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Proteinuria and the Nephrotic Syndrome
William Primack MD UNC Division of Nephrology and Hypertension October 4, 2006 No relevant financial disclosures
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“When bubbles settle on the surface of the urine, it indicates disease of the kidneys and that the complaint will be protracted” Hippocrates
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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.
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BP=95/58 mmHg T=37 C RR=26/min P=97/min
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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
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NEPHROTIC SYNDROME PROTEINURIA HYPOALBUMINEMIA HYPERLIPIDEMIA
+/- EDEMA
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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
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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
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Nephrotic Syndrome--Etiology vs. Age
Cameron et al. Am J Kidney Dis 1987; 10:157
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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
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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
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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
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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%
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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
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PROTEINURIA
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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)
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PROTEINURIA 24 HOUR URINE COLLECTION Sources of error
incomplete/inaccurate collection posture/exercise/intercurrent illness
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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)
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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)
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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
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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
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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
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Nephrotic syndrome in childhood Response to 4 weeks of daily steroids
ISKDC
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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
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Nephrotic Syndrome in Childhood Complications (if not in remission)
Infection Spontaneous bacterial peritonitis cellulitis Edema Subpulmonic effusion, gut wall edema genital edema Thombosis Hyperlipidemia
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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
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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
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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
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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
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SSNS—Long term Median 22 y f/u More relapses=more likely adult relapse
No ESRD Ruth. J Pediatr 2005;147:202-7
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Nephrotic Syndrome in Childhood
Cameron et al. Am J Kidney Dis 1987; 10:157
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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
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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”
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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
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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
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NEPHROTIC SYNDROME PRESENTATION FSGS MCNS STEROIDS NO RESPONSE
Late Non-resp BIOPSY Good prognosis Relapses likely FSGS MCNS OTHER IMMUNOSUPPRESSION
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?
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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
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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
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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
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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
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The glomerular Podocyte
Direction of filtration
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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
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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
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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
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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
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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
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