1. Proteinuria and the Nephrotic Syndrome
William Primack MD
UNC Division of Nephrology and Hypertension
October 4, 2006
No relevant financial disclosures

2. “When bubbles settle on the surface of the urine, it indicates disease of the kidneys and that the complaint will be protracted”
Hippocrates

3. CASE 1 5 y.o. girl CC: eye swelling Dx: Allergic conjunctivitis
Rx given without improvement
About 1 week later abdominal distension noted and brought in for further evaluation.

4. BP=95/58 mmHg
T=37 C
RR=26/min
P=97/min

5. Case 1 Labs U/A 4+ protein, trace heme micro: 1-3 rbc/hpf, 0-1 wbc/hpf
BUN 26 mg/dl, creat 0.5 mg/dl
S albumin<1 g/l, cholesterol 568 mg/dl

6. NEPHROTIC SYNDROME PROTEINURIA HYPOALBUMINEMIA HYPERLIPIDEMIA
+/- EDEMA

7. Nephrotic Syndrome in Children
CONGENITAL
PRIMARY
SECONDARY
Systemic Illness
SLE, HSP, IDDM, obesity
Infections
Hep B, C; HIV, malaria, syphilis, schistosomiasis, parvo B19
Allergy
Bee stings, milk, pork
Exposures
NSAID’s, Penicillamine, gold, ampicillin, heavy metals
Lymphomas, S-S disease

8. Case 1 Labs U/A 4+ protein, trace heme micro: bland
BUN 26 mg/dl, creat 0.5 mg/dl
S albumin<1 g/l, cholesterol 568 mg/dl
C3 complement nl, ANA neg, HbsAg neg, HIV neg

9. Nephrotic Syndrome--Etiology vs. Age
Cameron et al. Am J Kidney Dis 1987; 10:157

10. Case 1 Clinical Course Prednisone 2 mg/kg/day
On day 12 of therapy, urine protein decreased to trace-negative with a prompt vigorous diuresis

12. Nephrotic Syndrome in Children History 1
1484—Roelans
swelling of the whole body of the child
Rx—’Take the tops of the elder plant, and danewort, cook in white wine and wrap the child in hot cloths by applying a poultice…and so cure him.’
1722—Zwinger
Associated generalized edema and kidney
1770—Cotugno
Associated edema and proteinuria
Adapted from: Cameron J, Ulster Med J 54:S5,1985

13. Nephrotic Syndrome in Children History 2
1827 Bright and Bostock
Edema, proteinuria, kidney disease
1940 Introduction antibiotics
1950 Steroids first used
ACTH and later cortisone
1954 Percutaneous renal biopsy
1970 ISKDC
First prospective study of treatment and developed current pathological classification

14. Nephrotic syndrome in children 5 year status in various eras
Pre
antibiotic
Post
Early
steroid
Current
Survival
51%
62%
78%
>95%
Persistent proteinuria
11%
23%
46%
20%
Remission
38%
39%
71%

15. Incidence of Nephrosis in Children
0.8 new cases per year/100,000
6.9 new cases per year/100,000
Children aged 1-9 years
6-15 cases/100,000 ages 1-16
Possibly more frequent in Southern Asians
Rothenberg et al. Pediatrics 1957; 19:446

16. PROTEINURIA

17. PROTEINURIA 24 HOUR URINE Normal <150 mg/24 hours (adult)
<4 mg/M2/hr or <100 mg/M2/day
<150 mg/24 hours (adult)
Nephrotic range
> 40 mg/M2/hr or >1000 mg/M2/day
>2 grams/24 hours (adult)

18. PROTEINURIA 24 HOUR URINE COLLECTION Sources of error
incomplete/inaccurate collection
posture/exercise/intercurrent illness

19. PROTEINURIA URINE PROTEIN TO CREATININE RATIO UProt/UCreat normal
<0.2 mg protein/mg creatinine
nephrotic
>2 mg protein/mg creatinine
some labs report urine protein in micrograms (mcg)

20. Correlation between UProt/UCr and quantitative protein excretion
10,000
1000
100
Total Protein Excretion (mg/m2/day)
R = .93
n = 20
,000
Up/Ucr (g/mg)

