial responders who do not relapse within 6 months.
MCD does not progress to Renal Failure

46. Membranous GN
Definition

47. Membranous Nephropathy(MN)
Membranous Nephropathy is a glomerular disease in which immune deposits of IgG and complement components develop predominantly or exclusively on the subepithelial surface of the glomerular capillary wall.
Deposition is associated with a marked increase in glomerular permeability to protein, which manifest clinically as nephrotic syndrome.
The pathogenesis of human MN is not known.

48. Membranous Nephropathy
ETIOLOGY

49. Membranous Nephropathy
Most common cause of idiopathic nephrotic syndrome in Caucasian adults.
Heavy proteinuria is common. Hypertension and azotemia develops as disease progresses.
Increased incidence of renal vein thrombosis.

50. Membranous nephropathy
2nd most common cause of nephrotic syndrome in adults (~30%)
Usually idiopathic
Associated with
Autoimmune diseases
Hepatitis B
Carcinoma
Drugs (eg penicillamine, captopril, NSAID)
Outcome very variable
1/3 spontaneous remission
1/3 partial remission or very slow progression
1/3 progressive renal impairment
Higher incidence of thromboembolism
Therapy very difficult

51. Membranous Nephropathy
Idiopathic
Secondary GN:
Immunological:
-SLE, MCTD
-Sjogren Syndrome
Rheumatoid Arthritis
Neoplasms:
-Ca of lung
-Ca of breast, Kidney
Non-Hodgin Lymphoma

52. Membranous Nephropathy
Infectious:
-Hepatitis B
-Malaria
-Schistosomiasis
Medications:
-NSAIDs, Gold, Penicillamine
-Capoten

53. Pathology
The pathologic feature of MN evolve from the initial formation of subepithelial immune complexes of IgG and complement.
Initial stage on EM ranging from minimal change with only small deposits( stage 1) through the evolution to thickened basement membrane with resolution of deposits (stage IV).

55. Membranous Nephropathy

56. Membranous Nephropathy
Clinical manifestation

57. Membranous Nephropathy
Is the most common cause of the idiopathic nephrotic syndrome in adults(30-50%)
Nephrotic Syndrome is the common presentation
Hypertension 30%
In children: 50% spontaneous remission, 10% to ESRD
Stage 1 >>>good prognosis
Stage 4>>>>bad Prognosis

58. Membranous Nephropathy
Natural History and Prognosis

59. Membranous GN
The prognosis of untreated MN is somewhat worse in adults: 20% will have progressed to ESRD at 5-10 years followup.
. Bad outcome: male, age>50, HTN, Pcr high at presentation.
Recurrence after Renal Transplantation

60. Membranous Nephropathy
Treatment

61. Treatment
Steroides
Cyclosporine
Imuran
Cyclophosphamide
Chlorambucil

62. Treatment of Membranous Nephropathy
Rule of 1/ /3 – Spontaneous remission 1/3 – Partial remission / slow deterioration
1/3 – Progress to ESRD
Steroids alone are not very effective
Methylprednisolone alternating with chlorambucil, Methylprednisolone alternating with cyclophosphamide.
Cyclosporin

63. Focal Segmental Glomerulosclerosis
Introduction and Definition

64. Focal Segmental Glomerulosclerosis
Etiology and Pathogenesis

65. Focal Segmental Glomerulosclerosis (FSGS)
Primary (Idiopathic)
Secondary:
-Sickle cell disease
-Heroin Nephropathy
-Morbid obesity
-HIV Nephropathy
-Aging Kidney
-Vesico-Ureteral Reflux
- Pamidronate

66. FSGS Most common idiopathic nephrotic syndrome in adults (33%)
Increasing incidence
More common in blacks
Treatment very difficult

67. Focal Segmental Glomerulosclerosis
Most common primary renal disease in African-Americans
Etiology: Idiopathic Drugs – Intravenous heroin Infections – HIV Others – reflux nephropathy, obesity
Patient usually hypertensive. Usually progresses to ESRD over 5-20 years.

68. FSGS
Pathology

69. Focal Segmental Glomerulosclerosis (FSGS)
FSGS is defined on histologic criteria by segmental capillary obliteration with increased mesangial matrix deposition, intracapillary hyaline deposits, and focal adhesions of the capillary tuft to Bowman’s capsule.
Primary FSGS occur in patient with nephrotic syndrome in the absence of any of the known causes of secondary FSGS.

72. FSGS Associations Idiopathic Morbid obesity Heroin abuse HIV infection
Collapsing
Mild
Moderate
Associations
Idiopathic
Morbid obesity
Heroin abuse
HIV infection
NSAID
(Minimal change disease)
Normal

73. FSGS
In FSGS, evidence for a circulating factor is more substantial, mainly based on the high incidence of recurrence following transplantation, with heavy proteinuria developing sometimes within hours.
Plasma exchange can lead to remission in tranplant recurrence of FSGS.

