Proteinuria and the Nephrotic Syndrome

William Primack MDUNC 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

• 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 1Labs

• 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 1Labs

• U/A 4+ protein, trace hememicro: 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 1Clinical 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 ChildrenHistory 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 ChildrenHistory 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 children5 year status in various eras

Pre

antibiotic

Post

antibiotic

Early

steroid

Current

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

• 6-15 cases/100,000 ages 1-16– Possibly more frequent in Southern Asians

Rothenberg et al. Pediatrics 1957; 19:446

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

100 1000 10,000 Up/Ucr (g/mg)

To

tal

Pro

tein

Exc

reti

on

(m

g/m

2 /d

ay)

10,000

1000

100R = .93

n = 20

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 childhoodInitial 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 childhoodDefinitions

• 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 ChildhoodComplications (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 ChildhoodComplications of Steroid Therapy

• 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 ChildhoodIndications 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

Cameron et al. Am J Kidney Dis 1987; 10:157

FSGSFSGS FOCALFOCAL

andand

SEGMENTALSEGMENTAL

GLOMERULO-GLOMERULO- SCLEROSISSCLEROSIS

Part of glomerulus Part of glomerulus damageddamaged

Some glomeruli Some glomeruli involved, others involved, others “minimal change”“minimal change”

Interstitium WNL earlyInterstitium WNL early ScarringScarring

FOCAL SEGMENTAL FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS)GLOMERULOSCLEROSIS (FSGS)

Most common non-urologic cause ESRD Most common non-urologic cause ESRD ages 5-20.ages 5-20.More common in Blacks and Hispanics More common in Blacks and Hispanics than Caucasiansthan CaucasiansMay recur post-transplantationMay recur post-transplantationMost pediatric cases are “idiopathic”Most pediatric cases are “idiopathic”

FSGSFSGS

Crossover between MCNS and FSGSCrossover between MCNS and FSGSSteroid responsive patients with FSGS Steroid responsive patients with FSGS have much lower incidence of renal have much lower incidence of renal insufficiency than steroid resistant patientsinsufficiency than steroid resistant patients

Common pathologic end-point for many Common pathologic end-point for many processes—”secondary FSFS”processes—”secondary FSFS”– Obesity, HIV, V-U reflux, decreased nephron Obesity, HIV, V-U reflux, decreased nephron

massmass

PRIMARY FSGSPRIMARY FSGSTHERAPYTHERAPY

Steroid responsive--?continuum with MCNSSteroid responsive--?continuum with MCNSLong term q.o.d. steroids—adultsLong term q.o.d. steroids—adults““Mendoza Protocol”Mendoza Protocol”– ‘‘Pulse’ steroids + cyclophosphamidePulse’ steroids + cyclophosphamideCyclosporineCyclosporineTacrolimus?Tacrolimus?MMF?MMF?

ACE and/or ARB to diminish proteinuriaACE and/or ARB to diminish proteinuriaFor recurrence post-transplantationFor recurrence post-transplantation– Plasmapheresis + CyA or cyclophosphamidePlasmapheresis + CyA or cyclophosphamide

NEPHROTIC SYNDROMEPRESENTATION

STEROIDS

RESPONSE

Good prognosisRelapses likely

NO RESPONSE

BIOPSY

FSGSMCNS

OTHER

IMMUNOSUPPRESSION

LateNon-resp

?

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

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

Glomerular basement membrane (GBM)

Epithelial cell foot processes

Endothelial cell with fenestrations

Protein

The glomerular Podocyte

Direction of filtration

Copyright ©2005 American Physiological Society

Tryggvason, K. et al. Physiology 2005;20:96-101

FIGURE 1. Renal glomerular filtration system Each human kidney contains ~1,000,000 glomeruli

Minimal Change Glomerulopathy Electron Microscopy

Normal Foot process effacement

Modified from: Curr Opin Genet Dev 2001; 11:322

Podocyte foot process

Endothelial cell

Direction offiltration

CD2AP-actinin-4

GBM

Urinary space

Slit diaphragm made of nephrin molecules from two opposite foot processes

F-actin Podocin Nephrin

GENETIC ETIOLOGIES GENETIC ETIOLOGIES Nephrotic syndromeNephrotic syndrome

CHILDHOOD ONSETCHILDHOOD ONSET– WT1WT1 Frasier syndrome—AD Frasier syndrome—AD

Denys-Drash SyndromeDenys-Drash Syndrome– PAX-2 PAX-2 (Renal Coloboma syndrome--AR) (Renal Coloboma syndrome--AR)– NPHS1NPHS1 (nephrin--congenital nephrotic syndrome (nephrin--congenital nephrotic syndrome

Finnish type--AR)Finnish type--AR)– NPHS2NPHS2 (podocin--AR) (podocin--AR)

ADULT ONSETADULT ONSET– 19q1319q13 (alpha-actinin--AD) (alpha-actinin--AD)– TRPC-6TRPC-6--AD--AD

Podocin—NPHS-2Podocin—NPHS-2

In Europe, accounts for ~ 50% familial NS In Europe, accounts for ~ 50% familial NS and 8-20% sporadic SRNSand 8-20% sporadic SRNS

Most patients have FSGSMost patients have FSGS

Most present first decadeMost present first decade

More than 50 mutations identifiedMore than 50 mutations identified

Most do not respond to immunosuppressivesMost do not respond to immunosuppressives

Heterozygote carriers generally unaffectedHeterozygote carriers generally unaffected

NEPHROTIC SYNDROMEPRESENTATION

STEROIDS

RESPONSE

Good prognosisRelapses likely

NO RESPONSE

BIOPSY

FSGSMCNS

OTHER

?GENETIC SCREENING?

IMMUNOSUPPRESSION

neg

LateNon-resp

SYMPTOMATIC Rx ONLY

NPHS2Wt-1