1. NEPHROTIC SYNDROME
Nephrotic range proteinuria, (>40mg/m2/hour), (> 50mg/kg/day), urine to protein creat ratio (>2mg/mg), +3-4 on dipstick
Hypoalbumenia (<2.5g/dl)
Hyperlipidemia
edema
Prevelance 2/100000
M:F 2:1, 80% <6 years

2. ETIOLOGY
Primary or idiopathic(MCD,FSGS,Membranous,MPGN,Mesangial proliferation)
Congenital nephrotic syndrome (first 3months) due TORCH,Finish type
Secondary to infections,systemic diseases (HSP,SLE)

3. Pathogenesis Pathophysiolgy
Defect in GBM,slit diaphram,genetic mutations in nephrin,podocin
Circulating factor,cytokine VPF explains early recurrence
Immunological abnormality,T cell dysfunction,ass with Hodgkin lymphoma
Pathophysiolgy
Decrease Intravascular volume,urine Na <20
Increased intravascular volume

4. Podocytes and the slit diaphragm
The glomerular filtration barrier separates the bloodstream from the urinary space
It forms a filter, which selects molecules according to size, shape and charge
Molecules the size of albumin and larger are retained, whereas water and small plasma solutes pass into the urinary space
The filtration barrier comprises 3 layers: the fenestrated capillary endothelium, the glomerular basement membrane (GBM) and the podocyte layer
Podocyte cell bodies are in the urinary space and extend processes towards the capillary loop
These primary processes divide into terminal foot processes that interdigitate and cover the outside of the GBM
Between the foot processes is the slit diaphragm which has multiple functions including action as a filtration barrier 4

5. Figure 13-2 Schema of a podocyte foot process cross section depicting important components involved in hereditary nephrotic syndrome.

6. Figure 12-2 Underfill hypothesis of edema formation in nephrotic syndrome. Proposed sequence of pathophysiologic events leading to the formation of edema in nephrotic syndrome according to the underfill hypothesis. Some authors have suggested that the underfill hypothesis is seen more in human clinical disease, whereas the overfill hypothesis is seen more in animal models of nephrosis. ADH, Antidiuretic hormone; ANP, atrial natriuretic peptide; RAAS, renin angiotensin aldosterone system; SNS, sympathetic nervous system. (From Schrier RW, Fassett RG: A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome, Kidney Int 53 (5): , 1998.)

7. Figure 12-3 Overfill hypothesis of edema formation in nephrotic syndrome. Shown is the proposed sequence of pathophysiologic events leading to the formation of edema in nephrotic syndrome according to the overfill hypothesis. Some authors have suggested that the overfill hypothesis is seen more in animal models of nephrosis than in the human clinical setting. ANP, Atrial natriuretic peptide. (From Schrier RW, Fassett RG: A critique of the overfill hypothesis of sodium and water retention in the nephrotic syndrome, Kidney Int 53 (5): , 1998.)

8. Histopathology
MCD:normal LM,neg IF,EM effacement of foot processes of podocytes
Mesangial proliferative,IgM nephropathy:positive IgM,C3 on IF
FSGS:juxtamedullary glomeruli
Most common is MCD.
80% of MCD were ≤6y,compared to 50% of FSGS

9. NORMAL
Figure 15-1 The glomerulus appears normal to light microscopic examination, with normal mesangial matrix and cellularity. Capillary loops are dilated with normal thin capillary walls. (H&E stain, ×400)

10. Figure 15-3 The glomerulus shows increased numbers of mesangial cells with mildly increased matrix. The capillary loops appear normal. (H&E stain, ×400)

11. Moderate FSGS
Moderate FGS
                                                

12. Figure 16-2A Histologies of renal biopsies of patients with steroid-resistant nephrotic syndrome. A, Histomorphology of FSGS NOS in a 9-year-old patient. Two glomeruli with segmental sclerosis. The right glomerulus with a recently sclerosed segment with foamy matrix at 3 o’clock, and the left glomerulus with a more mature, dense segmental sclerosis at 9 o’clock to 1 o’clock . PAS, original magnification ×200. B, Histomorphology of tip-lesion variant FSGS in a 19-year-old patient. The sclerosed glomerular segment at the 6 o’clock position is situated directly at the glomerulotubular junction. PAS, original magnification ×400. C, Histomorphology of diffuse mesangial sclerosis in Denys-Drash syndrome in a 12-year-old male patient. Mesangial proliferation with a slightly nodular appearance. PAS, original magnification ×400.

