OfficeNephrology Walker

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Office Nephrology : 

Office Nephrology Chair: Paul Roy

Management Of Proteinuria : 

Management Of Proteinuria Amanda Walker Chair: Paul Roy

Office management of proteinuria in children: 

Office management of proteinuria in children Dr. Amanda M. Walker Paediatric Renal & Continence Service, Monash Medical Centre Melbourne

What are the proteins in urine?: 

What are the proteins in urine? Plasma proteins Renal tissue enzymes antigens tubular secretions

Proteinuria - plasma proteins (Albumin): 

Proteinuria - plasma proteins (Albumin)

Mechanisms of Albuminuria: 

Mechanisms of Albuminuria Altered filtration Glom haemodynamics Incr intraglom blood flow or pressure Glom pathology Reduced filtration barrier (size & charge) Altered reabsorption Prox conv tubule pathol Combination

Selectivity index: 

Selectivity index Selectivity index = u IgG x s Tf s IgG u Tf Albumin 66,000 Transferrin 90,000 IgG 160,000 ≤0.10 highly selective ≥0.11 ≤0.20 mod selective ≥0.21 poorly selective May have prognostic signif with nephrotic syndrome response & progression to ESRF (Bazzi et al., Kidney Int, 2000, 58, 1732)

Effect of proteinuria: 

Effect of proteinuria Tubular cell culture Proteinuria Stim inflamm mediators Endothelin-1 Monocyte chemottractive protein (MCP-1) Bazzi et al., Kidney Int, 2000, 58, 1732

Proteinuria - tubular proteins: 

Proteinuria - tubular proteins

LMW proteins - tubular pathology: 

Normal values (spot) Lysozyme (10 – 66mg/mol Cr) ß2 microglobulin (6 – 41 mg/molCr) RBP (<1 – 24 mg/mol Cr) LMW proteins - tubular pathology LMWP <40,000 Daltons Freely filtered by glom; 99.9% reabsorbed - prox tubule Catabolized by tubular lysosomes Sensitive marker for tubular pathology i.e. small dec prox tub fx ---- large incr LMWP (Pediatric Nephrology, 1994 ed Holliday, Barratt & Avner 403)

Tubular proteinuria: 

Tubular proteinuria

Summary of proteins found in urine: 

Summary of proteins found in urine Alb /transferrin/ IgG glomerular filtration/ prox tubule Retinol Binding Protein/amino acids prox tubular dysfunction (reabsorption)  1 microglobulin / NAG prox tubular necrosis/damage

Detection of proteinuria: 

Detection of proteinuria extremely sensitive albumin (as it contains the most amino groups), much less sensitive globulins insensitive Bence-Jones proteins. amino groups in proteins bind and alter the colour of pH indicator (tetra-bromophenol blue) even though the pH is unchanged.

False negatives and positives on FWT: 

False negatives and positives on FWT Screening FWT +++/++++ >1gm/m2/day pos predictive value of 89% 0/trace <0.1g/m2/day neg predictive value 60% Improved with automated colour reading Abitbol, J Ped, 1990,116(2),243 false positive radiographic contrast media, low pH false negative high urinary conc of penicillin, sulphonamides high pH, moving urine, dilute urine

Quantification of proteinuria: 

Quantification of proteinuria 24 hour protein excretion N <150 mg/day Timed urine collection Total protein Albumin Urinary Pr:Cr ratio

Proteinuria – normal values: 

145 mg/ m2/day 110 mg/ m2/day 85 mg/ m2/day 150 mg/day Proteinuria – normal values 2 – 10 yrs Wingo & Clapp, 2000,AmJ Med Sci, 320, 188;

Proteinuria – normal values: 

Proteinuria – normal values Relatively constant after 12 months of age < 4mg/m2/hr or <100 mg/ m2 /24 hr Nephrotic range proteinuria > 40mg/ m2 /hr overnight sample (ISKDC) 1.7g/24 hr for adults Suggested 3.5g/1.73 m2 /day (80mg/ m2 /hr) Glassock, 1988 in Cameron, JS Glassock RJ (ed) The Nephrotic syndrome, 219

Urinary Pr:Cr ratio: 

Urinary Pr:Cr ratio High correlation b’t timed urine collections & U Pr:Cr ratio UCr excretion stable Comparison 1st am sample & 24hr/overnight R= 0.81 - 0.99 (>11 studies - CARI draft guidelines) U Pr:Cr < 20 - 25mg/mmol  <4mg/m2/hr <2 yr old N < 50mg/mmol Nephrotic range U Pr:Cr 200 - 250 mg/mmol

Urinary Alb:Cr ratio: 

Urinary Alb:Cr ratio Good for detection of glomerular pathology, miss tubular proteinuria More expensive, N range less well defined for children MicroAlbUria  U Alb:Cr >2.5 mg/mmol Proteinuria  U Alb:Cr >30 mg/mmol UAlb:Cr Diabetics, known glomerular disease


Ringsrud & Linne, 1995 Urinalysis & body fluids, Mosby

Classification of isolated proteinuria: 

Classification of isolated proteinuria Character (intermittent/ constant) Posture (orthostatic/ non – ortho) Quantity (non- nephrotic / nephrotic)

Transient proteinuria: 

Transient proteinuria Common children, adolescents & adults Fever, exercise, extreme cold, Adrenaline admin, CCF, seizures Asymptomatic usu screening abn Normal urinary sediment Resolves spontaneously Repeat sample 2 -3 times before Ix Hogg et al., 2000, Pediatrics, 105, 1242

Idiopathic intermittent proteinuria: 