21. Orthostatic proteinuria
Proteinuria present only in up-right but not recumbent position
Felt to be benign process
42-50 year follow-up--no increased risk renal disease (Rytand NEJM 305:618,1981)
Measure carefully collected first morning Uprot/creat

22. Nephrotic syndrome in childhood Initial Therapy
2 mg/kg/day prednisone
Controversies
Single or divided dose
Duration of initial therapy
My approach--b.i.d. for 8 weeks
Taper
60% of daily dose q.o.d. x 4 weeks and then fairly rapid taper

23. Nephrotic syndrome in childhood Definitions
Remission
Neg or tr urine protein for 3 consecutive days
Relapse
2 + or > urine protein for 3 consecutive days
Frequent relapser (FRNS)
2 or more relapses in 6 months
Steroid dependent (SDNS)
In remission only when on steroids
Primary non-responder

24. Nephrotic syndrome in childhood Response to 4 weeks of daily steroids
ISKDC

25. Nephrotic syndrome in childhood
10-15% of children < 10 years will be steroid resistant
This percentage increases with age and A.A. ethnicity
About half of those who respond to steroids are FRNS or SDNS

26. Nephrotic Syndrome in Childhood Complications (if not in remission)
Infection
Spontaneous bacterial peritonitis
cellulitis
Edema
Subpulmonic effusion, gut wall edema genital edema
Thombosis
Hyperlipidemia

27. Nephrotic syndrome in childhood
10-15% of children < 10 years will be steroid resistant
This percentage increases with age and A.A. ethnicity
About half of those who respond to steroids are FRNS or SDNS

28. Nephrotic Syndrome in Childhood Complications of Steroid Therapy
Behavior/sleep changes
Weight gain & distribution
“Cushingoid facies”
Striae
Growth arrest
Osteoporosis
Hyperglycemia
Hypertension
Risk of ulcer
Hyperlipidemia

29. Nephrotic Syndrome in Childhood “Steroid Sparing” Medications
If a child with FRNS/SDNS remains steroid responsive, e.g. urine becomes neg or tr with therapy, a biopsy will nearly always show MCNS, indicating good prognosis.
If unacceptable steroid side effects:
Alkylating drugs
Cyclophosphamide, chlorambucil
Calcineurin inhibitors
cyclosporin, tacrolimus
Cell cycle inhibitors
Mycophenolate mofetil (MMF), immuran

30. Nephrotic Syndrome in Childhood Indications for Renal Biopsy
Steroid non-responsive
Primary or secondary
Lower likelihood of MCNS at onset
Older age, A.A., HTN, rbc casts, low C3
Suspicion that NS is secondary
Parental needs
Reticence to use steroids
Need to know before (during) treatment

31. SSNS—Long term Median 22 y f/u More relapses=more likely adult relapse
No ESRD
Ruth. J Pediatr 2005;147:202-7

32. Nephrotic Syndrome in Childhood
Cameron et al. Am J Kidney Dis 1987; 10:157

33. FSGS FOCAL SEGMENTAL GLOMERULO- SCLEROSIS Part of glomerulus damaged
and
SEGMENTAL
GLOMERULO-
SCLEROSIS
Part of glomerulus damaged
Some glomeruli involved, others “minimal change”
Interstitium WNL early
Scarring

35. FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)
Most common non-urologic cause ESRD ages 5-20.
More common in Blacks and Hispanics than Caucasians
May recur post-transplantation
Most pediatric cases are “idiopathic”

36. FSGS Crossover between MCNS and FSGS
Steroid responsive patients with FSGS have much lower incidence of renal insufficiency than steroid resistant patients
Common pathologic end-point for many processes—”secondary FSFS”
Obesity, HIV, V-U reflux, decreased nephron mass

38. PRIMARY FSGS THERAPY ACE and/or ARB to diminish proteinuria
Steroid responsive--?continuum with MCNS
Long term q.o.d. steroids—adults
“Mendoza Protocol”
‘Pulse’ steroids + cyclophosphamide
Cyclosporine
Tacrolimus?
MMF?
ACE and/or ARB to diminish proteinuria
For recurrence post-transplantation
Plasmapheresis + CyA or cyclophosphamide

39. NEPHROTIC SYNDROME PRESENTATION FSGS MCNS STEROIDS NO RESPONSE
Late
Non-resp
BIOPSY
Good prognosis
Relapses likely
FSGS
MCNS
OTHER
IMMUNOSUPPRESSION

40. ?