74. FSGS
Clinical Manifestations

75. FSGS
Typically patients present with edema that develops over a short period of time.
Very rapid onset of nephrotic syndrome
Microscopic hematuria 14-30%
Arterial Hypertension especially with renal insufficiency.
Increased incidence pf venous thromboembolism.

76. Focal Segmental Glomerulosclerosis
Microscopic Hematuria
Proteinuria >>20-30 gram/daily
Both children and adults usually develops ESRD 5-20 yrs from presentation.
Idiopathic FSGS may recur in the transplanted kidney with severe proteinuria and Nephrotic Syndrome and rapid course to ESRD.

77. Collapsing FSGS
Collapsing FSGS is a histologic variant of FSGS characterized by extensive focal or global glomerular capillary tuft collapse, podocyte hypertrophy and hyperplasia.
Varying degree of tubulointerstitial injury.
African Americans
Severe nephrotic syndrome at presentation, steroid resistance, and rapid developing ESRD (median time of 13 month).

78. FSGS-Treatment 1mg/kg Prednisone daily for 6 month PO Cyclosporine
Cytotoxic Treatment (Cytoxan, Imuran)
Symptomatic treatment with ACEI
CellCept (Mycophenolate Mofetil).

79. Nephrotic Syndrome Secondary To Systemic Disease
Diabetes Mellitus—Type I, Type II
Amyloidosis

80. Diabetes Mellitus INTRODUCTION

81. Diabetic Nephropathy
Diabetic Nephropathy is a common problem that is most likely to occur in patients who have worse glycemic control, Hypertension, glomerular hyperfiltration, Blacks, Mexican, or Pima Indian.

82. Diabetic Nephropathy
Diabetic nephropathy is a leading cause of end-stage renal disease (ESRD) in Western societies
Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria(>300 mg/24hr or >200ug/min) on at least two occasions separated by 3-6 months.
Patients invariably develop hypertension, progressive increase in proteinuria, and decline in GFR.

83. Diabetic Nephropathy Major Risk Factors For DN
1. Genetic Susceptibility
2. Arterial Hypertension
3. Increased glomerular filtration rate
4. Worse Glycemic Control
5. Blacks, Pima Indian

84. Microalbuminuria
. Increased protein excretion is the earlies clinical finding of diabetic nephropathy.
The normal rate of albumin excretion is less than 20 mg/day; persistent values between 30 and 300 mg/day( 20 to 200 ug/min) in a patient with diabetes is called Microalbuminuria .

85. Microalbuminuria and correlation with DN
Great attention to control of both hyperglycemia and hypertension (with ACEI) may also contribute to the apparent improvement in the course of the disease.
Patient who progress are more likely to have higher HbA1c values and higher blood pressure than non progresses.
The incidence of overt hypertension is approximately 15 to 25 percent in all patients with microalbuminuria and much higher as the patient progress to overt nephropathy.

86. Epidemiology
Type 1 diabetic nephropathy, occur in 30-40% of patients with type 1 diabetes after years with diabetes
In type 2 diabetes, the cumulative incidence of nephropathy is similar to that seen in type 1 , 25% at 20 years after diagnosis.
Since type 2 diabetes is times more common than type 1, the prevalence of type 2 diabetic nephropathy is substantialy higher.

87. Renal Pathology
The kidneys of patients with diabetes are, on average larger than those of nondiabetic control subjects(15%).
Nodular glomerular intercapillary lesions, described by Kimmelsteil and Wilson.
Diffuse glomerular lesion is more frequent than the nodular lesion, with an incidence of over 90% for patients with type 1 DM of over 10 years duration and an incidence of 25-50% in patients with type 2 DM.

88. Diabetic Nephropathy

89. Diabetic Nephropathy
Most common cause of nephrotic syndrome in adults.
Leading cause of ESRD in USA
30% of patients with Type I and 20% of patients with Type II DM develop diabetic nephropathy.
Initially microalbuminuria followed by heavy proteinuria and decline in renal function.
Diagnosis usually made on clinical grounds and biopsy not needed.

90. Clinical Manifestations and Natural History
Diabetic Nephropathy
Clinical Manifestations and Natural History

93. Treatment of Diabetic Nephropathy
Blood glucose control
Control of hypertension
Use of ACE inhibitors/ARBs
Control of hyperlipidemia
Smoking cessation
Protein Restriction

94. Nephrotic Syndrome Secondary To Systemic Disease: Amyloidosis
-Primary Amyloidosis
-Secondary Amyloidosis

95. Amyloidosis
The Amyloidosis are a group of disorders in which soluble proteins aggregate and deposit extracellulary in tissues as insoluble fibrils, causing progressive organ dysfunction. The kidney is one of the most frequent sites of amyloid deposition in AA, AL, and several of the hereditary amyloidoses.