Idiopathic intermittent proteinuria Proteinuria independent of body posture in most (>50%) but not all random urine samples Usu <30 yrs old , N renal function & N BP Renal Bx of 51 pts 40% normal/ min histological change 60% variety of lesions Glom hypercellularity and sclerosis No em studies done, no clinicopath correlations Benign prognosis if proteinuria resolves over a few years

Orthostatic proteinuria: 

Orthostatic proteinuria Definition: absence of proteinuria during recumbency and its appearance during quiet upright ambulation or standing Transient (80%) not well studied Persistent (20%) Sinniah et al., 1977, Clin Nephrol, 7,1

Orthostatic proteinuria: 

Orthostatic proteinuria 60% proteinuria in childhood 75% proteinuria in adolescents Rare >30 yrs old Rarely >1g/m2/day Dodge et al 1976, J Pediatr, 88, 327 Hogg et al., 2000, Pediatrics, 105, 1242

Orthostatic proteinuria: 

Orthostatic proteinuria ?normal variant Postural changes in protein excretion seen with N pop’n 20% of 120 N volunteers (<150 mg/day) incr protein excretion when upright Mahurkar et al, Br Med J, 1975,1, 712 116 adolescents Incr U Pr:Cr in upright position Houser et al., 1986, J Pediatr, 109, 556

Orthostatic proteinuria ?glomerular abnormality: 

Orthostatic proteinuria ?glomerular abnormality Bx - N or Mild focal and segmental mesangial hypercellularity Focal or diffuse capillary wall thickening Occ focal foot process fusion Mesangial & capillary deposits C3, IgG Sinnah et al, 1977, Clin Nephrol, 7,1-14

Orthostatic proteinuria ?haemodynamic abnormality: 

Orthostatic proteinuria ?haemodynamic abnormality Upright position Venous pooling in legs Renal vein congestion Decr renal blood flow (incr Ang II) Incr efferent arteriolar resistance Incr proteinuria

Orthostatic proteinuria ?Nutcracker phenomenom: 

Orthostatic proteinuria ?Nutcracker phenomenom Entrapment of L renal vein bt Aorta & sup mesenteric artery L flank pain, macrohaem, peripelvic & ureteric varices Isolated orthostatic proteinuria

Orthostatic proteinuria ?Nutcracker phenomenon: 

Orthostatic proteinuria ?Nutcracker phenomenon Cho et al, 2001, Nephrol Dial Transplant, 16,1620 1997 - 1999, Seoul 6 - 16 yrs 39 orthostatic proteinuria 22/39 (54%) +ve 28 control 0/28 +ve Renal venography (gold standard) Doppler U/s AP diameter L renal vein Peak LRV velocities Renal hilum As passes bt Ao & SMA Ratio >5 = highly suggestive

Orthostatic proteinuria prognosis: 

Orthostatic proteinuria prognosis 20 yrs 43 pts orthostatic proteinuria 85% no proteinuria No deterioration in renal function Springberg et al.,1982, Ann Intern Med., 97, 516 6 pts Dx orthostatic proteinuria 42 -50 yrs earlier Resolution of proteinuria, N renal fx Rytand,1981, N Eng J Med., 305, 618

Persistent isolated proteinuria: 

Persistent isolated proteinuria X’s in upright & recumbent position Male predominance Structural disease Tendency to progress

Causes of constant proteinuria: 

Causes of constant proteinuria Early glomerular disease FSGS (primary or secondary), IgA nephropathy Essential hypertension Early diabetic nephropathy Membranous GN Overflow proteinuria Low molecular weight proteins (myoglobin, Hb, a.a.) Tubular proteinuria

Investigation of proteinuria: 

Investigation of proteinuria Personal & family Hx of renal disease Thorough examination include BP, growth Urine M & C (?haematuria) U Pr:Cr (Early morning and late evening) Timed urine collection Serum biochem, (include Alb, TPr, lipids) Imaging (Ultrasound ± Doppler, DMSA) Renal Bx

Management of isolated proteinuria: 

Management of isolated proteinuria Transient Nil i.e. discharge Orthostatic (<1g/m2/day; N AM UPr:Cr) Intermittent review, early AM UPr:Cr Persistent Define disease Monitor for  proteinuria,  GFR, HPT

Progression of persistent proteinuria: 

Progression of persistent proteinuria

Persistent proteinuria: 

Persistent proteinuria  proteinuria,  GFR, HPT Consideration for ACEI Reduce proteinuria Delays progression of CRF in adults with Chronic nephropathies & >2g/day proteinuria and/or HPT (REIN study; Ruggenenti et al, AmJKD,2000, 35, 1155)

Office management of proteinuria: 

Office management of proteinuria Detect and define the pattern of isolated protein loss FWT will not detect all proteins Intermittent and low grade - good Px Persistent or mod grade - closer evaluation disease definition more guarded Px

Proteinuria in children: 

Proteinuria in children Positive (+) protein on first morning urine by dip-stick Preschool children (age 4.5 yrs) in South Aus 23/9355 children (0.25%) 7/23 children (+) on retesting Hogg et al., 1998, J Paediatr Child Health, 34, 420 School aged children 4 urine samples 1 of 4 (+) protein in 10.7% children, 0.1% 4/4 Vehaskari et al., 1982, J Pediatr, 101, 661

Prevalence of proteinuria: 

Prevalence of proteinuria Taiwan screening program 10,288,620 elementary & junior high school students 1992 - 1996 4 yr prevalence of (++) proteinuria Girls Lowest at 7 yrs 3.48 x 10-4 Peak at 12 yrs at 10.02 x 104 Boys Lowest at 7 yrs at 2.21 x 10-4 Peak at 13 yrs at 8.7 x 10-4 Lin et al.,2000, Pediatr Nephrol, 14, 953