42. CASE 2--Jessica
7 y.o. girl with 4+ proteinuria at routine PE. No edema. Neg PMH, normal G & D
BUN=14 mg/dl, S cr=0.5 mg/dl
S alb=3.5 g/dl, chol=301 mg/dl
24 hour urine protein=4.6 grams
Normal C3, neg ANA
Prednisone 4 weeks at 2 mg/kg/day, no response
Renal biopsy=FSGS
Cyclophosphamide non-responsive
No further treatment except ACE inhibitor

43. Case 3--The sister, Julie
3-4+ proteinuria found at age 5 (by her mother) with dip sticks given test her sister, Jessica’s, urine
Normal PE, BP 92/58
U/A=3+ protein, occasional rbc
24 hr U protein= 1.7 g
S creat=0.5 mg/dl, S alb=3.9 g/dl
Biopsy=FSGS
Therapy--ACE inhibitor only
Menarche age 11

44. Jessica (cont)
Primary amenorrhea age 16
Urine prot/cr=6.7, s cr=1.0 mg/dl
Tanner 2 breasts, unambiguous female Tanner III genitalia
Very high gonadotropins
Karyotype 46 XY
SRY present by FISH
Surgical evaluation showed streak gonads with several adenomas, small uterus
No evidence of kidney tumor
Begun on replacement estrogen/progestin

45. FRASIER SYNDOME
Proteinuria in a phenotypically normal female, FSGS, renal insufficiency by adolescence or young adulthood
Normal female external genitalia, primary amennorhea
Streak gonads, XY karyotype (with normal sex determining gene, SRY)
gonadoblastoma, but no reported Wilm’s tumor

46. Wilms Tumor Suppressor Gene--WT1
Chromosome 11p13
Expression peaks during embryogenesis, especially in meso- and metanephros.
Persistent expression in mature podocytes suggests WT1 necessary for terminal differentiation and proper function
WT1 knock out mice lack kidneys or gonads
Both girls have a mutation at exon 9 of WT1

50. The glomerular Podocyte
Direction of filtration

51. FIGURE 1. Renal glomerular filtration system Each human kidney contains ~1,000,000 glomeruli
Tryggvason, K. et al. Physiology 2005;20:96-101
Copyright ©2005 American Physiological Society

55. Modified from: Curr Opin Genet Dev 2001; 11:322
Urinary space
Podocyte foot process
Direction of
filtration
Nephrin
F-actin
Podocin
Slit diaphragm made of nephrin molecules from two opposite foot processes
GBM
-actinin-4
CD2AP
Endothelial cell
Modified from: Curr Opin Genet Dev 2001; 11:322

56. GENETIC ETIOLOGIES Nephrotic syndrome
CHILDHOOD ONSET
WT1 Frasier syndrome—AD
Denys-Drash Syndrome
PAX-2 (Renal Coloboma syndrome--AR)
NPHS1 (nephrin--congenital nephrotic syndrome Finnish type--AR)
NPHS2 (podocin--AR)
ADULT ONSET
19q13 (alpha-actinin--AD)
TRPC-6--AD

57. Podocin—NPHS-2
In Europe, accounts for ~ 50% familial NS and 8-20% sporadic SRNS
Most patients have FSGS
Most present first decade
More than 50 mutations identified
Most do not respond to immunosuppressives
Heterozygote carriers generally unaffected

58. NEPHROTIC SYNDROME PRESENTATION FSGS MCNS STEROIDS NO RESPONSE
Late
Non-resp
BIOPSY
Good prognosis
Relapses likely
FSGS
MCNS
OTHER
?GENETIC SCREENING?
neg
IMMUNOSUPPRESSION
Wt-1
NPHS2
SYMPTOMATIC Rx ONLY