96. Amyloidosis
Amyloidosis is defined by the ability of a variety of proteins to form B-pleated sheets. These fibrils can be identified on biopsy specimens both by their characteristic appearance on electron microscopy and by their ability to bind Congo Red(leading to green birefringence under polarized light) and thioflavine-T (producing an intense yellow-green fluorescence).

98. Amyloidosis Amyloid A in secondary amyloidosis
Immunoglobulin light chains in primary amyloidosis
B2-microglobulin in dialysis-patients associated arthropathy
Amyloid beta protein in Alzheimer’s disease

99. Amyloidosis
Renal involvement occurs in over 90% of patients with either primary or secondary amyloidosis.
Primary forms(> 90%) is a plasma cell dyscrasia and may be associated with MM.
Light Chain Deposition Disease (LCDD) is a disorder of similar pathogenesis. The abnormal protein do not form the B-pleated amyloid fibrils.
Secondary amyloidosis is a consequence of chronic inflammatory diseases such as : Rheumatoid arthritis, FMF, Osteomyelitis, Hypernephroma, PID.

100. Amyloidosis-Secondary
Clinically evident renal involvement occurs only in primary or secondary amyloidosis
Secondary amyloidosis is associated with increased hepatocyte production of the acute phase reactant serum amyloidosis A (SAA); this process may be stimulated by the release of cytokines ( Interleukin-1) from activated macrophages. Cleavage in circulating monocyte/macrophages results in the generation of smaller fragments, called AA protein, that can then deposit in the tissue.

101. Primary Amyloidosis (AL)
The fibrils in AL consist of segments of the variable portions of monoclonal light chains
AL Amyloidosis is a plasma cell dyscrasia in which the malignant characteristic of M.M are usually absent and circulating light chains are frequently demonstrated .
Only a minority of patients who produce an excessive amounts of light-chains (as M.M) develop amyloidosis.
Lambda light-chains are much more likely to produce amyloidosis than Kappa light chains.

102. Dysproteinemia Myeloma Cast Nephropathy
Path shows multiple intraluminal proteinaceous casts
Pathogenesis
Disorder of plasma cells with overproduction the antibody light chain
Treatment
Hydration, plasmapheresis to remove the abnormal protein and chemotherapy to suppress plasma cells

103. Myeloma Cast Nephropathy

104. Light Chain Deposition Disease
Amyloid protein produced in plasma cell dyscrasias is preferentially lamda light chains
Kappa chain can occur and termed light chain deposition disease
Kappa chain deposits tend to deposit in tubules and glomeruli, spare vessels
Kappa more aggressive than lambda

105. Diagnosis Documentation of tissue deposition of amyloid fibrils.
Kidney biopsy> 90% of patients
Abdominal fat pad> 80-90%
Rectal> 50-80%
Gingival>60%
Once the DX of primary amyloidosis is made, the patient should be evaluated for M.M ! ! !

106. Pathology
On light microscopy> >>Diffuse deposition of amorphous hyaline material in the mesangium and then capillary loops.
Amyloid deposition in the glomeruli can result in the formation of nodules.
Congo Red induces green birefringence when viewed under polarized light.
Immunofluorescence for immunoglobulin and complement is negative.

107. Key things to Remember Amyloid is hyaline, eosinophils, Congo Red + Green Birefringence when polarized Small non-branching fibrils on EM

110. Amyloidosis More common in elderly Two main types of renal amyloid
Normal
More common in elderly
Two main types of renal amyloid
AL amyloid
AA amyloid

111. Clinical Presentation
Non-specific symptoms, Fatigue, Weight loss, Anemia
Proteinuria, edema>>>Nephrotic Syndrome
Carpal tunnel syndrome
Peripheral neuropathy
Hepato-Splenomegaly, Macroglossia
Renal insufficiency
Tubular involvement : RTA, NDI, Hyperkalemia

112. Course and Treatment Prognosis depend on type of amyloidosis
MM= bad Prognosis
In primary Amyloidosis usually progress slowly to CRF
Prednisone an Melphalan is the major mode of therapy for primary amyloidosis
Colchicine in AL, AA amyloidosis
In AA the progression depend upon the ability to control the underlying disease.

114. Asymptomatic Non-Nephrotic Proteinuria
Overflow Proteinuria: Multiple Myeloma
-Light Chain
Tubular Proteinuria: Tubulointerstitial dis.
< 2 gr/day
Glomerular proteinuria

115. Treatment
Steroid Treatment induces remission in almost all patients with MCD.
Adults usually biopsied before treatment (KNB).
Controll first volume overload (Diuretics).

116. Treatment
Steroid responsive
Steroid dependent
Frequent relapsers