13. History and examination
Periorbital swelling mistaken as allergy
Increase in weight,abdominal distention ascitis
Scrotal and sacral edema,pleural effusion
Abdominal pain due to hypovolemia,peritonitis
Decrease in urine output
Symptoms preceded by URTI
Blood pressure normal or high

14. Laboratory investigation
Electrolytes: low Na,low albumin and calcium
ANA,C3,C4,hepatitis B,C
Hemoglobin high,platlet high
Urine Na less than 10
Urine analysis: proteinuria,microscopic hematuria
Urine protein/creatinine more than 2 mg/mg
Elevated cholesterol and triglycerides

15. Periorbital oedema in a child with nephrotic syndrome
This child has periorbital oedema due to nephrotic syndrome. The facial swelling is often mistaken for conjunctivitis or an allergy so the children are treated for these conditions before the urine is tested and it is noted that the child has oedema elsewhere.
Nephrotic syndrome in children is most commonly due to minimal change disease (ie the glomeruli appear normal on microscopy). Most children respond to treatment with corticosteroids though 75% or more will have one or more relapses. The majority grow out of the condition by their teens and their renal function remains normal. Failure to respond to steroids is an indication for renal biopsy.

17. Course and outcome 93 % of MCD respond to steriods by 4 weeks.
30% single episode,70% relapse
35-50% frequent relapses
Long term:80 % have complete remission by 8 years.
SRNS can progress to CKD

18. CLASSIFICATION
DEFINTION
REMISSION
Urine prot <4mg/m2/hour,urine prot/creat <.2 mg/mg, 0 on dipstick for 3 days
STERIOD RESISTANCE
Failure to respond after initial 4-8 weeks of steroids
RELAPSE
Urine prot >40mg/m2/hour,urine prot/creat >2mg/mg,+3 prot on dipstick for 3 days or edema
INFREQUENT RELAPSE
1 relapse in 6 months,1 to 3 in 12 months
FREQUENT RELAPSE
2 or more relapse in 6 months,4 or more in 12 months
STERIOD DEPENDANT
Two consecutive relapses during steroid therapy or within 14 days of ceasing therapy

19. When a renal biobsy is done
Age less than 1.
SRNS
ARF
Gross or persistent microscopic hematuria
Biobsy sent for LM,IF,EM

20. TREATMENT
First episode :Steriods 2mg/kg/day,60 mg/m2/day single daily dose for 4 weeks,followed by alternate dose for 3-6 months.
Response in 10 to 14 days
Recent Cockrane metaanalysis found that treatment for 3m compared to 2m reduces risk of relapse by 30% at 12-24m
No significant diff in risk of side effects or cumulative steriod dose
With each 1 m over 2m,RR of relapse falls by 11%

22. Treatment of relapses:2mg/kg/day till remission for 3 days,then alternate days for 2-3m.
Treatment of FR or SD SSNS:
1.Long alternate steriods for m
2.Cyclophosphamide
3.cyclosporine
4.Levimazole
5.Mycophenolate acetate

23. Side effects Steriods:growth,osteopenia,cataract,cushingoid,glaucoma
Cyclosporine:hirsuitism,gum hypertrophy,HTN,reduced GFR
CPM:infertility,alopecia,leucopenia,hemmrhagic cystitis.
MMF:abdominal pain,anemia,leucopenia

24. COMPLICATIONS
1-Infections:losses of IgG in urine,abn T cell function,low factor B (C3 proactivator),steriod use,impaired opsonization
Encapsulated bact streptococcus pneumonia,staph,Ecoli
Primary bacterial peritonitis
Immunization against pneumococcus,varicella

25. 2-Thromboembolism:inc clotting factors,fibrinogen,low AT3,plat aggreg,hyperviscosioty
Venous,RVT,sagital sinus,veins of legs
3.ARF

26. Supportive treatment Salt restriction
Albumin 25% 1-2g/kg/day over 4 hours with frusemide
ACEI decrease proteinuria in SRNS

27. CNS Finish Type
AR,Mutation in nephrin gene,codes for nephrin part of slit diaphragm
Two mutations (Finmaj,Finminor)
Born premature,large placenta
Edema at birth,severe proteinuria, very low albumin
High amnoitic AFP
GFR normal first 6-12m

30. Diffuse Mesangial Sclerosis
AD,isolated or Denys-Drash (wilms tumor,male pseudohermaphrodite)
Proteinuria in first 3m or later in infancy,less severe than CNS
ESRD months after presentation
Mesangial sclerosis,interstitial fibrosis
Mutations of WT1

31. Treatment No role for steriods Albumin infusions
Nutrition:130kcal/kg,4g/kg protein
Hypothyroidism
ACEI
Indomethacin
diuertics
Anticoagulants,prophylactic pencillin
Nephrectomy,dialysis,tranplantation

32. Hereditary nephrotic syndrome
Disease
inheritance
locus
gene
protein
Denys-Drash
DMS AD 11
WT1
CNS,Finish AR 19
NPHS1
nephrin
Familial SRNS, 1
NPHS2
podocin
pierson 3
LAMB2
laminin
FSGS1(late)
ACTN4
Actinin
FSGS2
TRPC6

33. SRNS Mostly FSGS,genetic forms,immune mediated recur after Tx
Cyclosporine better than cyclophospamide
ACEI,diuertic to control edema.
rituximab