Transcript Slide 1

Proteinuria and the Nephrotic
Syndrome
William Primack MD
UNC Division of Nephrology and Hypertension
October 4, 2006
No relevant financial disclosures
“When bubbles settle on the
surface of the urine, it indicates
disease of the kidneys and that
the complaint will be protracted”
Hippocrates
CASE 1
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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.
BP=95/58 mmHg
T=37 C
RR=26/min
P=97/min
Case 1
Labs
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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
NEPHROTIC SYNDROME
PROTEINURIA
HYPOALBUMINEMIA
HYPERLIPIDEMIA
+/- EDEMA
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
Case 1
Labs
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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
Nephrotic Syndrome--Etiology vs. Age
Cameron et al. Am J Kidney Dis 1987; 10:157
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
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
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
Nephrotic syndrome in children
5 year status in various eras
Pre
Post
Early Current
antibiotic antibiotic steroid
Survival
51%
62%
78%
>95%
Persistent
proteinuria
11%
23%
46%
20%
Remission
38%
39%
39%
71%
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
Rothenberg et al. Pediatrics 1957; 19:446
• 6-15 cases/100,000 ages 1-16
– Possibly more frequent in Southern Asians
PROTEINURIA
PROTEINURIA
• 24 HOUR URINE
– Normal
• <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)
PROTEINURIA
• 24 HOUR URINE COLLECTION
– Sources of error
• incomplete/inaccurate collection
• posture/exercise/intercurrent illness
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)
Correlation between UProt/UCr and
quantitative protein excretion
Total Protein Excretion (mg/m2/day)
10,000
1000
R = .93
100
n = 20
100
1000
Up/Ucr (g/mg)
10,000
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
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
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
Nephrotic syndrome in childhood
Response to 4 weeks of daily steroids
ISKDC
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
Nephrotic Syndrome in Childhood
Complications (if not in remission)
• Infection
– Spontaneous bacterial peritonitis
– cellulitis
• Edema
– Subpulmonic effusion, gut wall edema
genital edema
• Thombosis
• Hyperlipidemia
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
Nephrotic Syndrome in Childhood
Complications of Steroid Therapy
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Behavior/sleep changes
Weight gain & distribution
“Cushingoid facies”
Striae
Growth arrest
Osteoporosis
Hyperglycemia
Hypertension
Risk of ulcer
Hyperlipidemia
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
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
SSNS—Long term
Median 22 y f/u
More relapses=more
likely adult relapse
No ESRD
Ruth. J Pediatr 2005;147:202-7
Nephrotic Syndrome in Childhood
FSGS
 FOCAL
and
 SEGMENTAL
 GLOMERULO SCLEROSIS
 Part of glomerulus
damaged
 Some glomeruli
involved, others
“minimal change”
 Interstitium WNL early
 Scarring
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”
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
PRIMARY FSGS
THERAPY
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
NEPHROTIC SYNDROME
PRESENTATION
STEROIDS
RESPONSE
NO RESPONSE
Late
Non-resp
Good prognosis
Relapses likely
BIOPSY
FSGS
MCNS
OTHER
IMMUNOSUPPRESSION
?
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
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
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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
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
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
Normal Glomerular Capillary
Glomerular Barriers to Proteinuria
Endothelial
cell with
fenestrations
Protein
Glomerular basement
membrane (GBM)
Epithelial
cell foot
processes
The glomerular Podocyte
Direction
of
filtration
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
Minimal Change Glomerulopathy
Electron Microscopy
Normal
Foot process effacement
Urinary space
Podocyte foot process
Direction of
filtration
Nephrin
F-actin
Podocin
GBM
-actinin-4
Endothelial cell
CD2AP
Slit diaphragm
made of nephrin
molecules from
two opposite foot
processes
Modified from: Curr Opin Genet Dev 2001; 11:322
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
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
NEPHROTIC SYNDROME
PRESENTATION
STEROIDS
NO RESPONSE
RESPONSE
Late
Non-resp
Good prognosis
Relapses likely
BIOPSY
FSGS
MCNS
?GENETIC SCREENING?
Wt-1
NPHS2
SYMPTOMATIC Rx ONLY
OTHER
neg
IMMUNOSUPPRESSION